Bone Loss Diseases & Imaging Considerations

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Fleitz Continuing Education

Jeana Fleitz, M.E.D., RT(R)(M) “The X-Ray Lady” 6511 Glenridge Park Place, Suite 6 Louisville, KY 40222 Telephone (502) 425-0651

Fax (502) 327-7921 Website www.x-raylady.com Email address [email protected]

Approved for 12 Category A CE Credits

American Society of Radiologic Technologists (ASRT) Course Approval Start Date 03/01/10 Course Approval End Date 04/01/16

Florida Radiologic Technology Program Provider Approval #3200615 Course Approval Start Date 02/01/10 Course Approval End Date 01/31/16

The course approval for this course will NOT be renewed. Please complete and submit your test before the above course approval end dates in order to receive credit for the course.

A Continuing Education Course for Radiation Operators

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X-Ray Lady CE® Jeana Fleitz, M.Ed., RT(R)(M) 6511 Glenridge Park Place, Suite 6 Louisville, KY 40222 Phone: (502) 425-0651 | Email: [email protected] Website: www.x-raylady.com

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X-Ray Lady CE® Jeana Fleitz, M.Ed., RT(R)(M) 6511 Glenridge Park Place, Suite 6 Louisville, KY 40222 Phone: (502) 425-0651 | Email: [email protected] Website: www.x-raylady.com

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This activity may be available in multiple formats or from different sponsors. Continuing education credit can be awarded only once for the same activity in the same or any subsequent biennium.

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X-Ray Lady CE® Jeana Fleitz, M.Ed., RT(R)(M) 6511 Glenridge Park Place, Suite 6 Louisville, KY 40222 Phone: (502) 425-0651 | Email: [email protected] Website: www.x-raylady.com

Bone Loss Diseases and Imaging Considerations (2012-2014) Approved for 12 Category A CE Credits

Course Description

Bone loss diseases affect millions of people, from newborns to the elderly, resulting in pain, disability, and even death. Osteoporosis is the most prevalent bone loss disease and a significant portion of the course focuses on the signs and symptoms, detection, and treatment of the disease. Diagnostic imaging plays a critical role in the diagnosis and monitoring of bone loss diseases. Technologists need to be knowledgeable of the scope of bone loss diseases, consequences, and implications for diagnostic imaging examinations. Radiation protection is an integral component of all imaging examinations and is included in this course.

Objectives: Upon completion of the course, the participant will be able to: 1. Identify general facts regarding bone loss diseases, their etiology, prevalence, characteristic symptoms and current treatment protocols. 2. Recognize the role of radiology and bone densitometry in the diagnosis and management of bone loss diseases. 3. Given clinical signs and symptoms, differentiate between the bone loss diseases presented in the course. 4. Recall facts about fracture risk and incidence in the United States. 5. Recall facts about risk factor questionnaires and the FRAX® risk assessment tool. 6. Select correct responses regarding the American College of Radiology Appropriateness Criteria® as related to osteoporosis and bone mineral density and relative radiation levels associated with imaging examinations for the conditions. 7. Define common terminology related to bone loss diseases and bone densitometry. 8. Correctly answer questions related to radiation protection during bone densitometry procedures. 9. Identify the indications and contraindications of various imaging modalities as related to the diagnosis and monitoring of osteoporosis and bone loss diseases to include -non-contrast conventional radiography, -magnetic resonance imaging (MRI), -quantitative computed tomography (QCT) -peripheral quantitative computed tomography (pQCT) -peripheral BMD measurements (i.e., radiographic absorptiometry (RA) -peripheral DXA (pDXA) -quantitative ultrasound (QUS) -technetium bone scan Bone Loss Diseases and Imaging Considerations (2012-2014) Approved for 12 Category A CE Credits

Table of Contents

Part 1: Introduction Part 2: Osteoporosis: Magnitude of the Problem Part 3: Bone Health & Implications for Bone Loss Part 4 Bone Loss Part 5: Genetic and Metabolic Diseases & Conditions and Bone Loss Part 6: Inflammation & Infection and Bone Loss Part 7: Malignancy and Bone Loss Part 8: Neurologic & Psychiatric Disorders and Bone Loss Part 9: Other Diseases and Bone Loss Part 10: Renal & Hepatic Diseases and Bone Loss Part 11: Respiratory Diseases & Conditions and Bone Loss Part 12: Osteoporosis in Men Part 13: Bone Fractures Part 14: Imaging Modalities Part 15: Bone Densitometry Part 16: Radiation Protection Part 17: Treatment of Bone Loss Diseases Part 18: Prevention of Bone Loss Diseases Part 19: Conclusion Bone Loss Diseases & Imaging Considerations

Part 1 Introduction

Bone loss diseases affect millions of people, from newborns to the elderly, resulting in pain, disability, and even death. Genetic inheritance, developmental abnormalities, and acquired conditions can produce weak, thin bones, or bones that are too dense. Two examples that have serious consequences for the bony structure of the vertebral column are osteogenesis imperfecta and osteopetrosis. Osteogenesis imperfecta is caused by abnormalities in the collagen molecule. These abnormalities weaken the bone matrix, leading to multiple fractures. Osteopetrosis, a metabolic disease, causes the bones to become too dense because of malformation of bone osteoclasts. Osteoporosis is the most serious and widespread of all the bone loss diseases. Osteoporosis affects not only the American population but also people worldwide and can be a primary condition or a secondary consequence of many systemic diseases and conditions. Nutritional deficiencies, particularly of vitamin D, calcium, and phosphorus, can result in the formation of weak, poorly mineralized bones. Nutritional deficiencies may arise not only from an inadequate intake of nutrients but also from improper metabolism of nutrients. Imbalances and or lack of certain hormones and enzymes can also affect the formation and maintenance of healthy bones. Overactive parathyroid glands or hyperparathyroidism can cause excessive bone breakdown and increase the risk of spinal fracture. Use of glucocorticoids, as a medication is a common cause of bone disease. Infections and acute or chronic inflammation of the skeleton can also lead to bone loss, fractures, and spinal deformities. Dual-energy x-ray absorptiometry (DXA) is the “gold standard” for measuring bone mineral density (BMD) in the lumbar spine, proximal femur, forearm, and whole body. In addition to DXA, several other imaging modalities are currently available to diagnose, evaluate, and monitor bone loss diseases and the effectiveness of treatment. These include non-contrast conventional radiography, magnetic resonance imaging (MRI), quantitative computed tomography (QCT), peripheral quantitative computed tomography (pQCT),

1 peripheral BMD measurements (i.e., radiographic absorptiometry (RA), peripheral DXA (pDXA), quantitative ultrasound (QUS), and technetium bone scan. Each imaging modality has indications based on the patient’s unique clinical signs and symptoms and contraindications and these will be discussed later in this course. The first report of the Surgeon General on bone health and osteoporosis, which was requested by Congress, was published in 2004. The report comes at a very critical time. Like many nations, the U.S. faces the prospect of an aging population and with it the expectation that the burden of chronic diseases, including osteoporosis, will increase. In fact, without concerted action to address this issue, it is estimated that in 2020 one in two Americans over age of 50 will have, or be at high risk of developing, osteoporosis. If these predictions come true, they will have a devastating impact on the well-being of Americans as they age. In recognition of the importance of promoting bone health and preventing fractures, the President has declared 2002-2011 as the “Decade of Bone and Joint”. With this designation, the U.S. has joined with other nations throughout the world in committing resources to accelerate progress in a variety of areas related to the musculoskeletal system, including bone disease and arthritis.1

This course provides information about the etiology, prevalence, and characteristic symptoms of common bone loss diseases with particular emphasis on osteoporosis. The importance of screening patients for bone loss diseases during the clinical examination and available laboratory tests is introduced. Common imaging modalities available for the detection, evaluation, and monitoring bone loss diseases will also be presented. The term technologist will be used in this course when reference is made to the person who operates imaging equipment.

2 Part 2 Osteoporosis: Magnitude of the Problem

The National Osteoporosis Foundation (NOF) estimates that more than 44 million Americans have osteoporosis, or 55% of the people 50 years of age or older.2 In the United States today, 10 million people already have the disease, and almost 34 million more have low bone mass (osteopenia), placing them at increased risk for osteoporosis.2 Osteoporosis is an under-diagnosed and silent condition that has financial, physical, and psychosocial consequences. The World Health Organization (WHO) Study Group defined osteoporosis (1994) as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increase in bone fragility and susceptibility to fracture.3 The impact of bone disease is more appropriately evaluated over a lifetime.1 Approximately 1 in 2 women and 1 in 4 men over age 50 will have an osteoporosis related fracture in their remaining lifetime. While the lifetime fracture risk for men and non-white women is less across all fracture types, it is significant for people in all ethnic backgrounds.1 Typically, those with osteoporosis have no pain or indication of the disease process until they break a hip or wrist, or sustain spinal fracture(s) that may leave a dowager’s hump or reduce their height by a few inches. A broken hip or crushed vertebrae may begin a downward spiral of lost mobility and illness, culminating in death. Fractures can have devastating consequences for both the individuals who suffer them and their family members.1 For example, hip fractures are associated with increased risk of mortality.1 The risk of mortality is 2.8 to 4 times greater among hip fracture patients during the first 3 months after the fracture, than it is among individuals of similar age who live in the community and do not suffer a fracture.1 For those who do survive, these fractures often precipitate a decline in physical and mental health that dramatically impairs quality of life.1 Nearly 1 in 5 hip fracture patients ends up in a nursing home, a living situation that a majority of participants in one study considered to be less favorable than death.1 Many fracture victims become isolated and depressed as the fear of falls and additional fractures paralyzes them.1 Spine fractures, which are not as easily diagnosed and treated as are fractures at other sites, can become a

3 source of chronic pain as well as disfigurement.1 Osteoporosis is the most important underlying cause of fractures in the elderly.1 Osteoporosis is recognized as one of the most common and serious health problems facing the aging population in the United States. The prevalence of osteoporosis and osteoporotic-related fractures is expected to increase significantly unless the bone health status of Americans is improved.1 For example, one only has to look at the historical trends to recognize the increase in this bone disease. In 2002, more than 10 million people already had osteoporosis, with approximately 80% being women.1 The National Osteoporosis Foundation estimated that in 2010, roughly 52 million individuals over age 50 were diagnosed with osteoporosis, and another 40 million received a diagnosis of low bone mass.1 By 2020, these figures are expected to jump to 14 million cases of osteoporosis and over 61 million cases of low bone mass.1 The age-related demographic changes in the United States and the prevalence of osteoporosis and low bone mass might result in double or triple the number of hip fractures by 2040.1 Bone disease takes a significant financial toll on society and the individuals that suffer from it. Annual direct expenditure for care of patients with osteoporotic fractures exceeds $17 billion dollars and is predicted to double by 2025.1 Approximately 90% of the expenditures of osteoporosis are related to the costs of treating fractures.1 Factoring in both the direct and indirect costs for caring for other bone diseases, would likely add billions of additional dollars to this tab.1 In the Surgeon General’s report on bone health and osteoporosis, several challenges are posed concerning the bone health of Americans. One challenge addresses significant gaps between clinical knowledge and its application in practice.1 This means that too little of what has been learned thus far about bone health has been applied in practice.1 The report states that the biggest problem is lack of awareness of bone disease on the part of both the public and healthcare professionals.1 Studies show that physicians frequently fail to diagnose and treat osteoporosis, even in elderly patients who have suffered a fracture.1 Contributing to this lack of awareness is the fact that managed care organizations and other insurers that provide coverage to individuals under age 65 may not see the full impact of bone disease in their enrollees, since most will

4 have moved on to Medicare by the time they suffer a fracture.1 Commercial insurance providers may not pay sufficient attention to bone health, and to the preventive strategies available to and suitable for younger people.1 Some of the most important barriers relate to men and racial and ethnic minorities.4 For the poor (especially the low-income elderly population), individuals with disabilities, individuals living in rural areas, and other underserved populations, timely access to care is difficult to obtain.4 Recognizing that bone health can have a significant impact on the overall health and well-being of Americans, the Public Health Service has already begun work on the issue.1 In the Healthy People 2010 Public Health Service Report there are specific objectives that aim to reduce the number of individuals with osteoporosis or hip fractures, and that seek to promote greater amounts of calcium intake and physical activity. Additional information is available from the Clinician’s Guide to Prevention and Treatment of Osteoporosis developed and published by the National Osteoporosis Foundation.5

Part 3 Bone Health & Implications for Bone Loss

The Bony Skeleton The bony skeleton serves a structural function, providing mobility, support, and protection for the body, as well as a reserve function, storing up essential minerals.1 Many assume that the adult skeleton is an inert framework, a sort of stone-like foundation for the living flesh of our bodies. This assumption is false, however, since bone is living tissue, and from birth to death is in a constant state of flux. Bone health is difficult to maintain because the skeleton is simultaneously serving two different functions that are in competition with each other.1 First, bone must be responsive to changes in mechanical loading or weight bearing activities, which require they have ample supplies of calcium and phosphorus. Yet when these elements are in short supply elsewhere, the regulating hormones take them out of the bone to serve vital functions in other body systems.1 The skeleton can be compared to a bank where calcium or phosphorus is deposited and then later withdrawn in times of need.1 Too many withdrawals weaken the bone, and can lead to the most common bone disorder, fractures.1 The amount of bone and its architecture or shape are determined by the mechanical forces that act on the skeleton.1 Both genes and the environment contribute to bone health. Genes generally determine elements of bone health like size and shape of the skeleton, and errors in signaling on the part of these genes can result in birth defects.1 External factors, such as diet and physical activity, are critically important to bone health throughout life, and can be modified.1 To respond to the dual roles of physically supporting the body and regulating the amounts of calcium and phosphorus within it, bone is constantly changing. Osteoporosis and many related bone diseases cause bones to become porous, gradually making them weaker and more brittle.2 The word osteoporosis literally means porous bones.

Skeletal Anatomy and Physiology Bone consists of approximately 25% organic substances and 75% inorganic substances, and is the supporting framework of the body. The major

6 organic component of bone is collagen, a strong and flexible protein. Calcium and phosphate in the form of calcium phosphate crystals are the primary inorganic substances found in bone. Together, the combination of organic and inorganic substances makes bone both flexible and able to withstand weight- bearing stresses (Figure 1).

Fig. 1. Bone tissue (A) Femur with distal end cut in longitudinal section. (B) Microscopic cross section of compact bone showing haversian systems. (Reprint permission from Scanlon. VC Sanders. Essentials of Anatomy and Physiology. Philadelphia, PA; FA Davis Company; 1991:103)

Microscopically, bone consists of a mixture of connective tissue, blood vessels, specialized cells, and crystals of calcium and phosphate. The skeleton contains 99% of the body’s total calcium, but being rich in calcium is not enough to make bones resistant to fracture. Bones can be dense yet brittle, lacking flexibility, which will cause them to break easily. The collagen protein content is

7 crucial for maintaining flexibility. It is thought that the quality and quantity of collagen protein in bones may be more essential to preventing fractures than the calcium content. In addition to calcium, bones are a reservoir of numerous other minerals that the body requires for day-to-day function. The bones act as a bank for nutrients, with a constant flow of deposits and withdrawals. Calcium, phosphorus, sodium, magnesium, and collagen protein enter and leave bone during the resorption and remodeling process. Humans obtain these nutrients from the foods they ingest. Food is broken down in the stomach and duodenum, where nutrients are absorbed through the walls of the small intestine and enter the bloodstream. Once in the blood, calcium migrates to the bones, and is deposited and stored. Bone resorption takes place as needed, liberating calcium for necessary functions in the blood, muscles, nerves, and elsewhere. The kidneys excrete excess calcium that is not absorbed. Deposition of calcium in the bones is increased by the influence of gravity, which occurs when the human body is in motion, for example when walking. A sedentary lifestyle contributes to the loss of bone mass by preventing deposition of calcium, so that the process of mineral resorption slowly uses up the available bone mass. Bone is classified as a connective tissue and contains three basic parts: cells (osteocytes, osteoblasts, and osteoclasts), the matrix, and inorganic calcium salts. The two cell types relevant to osteoporosis and bone density measurements are osteoblasts and osteoclasts. These cells react to hormones, physical stress, and calcium blood levels, and bone repair demands. The osteoblasts, or bone-producing cells, produce the organic bone matrix components that later become mineralized through a process that is not well understood. The osteoclasts are responsible for bone remodeling and have large multinucleated cells that contain and secrete calcium-dissolving acids. Excessive bone breakdown by osteoclasts is an important cause of bone fragility, not only in osteoporosis but in other bone disease such as hyperparathyroidism, Paget’s disease, and fibrous dysplasia, both of which will be discussed later in this course.1 Inhibitors of osteoclastic bone breakdown have been developed to treat these disorders.

8 The balance of the calcium moving in and out of bone forms the basis for bone remodeling (Figure 2).

Fig. 2. Bone remodeling. (Reprint permission from “Boning up on Osteoporosis: A Guide to Prevention and Treatment”. National Osteoporosis Foundation. (4/02) B107.

Calcium in the blood moves into bone as osteoblasts make new bone, and returns into the blood when the osteoclasts break bone down. Osteoclasts are sensitive to blood calcium levels, and respond by increasing or decreasing activity levels. Other factors, whether physiological, environmental, or behavioral, can also alter the delicate balance between osteoblast and osteoclast equilibrium. Some of these factors include low estrogen and testosterone levels, calcium and vitamin D deficient diets, and a sedentary lifestyle. There are two major bone classifications: cortical (compact) bone and trabecular (spongy) bone. Cortical bone consists of dense, tightly aligned lamellar osteons (tubules), and is found in locations where bone compresses in a limited number of directions. Cortical bone may be found in the skull and femur shafts. Cortical bone is organized into units called haversian systems, each containing osteocytes and an intracellular matrix arranged in circular layers around central haversian canals, (Figure 1). Trabecular bone has a honeycomb appearance, with a partitioned internal design, and weighs less than cortical bone, thus reducing skeletal weight.

9 Trabecular bone is found in locations that receive either low mechanical stresses or multi-directional stresses. The femoral head, calcaneus, and spine are all examples of predominately trabecular bone. Trabecular bone is more metabolically active than cortical bone, and responds quickly to factors that affect the skeleton. The differentiation of bone as either cortical or trabecular is important in bone densitometry because certain diseases show a preference for one type of bone over another. Thus, the selection of the site or sites to be scanned for a DXA examination is an important consideration in the diagnostic process, and is generally made by the requesting physician. The technologist should be knowledgeable about the differences between cortical and trabecular bone, and about how various disease conditions and drug therapies affect each type. In addition to describing skeletal bones as predominantly cortical or trabecular, there are three other ways to characterize skeletal sites:  Weight-bearing or non-weight bearing  Axial or appendicular  Central or peripheral

Weight-bearing sites include the lower extremities, the cervical, thoracic, and lumbar spines, and the calcaneus, with all other bones being non-weight bearing. The axial skeleton includes the skull, ribs, sternum, and spine; and the appendicular skeleton include the extremities. The thoracic and lumbar vertebrae and the proximal femur are central skeletal sites. Peripheral skeletal sites are non-central sites, and include the calcaneus, tibia, and forearm. The mature skeleton gradually increases in mass during early adult life. Peak bone mass is achieved between 30 and 35 years of age. Peak bone mass is affected by genetics, mechanical loading, and hormonal and nutritional levels, and is approximately 30% higher in men than in women. After reaching its peak, bone mass declines throughout life due to an imbalance in remodeling. In women, bone mass decreases rapidly for 3 to 7 years after menopause. Estrogen produced by the female ovaries, plus other hormones, regulate the absorption and release of calcium in the bones. After menopause, the ovaries no longer produce estrogen, and bone loss accelerates, finally slowing down at

10 about age 65. Bone loss may also be accelerated by a variety of diseases and drugs, (Figure 3).

Fig. 3. Bone loss over the aging continuum. Retrieved with permission from http://www.emedicinehealth.com on December 2, 2011.

In males, testosterone affects bone mass.9 Recent research in the United States and Germany demonstrates that testosterone replacement therapy for men with deficient hormone levels has helped to increase both cortical and trabecular bone density.9-11 As humans age, bone formation does not keep pace with bone loss. The rate of bone loss increases with advancing age. When the long-term rate of bone dissolution is greater than the rate of replacement, mineral content slowly decreases, and the bones become thin, brittle, and easily broken.12 This cycle is called the process of destruction, or resorption, and renewal formation, known as remodeling. In the mature adult, approximately 25% of trabecular bone and about 3% of cortical bone is renewed on an annual basis. 12 The remodeling cycle consists of 2 distinct stages referred to as resorption and formation, (Figures 2 and 4). The resorption stage begins when osteoclasts become active on the surfaces of bone and create small cavities. The resorption process forms hollows in trabecular bone and cylindrical cavities in cortical bone. The stage of resorption is followed by bone formation, during which bone-building osteoblasts fill the cavities with new bone. After formation, the

11 bone that returns to a resting state is referred to as quiescence. About 90% of bone surfaces are normally at rest.5 Resorption is more rapid than formation, and by age 40 the entire resorption stage may last one month, while the formation stage may take up to 3 months.5 By age 65, the entire process of resorption and formation may take up to 5 months.5 Modeling and remodeling continues throughout life, so that most of the adult skeleton is replaced about every 10 years.5

Steps in Normal Bone Regeneration Steps in Abnormal Bone Regeneration

Osteoclasts attach to bone surface Osteoclasts attach to bone surface Osteoclasts resorb bone Osteoclasts resorb more bone tissue and leave a deeper resorption cavity Osteoblasts enter cavity and build new bone Osteoblasts build less bone than the amount resorbed Amount of bone formed is equal to the amount Bone resorption exceeds bone formation, of bone resorbed so that bone mass/strength leading to a progressive decline in bone mass, are maintained weakening bones and increasing risk of fractures Fig. 4. Steps in Normal and Abnormal Bone Regeneration.

Bone Metabolism Alkaline phosphatase, which raises calcium and phosphate levels, is thought to play a role in bone mineralization. However, many factors influence the bone metabolism and remodeling process by direct action on the osteoblasts and osteoclasts. The most critical systemic hormones regulating bone growth include:  Calcium-regulating hormones; Parathyroid hormone (PTH) Calcitriol (active vitamin D) Calcitonin  Sex hormones; and, Estrogen Testosterone  Other systemic hormones Growth hormone/insulin-like hormone Growth factor Thyroid hormone Cortisol

12 Four small glands adjacent to the thyroid gland produce parathyroid hormone (PTH). These glands control the level of calcium in the blood, and are sensitive to small changes in calcium concentration. PTH acts on the kidneys to conserve calcium and stimulate calcitriol production, which increases intestinal absorption of calcium. PTH also acts on the bone to increase movement of calcium from bone to blood. Excessive production of PTH, usually due to a small tumor of the parathyroid glands, is called hyperparathyroidism and can lead to bone loss. PTH stimulates bone formation as well as absorption. Recently discovered, a second hormone, parathyroid hormone-related protein (PTHrP), related to PTH, normally regulates cartilage and bone development in the fetus.1 The hormone has been found to be overproduced in individuals with certain types of cancer. PTHrP then acts like PTH, causing excessive bone breakdown and abnormally high blood calcium levels, a condition called hypercalcemia of malignancy.1 Calcitriol, 1,25 dehydroxycholecalciferol, is a hormone formed in the liver and kidneys. Calcitriol acts on many different tissues, but its most important action is to increase intestinal absorption of calcium and phosphorus. Vitamin D can be made in the skin through the action of ultraviolet light from the sun on cholesterol. Many people need vitamin D in their diet because they do not derive adequate levels of it from exposure to the sun. Vitamin D deficiency leads to a disease of defective mineralization called rickets in children and osteomalacia in adults. These conditions can cause bone pain, bowing and deformities of the legs, and fractures. Treatment with vitamin D can restore calcium supplies and reduce bone loss. Calcitonin is a calcium-regulating hormone produced by cells of the thyroid gland. Calcitonin is thought to be more important for maintaining bone development and normal blood calcium levels in early life. Excesses or deficiencies of calcitonin in adults do not cause problems in maintaining calcium concentration or the strength of bone. Calcitonin can be used as a drug for treating bone disease. Sex hormones, along with calcium-regulating hormones, are extremely important in regulating the growth of the skeleton and maintaining the mass and strength of bone.13,14 Estrogen and testosterone have effects on bone in both men and women.13,14 Estrogen acts on the osteoclasts and osteoblasts to inhibit

13 bone breakdown at all stages of life.15 Testosterone is important for skeletal growth because of its direct effects on bone, and its ability to stimulate muscle growth.13,14 Growth hormone from the pituitary gland is also an important regulator of skeletal growth. It acts by stimulating the production of another hormone, called insulin-like growth factor (IGF-1), which is produced in large amounts in the liver and released into circulation. IGF-1 is produced locally in other tissues, particularly in bone, and is also under the control of growth hormone. Thyroid hormones increase the energy production of all body cells, including bone cells. Thyroid hormones increase the rates of both bone formation and resorption. Thyrotropin (TSH), the pituitary hormone that controls the thyroid gland, also may have a direct effect on bone. Cortisol, the major hormone of the adrenal gland, is a critical regulator of metabolism, and is important to the body’s ability to respond to stress and injury. Small amounts are necessary for normal bone development, but large amounts block bone growth. Synthetic forms of cortisol, called glucocorticoids, are used to treat many diseases such as asthma and arthritis. They can cause bone loss due to decreased bone formation and increased bone breakdown, both of which lead to a high risk of fracture.1

Bone Strength Bone fractures and especially vertebral compression fractures present serious consequences following trauma and non-trauma (i.e., low bone strength). Persons with a vertebral fracture experience a decreased quality of life and also show increases in digestive and respiratory morbidity, anxiety, depression, and death. The ability of bone to resist fracture depends on the amount of bone (i.e., mass), and the spatial distribution of the bone mass (i.e., shape and microarchitecture), and the intrinsic properties of the materials that comprise the bone, Figure 5. Diseases and drugs that influence bone remodeling will affect bone’s resistance to fracture. Living bone tissue is continually changing under the influences of mechanical and hormonal impacts and in response to increased mechanical loading, may adapt by altering its size, shape, and/or matrix properties. The properties that influence bone strength are related to

14 microarchitectural and macroarchitectural changes at the cellular and matrix levels.

Fig. 5. The relationship of variables to whole bone strength. Courtesy drawing by DGMConsulting: 2011.

In daily life, the skeleton must withstand a combination of compression or tension forces with bending and twisting motions. The highest stress impacts occur to the vertebral spine due to compression loading. Research has proven that the best bone design to withstand bending loads is when the axis is near the center of the bone. This area is referred to as the area moment of inertia.

Area moment of inertia is a geometric property that describes the distribution of mass around the neutral bending axis of an object (i.e., bone).

In essence this means that as the external diameter of a long bone increases, the bone assumes more resistance to bending and twisting loads applied to it, thus reducing potential fractures. The material properties of bone tissue declines with age and is accompanied by a redistribution of cortical and

15 trabecular bone. This decline is greater in the appendicular skeleton, which involves endosteal resorption with bone along with periosteal apposition on the bone’s exterior surface. The process results in an age-related increase in the diameter of long bones with a decrease in cortical thickness.16 Once thought to occur to a greater degree in women, research data has demonstrated that both men and women undergo these geometric bone changes with aging. Microarchitecture has an important role in bone strength. Newer imaging modalities such as high-resolution microcomputed tomography (mCT) and magnetic resonance imaging (MRI) that provides 3-dimensional evaluation of trabecular bone have been able to show altered trabecular microarchitecture associated with vertebral fracture.17 Bone matrix properties of mineralization, collagen characteristics, and microdamage also affect the mechanical properties of bone. The quantity and quality of bone matrix content relates directly to stiffness and strength of bone. When bone matrix is undermineralized or decreases due to a disease state, the ability of the bone to withstand energy impacts decreases. 17 The quality and quantity of collagen has an important role in bone strength. Bone is primarily composed of minerals and collagen which gives bone the ability to withstand energy impacts (i.e., reduces fracturing). Along with adequate bone matrix and collagen, the ability of bone to withstand energy impacts is also dependent upon microdamage. Microdamage or fatigue to bone occurs from the daily physiologic loading to the skeleton. The concept of fatigue microdamage to bone may be related to both age-related fragility bone fractures and certain diseases and conditions.17

Part 4 Bone Loss

Introduction

Bone loss was once thought to be an expected consequence of aging. Although aging is a major factor associated with bone loss, there are many diseases and conditions that result in the quantity and quality of bone; however, of those, osteoporosis is the most common and exists worldwide.

What is Osteoporosis

The National Institutes of Health (NIH) defines osteoporosis as “a skeletal disorder characterized by compromised bone strength, predisposing an individual to an increased risk of fracture.” The NIH definition recognizes factors that prevent people from achieving optimal bone mass, as well as conditions that lead to bone loss later in life. The NIH also states that bone strength is a combination of bone density and bone quality, Figure 6.2

Fig. 6. Normal bone and bone with osteoporosis. Image courtesy of the 2004 U.S. Surgeon General Report on Bone Health and Osteoporosis: What it means to you. U.W. Department of Health and Human Services, Office of the Surgeon General, 2004.

17 There are 2 types of osteoporosis characterized by etiology and referred to as primary and secondary osteoporosis. Primary osteoporosis is mainly a disease of the elderly, the result of the cumulative impact of bone loss and the deterioration of bone structure that occurs as people age.1 Primary osteoporosis may also be referred to as Type I, or age-related, osteoporosis. Since postmenopausal women are at greater risk, the term “postmenopausal” osteoporosis may also be used.1 Younger individuals (including children and young adults) rarely get primary osteoporosis, although it can occur; this type of osteoporosis is referred to as “idiopathic” osteoporosis, since in many cases the exact causes of the disease are not known. Idiopathic primary osteoporosis can affect both children and adolescents, although such an occurrence is quite rare.1 Juvenile osteoporosis affects previously healthy children between the ages of 8 and 14. The condition may be mild, causing only one or two collapsed bones in the spine, or it may be severe, affecting the entire spine.1 Primary osteoporosis in children and adolescents occurs for reasons, which are still unknown. For example, bone loss occurs in adolescents with anorexia nervosa, an eating disorder. Although it is mainly girls who suffer from this condition, boys and men can also be affected. Many studies have shown a state of imbalanced bone turnover in young people with anorexia nervosa, with both decreased bone formation and increased bone resorption. Approximately 25% of adolescent patients with inflammatory bowel disease (IBD) are diagnosed with osteopenia.18 This condition is controlled with minimal corticosteroid use, which has direct impacts on bone formation and remodeling.18 Transient osteoporosis, an unusual but distinct syndrome characterized by self-limited pain and radiographically evident osteopenia has been documented. Transient osteoporosis is considered one of several related conditions, most commonly affecting the hip.19 The condition was first described in 1959 by Curtiss and Kincaid who reported the condition in two women, both in their third trimester of pregnancy. Thus, transient osteoporosis has been typically documented in middle-aged men or in women in the third trimester of pregnancy.19 The condition often improves over several weeks to months without specific treatment; however, in some individuals with hip involvement,

18 similar changes may be seen in the opposite hip, referred to as regional migratory osteopososis.19 With the use of magnetic resonance imaging (MRI), transient osteoporosis can be differentiated from other conditions such as bone marrow edema, osteonecrosis, trauma, infection, and infiltrative tumors.19 Possible causes of transient osteoporosis include trauma, synovitis, neurovascular dysfunction, and transient ischemia. The presence of joint effusion in most cases of transient osteoporosis, indicated a possible synovial origin.19 In most cases; however, laboratory cultures of synovial fluid have not isolated any infective organisms. Some speculate that one possible cause of transient osteoporosis is the consequences of bone trauma, resulting in ischemia. Despite many assumptions, the actual cause of transient osteoporosis remains unknown. Primary osteoporosis related to age is by far the most common form of the disease. There are many different causes, but the bone loss that leads to the disease typically begins early in life, at a time when corrective action (such as changes in diet and physical activity) could potentially slow down its course.1 While osteoporosis occurs in both sexes, the disease is 2 to 3 times more common in women.1 This is partly due to the fact that women have 2 phases of age-related bone loss. The first, a rapid phase that begins at menopause and lasts 4-8 years, followed by a slower continuous phase that lasts throughout the rest of life.1 Men go through only the slow, continuous phase. As a result, women typically lose more bone than do men. The rapid phase of bone loss alone results in losses of 5-10% of cortical bone and 20-30% of trabecular bone in women. The slow phase of bone loss results in losses of 20-25% of cortical and trabecular bone in both men and women, but over a longer period of time.1 Although other factors such as genetics and nutrition contribute, both the rapid phase of bone loss in postmenopausal women and the slow phase of bone loss in aging women and men appear to be largely the result of estrogen deficiency.1 For women, the rapid phase of bone loss is initiated by a dramatic decline in estrogen production by the ovaries at menopause. The loss of estrogen action on estrogen-receptors in bone results in large increases in bone resorption, as well as reduced bone formation. By contrast, the slower phase of bone loss is caused by a combination of factors. These factors include age-related impairment of bone formation, decreased calcium and vitamin D intake,

19 decreased physical activity, and the loss of estrogen’s positive effects on calcium balance in the intestines and kidneys as well as bone. For aging men, sex steroid deficiency also appears to be a major factor in age-related osteoporosis.1 Although testosterone is the major sex steroid in men, some of it is converted by the aromatase enzyme into estrogen.1 Between 30-50% of elderly men are deficient in biologically active sex steroids.1 Secondary, or Type II, osteoporosis is often referred to as senile osteoporosis, and occurs particularly in the seventh decade of life. Secondary osteoporosis is caused by decreased absorption of calcium from the intestines, as well as by a diminished secretion of calcitonin, a naturally produced non-sex hormone that is involved in calcium regulation and bone metabolism.12 The type of osteoporosis that occurs in individuals as a consequence of some condition or medication use is also referred to as secondary osteoporosis. Those with secondary osteoporosis typically experience greater levels of bone loss than would be expected for a normal individual of the same age, gender, and race. Examples of factors contributing to secondary osteoporosis includes various disorders of the endocrine glands, a sedentary lifestyle, malnutrition, iatrogenic or pharmacologic conditions, other illnesses of the liver and gastrointestinal tract, and cancer. Some additional contributing factors and causes of secondary osteoporosis include:  Dietary deficiencies: low calcium, low vitamin D, and anorexia.  Skeletal diseases: osteogenesis imperfecta and hypophosphatasia.  Medications: corticosteroids, thyroid drugs, heparin, and antiseizure drugs.  Sedentary lifestyle.  Spinal cord injury.  Alcohol and tobacco use.  Endocrine disorders.  Gastrointestinal tract disorders.  Renal disease.  Cancer.  Rheumatoid arthritis and connective tissue disease.

20 Many of the most common causes of bone loss and osteoporosis can be categorized as bone diseases, metabolic disorders, and inflammatory conditions and these will be discussed later in this course.

Demographics of Bone Loss and Osteoporosis

The current data on osteoporosis supports the concern that osteoporosis is increasing at an alarming rate in the United States. Nearly 44 million Americans are affected by bone loss, of these, approximately 10 million already have the disease, and 34 million have low bone mass.2 According to the World Health Organization (WHO), a woman’s lifetime risk for an osteoporotic-related fracture may be as high as 1 in 2 women.12 Osteoporosis does not affect everyone to the same degree. Women, especially older women, are much more likely to get the disease than are men.1 Women who have been determined by a physician or qualified practitioner to be estrogen-deficient and based on the medical history and other findings, may be determined to be at increased risk of osteoporosis. Additional risk factors include a body weight of less than the 25th percentile and a history of amenorrhea for a period of at least 1-year before age 45. Also vertebral abnormalities that are radiographically demonstrated may be indicative of osteoporosis, osteopenia, or vertebral fracture. According to both the WHO and the National Osteoporosis Foundation (NOF), a BMD of 2.5 standard deviations (SD) or more below that of a “young normal” adult (T-score at or below –2.5)) indicates osteoporosis.3,5 Individuals in this group who have already experienced one or more fractures are deemed to have severe or “established” osteoporosis. A BMD between 1.0 and 2.5 SD below that of a “young normal” adult (T-score between –1.0 and –2.5) is considered low bone mass. In data from the National Osteoporosis Risk Assessment (NORA) study (done on 149,524 white, postmenopausal women), researchers found that only 18% of the women who had fractures would have been treatment candidates if the intervention threshold had been set at –2.5 (T-score) or less. They concluded that this would have resulted in no intervention for 82% of the women who actually experienced a new fracture during the first year after BMD was

21 measured. The researchers believe that this demonstrates the unmet need to identify those women, who are most likely to fracture, which might benefit from targeted drug intervention. The public misconception that osteoporosis is a woman’s disease is rampant. According to recent polls, men are more likely to reply; when asked about who gets osteoporosis that only women are at risk of developing the disease. Researchers estimate that at least 10 million men are considered to have low bone mass and osteoporosis.20 Demographic information about the significance of the aging United States population also indicates that of the number of men older than 70 will double between 1993 and 2050, thus increasing the potential number of cases of osteoporosis in males.2 Recent data shows connections between male gender, osteoporosis, and the following risk factors:  Chronic diseases that affect the lungs, kidneys, stomach, and intestines, or which can alter hormones;  Low testosterone levels; and  Advanced age and unhealthy lifestyle.13,14

Risk Factors The WHO and other medical research groups have identified certain factors that predispose a person to osteoporosis. These involve physiological, genetic, behavioral, and environmental factors that have been thought to influence the probability of a person developing the condition. Physicians apply known risk factors to an individual’s health profile to help determine the likelihood that the person will develop a particular disease or disorder. Post-menopausal women are at the greatest risk of osteoporosis.15,21 Menopause usually begins when a woman is about 50, though it can occur earlier if a woman has surgery to remove her ovaries. The WHO and other medical research organizations have identified the following factors as potentially contributing to the risk of developing osteoporosis:  A family history of osteoporosis and bone fracture;  White or Asian ethnicity;  A thin or small body frame with a premenopausal body weight of less than 127 pounds;

22  Smoking;  Excessive alcohol consumption;  A sedentary lifestyle;  A calcium-deficient diet (either at the present time or as a child);  Use of certain medications, such as steroids commonly used to treat asthma and arthritis, and high dosages of thyroid hormone;  Early menopause (before the age of 45); and,  Other pathologies such as rheumatoid arthritis, chronic active hepatitis, chronic congestive pulmonary disease, and inflammatory bowel disease.

Lower risk factors

 White women with a dark complexion.  Women of African or black ancestry.  Women who are overweight.  Women who eat large amounts of dairy products and vegetables.  Women who exercise regularly.

The most prevalent myths about osteoporosis are that it is a woman’s disease and that it affects only the elderly.

Medications and Therapies that Contribute to Bone Loss Osteoporosis can be a side effect of particular medical therapies, Figure 7.

 Anticoagulants (Heparin)  Anticonvulsants  Cyclosporine A and Tacrolimus  Cancer Chemotherapeutic Drugs  Gonadotropin-releasing Hormone Agonists  Lithium  Methotrexate  Parenteral Nutrition  Thyroxine

Fig. 7. Medications associated with secondary osteoporosis.

23 Glucocorticoid-induced osteoporosis (GIO) is by far the most common form of osteoporosis produced by drug treatment. While it has been known for many years that excessive production of the adrenal hormone cortisol can cause thinning of the bone and fractures, this condition, a form of Cushing’s syndrome, remains uncommon. With the increased use of prednisone and other drugs that act like cortisol for the treatment of many inflammatory and autoimmune diseases, this form of bone loss has become a major clinical concern. The concern is greatest for those diseases in which the inflammation itself and/or the immobilization created by the illness causes increased bone loss and fracture risk. Glucocorticoids are used to treat a wide variety of inflammatory conditions (e.g., rheumatoid arthritis, asthma, emphysema, and chronic lung disease). The use of glucocorticoids can cause profound reductions in bone formation and may, to a lesser extent, increase bone resorption, leading to loss of trabecular bone at the spine and hip, especially in postmenopausal women and older men. Glucocorticoid induced bone loss occurs in more than 50% of patients receiving long-term glucocorticoid therapy. The most rapid bone loss occurs early in the course of treatment, and even small doses (equivalent to 2.5 – 7.5 mg prednisone per day) are associated with an increase in fractures. Bone loss is usually rapid with as much as a 20% decrease in one year and continues indefinitely. Trabecular bone is lost more rapidly than cortical bone. The risk of fracture increases rapidly in those treated with glucocorticoids, even before much bone has been lost. This rapid increase in fracture risk is attributed to damage to the bone cells, which results in less healthy bone tissue. To avoid this problem, health care providers are urged to use the lowest possible dose of glucocorticoids for as short a time as possible. Medical care providers should also consider prescribing the use of local or inhalant glucocorticoids in certain conditions, which has been proven to cause much less overall bone loss. Recommendations from several bone health groups advocate that before someone is initially started on glucocorticoids that they undergo a bone health assessment. This assessment includes a review of the nutritional status, muscle strength and mobility. Additional measurements of bone density in the spine and hip should be taken to establish a baseline for later comparison. Additional tests include a 24 hour urine for calcium, creatinine and sodium levels, serum 25

24 OH and vitamin D, and determination of testosteone levels in men and estradiol in premenopausal women. The emergence of heart transplantation as the ultimate treatment for end- stage heart failure has been accompanied by new challenges.22 Cyclosporine A and tacrolimus are widely used in conjunction with glucocorticoids to prevent rejection after organ transplantation, and high doses of these drugs are associated with a particularly severe form of osteoporosis.1 Pediatric oncology patients are at risk for the development of numerous skeletal complications. Methotrexate, a folate antagonist used to treat malignancies and (in lower doses) inflammatory diseases, such as rheumatoid arthritis, may also cause bone loss, although research findings are not consistent. Methotrexate osteopathy in children often manifests as osteopenia, dense provisional zones of calcification, pathologic fractures, and sharply outlined epiphyses. Both organ transplant recipients and oncology patients should be closely monitored during and after therapy for evidence of bone loss. Bone disease has also been reported among those that are taking several frequently prescribed drugs. These are anticonvulsant drugs, including diphenylhydantoin, phenobarbital, sodium valproate, and carbamazepine.1 Individuals who are most at risk of developing this type of bone disease include those on long-term therapy, high medication doses, multiple anticonvulsants, and/or simultaneous therapy with medications that raise liver enzyme levels. Low vitamin intake, restricted sun exposure and the presence of a chronic illness increase the risk, particularly among elderly and institutionalized individuals. In contrast, high intakes of vitamin A (retinal) may increase fracture risk. Gonadotropin-releasing hormone agonists, which are used to treat endometriosis in women and prostate cancer in men, reduce both estrogen and testosterone levels, which may cause significant, bone loss and fragility fractures.1

Alcohol and Smoking and Bone Loss According to statistics on alcohol abuse and alcoholism by the World Health Organization, about 140 million people throughout the world suffer from alcohol-related disorders. The prevalence of alcoholism varies in different countries; however, in the United States approximately 15% of the population experiences some problem that is associated with their consumption of alcohol.26

25 Of these individuals, alcoholism affects roughly 4% of the overall population, or 12.5 million men and women.26 According to United States statistics, men are 3 times more likely than women to become dependent on alcohol while seniors aged 65 and older have the lowest rates of alcoholism.23 In addition, in the United States, estimates reveal that 40% of people who begin to drink before the age of 15 will become an alcoholic at some time in their adult lives.23 These early drinkers are 4 times more likely to become alcoholic than those who do not start drinking until the age of 21.26 Men and women who drink heavily are more prone to bone loss and fractures. According to published statistics 33% of current drinkers have 5 or more drinks on at least one day and nearly 14 million Americans meet diagnostic criteria for alcohol use disorders. Consumption of 2 to 3 ounces of alcohol per day prevents attainment of peak bone mass. Alcohol consumption negatively affects bone health on several fronts.5 Excessive alcohol interferes with the balance of calcium, and increases parathyroid hormone levels, which reduce the body’s calcium reserves. The calcium balance is further disrupted by alcohol’s ability to interfere with the production of vitamin D. Also, chronic heavy drinking can cause hormone deficiencies in men and women. Men with alcoholism tend to produce less testosterone. In women, chronic alcohol intake often produces irregular menstrual cycles, a factor that reduces estrogen levels, increasing the risk for osteoporosis. Because of the effects of alcohol on balance and gait, those with alcoholism tend to fall more frequently. Heavy alcohol consumption has been linked to an increase in risk of hip and vertebral fracture. The most effective strategy to combat alcohol-induced bone loss is abstinence. Rapid recovery of osteoblastic activity has been reported when alcoholics quit drinking.1 Some studies have even found that lost bone can be partially restored when alcohol abuse ends. Adequate nutrition and calcium and vitamin D supplementation is an important aspect of an alcohol recovery program. Those in a recovery program should be evaluated for overall bone health including measurement of BMD and preventative strategies implemented as indicated.

26 Smoking Analyzing the impact of cigarette smoking on the skeleton has proven difficult since it has been suggested that differences in bone density between smokers and non-smokers may be due to accompanying lifestyle factors. For example, smokers are often thinner than their non-smoking counterparts.24 Smokers also tend to have a higher consumption of alcohol, may be less physically active, often have nutritional deficiencies, and tend to have an earlier menopause than non-smokers.24 These characteristics place smokers at an increased risk for osteopenia and osteoporosis. Smoking prevents young people from reaching peak bone mass and increases bone resorption in older smokers.24 Women who smoke have lower bone mineral density because smoking lessens estrogen production thus increasing the risk of bone loss.

Part 5 Genetic and Metabolic Diseases Conditions and Bone Loss

Introduction Genetic inheritance of certain diseases and developmental abnormalities can produce weak, thin bones, or bones that are too dense. Metabolic diseases and conditions may have genetic origins or may originate from unknown factors. Nutritional deficiencies, particularly of vitamin D, calcium, and phosphorus, can result in the formation of weak, poorly mineralized bone.

Genetic Diseases and Conditions General Information A genetic contribution to certain diseases and conditions is indicated by the increased incidence in certain families. Individuals may have a family history of bone loss diseases, and in some where multiple family members are affected there may be a direct pattern compatible with autosomal dominant inheritance.25,26

Family history refers to the genetic relationships within a family combined with the medical history of individual family members. When represented in diagram form using standardized symbols and terminology, it is usually referred to as a pedigree or family tree.

Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a gene (i.e., the person is heterozygous).

Autosomal recessive inheritance refers to genetic conditions that occur only when a mutation is present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).

Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to certain diseases and

28 conditions and have led to the identification of several highly penetrant genes as the cause of inherited disease in certain families.26

Linkage analysis is a gene-hunting technique that traces patterns of disease in high-risk families. It attempts to locate a disease-causing gene by identifying genetic markers of known chromosomal location that are co-inherited with the trait of interest.

Genetic marker is an identifiable segment of deoxyribonucleic acid (DNA) (e.g., Single nucleotide Polymorphism, Restriction Fragment Length Polymorphism, Variable Number of Tandem Repeats, microsatellite) with enough variation between individuals that its inheritance and co-inheritance with alleles of a given gene can be traced and used in linkage analysis.

Deoxyribonucleic Acid (DNA) is a molecule, which encodes the genes responsible for the structure and function of an organism and allows for transmission of genetic information from one generation to the next.

Nucleotide is a molecule consisting of a nitrogen-containing base (adenine, guanine, thymine, or cytosine in DNA; adenine, guanine, uracil, or cytosine in RNA), a phosphate group, and a sugar (deoxyribose in DNA; ribose in RNA). DNA and RNA are polymers comprised of many nucleotides, strung together like beads in a necklace.

Penetrance is a characteristic of a genotype; it refers to the likelihood that a clinical condition will occur when a particular genotype is present.

Mutation is a change in the usual DNA sequence at a particular gene locus. Mutations (including polymorphisms) can be harmful, beneficial, or neutral in their effect on cell function.

Polymorphism refers to a common mutation. “Common” is typically defined as an allele frequency of at least 1%. All genes occur in pairs, except when x and y chromosomes are paired in males; thus a polymorphism with an allele frequency of 1% would be found in about 2% of the population, with most carriers having one copy of the polymorphism and one copy of the normal allele. Today, diagnostic testing for certain hereditary diseases and disorders is a routine aspect of prenatal care.27 The process involves testing the fetus before birth to determine whether the fetus has certain abnormalities, including hereditary or spontaneous genetic disorders. Many of the available tests, include ultrasonography and blood tests that are non-invasive and certain invasive prenatal genetic tests such as chorionic villus sampling, amniocentesis, and percutaneous umbilical blood sampling, as indicated.27 Usually the invasive tests are done when couples have an increased risk of having a baby with a genetic abnormality (such as neural tube defects) or a chromosomal abnormality. Invasive prenatal tests have risk, although very small, particularly for the fetus. If in vitro fertilization is done, genetic disorders can sometimes be diagnosed before the fertilized egg is transferred from the culture dish to the uterus. A few of the most common genetic disorders that can be detected before birth includes:  Cystic fibrosis an autosomal recessive condition that is more common among Caucasians at an occurrence rate of 1 in 3,300 births;  Hemophilia A an X-linked recessive condition occurring at a rate of 1 in 8,500 male births; and,  Sickle cell anemia an autosomal recessive condition that is more common among African-Americans at an occurrence rate of 1 in 400 births.

Screening pregnant women during the prenatal period involves measuring substances (called markers) in the blood to identify increased risk of certain diseases and conditions (i.e., Down syndrome, neural tube defect). First trimester screening done at about 11 to 14 weeks of pregnancy includes tests measuring levels of pregnancy-associated placental protein A and beta-human chorionic gonadotropin. 27 Ultrasonography is done to measure a fluid-filled fetal nuchal translucency, which if abnormal indicates an increased risk of Down's syndrome.27

30 During the second trimester, markers in the pregnant woman’s blood are measured and ultrasonography may be conducted to identify women at increased risk of certain conditions. These tests include markers for alpha- fetoprotein, estriol, human chorionic gonadotropin, and inhibin A.

Chondrodysplasias The chondrodysplasias are a group of rare genetic disorders of collagen at the growth plates, which cause skeletal deformity and short stature (dwarfism).28 There are several types of chondrodysplasias, each with its particular skeletal profile, severity, and prognosis.28 Skeletal deformities associated with defects of collagen can lead to fracture.28

Ehlers-Danlos Syndrome Ehlers-Danlos syndrome is a relatively rare group of inherited disorders that affect collagen production.28 Defects in collagen weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder, which vary from mildly loose joints to life-threatening complications. Fractures are often seen in those with Ehlers-Danlos syndrome.28 The severity of the disease can be from mild to life-threatening.29 Common symptoms are unstable, flexible joints (hypermobility) with a tendency to dislocate and subluxate, due to ligaments which are overly stretchable; and, elastic, fragile, soft skin that easily forms welts and scars.29 Those with Ehlers-Danlos syndrome often have intense pain where the joints are dislocated.29 Other symptoms can include eye problems, such as lens dislocation and myopia.29 Bone deformities such as pectus excavatum (sunken chest) or scoliosis may present early. Most serious consequences are due to vascular and organ fragility, which are less frequent.29 Mutations in certain genes (ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, PLOD1 and TNXB) cause Ehlers-Danlos syndrome.29 Inheritance patterns depend on the type of Ehlers-Danlos syndrome. Most forms of the condition are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause the disorder. The overall prevalence of all types of Ehlers- Danlos syndrome may be about 1 in 5,000 births worldwide.29 The prevalence of the 6 types differs dramatically.29 The most common are the hypermobile forms

31 with other forms being very rare. For example, fewer than 10 infants and children with the dermatosparaxis type have been described worldwide. It affects both males and females of all racial and ethnic backgrounds. 29

Gaucher’s Disease Gaucher’s disease is an inherited metabolic disorder characterized by the accumulation of glucocerebroside in the spleen, liver, lungs, bone marrow, and sometimes in the brain, causing damage to these organs.30 It is the most common of the lysosomal storage diseases. 30 Symptoms may include enlarged spleen and liver, liver malfunctions, skeletal disorders and bone lesions. The disease may cause pain, severe neurologic complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the sclera.30 Persons that are the most seriously affected may also be susceptible to infections. The disease shows autosomal recessive inheritance, therefore affects males and females equally.30 The disease is named after the French doctor Philippe Gaucher who originally described it in 1882.30 In populations with high rates of carriage (Ashkenazi Jews and Norrbottnian Swedes), some family members of the index patient may already have been diagnosed with Gaucher’s.30 Truly sporadic cases may result in a delay of diagnosis due to the array of possible symptoms of the disease. Pharmacological enzyme-replacement therapy is available, but the consequences of Gaucher's disease in bone (including fracture) seem to continue. 30 There are few reports of the successful use of bisphosphonates for this condition.

Hypophosphatasia Hypophosphatasia is a rare genetic disease characterized by deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity, excessive urinary excretion of phosphoethanoamine, poor bone mineralization, and skeletal anomalies.31 Hypophosphatasia is one of several disorders that resemble osteogenesis imperfecta (OI). The condition causes low levels of TNSALP specific enzymes, which are normally present in large amounts in the bones and

32 the liver. In hypophosphatasia, abnormalities in the gene that produces TNSALP leads to the production of inactive TNSALP. Subsequently, several chemicals, including phosphoethanolamine, pyridoxal 5-phosphate (a form of vitamin B6) and inorganic pyrophosphate, accumulate in the body and are found in large amounts in the blood and urine.31 It appears that the accumulation of inorganic pyrophosphate is the cause of the characteristic defective calcification of bones seen in infants and children (rickets) and in adults (osteomalacia). The severity of hypophosphatasia is remarkably variable from patient to patient. The most severely affected fail to form a skeleton in the womb and are still- born. Mildly affected patients may show only low levels of TNSALP in the blood, yet never suffer bone problems. In general, patients are categorized as having perinatal, infantile, childhood, or adult forms of hypophosphatasia depending on the severity of the disease and the age at which the bony manifestations are first detected.31 Radiographic changes are quite distinct to the trained eye, and measuring TNSALP in a routine blood test substantiates the diagnosis. It is important that physicians use appropriate age ranges for normal TNSALP levels when interpreting the blood test.31 Odontohypophosphatasia refers to children and adults who have only dental, not skeletal, problems. This usually involves premature loss of teeth. It has been estimated that the severe forms of hypophosphatasia occur in approximately 1 per 100,000 live births.31 The more mild childhood and adult forms are probably more common. About 1 out of every 300 individuals in the United States is thought to be a carrier for hypophosphatasia.51 There are reports of blue sclera during infancy and childhood that may resemble OI. Depending on the severity of the skeletal disease, there may be deformity of the arms, legs, and chest. Frequent bouts of pneumonia can result if the chest distortion is severe. Recurrent fractures can also occur. Teeth may be lost prematurely and the teeth may have a wide pulp chamber that predisposes them to cavities. These symptoms resemble some of those found in OI. The outcome following a diagnosis of hypophosphatasia is variable. Cases detected in the womb or with severe deformities at birth almost invariably result in death within days or weeks.

33 Osteogenesis Imperfecta Osteogenesis imperfecta (OI) is a genetic disorder characterized by bones that break easily, often from little or no apparent cause. There are at least four recognized forms of the disorder, representing extreme variation in severity from one individual to another. For example, a person may have just a few or as many as several hundred fractures in a lifetime.32 While the number of people affected with OI in the United States is unknown, the best estimate suggests a minimum of 20,000 and possibly as many as 50,000.32 OI is caused by a genetic defect that affects the body’s production of collagen. In OI, a person has either less collagen than normal, or a poorer quality of collagen than normal, leading to weak bones that fracture easily. Osteogenesis imprefecta is the result of a mutation in one of the two genes that carry instructions for making type 1 collagen, the major protein in bone and skin.32 The mutation may result in a change in the structure of type 1 collagen molecules, or in the number of collagen molecules made. Either of these changes results in weak bones that fracture easily. In recent years, researchers have studied skin cells, collagen molecules, and genes from individuals with different forms of OI. Results of these studies show that the great majority of people with OI, even those who are the only affected person in a family have dominantly inherited forms of the disorder.32 Most cases of OI involve a dominant mutation. When a gene with a dominant mutation is paired with a normal gene, the faulty gene “dominates” the normal gene. In OI, a dominant genetic defect causes one of two things to occur:  The dominant altered gene directs cells to make an altered collagen protein. Even though the normal gene directs cells to make normal collagen, the presence of altered collagen causes types II, III, or IV OI, which are caused by defective quality collagen; or,  The dominant altered gene fails to direct cells to make any collagen. Although some collagen is produced by instructions from the normal gene, there is an overall decrease in the amount of collagen produced, resulting in type I OI. Type I OI results from a deficiency in the quantity of collagen.32

34 When a genetic mutation is dominant, a person has to receive only one faulty gene to have a genetic disorder. This is the case with most people who have OI: they have one faulty gene for type 1 collagen, and one normal gene for type I collagen.32 With recessive inheritance, both copies of a gene must be defective for a person to have a genetic disorder and this occurs when both parents carry a single altered copy of the gene. The parents do not have the genetic disorder (because they have only one faulty gene), but they are carriers of the disorder. With each pregnancy, there is a 25% chance that the child will receive two altered genes, one from each parent.32 In this case, the child would have the genetic disorder. There is a 50% chance that the child will receive only one altered gene, in which case the child will be a carrier (like the parents), but will not have the disorder. Most researchers now agree that recessive inheritance rarely causes OI. Some children with OI inherit the disorder from a parent. Other children are born with OI even though there is no family history of the disorder. In these children, the OI occurred as a spontaneous genetic mutation.32 Because the genetic defect, whether inherited or due to a spontaneous mutation, is usually dominate a person with OI has a 50% chance of passing on the disorder to each of his or her children. Genetic counselors can help people with OI and their family members further understand OI genetics and the possibility of recurrence, and assist in prenatal diagnosis for those who wish to exercise that option. It is often, though not always, possible to diagnose OI based solely on clinical features. Clinical geneticists can perform biochemical (collagen) or molecular tests that can help confirm a diagnosis of OI, in some situations. These tests generally require several weeks before results are known, and approximately 10% to 15% of individuals with mild OI who have collagen testing, and approximately 5% of those who have genetic testing, test negative for OI despite having the disorder.33 Ultrasonography is the least invasive procedure for prenatal diagnosis of OI and therefore carries the least risk. Using ultrasound images of the fetus, physicians look for skeletal bowing, fractures, and shortening or other bone abnormalities that may indicate OI. The age of the fetus when the ultrasound is performed is important to achieve an accurate diagnosis. For example, if a type

35 II OI is suspected, ultrasound studies performed prior to 24 weeks gestation will very likely detect severe long bone shortening and numerous fractures of the limbs and thoracic cage. A fetus with type III OI is often detectable by ultrasound, easily in the second trimester, due to the presence of multiple fractures and shortened limbs. When faced with these findings, parents are typically advised that type II is lethal and that type II is often associated with significant disability and early mortality. It must also be realized that cases have been reported where children with severe forms of OI have survived and lived fulfilling productive lives. Many reports discredit the belief that infants with type II and type III cannot survive. While bowing of the long bones may be present in the second trimester, fractures in types I and IV, may not be seen with ultrasound studies until the third trimester, if at all. Although ultrasound studies have been used occasionally to diagnose milder forms of OI, mild OI is often not detected until late in the pregnancy, if at all. There are different levels of ultrasound studies that can be used in detecting OI, some of which are more useful than others. Even when a highly qualified ultrasonographer performs the procedure, it may be difficult to accurately pinpoint the type of OI before birth. Historically type I OI has also been referred to as “OI Tarda”. Type I OI is different from other types of OI in an important way. A person with type I OI has approximately half the normal amount of type I collagen. However, the collagen that is present is normal in structure. The impact of OI can vary among people. Many people with type I OI have only some; not all, of the following signs and symptoms:  The bones are predisposed to fracture with most fractures occurring before and during puberty;  The person is somewhat predisposed to other connective tissue injuries, such as dislocations;  The skin bruises easily;  The person may have normal or near-normal stature, as compared with unaffected family members;  The person may have loose joints, muscle weakness, and lax ligaments;  The sclera (whites of the eyes) usually have a distinctly blue, purple, or gray tint;

36  The person may have a somewhat triangular face and a tendency toward spinal curvature (scoliosis). Bone deformities may be absent or minimal and brittle teeth are possible; and,  The person may have a hearing loss, often beginning as a teen or young adult, but which may occur sooner.

Some people with type I OI are very mildly affected and they may suffer only a few fractures, be average or even above-average in height and be able to walk and run. They may have barely noticeable signs of OI, such as blue sclera or loose joints. In fact, some people are so mildly affected that they are not diagnosed until their teen or adult years, and in some cases only after they have borne a child who is diagnosed with type I OI. Other people with type I OI have more distinct signs and symptoms. They may have several dozen or more fractures and they may be somewhat smaller than the rest of their family members. In most cases, people with type I OI experience fewer fractures after puberty, when the bones are no longer growing quickly. Though it may seem that some people with mild OI “grow out of it” after puberty, the genetic defect still exists, and adults with type I OI need to be aware of how the disorder may affect them throughout their life, especially women as they approach and go through menopause. Babies with type I OI may or may not be born with fractures. A baby may have other outward signs of OI, such as blue sclera or loose joints, but these signs may go unnoticed in a family with no history or knowledge of OI. Furthermore, blue sclera can occur even in healthy infants until about 18 months of age. A child with type I OI may sustain his or her first fracture during ordinary activity, such as when a caregiver pulls on the ankles when changing a diaper, a physician does a physical examination, or a toddler falls while learning to walk. Other children with OI may not experience fractures until the school years, when they begin participating in physical education, sports, and recreational activities. The occurrence of fractures after little or no trauma is often the first clue that a child may have OI. To diagnose the disorder, a physician can look for other clinical features of OI, and obtain a family history to determine if other family members have a history of fractures or other OI symptoms. Families in which one parent has OI may be able to arrange for prenatal testing through

37 chorionic villus sampling or amniocentesis. In most cases, to confirm a diagnosis, knowledge of the affected patient’s genetic mutation must be known and this may be difficult to determine. Ultrasound may not detect type I OI in a fetus because the child is unlikely to have fractures or bone deformity before birth. When prenatal diagnosis is not possible, or not desired, a sample of the child’s umbilical cord can be taken at birth and sent to a laboratory for collagen testing. When a parent has OI, it is recommended that the newborn be tested and examined by a knowledgeable clinician as soon as possible. The information will help parents make decisions about their baby’s care. Dual energy x-ray absorptiometry (DXA) to measure bone mineral density (BMD) will not by itself provide a diagnosis of OI but, when combined with personal and family medical history, findings on physical examination, x-rays and biochemical testing, it can provide important information to support a diagnosis of OI.34 For example, if a person (usually a child not known to have OI) suffers a fracture, there may be a question about whether the trauma was sufficient to have caused the fracture. One of the most consistent features of the skeletal defect in OI is low BMD, a major reason for excess skeletal fragility and fractures. DXA measurements can be helpful if assessing skeletal development in children with OI and determining the likelihood of fractures. Bone densitometry technology allows physicians to assess the effects of treatments designed to build up bone mass or prevent bone loss.34 Finally, it is necessary to understand that some DXA measurements can be misleading. Skeletal deformities (such as spine curvature, compression fractures in vertebrae, or orthopedic metal) can significantly impair or destroy the usefulness of DXA measurements. Furthermore a patient’s body size has an important effect on DXA values and how they should be interpreted. DXA measurements in short stature adults or children can be artificially low and therefore especially difficult to interpret. Most DXA machines now provide normal ranges for other skeletal sites; however, these may not be readily available for children. These concerns, however, are now being addressed in medical research. Treatment for a child with type I OI includes fracture management, therapy to regain strength and mobility after fractures, and an ongoing program of safe exercise and activity to develop muscle control and build strength.

38 Recognizing that prolonged immobilization can weaken muscles and bones, many physicians prefer short-term casting of fractures, followed, as soon as possible, by a splint or brace that can be removed for appropriate exercise. Bisphosphonate medications (such as pamidronate and alendronate) show promise for strengthening bone and improving function in children with OI. These medications are currently being studied in clinical trials. Most clinical trials initially accepted only severely affected children, but some trials have since expanded to include children with type I OI. Because the long-term effects of these medications on children are still being studied, they are generally given to children for whom frequent fractures are a problem. Children with type I OI should be monitored regularly for OI-related problems such as hearing loss and scoliosis. Osteoporosis is a consequence of having OI and it is important for teens and adults with OI (both male and female) to build bone density and prevent bone loss through safe exercise, diet, and in some cases, medication. It is recommended that adults with OI have a BMD test to establish a baseline, which will allow their physician to monitor whether their bone density is changing over time. In addition to its importance for bone density, exercise is also important for maintaining strength, function, and general health. Calcium does not improve the basic collagen defects that causes OI, but people with OI need to get adequate calcium in their diets to develop bone mass and prevent bone loss, which can worsen bone fragility. Adults with OI have the same needs for calcium as other adults; excessive consumption of calcium or use of supplements is neither necessary nor recommended, as it can lead to other health problems. Caffeine and alcohol should be consumed in moderation, as excessive intake can lead to bone loss if adequate calcium is not present. Some medications, such as steroids (for example, prednisone) contribute significantly to bone loss, as does smoking. Many women with type I OI are concerned about menopause and the possibility of more frequent fractures, as osteoporosis may develop. The experience of postmenopausal women with OI varies greatly; some experience an increase in fractures, while others do not. The strategies that are discussed in this course in regard to maintaining bone density and general health will help each woman maximize her chances to stay active and healthy as she ages.

39 Many people with OI type I do not appear disabled, so there is potential for others to misunderstand or underestimate the disorder. Parents may provide information about preventing fractures to teachers, baby-sitters, or other caregivers, only to have the caregivers dismiss them as being “overprotective.”35 Providing written information, such as materials from the OI Foundation and a letter from the child’s physician briefly explaining the OI diagnosis and the recommended precautions can help reinforce the information provided by parents. Likewise, it is important for a child’s siblings and peers to receive age- appropriate information about OI 35 False accusations of child abuse may occur in families with children who have milder forms of OI and/or in whom OI has not previously been diagnosed.35 The type of fractures that are typically observed in both child abuse and OI include the following:  Fractures in multiple stages of healing;  Rib fractures;  Spiral fractures; and,  Fractures for which there is not adequate explanation of trauma.

Once a diagnosis of OI is made, families should ask for a letter on medical letterhead confirming the diagnosis, and explaining what it means. Copies of the letter should be kept in the diaper bag, the car, with the child’s medical and school records, and anywhere else it might be useful, particularly when the family is traveling or visiting the emergency room.35 A person with type II, type III, or type IV OI (the moderate to severe types of OI) not only has a reduced amount of type 1 collagen, but also collagen that is abnormal in structure. In other words, type I OI is caused by deficient type 1 collagen. Low levels of defective type 1 collagen cause the other types of OI. Type II OI, caused by improperly formed collagen, is the most severe form and frequently lethal at or shortly after birth often due to respiratory problems. In recent years, some people with type II have lived into young adulthood but they generally will experience numerous fractures and severe bone deformity. Persons with type II OI will have a small stature with underdeveloped lungs.

40 In type III OI, the bones fracture easily and fractures are often present at birth. Radiographs of patients with type III OI may reveal healed fractures that occurred before birth. In type IV OI, the bones fracture easily, most before puberty with mild to moderate bone deformity. There is not a cure for OI and treatment is directed toward preventing or controlling the symptoms, maximizing independent mobility, and developing optimal bone mass and muscle strength. Care of fractures, extensive surgical and dental procedures, and physical therapy are often recommended for people with OI. Use of wheelchairs, braces, and other mobility aids is common, particularly (although not exclusively) among people with more severe types of OI. People with OI have some special risks that distinguish them from the general population regarding the use of anesthesia. Because of physical deformity, the mobility of the neck and the jaw may be reduced. Chest and rib deformities and scoliosis may affect breathing. Other hazards may be posed by complicating factors such as dental problems, cleft palate, and joint stiffness or heart valve disease.36 The prognosis for an individual with OI varies greatly depending on the number and severity of the symptoms. Despite numerous fractures, restricted activity, and short stature, most adults and children with OI lead productive and successful lives. For individuals with OI, the pain associated with multiple fractures can lead to needless suffering and, when untreated, may result in chronic pain. Individuals with OI may experience multiple fractures, vertebral collapse, joint deformity, osteoarthritis, contractures, deformity/misalignment of limbs, and recurrent abdominal pain. Pain management for adults and children with OI requires adequate assessment and implementation of a regimen that should address the multifaceted presentation of acute and chronic pain.37 Chronic pain may impair a person’s ability to lead a productive life, which might lead to serious economic as well as medical problems. Physical coping strategies for pain management include the application of heat and ice, transcutaneous electrical nerve stimulation (TENS), exercise or physical therapy, acupuncture, accupressure and massage therapy. Psychological methods of pain management include relaxation training, biofeedback, visual imagery, hypnosis, and individual and/or family therapy.

41 Medications for pain management may be over-the-counter pain relievers, non- steroid anti-inflammatory medications, topical pain relievers, and narcotic pain medications. Osteogenesis imperfecta is a complex disorder that affects each individual and family in a unique way. The impact of OI on an individual depends on the type of OI the person has and the extent to which their physical appearance and personal mobility are affected. For the family with OI, the ability to balance the reality of the disability and the quality of life is essential. Because of ongoing concern for and reality of recurrent bone breaks and other medical complications, families need added psychological resiliency to maintain equilibrium. Preparing a child with a disability to manage on his own requires greater thought and foresight than a non-disabled child.

Osteoporosis Pseudoglioma Syndrome Osteoporosis pseudoglioma syndrome is an autosomal recessive disorder caused by inactivating mutations in the gene that encodes low-density lipoprotein receptor-related protein-5 (LRP-5).38 Osteoporosis pseudoglioma syndrome is characterized by severe juvenile-onset osteoporosis, congenital or juvenile-onset blindness, short stature, and skeletal deformity due to multiple fractures.38 Small uncontrolled studies have shown that intravenous bisphosphonate therapy can be beneficial in patients with this condition and may prevent progressive vertebral deformity.38

Cystic Fibrosis Reduced bone density is often observed in children and adults with cystic fibrosis (CF).38 Cystic fibrosis is a disease resulting from an autosomal recessive genetic defect causing a malfunction of the exocrine glands. The recessive gene that is responsible for CF has been identified on chromosome 7q. The disease, which is often thought of as affecting only the respiratory system, also affects nearly all exocrine glands. The exocrine glands and other organs affected include the salivary glands, small bowel, pancreas, biliary tract, female cervix, and male genital system. The respiratory damage occurs when increasing

42 secretions from hypertrophy of the bronchial glands leads to obstructions and the resultant plugging provides opportunity for infection. Cystic fibrosis is the most common lethal genetic disease for white children although the life span to the age of 20 years or older occurs as a result of improved treatments. Osteopenia and osteoporosis is a possible consequence of CF because affected individuals have the tendency toward lower bone mass.23 Levels of vitamin D, a fat-soluble vitamin, affects calcium absorption. Many CF victims may be unable to absorb vitamin D. Also those with CF may have reduced weight-bearing activities, be underweight, have inadequate intake of calcium and low levels of sex hormones. Another contributing factor leading to loss of bone density is that glucocorticoid drugs are used to treat CF patients. Delayed puberty and gonadal dysfunction is common in CF and means that there are low levels of sex hormones in both males and females.

Klinefelter and Turner Syndromes Klinefelter and Turner syndromes are associated with hypogonadism and delayed maturation due to genetic abnormalities that compromise the function of testes and ovaries, respectively.38 Low bone mineral content is common and is particularly severe in patients who are not treated adequately with sex hormone replacement therapy. The genetic defects in both syndromes may also contribute to variable degrees of low bone density that is unrelated to low circulating levels of sex hormones. Increased fracture rates in untreated patients have been documented. Bisphosphonates have been shown to increase bone density in Klinefelter patients.38 In people with Turner’s syndrome, a combination of growth hormone and estrogen replacement therapy have been shown to be effective in improving height and bone mass.38 Klinefelter’s syndrome, 47, XXY, or XXY syndrome is a condition caused by a chromosome aneuploidy.39 The principal effect is small testes development and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms.39 The syndrome, first described in 1942, is the second most common extra chromosome condition and was named after Dr. Harry Klinefelter, an endocrinologist at Massachusetts General Hospital,

43 Boston, Massachusetts.39 The condition exists in roughly 1 out of every 500 to 1,000 males.39 Affected males are almost always effectively sterile, although advanced reproductive assistance is sometimes possible and some degree of language learning impairment may be present.39 In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).39 Gynecomastia to some extent is present in about a third of individuals affected, a slightly higher percentage than in the normal XY population, but only in about 10% of XXY males’ gynecomastia is noticeable enough to require surgery.39 The more severe end of the spectrum of symptom expression is also associated with an increased risk of breast cancer, and osteoporosis, risks shared to varying degrees with females.39 Additionally, medical literature shows some individual case studies of Klinefelter’s syndrome coexisting with other disorders, such as pulmonary disease, varicose veins, diabetes mellitus, and rheumatoid arthritis, but etiologies between Klinefelter’s and these other conditions are not well characterized or understood.39 Treatment of the genetic variation of Klinefelter’s syndrome is irreversible, but its symptoms can be altered or treated in a number of ways, including testosterone treatment and other therapies.39 Inadequately treated hypogonadism in Klinefelter’s syndrome increases psychosocial morbidity.39 Patients with Klinefelter syndrome have a 50 times greater risk of germ cell tumors (GSTs).39 In these patients, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are testicular in location.39 Turner’s syndrome or Ullrich-Turner’s syndrome encompasses several chromosomal abnormalities, of which monosomy X is the most common.40 It occurs in 1 out of every 2500 female births.54 Instead of the normal XX sex chromosomes for a female, only one X chromosome is present and fully functional.40 A normal female karyotype is labeled 46,xx; individuals with Turner’s syndrome are 45,x, though other genetic variants occur.40 In those affected by Turner’s syndrome, the female sexual characteristics are present but generally underdeveloped.40 Common symptoms of Turner’s syndrome include:  Short stature;  Lymphoedema of the hands and feet;

44  Broad chest and widely-spaced nipples;  Low hairline and low-set ears;  Amenorrhea, or the absence of a menstrual period;  Reproductive sterility; and,  Increased weight, obesity. 40

Other symptoms may include a small lower jaw, cutibus valgus (turned- out elbows), a webbed neck, soft upturned nails, Simian crease and drooping eyelids.40 Less common are pigmented moles, hearing loss, and a high-arch palate (narrow maxilla).40 Turner’s syndrome manifests itself differently in each female affected by the condition, and no two individuals will share the same symptoms.40 Approximately 98% of all fetuses with Turner’s syndrome spontaneously abort.40 Turner’s syndrome accounts for about 10% of the total number of spontaneous abortions in the United States and the incidence in live female births is believed to be 1 in 2500.40 While most of the symptoms of Turner’s syndrome are harmless, some can lead to significant medical problems. Normal skeletal development is inhibited due to a large variety of factors, mostly hormonal.40 The head, neck, and chest of women with Turner’s syndrome are usually of normal size, but the arms and legs are unusually short.40 The average height of a women with Turner’s syndrome is 4 feet 7 inches. The fourth metacarpal bone may be unusually short and due to inadequate circulation of estrogen, many of those with Turner’s syndrome develop osteoporosis.40 This can decrease height further, as well as exacerbate the curvature of the spine, possibly leading to scoliosis.40 It is also associated with an increased risk of bone fractures. There is no “cure” for Turner’s syndrome, a chromosomal condition.40 However, much can be done to minimize the symptoms. Growth hormone, either alone or with a low dose of androgen, will increase growth and probably final adult height.40 Estrogen replacement therapy has been used since the condition was described in 1938 to promote development of secondary sexual characteristics.54 Estrogens are also important for maintaining good tissue and bone integrity.40

45 Gastrointestinal Disease and Bone Loss Diseases that reduce intestinal absorption of calcium and phosphorus, or impair the availability of vitamin D, can also cause bone loss. Moderate malabsorption results in osteoporosis, but severe malabsorption may cause osteomalacia. Celiac disease or sprue, due to inflammation of the small intestines by ingestion of gluten, is an important and commonly overlooked cause of secondary osteoporosis. Celiac disease is an inherited intestinal disorder that alters the body’s ability to absorb calcium and other nutrients.41 Gluten is a protein found in wheat, rye, farina, semolina and bulgar. Individuals with celiac disease often consume adequate amounts of calcium and vitamin D however absorption may be compromised.41 For this reason, low bone density is common in untreated and newly diagnosed cases of celiac disease. When foods containing gluten are eliminated from the diet, normal absorption from the intestines is restored. In some cases, the diagnosis of celiac disease is missed because the only symptom the person has is occasional diarrhea or failure to gain or maintain body weight. The amount of bone a person loses will depend on the age at diagnosis and the onset of treatment with a gluten-free diet. When celiac disease is diagnosed and treated in childhood, peak bone density may be achieved. Even adults with untreated celiac disease have improvement in bone density once they are treated with a gluten-free diet.40,41 Additionally those having celiac disease should have optimal intake of vitamin D, participate in an exercise program, and avoid all products containing gluten. Diagnosis is usually made with a special antibody blood test or by examining a piece of intestinal tissue removed in biopsy. Osteoporosis and fragility fractures, especially in women, have been found following surgery to remove part of the stomach. Increased osteoporosis and fragility fractures are also seen in individuals with Crohn’s disease and ulcerative colitis. Glucocorticoids, commonly used to treat both disorders, probably contribute to the bone loss. Similarly, diseases that impair liver function (i.e., primary biliary cirrhosis, chronic active hepatitis, cirrhosis due to hepatitis B and C, and alcoholic cirrhosis) may result in disturbances in vitamin D metabolism and may also cause bone loss by other mechanisms. Primary biliary cirrhosis is associated with particularly severe osteoporosis. Fractures are more

46 frequent in those with alcoholic cirrhosis than any other type of liver disease, although this may be related to the increased risk of falling among heavy drinkers. Bone loss is seen after gastric bypass surgery even in morbidly obese women who do not have low bone mass initially. Obesity is a major public health issue and weight loss from diet and exercise alone are often not adequate to reduce weight to healthy levels in many people. As a result, there has been a marked increase in bariatric surgery procedures in the United States over the past decade. Advances in bariatric surgery have addressed many of the more serious issues of malabsorption associated with early techniques. Weight loss, either surgically induced through gastric bypass or banding procedures and nonsurgical weight loss, has been associated with an increased risk of osteoporosis. The connection between weight loss and osteoporosis has been associated with alterations in serum hormone levels, reduced beneficial mechanical impact of excess weight on bone, and nutritional factors. The two most frequently performed types of bariatric surgery are the Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB). The LAGB is a restrictive procedure, whereas the RYGB is both a restrictive and malabsorptive procedure. The strictly malabsorptive operation, also called intestinal bypass, is no longer performed because it results in severe nutritional deficiencies and increased morbidity and mortality. Recommendations for patients after bariatric surgery currently include measures to prevent and detect bone loss. Those who have had bariatric surgery should be screened for osteoporosis with DXA testing, and their nutritional status should be evaluated carefully at baseline and at regular postoperative intervals. Follow-up examinations of bariatric patients should include measurement of 25-hydroxyvitamin D-3 levels, especially in those with very low 25-OHD levels. Bariatric patients should receive calcium and vitamin D-3 (cholecalciferol) supplementation.

Sickle Cell Disease Children with sickle cell disease have significantly reduced bone mineral content as compared with control subjects, adjusted for age, height, pubertal status, and lean mass.38 This puts such patients at risk for suboptimal bone

47 density and future fragility fracture.38 Similar reductions in bone density occur in children and adults with other chronic anemias or bone marrow disorders such as Gaucher’s diseases and thalassemias.38 Sickle cell disease also known as sickle cell anemia is a blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells’ flexibility and increases the risk of other various complications. Life expectancy is shortened, with studies reporting an average of 42 and 48 years for males and females, respectively. Sickle cell disease occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria is or was common. One-third of all aboriginal inhabitants of Sub-Saharan Africa carries the gene.43 Only those individuals with one of the two alleles of the sickle cell disease are resistant to malaria and an infection of the malaria plasmodium is halted by the sickling of the cells which it infests. In areas where malaria is common, there is a survival value in carrying a single sickle cell gene. Prevalence of the disease is approximately 1 in 5,000 in the United States, mostly African-Americans according to the National Institute of Health.43 Sickle cell anemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes hemoglobin S. There are other forms or permutations of the disease, but these are very rare. Sickle cell anemia usually occurs in African American children but sometimes occurs in Hispanic children. Sickle cell disease may lead to various acute and chronic complications, several of which are potentially lethal. Normal red blood cells are disc shaped and look like doughnuts without holes in the center. These move easily through the blood vessels. Red blood cells contain the protein hemoglobin. Sickle cells contain abnormal hemoglobin that causes the cells to have a sickle shape. Cells that are sickle shaped do not move easily through the blood vessels because they are stiff and sticky and tend to form clumps and stick in the blood vessels. Blocked blood vessels can cause pain, serious infection, and organ damage. In the sickle cell anemia condition, a lower than normal number of red blood cells occurs because sickle cells do not last very long, dying after only about 10-20 days. The bone marrow cannot make enough new red blood cells to replace those that are so short lived.

48 Sickle cell anemia is an inherited, lifelong disease. Those who have the disease are born with it, inheriting two copies of the sickle cell gene, one from each parent. Those who inherit a sickle cell gene from one parent and a normal gene from the other parent have a condition called sickle cell trait. Sickle cell trait is different from sickle cell anemia. Those who have sickle cell trait do not have the disease but have one copy of the gene that causes it and can pass this trait to future children. When each parent has a normal gene and an abnormal gene, each child has a 25% chance of inheriting two normal genes; a 50% chance of inheriting one normal gene and one abnormal gene; and a 25% chance of inheriting two abnormal genes.43 Sickle cell anemia is present at birth but symptoms do not usually manifest until after 4 months of age. A common symptom of sickle cell anemia is fatigue and:  Shortness of breath;  Dizziness;  Headache;  Coldness in the hands and feet;  Pale skin; and,  Chest pain.43

Sudden pain throughout the body is a common symptom of sickle cell anemia. This pain is called a “sickle cell crisis”. A sickle cell crisis often affects the bones, lungs, abdomen, and joints. A sickle cell crisis occurs when sickled red blood cells form clumps in the bloodstream. These clumps of cells block blood flow through the small blood vessels in the limbs and organs causing pain and organ damage. The pain from sickle cell crisis can be acute or chronic, but acute pain is common. The pain usually lasts from hours to a few days. Chronic pain often lasts from weeks to months and may severely limit daily activities and quality of life. The effects of sickle cell crisis on different parts of the body can cause a number of complications. These include hand-foot syndrome, splenic crisis, infections, acute chest syndrome, pulmonary arterial hypertension, delayed growth and puberty in children, stroke, eye problems, priapism, gallstones, leg ulcers, and multiple organ failure. In the United States, all States

49 mandate testing for sickle cell anemia as part of their newborn screening program. Sickle cell disease is known to affect the shape of the vertebral bodies in many of its victims. The vertebral shape takes on a cup-like depression that is formed in the upper and lower surfaces of the centrum resulting in a contour distinctive of hemoglobinopathy.44 Such lesions are usually caused by compression of weakened bone, which has been subjected to the stress of weight bearing. A complex biconcave deformity results when the normal resilient intervertebral tissue protrudes into the weight bearing aspect of the weakened bone.44 The shape of the centrum resembles that found in certain lower vertebrates and is often referred to as “fish vertebra deformity”.44 Vertebral deformity in sickle cell disease develops as a direct result of complex pathologic mechanisms, which are peculiar to hemoglobinopathy. During the disease progression, radiography, magnetic resonance imaging (MRI), and computed tomography (CT) may be used to diagnose the various complications that are common to sickle cell disease.

Fibrous Dysplasia Fibrous dysplasia is a chronic disorder of the skeleton that causes expansion of one or more bones due to abnormal development of the fibrous, or connective, tissue within the bone.45 The abnormality causes uneven growth, brittleness and deformity in the affected bones. Some patients have only one bone affected, whereas other patients have numerous bones affected. While any bone can be affected by fibrous dysplasia, the most common sites of the disease are the femur, tibia, ribs, skull, facial bones, humerus, and pelvis. The vertebrae are less frequently involved. Although many bones can be affected at once, fibrous dysplasia is not a disease that spreads from one bone to another. Multiple affected bones are often found on one side of the body. Fibrous dysplasia is a very uncommon disorder, and the total number of cases is not known. It is usually diagnosed in children and young adults. If the disease involves more than one bone, it is more likely to produce problems before age 10.45 The disease is found equally in males and females and does not appear to vary in incidence among races.

50 Fibrous dysplasia may be caused by a chemical abnormality in a protein in the bone that leads to an overgrowth of bone cells that produce fibrous tissue. The chemical abnormality occurs because of a mutation in the structure of the gene that produces protein. Fibrous dysplasia is thought to be a congenital disorder; however, there is no scientific evidence to indicate that the disorder can be inherited. Depending on the area affected by dysplasia, various problems can develop. The most common are bone pain, bone deformity, and fracture. Bone pain may occur due to the expanding fibrous tissue in the bone. The onset of pain may signal an impending fracture in a bone that has been weakened by this gradual expansion. It is also possible, although less common, for abnormal bone to produce pain by pressing on an adjacent nerve. Individuals with considerable deformity of the weight-bearing long bones can develop arthritis in the hips and knees. Because fibrous dyplasia can affect any bone, bone deformity can occur anywhere in the skeleton. Bone deformity caused by fibrous dysplasia is most obvious when it occurs in the skull and facial bones. Fibrous dysplasia of the skull may cause loss of vision and hearing. When a bone is affected by fibrous dysplasia, the fibrous tissue expands while the bone surrounding the fibrous tissue breaks down. Therefore, even through the fibrous tissue thickens, the bone itself becomes thin and fragile and fractures can occur. This occurs most often in the long bones of the legs. The bones affected by fibrous dysplasia usually have a characteristic appearance on a radiograph. Where there is doubt about the diagnosis, a small bone specimen may be obtained for a pathology study. Those affected most commonly are evaluated and treated by orthopedic surgeons, craniofacial or cosmetic surgeons, neurosurgeons, and endocrinologists. Surgery is recommended for fibrous dysplasia to relieve intractable bone pain, improve mobility that may be impaired due to skeletal deformity, facilitate the healing of fractures, relieve local pressure on the spinal cord, spinal nerves, or brain, and to treat unusual complications of bone sarcoma. Some of the surgical procedures commonly used are:  Removal of affected bone followed by bone grafting in patients with persistent bone pain; and,

51  Removal of a wedge of bone with placement of pins and bone grafts to correct deformities.45

Studies have shown that some individuals with fibrous dysplasia may have considerable benefit from the drug pamidronate (Aredia®).

McCune-Albright Syndrome Some individuals with fibrous dysplasia may also develop hormonal problems such as early puberty, hyperthyrodism, excessive secretion of several pituitary hormones, and high blood calcium from parathyroid hormone. Individuals with hormonal disturbances may also exhibit areas of darkly pigmented skin called “café-au-lait,” or “coffee-milk” spots.45 The combination of fibrous dysplasia, hormonal disturbances, and skin pigmentation is called McCune-Albright syndrome, named for Dr. Donovan McCune and Dr. Fuller Albright, who independently described the syndrome in 1937. Patients who have fibrous dysplasia in only one bone usually do not develop McCune-Albright syndrome.

Osteopetrosis Oteopetrosis is a congenital condition present at birth in which the bones are overly dense. This results from an imbalance between the formation of bone and the breakdown of bone, both of which are necessary in the development and maintenance of normal bone. In osteopetrosis, the cells that breaks down bone, or the osteoclasts, usually are either fewer in number or are ineffective in breaking down bone. When an individual has osteopetrosis, all of the bones are affected and they are overly dense and the skeleton is extremely heavy.46 There are 3 major types of osteopetrosis: malignant infantile form, intermediate form, and adult form. The malignant infantile form of osteopetrosis is very severe and it is inherited when both parents have an abnormal gene that is passed to the child. The disease is apparent from birth and frequently ends in death. Despite its name, the disease is not related to cancer. The following is common in children with malignant infantile osteopetrosis:  Anemia and frequently complete bone marrow failure;

52  Frequent infections due to a reduction in white blood cells and white blood cells that are inactive in fighting infection;  No tooth eruption or inadequate tooth eruption;  Increased pressure within the skull;  Failure to thrive;  Delays in psychomotor development that includes delays in sitting, walking, and talking;  Blindness, deafness and other nerve problems within the head; and,  Death during the first 10 years of life in 30% of the children.46

The intermediate form of osteopetrosis is less severe than the malignant infantile form. It is found in children younger than 10 years old and is more severe than the adult form but usually does not shorten life expectancy.48 The adult form of osteopetrosis is a milder type found in adults between the ages of 20-40 years. The adult form of osteopetrosis rarely causes a significant reduction in life expectancy. The following are symptoms found in children and adults with intermediate and adult forms of osteopetrosis:  An increase number of fractures because the bones although dense, are also weak;  Frequent infections due to bone marrow involvement that impairs white blood cell production; and,  Blindness, deafness and strokes due to overgrowth of bone that damages nerve and blood vessels.46

The adult form of osteopetrosis occurs in about 1 in 20,000 people. There are about 1,250 people with the adult form of osteopetrosis in the United States.46 The malignant infantile form of osteopetrosis is present from 1 and 100,000 to 1 in 500,000 births. Approximately only 8 to 40 children with this severe form of osteopetrosis are born per year in the United States.46 The adult form of osteopetrosis is inherited as an “autosomal dominant trait,” meaning that it can be passed from generation to generation and children can inherit osteopetrosis even if only one parent is affected. There is a 50% chance that a child of someone with adult osteopetrosis will have the disease.46

53 Many cases, however, occur without a family history. It is possible that these cases are new or caused by spontaneous gene mutations. The severe malignant infantile form is inherited as an “autosomal recessive disorder,” meaning that both parents have an abnormal gene that is passed to the affected child. Because the gene is recessive, each parent will be normal, not showing any symptoms of the disease. Usually, there is no history of severe, congenital osteopetrosis in the family prior to the diagnosis of the first child. The intermediate form may be inherited in either an autosomal recessive or an autosomal dominant fashion. Most cases occur sporadically, however, with no known inheritance pattern. Diagnosis for osteopetrosis is made when dense bones are seen on radiographs. The diagnosis is usually confirmed by taking a bone sample to determine the precise nature of the disease. A variety of additional studies may be conducted to diagnose osteopetrosis, such as hearing and vision testing, radiography examinations, blood counts and brain imaging. Physicians who usually treat osteopetrosis include hematologists, endocrinologists, and orthopedic surgeons. The FDA recently approved Actimmune® (Interferon gamma-1b) injection for delaying the progression of the disease for those with severe malignant osteopetrosis. Actimmune® is the only therapy approved specifically for the treatment of osteopetrosis. Both adult and pediatric patients may benefit from Actimmune®. Bone marrow transplantation (BMT) is the only therapy that has resulted in a complete cure of the severe malignant infantile form of osteopetrosis. BMT replaces the abnormal osteoclasts and cures the defect if the transplantation is successful. The survival rate after BMT in children who have osteopetrosis is 40% to 70% depending on how well matched the bone marrow donor is to the patient.46 BMT is only used in severely affected patients because of the high risk of failure with the potential of a fatal outcome. Calcitriol is the active form of vitamin D and stimulates the bone destruction function of the osteoclasts. Given orally in high doses, it can reverse some of the problems of severe osteopetrosis and significantly improve the adult form. Prednisone, given orally, has improved blood counts in those with anemia and low platelet counts as it may slow blood cell destruction. Prednisone treatment provides a short-term boost to the blood system, allowing other

54 therapies to continue. If taken for long periods, however, prednisone may actually reduce the growth rate of children and predispose them to infection. Physical and occupational therapy are extremely useful in helping children with osteopetrosis reach their full developmental potential. The heavy skeleton results in gross motor delays and blindness can delay speech. The average severely affected child walks at about two years and begins to speak between 20 to 24 months old. Patients with the adult form of osteopetrosis have a normal life span. The major complications are fractures and compression of the cranial nerves, or those nerves pertaining to the bones of the head. These complications can lead to blindness, deafness and facial nerve paralysis. Less than 30% of all children with the severe malignant infantile form of osteopetrosis survive to their tenth birthday, unless they are treated with BMT or a combination of interferon gamma and calcitriol.48 Only 10% of infants who have blindness and anemia before six months old survive more than one year unless they are successfully treated.48

Metabolism Diseases and Conditions Linked to Bone Loss

General Information The endocrine system includes 8 major glands that produce hormones that regulate important processes that includes:  Growth and development;  Metabolism (digestion, elimination, respiration, circulation, and homeostasis);  Sexual function;  Reproduction; and,  Mood regulation.

The foundations of the endocrine system are the hormones and glands, which serve as the body’s chemical messengers. Hormone levels can be influenced by factors such as stress, infection, and changes in the balance of fluid and minerals in the blood. The major glands of the endocrine system are

55 the hypothalamus, pituitary, thyroid, parathyroids, adrenals, pineal body, and the reproductive glands, which include the ovaries and the testes. The pancreas is also part of the endocrine system, even though it is also associated with the digestive system because it produces and secretes digestive enzymes. The hypothalamus is located below the thalamus, just above the brain stem. It is responsible for certain metabolic processes and other activities of the autonomic nervous system. The hypothalamus synthesizes and secretes neurohormones, often called hypothalamic-releasing hormones, which stimulate or inhibit the secretion of pituitary hormones. These hormones control body temperature, hunger, thirst, fatigue, and circadian cycles. The hypothalamus contains neurons that react strongly to steroids and glucocorticoids. The pituitary gland, about the size of a pea, is located at the base of the brain. The pituitary is often referred to as the master gland because it produces and secretes many hormones that travel throughout the body. These hormones direct other endocrine glands to produce and secrete hormones. The types of hormones produced and secreted by the pituitary gland include prolactin, growth hormone (GH), adrenocorticotropin (ACTH), thyroid-stimulating hormone (TSH), antidiuretic hormone (ADH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Disorders and tumors of the pituitary gland result in hypersecretion or hyposecretion of hormones. The parathyroid glands are 4 pea-sized glands located on the thyroid gland in the neck. The parathyroid glands secrete parathyroid hormone (PTH), a substance that helps maintain the correct balance of calcium and phosphorus in the body. PTH regulates the level of calcium in the blood, release of calcium from bone, absorption of calcium in the intestine, and excretion of calcium in the urine. When the level of calcium in the blood falls too low, the parathyroid glands secrete just enough PTH to restore the blood calcium level. Hyperparathyroidism is a condition that occurs if the parathyroid glands secrete excessive hormone. In the United States, about 100,000 people develop the disorder with women outnumbering men by about 2 to 1. Risk of hyperparathyroidism increases with age and approximately 2 out of 1,000 women, 60 years and older are expected to develop the condition. The majority of cases of hyperparathyroidism occur in people with no known family history of

56 the disorder. However, about 5% of cases can be linked to a condition called inherited familial multiple endocrine neoplasia type 1. In this condition, the blood calcium rises causing excess of calcium in the blood, hypercalcemia. Excess PTH triggers the release of too much calcium into the bloodstream causing the bones to lose calcium. The levels of calcium may increase in the urine, resulting in the formation of kidney stones. It is estimated that the primary cause of primary hyperparathyroidism is a benign tumor called an adenoma. In the remainder of cases, the excess production of PTH is caused by hyperplasia of the glands. Hyperparathyroidism results in increases in blood calcium levels and thus leads to bone loss. Primary hyperparathyroidism is a relatively common condition in older individuals, especially postmenopausal women. Most affected individuals first come to clinical attention when they are unexpectedly found on routine examination to have an abnormally high calcium level in the blood. The clinical presentation has changed over the past 30 years from an uncommon but highly symptomatic disorder involving renal stones and bone disease (osteitis fibrosa cystica) to a common but a relatively non-symptomatic condition. Typically, cortical bone (e.g., the distal forearm) is affected to a greater extent than trabecular bone (e.g., in the spine) in primary hyperparathryroidism. It is presumed that the reduction in bone mass is associated with the increased risk of fracture seen in these patients. Excess PTH also lowers blood phosphorus levels by increasing excretion of phosphorus in the urine. Hyperparathyroidism is generally diagnosed by laboratory tests that measure blood levels of calcium and parathyroid hormone. The primary treatment of the condition is surgical removal of the gland, which is known to cure 95% of those with the condition. The thyroid is a small butterfly-shaped gland inside the neck, located anterior to the trachea and below the larynx. It produces 2 thyroid hormones, tri- iodothyronine and thyroxine. These hormones are released by the gland and regulate the body’s metabolism. The pituitary gland exerts control over normal functioning of the thyroid gland. If too much thyroid hormone is released a condition referred to as hyperthyroidism results. Hyperthyroidism is more common in women than men and is estimated to affect about 1% of all women. Graves’s disease, an autoimmune disorder, is one of the most frequent forms of

57 hyperthyroidism and is thought to have a genetic linkage since the condition may affect multiple members in a genetic family. Hypothyroidism occurs when the thyroid gland releases insufficient amounts of the thyroid hormone. Thyroid nodules, which are considered common in almost half of the population, may interfere with the proper functioning of the gland. The adrenal glands are star shaped structures that are located above each kidney at approximately the level of the 12th thoracic vertebra. The adrenal glands release 3 different classes of hormones, which control the following important bodily functions:  Maintain metabolic processes (i.e., managing blood sugar levels and regulating inflammation);  Regulate the balance of salt and water;  Control the “fight or flight” response to stress;  Maintain pregnancy; and  Initiate and control sexual maturation during childhood and puberty.

The adrenal glands are also an important source of sex steroids, such as estrogen and testosterone. Adrenal disorders occur when the adrenal glands fail to function properly. The failure may not be due to an inherent problem with the adrenal gland itself; rather, a problem in another gland that helps to regulate the adrenal gland. Some of the more common diseases and disorders of the adrenal glands include:  Primary adrenal insufficiency (Addison’s disease); and,  Cushing’s Syndrome.

Adrenal insufficiency is a disorder that occurs when the adrenal glands do not produce enough of certain hormones and can be either primary or secondary. Primary adrenal insufficiency, also called Addison’s disease, occurs when the adrenal glands are damaged and cannot produce enough of the hormone cortisol and often the hormone aldosterone. Addison’s disease affects 1 to 4 of every 100,000 people, in all age groups and both sexes. Secondary adrenal insufficiency occurs when the pituitary gland fails to produce enough adrenocorticotropin (ACTH), a hormone that stimulates the adrenal glands to produce cortisol. If ACTH output is too low, cortisol production

58 drops. Eventually, the adrenal glands can shrink due to lack of ACTH stimulation. Secondary adrenal insufficiency is much more common than Addison’s disease. Cortisol belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. The function of cortisol is to help the body respond to stress by:  Maintaining blood pressure and cardiovascular function;  Slowing the immune system’s inflammatory response;  Maintaining levels of glucose in the blood; and,  Regulating the metabolism of proteins, carbohydrates, and fats.

The amount of cortisol produced by the adrenals is precisely balanced. The hypothalamus and the pituitary gland regulate the release of cortisol. Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. Aldosterone helps maintain blood pressure and the water-salt balance in the body by helping the kidneys retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate the water-salt balance, leading to a drop in both blood volume and blood pressure. The initial symptoms of adrenal insufficiency have an insidious onset and include chronic fatigue, muscle weakness, loss of appetite, and loss of weight. Hyperpigmentation can occur in Addison’s disease but not in secondary adrenal insufficiency. The hyperpigmentation is most visible on scars, skin folds, mucous membranes, and pressure points in the elbows, knees, and toes. If untreated, Addison’s disease can be fatal. Addison’s disease is an autoimmune disorder, which gradually destroys the adrenal cortex. Adrenal insufficiency occurs when at least 90% of the adrenal cortex has been destroyed. In the mid-1840s, tuberculosis (TB) was the primary cause of adrenal insufficiency; however today in developed countries, TB accounts for less than 20% of the cases. Less common causes of Addison’s disease are chronic infection, AIDS associated infections, cancer, and genetic defects of the glands. Secondary adrenal insufficiency is caused by a lack of ACTH. A temporary form of secondary adrenal insufficiency may occur when a person who

59 has been taking a synthetic glucocorticoid hormone such as prednisone for a long time and stops taking the medication, either abruptly or gradually. Another cause of secondary adrenal insufficiency is surgical removal of a noncancerous, ACTH-producing tumor of the pituitary gland that causes Cushing's disease.

Cushing’s Syndrome and Cushing’s Disease Cushing’s syndrome is the name for what happens to the body when too much cortisol is produced. Cortisol, often called a “stress hormone”, modifies the body’s response to inflammation, stimulates the liver to raise the blood sugar, and helps control the amount of water in the body. The most common cause of Cushing’s syndrome is oral ingestion of cortisone-like medications for an extended period of time. Inhaled steroid medicines for asthma and steroid skin cream used to treat eczema and other skin conditions do not cause Cushing’s syndrome. Also ingestion of oral steroid medications taken every day for short periods of time or every other day for longer periods of time do not cause Cushing’s syndrome. Tumors in the adrenal glands or elsewhere in the body can also cause Cushing’s syndrome. The second most frequent cause of Cushing’s syndrome is Cushing’s disease. Cushing’s disease is caused by a tumor in the pituitary gland, which is generally a benign growth. Cushing’s disease is rare and is more often found in women than in men.47 Those affected with Cushing’s may feel generally unwell, have depression and mood swings, and tend to gain in the abdomen while their arms and legs remain slim. The face of affected individuals tends to be round and red and they report that their muscles feel weak. If untreated, Cushing’s disease will cause continued weakness of the muscles, fatigue, poor skin healing, weakening of the bones of the spine, and increased susceptibility to some infections. Low bone mass (osteopenia) and osteoporosis are a direct consequence of untreated Cushing's disease.47 The treatment for Cushing’s disease is surgery to remove the pituitary tumor, if possible. After surgery, the pituitary may slowly start to work again and return to normal. During the recovery process, cortisol replacement treatments may be necessary. Radiation treatment of the pituitary gland may also be used. If the tumor does not respond to surgery or radiation, medications are given to stop the body from making cortisol.

60 Untreated, Cushing’s disease can cause severe illness, even death. Removal of the tumor may lead to full recovery, but the tumor can grow back.

Diabetes Diabetes is a disorder of metabolism. After food is digested, glucose (sugar) enters the bloodstream, where it is used by the cells for energy. For glucose to get into the cells, insulin must be present.48 Insulin is a hormone produced by the pancreas, an organ located behind the stomach. It is responsible for moving glucose from the bloodstream into the cells to provide energy needed for daily life.48 In people with diabetes, the body produces too little or no insulin or the body does not respond properly to the insulin that is produced.48 As a result, glucose builds up in the blood and may overflow into the urine where it is excreted from the body.48 Therefore, the cells lose their main source of energy.48 More than 20 million Americans have diabetes.48 Of these, approximately 5% to 10% have type 1 diabetes and 90% to 95% have type 2 diabetes.48 In type 1 diabetes, the body produces little or no insulin. This form of the disease typically appears in children and young adults, but it can develop at any age.48 In type 2 diabetes, the body produces insulin but not enough, and the body does not respond properly to the insulin that is produced. This form of the disease is more common in people who are older, overweight, and inactive.48 Type 1 diabetes is linked to low bone density, although researchers don’t know exactly why.48 Insulin, which is deficient in type 1 diabetes, may promote bone growth and strength. The onset of type 1 diabetes typically occurs at a young age when bone mass is still increasing.48 It is possible that people with type 1 diabetes achieve lower peak bone mass, the maximum strength and density that bones reach.48 People usually reach their peak bone mass by age 30. Low peak bone mass increases one’s risk of developing osteoporosis later in life. Some people with type 1 diabetes also have celiac disease which is associated with reduced bone mass.48 It is also possible that cytokines, substances produced by various cells in the body, play a role in the development of both type 1 diabetes and osteoporosis. Recent research also suggests that women with type 1 diabetes may have an increased fracture risk, since vision problems and nerve damage

61 associated with the disease have been linked to an increased risk of falls and related fractures.48 Hypoglycemia, or low blood sugar reactions, may also contribute to falls. Increased body weight can reduce one’s risk of developing osteoporosis.48 Since excessive weight is common in people with type 2 diabetes, affected people were long believed to be protected against osteoporosis.48 However, while bone density is increased in people with type 2 diabetes, fractures are increased.48 As with type 1 diabetes this may be due to increased falls because of vision problems and nerve damage.48 Moreover, the sedentary lifestyle common in many people with type 2 diabetes also interferes with bone health.48 Strategies to prevent and treat osteoporosis in those affected with diabetes are the same as for individuals without diabetes and will be discussed in detail later in this course.

Acromegaly Acromegaly is a hormonal disorder that results from too much growth hormone (GH) in the body. The pituitary gland is responsible for the production of GH however in acromegaly the pituitary produces excessive amounts of GH. A benign tumor on the pituitary gland (i.e., adenoma) is usually the cause of excess GH. Acromegaly is most often diagnosed in middle-aged adults, although symptoms can appear at any age. If not treated, acromegaly can result in serious illness and premature death. The most serious health consequences of acromegaly are type 2 diabetes, high blood pressure, increased risk of cardiovascular disease, and arthritis.49 When GH-producing tumors of the pituitary occur in childhood, the disease that results is called gigantism rather than acromegaly. The length of the long bones in the legs determines a child’s height. In response to GH, these bones grow in length at the growth plates, near the end of the bone. Growth plates fuse after puberty, so the excessive GH production in adults does not result in increased height. Prolonged exposure to excess GH before the growth plates fuse causes increased growth of the long bones and thus increased height.

62 The name acromegaly comes from the Greek words for “extremities” and “enlargement,” reflecting one of its most common symptoms, the abnormal growth of the hands and feet.49 Swelling of the hands and feet is often an early feature, with those affected noticing a change in ring or shoe size, particularly shoe width. Gradually, bone changes alter the patient’s facial features, which includes protrusion of the lower jaw and upper brow, enlargement of the nasal bone, and increased spacing between teeth. Overgrowth of bone and cartilage often leads to arthritis. When tissue thickens it may trap nerves, causing carpal tunnel syndrome and may affect multiple organs including the heart. Once a positive diagnosis of acromegaly has been established, several imaging modalities may be used to locate and detect the size of the pituitary tumor causing GH overproduction. Magnetic resonance imaging (MRI) is the most sensitive modality, but computed tomography (CT) can be used if there are contraindications to MRI.49 Surgery to remove the pituitary tumor is the first option recommended for most individuals affected with acromegaly.

Growth hormone (GH) deficiency Adults with growth hormone (GH) deficiency of childhood or adult onset are at risk of developing osteoporosis. The GH deficiency is believed to interfere with acquisition of bone mass. An alternative mechanism is required to explain the reduction in bone mass present in adults who acquire GH deficiency after peak bone mass has been achieved. Growth hormone replacement increases bone turnover and may increase bone mass in the longer term, although short- term studies show a decrease in bone mass, which can be explained by an increase in bone resorption before new bone formation occurs. Abnormalities of GH secretion have also been implicated in the development of osteoporosis, but the effect of GH treatment on bone mass in such patients is disappointing.

Sex steroids Sex steroids play an important role in the acquisition of bone mass, and reduced levels during adolescence have a deleterious effect on bone mass.50 The importance of sex steroids in the maintenance of bone mass is exemplified by the development of osteopenia in men and women with hypogonadism and by

63 the preservation of bone mass with restoration of normal endogenous sex steroid levels, or by treatment with exogenous sex steroid.50

Part 6 Inflammation and Infection and Bone Loss

Introduction Inflammatory conditions and infections can either directly or indirectly impact the integrity of the skeletal system. Inflammation is a process in which the white blood cells release chemicals to protect the body from foreign substances such as bacteria and viruses. In some diseases, the body’s immune system inappropriately triggers an inflammatory response when there are no foreign substances to actually fight off. In a broad sense, these diseases are classified as autoimmune diseases, which cause the body’s normal protective immune system to damage its own tissues. When inflammation occurs, chemicals from the white blood cells are released into the blood or affected tissue in an attempt to rid the body of the foreign substance. This chemical release increases blood flow to the area causing redness and warmth. Some chemicals cause leakage of fluid into the tissues, resulting in swelling, which can stimulate nerves, and ultimately causes pain.

Osteoarthritis Osteoarthritis is the most common type of arthritis and the percentage of people affected increases with age and as the United States population ages, the number of people with the condition will only grow. By 2030, 20% of Americans, about 72 million people, will have passed their 65th birthday and will be at risk for the disease.51 An estimated 12.1% of the United States population (nearly 12 million Americans) age 25 and older have osteoarthritis.51 Although osteoarthritis is more common in older people, younger people can develop it; usually as a result of a joint injury, joint malformation, or genetic defect in the joint cartilage. Both men and women have the disease but before age 45, more men than women have osteoarthritis. After age 45, it is more common in women.52 It is also more likely to occur in people who are overweight and in those whose jobs or leisure activities puts stress on particular joints. Osteoarthritis most often occurs in the hands (at the ends of the fingers and thumb), spine (neck and lower back), knees, and hips.52 Osteoarthritis, also known as degenerative arthritis and degenerative joint disease, is a condition in which low-grade inflammation results in pain in the

65 joints. It is associated with abnormal wearing of the cartilage that covers the joints.52 The condition destroys or decreases the synovial fluid that lubricates the joints and as the bone surfaces become less well protected by cartilage, the individual experiences pain upon weight bearing, including walking and standing. Healthy cartilage allows bones to glide over one another and it also absorbs energy from the shock of physical movement. In osteoarthritis, the surface layer of cartilage breaks down and wears away.

Cartilage is a hard but slippery coating on the ends of bones. Cartilage is a type of connective tissue composed of cells called condrocytes that are embedded in a matrix strengthened with fibers of collagen. Cartilage supports body tissues and provides a cushion effect in the joint spaces.

Once the surface layers of the cartilages are reduced, the bones under the cartilage rub together, causing pain, swelling, and loss of joint motion. Over time, the joint may lose its normal shape and small deposits of bone called osteophytes or bone spurs may grow on the edges of the joint. Bits of bone or cartilage can break off and float inside the joint space causing pain and damage.

A joint capsule is a tough membrane sac that encloses the articulating ends of bones.

Synovium is a thin membrane inside the joint capsule that secretes synovial fluid.

Synovial fluid is a fluid that lubricates the joint and keeps the cartilage smooth and healthy.

Collagen is a family of fibrous proteins, which are the building blocks of skin, tendon, bone, and other connective tissues.

Proteoglycans are made up of proteins and sugars that interweave with collagens and form a mesh-like tissue. This allows cartilage to flex and absorb physical shock.

Chondrocytes are found throughout the cartilage and are cells that produce cartilage and help it stay healthy as it grows.

Ligaments, tendons, and muscles are tissues that surround the bones and joints, and allow the joints to bend and move. Ligaments are tough, cord-like tissues that connect one bone to another. Tendons are tough, fibrous cords that connect muscles to bones. Muscles are bundles of specialized cells that, when stimulated by nerves, either relaxes or contracts to produce movement. Those affected with osteoarthritis may have muscular atrophy due to decreased movement because of pain, regional muscle atrophy, and lax ligaments. Age is positively correlated with osteoarthritis; however, this does not account for the condition in younger people.51 There is usually an underlying cause of osteoarthritis, for example, a previous injury or cumulative trauma, in which case it is described as secondary osteoarthritis.52 If no underlying cause can be identified it is described as primary osteoarthritis. The warning signs of the condition consist of stiffness in a joint, swelling of one or more joints, and a crunching feeling or sound of bone rubbing on bone. Radiographs of the area under investigation are usually the first imaging procedures requested when osteoarthritis is suspected. MRI is used to visualize joint tissue such as ligaments and muscles. CT may also be used when MRI is contraindicated or when bony structures require additional investigation. Arthritis of the zygapophyseal joints (facet joints), costovertebral joints, and costotransverse joints is similar to arthritis of peripheral joints in terms of imaging features and progression of abnormal changes. The overlying ribs and lung structures may limit radiographic imaging when the thoracic spine is under investigation. Also many of the changes due to osteoarthritis are initially subtle and are best detected by sagittal MRI images. Osteoarthritis accounts for 25% of visits to primary care physicians, and half of all non-steroidal anti-inflammatory drug (NSAID) prescriptions.52 It is estimated that 80% of the population will have radiographic evidence of osteoarthritis by age 65, although only 60% will be symptomatic.52 Individuals who are overweight or obese increase their risk for the development of osteoarthritis.53 The association between increased weight and the risk for

67 development of knee osteoarthritis is stronger in women than in men. In a study of twin middle-aged women, it was estimated that for every kilogram increase of weight, the risk of developing osteoarthritis increases by 8 to 14%.53 An increase in weight is significantly associated with increased pain in weight-bearing joints. There is no evidence that the development of osteoarthritis leads to the subsequent onset of obesity.53 A decrease in body mass index (BMI) of 2 units or more during a 10-year period decreases the odds for developing knee osteoarthritis by more than 50%; weight gain was associated with a slight increased risk.53

Impact of Obesity on the Skeleton Obesity is a potential risk factor for the onset and deterioration of musculoskeletal conditions of the hip, knee, ankle, foot, shoulder, and the vertebral spine. The majority of research has focused on the impact of obesity on bone and joint disorder, such as the risk of fracture and osteoarthritis. However, evidence indicates that obesity may also have a profound effect on soft-tissue structures, such as tendon, fascia and cartilage. Although the mechanism remains unclear, the functional and structural limitations imposed by the additional loading of the musculoskeletal system in obesity have been accepted to unduly cause stress within connective-tissue structures, resulting in injury. The vertebral spine is designed to carry the body’s weight and distribute the mechanical loads encountered during activity and rest. When excess weight is carried, the vertebral spine is forced to assimilate the burden, which may lead to structural compromise and damage (e.g., sciatica).

Sciatica is a set of symptoms including pain that may be caused by general compression and/or irritation of one of five nerve roots that give rise to the sciatic nerve, or by compression or irritation of the sciatic nerve itself.

One region of the vertebral spine that is most vulnerable to the effects of obesity is the lumbar region.54 Lack of exercise and bodily conditioning leads to poor flexibility and weak muscles in the back, pelvis, and thighs. This can

68 increase the curve of the lower back, causing the pelvis to tilt too far forward. This is detrimental to proper posture and as posture weakens, other regions of the spine may become affected. Conditions such as osteoporosis, osteoarthritis, degenerative disc disease, spinal stenosis, and spondylothisthesis are also associated with obesity.96 The deterioration in the discs between the vertebrae of the spine can be accelerated due to overweight or obesity, which puts more burdens on the weightbearing ability of the joints. This deterioration usually occurs gradually and leads to narrowing of the spaces between the vertebrae and the development of bone spurs or osteophytes. As bone rubs on bone, the vertebral joints become inflamed resulting in progressive joint degeneration. The symptoms are generally loss of flexibility in the spine. Current treatment approaches include exercise, weight control, rest and relief from stress on joints, non-drug pain relief techniques, and medications to control pain, surgery, and complementary and alternative therapies.96

Rheumatoid Arthritis Rheumatoid arthritis is an inflammatory disease that causes pain, swelling, stiffness, and loss of function in the joints. It has several special features that distinguish it from other kinds of arthritis.55 For example, rheumatoid arthritis generally occurs in a symmetrical pattern, meaning that if one knee or hand is involved, the other one is also involved.55 The disease often affects the wrist joints and the proximal finger joints. In addition, those with rheumatoid arthritis may have fatigue, occasional fevers, and a general malaise. Rheumatoid arthritis affects people differently for example in some it lasts only a few months or a year or two and disappears without causing any noticeable damage. Others have mild or moderate forms of the disease, with periods of worsening symptoms, called flares, and periods of remission. The following are common features of rheumatoid arthritis:  Tender, warm, swollen joints;  Symmetrical pattern of affected joints;  Joint inflammations that can affect the neck, shoulders, elbows, hips, knees, ankles, and feet;  Fatigue, occasional fevers, and general malaise;

69  Pain and stiffness lasting for more than 30 minutes in the morning or after a long rest;  Symptoms that last for many years; and,  Variability of symptoms among people with the disease.

Like other rheumatic diseases, rheumatoid arthritis is an autoimmune disease (i.e., one in which the immune system attacks joint tissues, for unknown reason). White blood cells travel to the synovium and cause inflammation (synovitis), characterized by warmth, redness, swelling, and pain. During the inflammation process, the normally thin synovium becomes thick and makes the joint swollen and puffy to the touch. As rheumatoid arthritis progresses, the inflamed synovium invades and destroys the cartilage and bone within the joint. The surrounding muscles, ligaments, and tendons that support and stabilize the joint become weak and unable to function normally. These effects lead to the pain and joint damage often seen in rheumatoid arthritis. Researchers studying rheumatoid arthritis now believe that the process begins to damage bones during the first year or two that a person has the disease, one reason why early diagnosis and treatment are so important. Scientists estimate that about 2.1 million people or between 0.5% and 1% of the United States adult population, have rheumatoid arthritis.55 The disease occurs in all races and ethnic groups. Although the disease often begins in middle age and occurs with increased frequency in older people, children and young adults also develop it. Rheumatoid arthritis occurs much more frequently in women than in men.55 Scientists still do not know exactly what causes the immune system to turn against itself in rheumatoid arthritis but several factors have been implicated. These include genetic (inherited) factors, environmental factors such as a viral or bacterial infection, and an interaction of many factors. To arrive at a diagnosis of rheumatoid arthritis, laboratory and imaging examinations are performed. One common laboratory examination is a test for rheumatoid factor, an antibody that is present eventually in the blood of most people with rheumatoid arthritis. Other common laboratory tests include a white blood cell count, a blood test for anemia, and a test of the erythrocyte sedimentation rate, which measures inflammation in the body. C-reactive protein

70 is another common test that measures disease activity resulting from inflammatory processes. Rheumatoid arthritis causes the skeleton of its victims to be vulnerable to fracture. In affected individuals, osteopenia, especially in those with longstanding disease, has been related to generalized or periarticular osteoporosis. Those with rheumatoid arthritis are further susceptible to bone loss due to inactivity, hypervascularity, osteomalacia, corticosteroid and salicylate therapy. Osteopenia in this population leads to structural weakening of the bone, contributing to its failure under normal or abnormal stress. Examples of such bone failure under stress include compression fractures of one or more vertebral bodies and insufficiency type stress fractures of the tubular bones of the lower extremity. Radiographs of the area under investigation are usually among the first imaging procedures requested when rheumatoid arthritis is suspected. MRI is used to visualize joint tissue such as ligaments and muscles. CT may also be used when MRI is contraindicated or when bony structures require additional investigation. Current treatment approaches include health behavior changes, medications, surgery, and routine monitoring and ongoing care. While osteoporosis and rheumatoid arthritis are two very different medical conditions with little in common, the similarity of their names causes great confusion.56 These conditions develop differently, have different symptoms, are diagnosed differently, and are treated differently. While it is possible to have both osteoporosis and arthritis, studies show that people with osteoarthritis are less likely to develop osteoporosis.56 On the other hand, people with rheumatoid arthritis may be more likely than average to develop osteoporosis.56 This is especially true because some medications used to treat rheumatoid arthritis can contribute to osteoporosis.56 Osteoporosis, osteoarthritis, and rheumatoid arthritis do share many coping strategies.56 With either or both of these conditions, many people benefit from exercise programs that may include physical therapy and rehabilitation.56 Most of those affected will use pain management strategies at some time.56 This is not always true for people with osteoporosis.56

71 Seronegative spondylosteoarthritis Seronegative spondylosteoarthritis is a general term for a group of joint conditions that are not associated with rheumatoid factors or rheumatic nodules. Five subgroups of spondylosteoarthritis are distinguished: ankylosing spondylitis, reactive arthritis (e.g., Reiter syndrome), psoriatic arthritis, arthritis associated with inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), and undifferentiated spondylosteoarthritis.57 The subtypes are generally distinguished on the basis of the patient’s history and clinical findings. Imaging does not play a major role in differentiating between the subtypes of spondylosteoarthritis because their imaging features are comparable, especially in early disease. Exceptions to this include undifferentiated spondylosteoarthritis and psoriatic arthritis, which is known to produce syndesmophytes.

A syndesmophyte is a bony growth inside a ligament, similar to osteophytes, appearing in the intervertebral joints of the spine.

All forms of spondylosteoarthritis may ultimately develop into ankylosing spondylitis in those with long-standing disease.57 Radiographically, fine, confluent syndesmophytes are characteristic of ankylosing spondylitis. The condition affects men 3 to 10 times more often than women, with the age of onset between 15 and 35 years.57 Erosions occur at the corners of the vertebral bodies leading to “squared vertebral bodies”.57 Those with ankylosing spondylitis are prone to minor stress and trauma leading to fractures through the intervertebral disc or the entire vertebral body. As with other rheumatic conditions, early diagnosis and treatment are essential for avoiding structural damage and functional impairment. In many cases, the radiographic request from will ask for detailed visualization of inflammatory changes in the entire vertebral column.

Lupus Erythematosus Lupus erythematous is an autoimmune disease, a disorder in which the body attacks its own healthy cells and tissues.58,59 Systemic lupus erythematosus (SLE) is the form of the disease that is commonly referred to as

72 lupus.58,59 According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (NIH), 90% of those diagnosed with lupus are women.58,59 The disease is three times more common in African American women than Caucasian women.58,59 Women of Hispanic, Asian, and Native American descent are also at increased risk.58,59 Lupus typically appears in people between the ages of 15 and 45.58,59 Studies have found an increase in bone loss and fracture in individuals with SLE.58,59 In fact, women with lupus may be nearly five times more likely to experience a fracture from osteoporosis.58,59 Lupus can affect any part of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. At present there is no cure for lupus. There are several types of lupus; including, lupus erythematosus (SLE), discoid lupus, erythematosus, subacute cutaneous lupus erythematosus, drug-induced lupus, and neonatal lupus.58,59 Treatments are tailored to a person’s needs; however, corticosteroids are the mainstay of treatment. These drugs work rapidly to suppress inflammation and are effective in reducing the symptoms. Long-term side effects of corticosteroids include osteopenia and osteoporosis.58,59 Studies strongly support the use of preventive bone loss therapy to minimize osteoporosis in people with lupus.58,59

Human Immunodeficiency Virus Patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are susceptible to a variety of complications that can affect the skeleton. The Centers for Disease Control and Prevention (CDC) estimate that 1.1 million people are living with HIV in the United States and approximately 56,000 new infections occur each year.60 Radiology plays an important role in early diagnosis and treatment planning in this affected population. MR imaging allows evaluation of the central nervous system and best demonstrates pulmonary and abdominal complications of the disease. Infection with the human immunodeficiency virus (HIV) weakens the body’s immune defenses by destroying CD+4 (T-cell) lymphocytes. CD+4 lymphocytes are a group of white blood cells that normally help guard the body against attacks by bacteria, viruses, and other invaders by coordinating the

73 immune system. When HIV destroys CD+4 lymphocytes, the body becomes vulnerable to many different types of opportunistic infections. Opportunistic infections are those that have an opportunity to invade the body because the immune defenses are weak. HIV infection also increases the risk of certain cancers, neurologic illnesses, body wasting, and death. The AIDS wasting syndrome is a devastating complication of the HIV viral infection. Progressive weight loss and a disproportionate decrease in lean body mass characterize the wasting syndrome. Osteopenia and osteoporosis are common conditions affecting HIV-infected patients.51,52 Deficits of bone mineralization are quite common in children with HIV, especially if they are receiving antiretroviral medication. For those who are HIV positive or have developed AIDS, national dietary guidelines recommend supplementation with vitamin D and calcium.52 If osteoporosis is severe, the addition of one of the Food and Drug Administration (FDA) approved osteoporosis drugs may be added to the prescriptive treatment.52

Osteomyelitis Osteomyelitis of the bone is a common cause of musculoskeletal complications in AIDS patients.61 The most frequently involved bones are the tibia, wrist bones, femoral heads, ribs, and thoracolumbar spine.61 Radiography is not sensitive in the detection of early osteomyelitis because it does not demonstrate changes until 10-14 days after the onset of the infectious process, when lytic lesions or periosteal reaction is evident.61 Radiographs at this stage generally demonstrate erosion of the anterior vertebral bodies with deformity. CT is useful for detecting destructive changes involving the cortical bone of the vertebral bodies and MRI is used when neural and cord impairment is suspected. Tuberculosis infection and bacillary angiomatosis are two specific forms of osteomyelitis that have been observed with increasing frequency in HIV- positive and AIDS patients. Bone scintigraphy is the most sensitive imaging method for detection of early osteomyelitis.61 Vertebral osteomyelitis accounts for approximately 2-7% of all cases of osteomyelitis.61 It is more common in the elderly and is more prevalent in men but can occur at any age and in both sexes. Any bacterial infection can lead to

74 vertebral osteomyelitis with the most common etiology being a recent history of urinary tract infection. The lumbar spine is the most common site for osteomyelitis followed by the thoracic and cervical spine. Osteomyelitis infection typically beings in the anterior aspect of the vertebral body and extends into the disc space, subligamentous area, and adjacent soft tissue.61 Abscess formation is more common in the cervical and thoracic spine than in the lumbar spine. In most cases, the infective organism involved is Staphyloccus aureus.61 Those affected present with localized back pain, fever, and muscle spasms and decreased range of motion. Treatment of osteomyelitis includes antibiotic therapy and surgery in some cases. The type of surgery depends on which bone is infected and may include drainage of the infected area, removal of diseased bone and tissue, and bone and tissue grafting.

Part 7 Malignancy and Bone Loss

Introduction Many skeletal disorders are not inherited but rather develop later in life. One of the most common of these acquired skeletal disorders is a tumor of the bone. Bone tumors can originate in the bone (primary tumors) or, much more commonly, result from metastatic seeding of bone by tumors outside of the skeleton. Both types of tumors can destroy bone, although some metastatic tumors can actually increase bone formation. Primary bone tumors can be either benign or malignant. The most common benign bone tumor is osteochondroma, while the most common malignant ones are osteosarcoma and Ewing’s sarcoma. Metastatic tumors are often the result of breast or prostate cancer that has spread to the bone. These may destroy bone (osteolytic lesion) or cause new bone formation (osteoblastic lesion). Breast cancer metastases are usually osteolytic, while most prostate cancer metastases are osteoblastic, though they still destroy bone structure. Many tumor cells produce parathyroid hormone related peptide, which increases bone resorption. This process of tumor-induced bone resorption leads to the release of growth factors stored in bone, which in turn increases tumor growth still further. Bone destruction also occurs in the vast majority (over 80%) of patients with another type of cancer, multiple myeloma.

Myeloma Bone Disease Myeloma means, literally, a “tumor composed of cells normally found in bone marrow.” Multiple myeloma is a malignancy of the plasma cells that produce antibodies. The myeloma cells secrete cytokines, substances that may stimulate osteoclasts and inhibit osteoblasts. The bone destruction can cause severe bone pain, pathologic fractures, spinal cord compression, and life- threatening increases in blood calcium levels. The majority of patients with myeloma develop destructive bone lesions also known as osteolytic bone lesions.62 These lesions or nests of myeloma cells accumulate primarily in the red bone marrow of the vertebrae, ribs, pelvis, and skull.62 Myeloma cells do not have a direct effect on the skeleton; rather, they cause bone destruction by producing signals that activate normal osteoclasts to reabsorb bone. A benign

76 form of overproduction of antibodies, called monoclonal gammopathy, may also be associated with increased fracture risk. Bone-resorbing cytokines are also produced in acute and chronic leukemia, Burkitt’s lymphoma, and non-Hodgkin’s lymphoma; patients with these chronic lymphoproliferative disorders often have associated osteoporosis. Osteoporosis and osteosclerosis have been reported in association with systemic mastocytosis, a condition of abnormal mast cell proliferation. In addition, there are other infiltrative processes that affect bone, including infections and marrow fibrosis. The incidence of myeloma is 3 to 4 per 100,000 in the United States, which translates into approximately 13,500 new cases of myeloma in the United States each year.62 Myeloma is more common in blacks than whites, and the male to female ratio is 3:2.62 The incidence varies from country to country, with a higher incidence found in most Western industrialized countries. Over the past 30 years there has been a 400% increase in the incidence of the disease.62 This apparent increase is probably due to better diagnostic techniques and the higher average age of the general population. However, over the past 3 decades, more frequent myeloma has been observed in individuals under age 55, which may indicate environmental causative factors.62 Approximately 70% of myeloma patients experience pain of varying intensity, often in the lower back.62 Sudden severe pain can be a sign of fracture or collapse of a vertebra. Patients also have general malaise and vague complaints. Hypercalcemia, which is present in 30% of patients, can cause tiredness, thirst, and nausea, and usually occurs when a patient has impaired kidney function. It is not yet possible to cure myeloma; but it is possible to improve the clinical status and the survival of certain patients with the use of chemotherapy, alpha interferon, and possibly, bone marrow transplantation. For myeloma patients with hypercalcemia, the goal is to treat the hypercalcemia and its potentially dangerous complications. In these patients, hypercalcemia is always associated with increased bone resorption and frequently with impaired kidney function. The best approach is to treat the myeloma itself and to treat the hypercalcemia with drugs that inhibit bone resorption, such as bisphosphonates,

77 and the careful use of intravenous fluids. Bisphosphonates have been very effective in the treatment of hypercalcemia of myeloma. The more common situation is the patient with myeloma bone disease who does not have hypercalcemia. Until recently, these patients have been treated for the bone disease with symptomatic therapy, namely; analgesics for pain, orthopedic treatment for fractures, or radiation therapy for localized bone pain. Recent studies have indicated that potent bisphosphonate drugs may have beneficial effects in the treatment of myeloma. In some affected individuals, pain is reduced, the need for analgesics is lessened, episodes of fracture and hypercalcemia are reduced, and the need for radiation therapy for bone pain is decreased. As a consequence, pamidronate has received FDA approval in the United States for treatment not only of hypercalcemia in myeloma, but also myeloma bone disease in the absence of hypercalcemia. Further studies are ongoing to determine the effects of bisphosphonates on survival of patients, the ideal dose and duration, and whether other new and more potent bisphosphonates have similar beneficial effects. One important and unanswered question is whether bisphosphonates should be used on individuals who do not as yet have symptoms or evidence of myeloma bone disease.

Breast Cancer and Osteoporosis The National Cancer Institute reports that 1 in 8 women in the United States (approximately 13%) will develop breast cancer in her lifetime.63 In fact, next to skin cancer, breast cancer is the most common type of cancer among U.S. women.63 While the exact cause of breast cancer is not known, the risk of developing it increases with age. The risk is particularly high in women over the age of 60.63 Because of their age, these women are already at increased risk for osteoporosis. Given the rising incidence of breast cancer and the improvement of long-term survival rates, bone health and fracture prevention have become important health issues among breast cancer survivors.63 Results of the Women’s Health Initiative Observational Study show that, in general, women with breast cancer have a 15% greater risk of fracture than the general population. In other studies it has been reported that patients with early stages of breast cancer

78 lost approximately 8% of their lumbar spine bone mineral density within the first year after receiving adjuvant chemotherapy and developing ovarian failure.64 Women who have had breast cancer treatment may be at increased risk for osteoporosis and fracture for several reasons. First, estrogen has a protective effect on bone, and reduced levels of the hormone trigger bone loss.63 Because of chemotherapy or surgery, many breast cancer survivors experience a loss of ovarian function, and consequently, a drop in estrogen levels. Women who were postmenopausal prior to their cancer treatment tend to go through menopause earlier than those who have not had the disease.63 Studies also suggest that chemotherapy may have a direct negative effect on bone. In addition, the breast cancer itself may stimulate the production of osteoclasts, the cells that break down bone.63 Several strategies can reduce one’s risk for osteoporosis or lessen the effects of the disease in women who have already been diagnosed. These include nutrition, exercise, healthy lifestyle, and medication, which will be discussed later in this course.

Prostate Cancer and Osteoporosis The National Institutes of Health (NIH) reports that next to skin cancer, prostate cancer is the most common type of cancer among American men.65 It is so common, in fact, that half to three-quarters of men older than 75 will have some cancerous changes in their prostate glands. The cancer usually grows very slowly, however, and most men who are diagnosed with prostate cancer live for many years.65 Still, prostate cancer can be serious and, in some cases, life- threatening. All men are at risk for prostate cancer, but most men diagnosed with it are older than 65.65 Additionally, as men get older, their risk for developing another disease, osteoporosis, increases.65 Osteoporosis is of particular concern for men with prostate cancer, because recent research has found a strong link between hormone deprivation therapy, which is one of the treatments for prostate cancer, and osteoporosis.65 Hormone deprivation therapy is also called androgen deprivation therapy because it deprives cancer cells of the male hormones (called androgens) that the cancer needs to grow.

79 Studies show that men who receive hormone deprivation therapy for prostate cancer have an increased risk of developing osteoporosis and broken bones.65 Hormones such as testosterone protect against bone loss. So, once they are blocked, bone becomes less dense and breaks more easily.65 Androgen-deprivation therapy (ADT) with leutinizing-hormone releasing hormone (LHRH) agnoists leads to castrate levels of both testosterone and estrogen which can result in osteoporosis. Hormone deprivation therapy is one of several treatment options available to men with prostate cancer. Traditionally, it has been used mainly to treat prostate cancer that has spread to other parts of the body. But because men are more likely today to be diagnosed in the early stages of prostate cancer, more of them are opting to be treated with hormone deprivation therapy earlier in the course of the disease.65 Survivors of breast and prostate cancer should participate in strategies to detect and treat bone loss. It is important that cancer survivors have a DXA to measure bone density. Calcium and vitamin D supplementation, as recommended, should be encouraged in this post-treatment population. In postmenopausal women with breast cancer, tamoxifen treatment is not only an effective therapy for prevention of breast cancer recurrence, but may also prevent bone loss.

Part 8 Neurologic/Psychiatric Disorders and Bone Loss

Many neurologic disorders are associated with impaired bone health and an increased risk of fracture. This may be due in part to the effects of these disorders on mobility and balance or to the effects of the drugs used in treating these disorders. Unfortunately, however, health care providers often fail to assess the bone health of patients who have these disorders or to provide appropriate prevention and therapeutic measures. Those with stroke, spinal cord injury, or neurologic disorders show rapid bone loss in the affected areas. There are many disabling conditions that can lead to bone loss, and thus it is important to pay attention to bone health in those with developmental disabilities, such as cerebral palsy, as well as diseases affecting the nerves and muscles, such as poliomyelitis and multiple sclerosis. Children and adolescents with these disorders are unlikely to achieve optimal peak bone mass, due both to an increase in bone resorption and a decrease in bone formation. Immobilization, in some cases can cause very rapid bone loss, increasing blood calcium levels to such a degree as to produce symptoms. Fractures are common in these individuals not only because of bone loss, but also because of muscular weakness and neurologic impairment that increases the likelihood of falls; however, bone loss can be slowed, but not completely prevented, by antiresorptive therapy. Epilepsy is another neurologic disorder that increases the risk of bone disease, primarily because of the adverse effects of anti-epileptic drugs. Many of the drugs used in epilepsy can impair vitamin D metabolism, probably by acting on the liver enzyme, which converts vitamin D to 25 hydroxy vitamin D. In addition, there may be a direct effect of these agents on bone cells. Due to the negative bone-health effects of drugs, most epilepsy patients are at risk of developing osteoporosis. In those who have low vitamin D intakes, intestinal malabsorption, or low sun exposure, the additional effect of anti-epileptic drugs can lead to osteomalacia. Supplemental vitamin D may be effective in slowing bone loss, although patients who develop osteoporosis may require additional therapy such as bisphosphonates. Psychiatric disorders can also have a negative impact on bone health. While anorexia nervosa is the psychiatric disorder that is most regularly

81 associated with osteoporosis, major depression which is a much more common disorder, is also associated with low bone mass and an increased risk of fracture. Many studies show lower BMD in patients who have been diagnosed with depression. Also, research data indicates an increased incidence of falls and fractures among depressed women. Higher scores for depressive symptoms have also been reported in women with osteoporosis. Yet what this data does not make clear is whether major depression causes low BMD and increased fracture risk, or whether depression is a consequence of the diminished quality of life and disability that occurs in many osteoporotic patients. One factor that may cause bone loss in severely depressed individuals is increased production of cortisol, the adrenal stress hormone. Whatever the cause of low BMD and increased fracture risk, measurement of BMD is appropriate in both men and women with major depression. While the response of individuals with major depression to calcium, vitamin D, or antiresorptive therapy has not been specifically documented, it would seem reasonable to provide these preventive measures to patients at high risk.

Part 9 Other Diseases and Bone Loss

Several diseases that are associated with osteoporosis are not easily categorized. Aseptic necrosis, also called osteonecrosis or avascular necrosis, is a well-known skeletal disorder that may be a complication of injury, treatment with glucocorticoids, or alcohol abuse. This condition commonly affects the ends of the femur and the humerus. The precise cause is unknown but at least two theories have been suggested. One theory is that collapsing bone blocks blood supply to the bone. The other theory is based on an assumption that microscopic fat particles block blood flow and cause bone cell death.

Pott Disease (Tuberculosis Spondylitis) Pott disease, also known as tuberculosis spondylitis, is one of the oldest demonstrated diseases of humankind. It has been documented in spinal remains from the Iron Age and in ancient mummies from Egypt and Peru. The disease is named after Percivall Pott (1779) who presented the first classic description of spinal tuberculosis.66 Today, with antituberculosis drugs and improved preventative health measures, spinal tuberculosis has become rare in developed countries, but is still a significant cause of death in developing countries. Bone and soft-tissue tuberculosis accounts for approximately 10% of extrapulmonary tuberculosis cases and between 1% and 2% of total cases.61 Tuberculosis spondylitis is the most common manifestation of musculoskeletal tuberculosis, accounting for approximately 40%-50% of cases.61 Approximately 1-2% of total tuberculosis cases are attributable to Pott disease.66 Spinal tuberculosis can result in serious health impairment ranging from permanent neurologic deficits, severe deformities, to death. Pott disease is the most dangerous form of musculoskeletal tuberculosis because if untreated or ineffectively treated it can lead to bone destruction, deformity, and paraplegia. Pott disease most commonly involves the thoracic and lumbosacral spine with 10% of cases involving the cervical spine.66 Pott disease is usually secondary to an extraspinal source of infection. The basic lesion of Pott disease is a combination of osteomyelitis and arthritis that usually involves more than one vertebra and may spread from one area to

83 adjacent areas of the spine. The anterior aspect of the vertebral body adjacent to the subcondral plate is usually the area affected. In adults, disc involvement is secondary to the spread of infection from the vertebral body. In children the disc is usually the primary site due to its extensive vascularity. Progressive bone destruction leads to vertebral collapse and lesions in the thoracic spine area may lead to kyphosis. The kyphotic deformity is caused by collapse of the anterior structures of the spine. Abscesses, granulated tissue, or direct dural invasion can narrow the spinal canal leading to cord compression and neurologic deficits. Abscesses in the lumbar region may descend down the sheath to the femoral trigone region and eventually erode into the skin. The presentation of Pott disease depends on the stage of the disease, affected site, and presence of complications such as neurologic deficits, abscesses, or sinus tracts. The reported average duration of symptoms at diagnosis is 4 months, but can be longer and is related to nonspecific presentation of chronic back pain. 101 Back pain is the earliest and most common symptom as well as constitutional symptoms of fever and weight loss. Cervical spine tuberculosis is a less common presentation but is potentially more serious because severe neurologic complications are more likely. The clinical presentation of spinal tuberculosis in those infected with human immunodeficiency virus (HIV) is similar to that of patients who are HIV negative; however, spinal tuberculosis is more common in persons infected with HIV. Tuberculosis involves 3-5% of those who test HIV-negative and as much as 60% in those who test HIV positive.66 Radiographic changes associated with Pott disease present relatively late in the course of the disease. When radiographic changes become evident those that are characteristic of spinal tuberculosis on plain radiography include:  Lytic destruction of the anterior portion of the vertebral body;  Increased anterior wedging;  Collapse of the vertebral body;  Reactive sclerosis on a progressive lytic process;  Enlarged psoas shadows with or without calcification;  Osteoporotic vertebral endplates;  Diminished height or destroyed intervertebral discs;  Variable degrees of destruction of the vertebral bodies

84  Fusion paravertebral shadows suggesting abscess formation; and,  Bone lesions occurring at more than one level.66

CT imaging provides better bony detail of the irregular lytic lesions, sclerosis, disc collapse, and disruption of bone circumference. Epidural and paraspinal areas are well visualized with the low-contrast resolution provided by CT. CT allows for characterization of the shape and extent of calcifications and soft-tissue abscesses.61 MR imaging is useful for differentiating tuberculosis spondylitis from pyogenic spondylitis.67,68 Contrast-enhanced MRI is an important tool in the differentiation of the two types of spondylitis. Radionuclide scanning is not indicated for diagnosis of Pott disease. Percutaneous CT-guided needle biopsy may be used to obtain tissue samples of bone lesions. The World Health Organization (WHO) declared tuberculosis a global emergency, the first time a disease had ever achieved that dubious distinction.69 Perhaps the most alarming aspect of the present epidemic is the rise in multidrug-resistant TB (MDR-TB). According to a survey conducted by the WHO, up to 4% of all TB cases worldwide are resistant to more than one antituberculosis drug. In parts of Eastern Europe, nearly half of all TB cases resist at least one first-line drug. Most of the burden of MDR-TB falls on poor countries, but the United States has seen outbreaks of drug-resistant TB as well. In early 1990s, New York City had an epidemic of MDR-TB that cost almost $1 billion to control. With proper treatment, almost all cases of TB are curable. But proper treatment is not always easy to attain. Typically, a TB patient takes four different antibiotics for at least two months, then two drugs for four more months.69 Treating TB with several drugs simultaneously lessens the chance that naturally occurring mutations in the bacteria will allow some to escape destruction. However, these drugs often cause unpleasant side effects and when patients start feeling better after a month or so, many discontinue the full course of treatment. In many less developed countries, where TB is most common, drug supplies may be inadequate or unavailable. Unfortunately, partial treatment for TB is worse than no treatment at all. TB bacteria that linger following incomplete drug therapy are likely to resist anti-

85 tuberculosis drugs in future flare-ups. Worse still, people with active cases of MDR-TB can pass those superbugs on to new victims.

Idiopathic Juvenile Osteoporosis Idiopathic juvenile osteoporosis (IJO) is a rare disease that typically occurs in otherwise healthy children.38 The average age of onset is 7 years, with a wide range from 1 to 13 years.38 Most common complaints on presentation are gait difficulties and pain in ankles, heels, or lower back.38 The skeleton of children with IJO shows reduced bone density with a resulting increase in the risk of fractures of the weight-bearing bones (particularly in the metaphyses) and spine, with collapsed or misshapen vertebrae. Early diagnosis of IJO is important so that steps can be taken to protect the child’s spine and other bones from fracture until remission occurs.38 Most children with IJO experience a complete recovery, although spinal scoliosis or kyphosis may persist. Growth may be somewhat impaired during the acute phase of the disorder; however, upon recovery normal growth resumes and catch-up growth often occurs. Bisphosphonates have been given to some children with IJO experimentally.38 The disorder seems to arise from a reduction in osteoblastic activity with impaired bone modeling that, upon recovery, shows catch-up activity.38 However, the disorder remains poorly understood at present, and researchers are uncertain as to its long-term consequences on bone health.38

Periodontitis and Bone Health Osteoporosis, periodontitis and tooth loss are public health concerns that affect significant numbers of older men and women.70 Periodontitis is an infection of the tissues surrounding and supporting the teeth and is a common cause of tooth loss. The presence of osteoporosis has a role in the bone density of the upper and lower jaw and consequently on dental health. It is estimated that periodontal disease affects more than half of the United States population, with 30% of older adults experiencing severe forms of the disease.70 While scientists suggest that additional research is needed to clarify the relationship between systemic and oral bone loss, they are hopeful that efforts to optimize skeletal bone density will have a favorable impact on dental health.70

Perthes’ Disease Perthes’ disease affects the hip joints in children.71 In the early stages of the disease, the child will have a limp that is sporadic but the limp may worsen as the disease progresses. The peak incidence of Perthes’ disease is between the ages of 4 and 7 years.71 It is more common in boys than in girls and only one hip is usually affected in over three-fourths of children.71 In children with Perthes’ disease, the femoral head softens because of a lack of blood supply. The cause of this is unknown but the decreased blood supply affects the bone cells in the head of the femur.71 This may cause the femoral head to become flattened or deformed so that it no longer fits perfectly in the acetabulum. Osteopenia and osteoporosis may be an eventuality of Perthes’ disease due to the forced inactivity and lack of weight bearing exercise on the affected limb. Radiographically, the earliest sign of Perthes’ disease is a widening of the joint space with a small-flattened femoral epiphysis. Also remodeling of the femoral head may be evident.71

Cerebral Palsy Osteoporosis has been reported in 5% of adult women with cerebral palsy and high levels of osteopenia among children with cerebral palsy.72 Lack of adequate intake of calcium, low body weight, and restriction of exercise, especially weight-bearing activities have been cited as factors contributing to osteopenia and osteoporosis in people with cerebral palsy.

Pregnancy, Lactation, and Bone Health Pregnancy-associated osteoporosis was first reported more than forty years ago.73 Approximately 56% of pregnancy-associated osteoporosis tends to be identified in the postpartum period and 41% in the third trimester.73 Women affected present with back pain, loss of height, and vertebral fractures.73 There is no direct evidence to determine whether the osteoporosis is a consequence of pregnancy or whether it occurs because of pre-existing conditions in the pregnant woman. Osteoporosis in pregnancy is assumed to occur because of the demands on maternal calcium reserves and an increase in urinary calcium excretion. A majority of the cases of pregnancy-associated osteoporosis occurs

87 during lactation from one week to seven months. Significant amounts of bone mineral density can be lost during breast-feeding but the loss is transient. This information supports the use of calcium and other supplements during pregnancy and the post-partum period.

Paget’s Disease Osteoporosis and Paget’s are both metabolic bone diseases characterized by low bone density.74 The majority of people affected by osteoporosis are women, while 60% of those affected by Paget’s disease are men.74 A notable difference between the two is that in Paget’s disease the bones grow abnormally large in some areas but not others, due to excess numbers of overactive osteoclasts. While bone formation increases to compensate for the loss, the rapid production of new bone leads to a disorganized structure. The resulting bone is expanded in size, and associated with increased formation of blood vessels and connective tissue in the bone marrow. Affected bone becomes more susceptible to deformity or fracture. Paget’s disease is a progressive, often crippling disorder of remodeling that commonly involves the spine, pelvis, legs, or skull (although any bone can be affected). Depending on the location, the condition may not produce any clinical signs or symptoms, or it may be associated with bone pain, deformity, fracture, or osteoarthritis of the joints adjacent to the abnormal bone. In very rare cases, probably occurring less than 1% of the time, the disease is complicated by the development of an osteosarcoma.74 If diagnosed early, its impact can be minimized. Although Paget’s disease is the second most common bone disease after osteoporosis, many questions remain regarding its pathogenesis. A strong familial predisposition exists for Paget’s disease, but no single genetic abnormality has been identified that can explain all cases.74 Paget’s disease can be transmitted across generations in an affected family; 15-40% of patients have a relative with the disorder.74 Some studies have suggested that Paget’s disease may result from a “slow virus” infection; however, more research is needed before conclusive evidence can be made available.74 Paget’s disease can be diagnosed through radiology, radionuclide bone scanning, biochemical testing of bone resorption parameters, or biochemical

88 testing of bone formation parameter. Radiographic characteristics of Paget’s disease display 3 distinctive stages.  In the earliest stage of the disease, an osteolytic lesion may be observed in the skull or a long bone.  In the second stage of the disease, a radiograph may reveal both osteolytic and sclerotic changes in the same bone.  In the last stage of the disease, the sclerotic lesion dominates the bone and there may be an increase in the dimensions of the bone itself.

A radionuclide bone scan using a radiolabeled bisphosphonate is the most efficient means of detecting Paget’s disease in the skeleton. The bisphosphonate is injected intravenously and concentrates in areas of increased blood flow and high levels of bone formation, both common characteristics of Paget’s disease. A radionuclide bone scan is used primarily to establish the full extent of skeletal involvement and identify lesions located in fracture risk areas. The minimum recommended level of evaluation to track and monitor progression and treatment of Paget's’ disease is at least one measurement of metabolic bone activity and radiographic examinations of affected bones. Radiographic studies are used alone or in conjunction with bone scans to confirm or eliminate the diagnosis of Paget’s disease. Bones affected by Paget’s disease have a characteristic radiographic appearance that is sometimes described as cotton wool. The technologist may have to increase the x-ray exposure factors when performing imaging procedures on the Pagetic patient, due to extensive sclerotic areas in the bones. Serial radiographs should be performed on those patients with lytic lesions in weight-bearing long bones in order to document healing. Because early diagnosis and treatment is important, siblings and children of someone with Paget’s disease may wish to have a serum alkaline phosphatase (SAP) blood test every 2 or 3 years, after age 40.

Part 10 Renal and Hepatic Diseases and Bone Loss

Patients with chronic renal disease are not only at risk of developing rickets and osteomalacia, but they are also at risk of a complex bone disease known as renal osteodystrophy. This condition is characterized by a stimulation of bone metabolism caused by an increase in parathyroid hormone and by a delay in bone mineralization that is caused by decreased kidney production of 1,25-dihydroxyvitamin D. In addition, some patients show a failure of bone formation, called adynamic bone disease. As a result of this complexity, bone biopsies are often needed to make a correct diagnosis. By the time the patient progresses to end-stage renal failure, clinical manifestations of the disease appear, including bone cysts that result from stimulation of osteoclasts by the excess production of parathyroid hormone. While dialysis can significantly extend the life expectancy of patients with chronic renal failure, it does nothing to prevent further progression of osteodystrophy. The medical management of a patient through dialysis may lead to further bone abnormalities that become superimposed on the underlying osteodystrophy, thus increasing the risk of fractures. While a renal transplant may reverse many features of renal osteodystrophy, the use of anti-rejection medication in transplant patients may cause bone loss and fractures. The pathogenesis of renal osteodystrophy is complex and thought to occur from several different mechanisms that contribute to poor bone health. Histologically, osteodystrophy may be classified as ostetis fibrosa, osteomalacia, adynamic disease, or mixed.75 Ostetis fibrosa is primarily caused by secondary hyperparathyroidism. This is characterized by increased bone turnover and osteoclast activity resulting in increased resorption. Osteomalacia is a mineralization defect with accumulation of unmineralized osteoid and low rates of bone turnover. Adynamic renal bone disease is characterized by decreased remodeling activity.75 Osteoporosis and fractures are relatively common in those with chronic liver disease. Approximately 37% to 53% of cirrhotic patients referred for liver transplantation are found to have osteoporosis.75 A wide range of vertebral fracture rates (3-44%) has been reported among cirrhotic patients and is related to the decreased bone formation in those with chronic liver disease. Several

90 factors, including excessive alcohol use, decreased hepatic synthesis of insulin- like growth factor-1 levels, and hyperbilirubinemia.75 Alcohol use by itself has been implicated, even in the absence of chronic liver damage. Additional factors contributing to osteoporosis in individuals with liver cirrhosis include vitamin D deficiency, due to decreased hepatic synthesis of 25-hydroxyvitamin D or to intestinal malabsorption, and glucocorticoid use.75

91 Part 11 Respiratory Diseases and Bone Loss

Introduction In the United States the third leading cause of death is from lung disease which is responsible for 1 in 6 deaths.76 Lung disease and other breathing problems constitute one of the leading causes of death in babies younger than 1 year old.76 Today, more than 35 million Americans are living with chronic lung disease such as asthma, and chronic obstructive pulmonary disease (COPD) otherwise known as emphysema and chronic bronchitis.76 An estimated 80,000,000 American adults (1 in 3) have one or more types of cardiovascular disease of whom 38,100,000 are estimated to be age 60 or older.77 Cardiovascular diseases range from high blood pressure, coronary artery disease, heart failure, stroke, and congenital cardiovascular defects.77 Because of their potent anti-inflammatory and immunosuppresive actions, glucocorticoids are commonly used to treat a large variety of debilitating and potentially life threatening pulmonary and cardiovascular conditions. The most frequent and devastative complication of glucocorticoid therapy is the occurrence of brittle and osteoporotic bone, and is believed to be the most common cause of secondary osteoporosis. Glucocorticoid-induced osteoporosis is not restricted to adults. Imaging examinations, image guided diagnostic and interventional procedures, and therapeutic radiation treatments are all critical to the early diagnosis, staging, and treatment of respiratory and cardiovascular diseases and conditions and the consequences of bone loss due to glucocorticoid therapy.

Airway Diseases Diseases collectively known as chronic obstructive pulmonary disease (COPD) include asthma, chronic bronchitis, bronchiectasis, and emphysema. The common pathology in obstruction is expiratory airflow, often created by inflammatory conditions.

Chronic Obstructive Pulmonary Diseases (COPD) COPD refers to a large group of disorders that is characterized by obstruction of airflow that interferes with normal breathing. Chronic bronchitis

92 and emphysema are the two most common conditions that comprise COPD and often co-exist. It is difficult to determine whether the pulmonary obstruction is caused by bronchitis, emphysema, or a combination of the 2 diseases so the designation of COPD is commonly used. COPD is a major cause of morbidity and mortality throughout the world and the fourth leading cause of death in America.76 Of the approximately 120,000 deaths in 2000; 61,000 were females as compared to 59,000 males.76 COPD is considered a major public health threat and is ranked 12th as a worldwide burden of disease and is projected to rank 5th by the year 2020 as a cause of lost quantity and quality of life.76 Smoking is the primary risk factor for COPD with 80% to 90% of the COPD deaths caused by smoking.1 Female smokers are nearly 13 times as likely to die from COPD as women who have never smoked.76 Other risk factors of COPD include air pollution, second-hand smoke, history of childhood respiratory infections and heredity. Occupational exposure to certain industrial pollutants also increases the risk for COPD. The quality of life for a person suffering from COPD diminishes as the disease progresses. COPD is a progressive disease and those affected may eventually require supplemental oxygen and may have to rely on mechanical respiratory assistance. Treatment of COPD includes pharmacotherapy to decrease symptoms and complications. Additional treatments include bronchodilator medications, antibiotics, oxygen therapy, and systemic glucocorticosteroids. Because glucocorticosteroids are used in the treatment and maintenance of COPD the long-term use of these drugs have been implicated in osteopenia and osteoporosis.

Asthma and Chronic Bronchitis Asthma is an airway disorder that exhibits rapid onset and is estimated to affect about 5% of the American population, representing a significant increase during the past 10 years.76 The increase in the number of people affected by asthma is attributed to an increase in environmental air pollution, cigarette smoking, infection, and exposure to toxic substances in the workplace. In California, American Indians were more likely to have been diagnosed with asthma than all racial/ethnic groups.76 Approximately 25.5% American

93 Indian children and 20% American Indian adults had been diagnosed with asthma in their lifetime, compared to 21% African American children and 16% African American adults.76 Only 14% white children and adults and 11.7% Asian children and 9.2% Hispanic children and 7% Hispanic adults has been diagnosed with asthma.76 The treatment for asthma includes decreasing contact with the inflammatory agent and use of anti-inflammatory drugs. Chronic bronchitis is defined as the excess production and expectoration of sputum that occurs on most days for at least 3 consecutive months in at least 2 consecutive years. Chronic bronchitis is common in individuals who smoke cigarettes and 50% of those with a history of chronic bronchitis will have a normal appearing chest radiograph.76 Females are more than twice as likely to be diagnosed with chronic bronchitis as males.76 Bronchitis is caused by irritants such as cigarette smoke, or infections and is characterized by an increased mucus-productive cough, mucosal swelling and impaired ciliary function which leads to impaired air flow.76 Neither asthma or bronchitis pose a direct threat to bone health; but, certain medications used to treat the disease have a negative impact on the skeleton.79 Anti-inflammatory corticosteroids are commonly prescribed for asthma and, taken by mouth, these medications can decrease calcium absorbed from food, increase calcium loss from the kidneys, and decrease bone formation. Corticosteroids also interfere with production of sex hormones in both women and men, which can contribute to bone loss. Exposure to glucocorticoids accounts for 16-18% of osteoporosis in men.80 Bone mass often decreases quickly and continuously with ongoing use of glucocorticoid medications, with most of the bone loss in the ribs and vertebrae. About one-third of patients have evidence of vertebral fractures after 5 to 10 years of treatment with glucocorticoids and their risk of hip fracture is increased nearly three-fold.80 A treatment plan to minimize damage to bone during long- term glucocorticoid therapy may include using the minimal effective dose, discontinuation of the drug when practical, and topical (skin) administration, if possible. Exercise can often trigger an asthma attack; so many people with asthma avoid weight-bearing physical activities that are known to strengthen bone. Asthmatics who must rely on corticosteroids to manage their asthma are at

94 significant risk for bone loss and may benefit from a bone density test. Also, since corticosteroids may increase bone resorption, blood or urine biochemical marker tests can be used to determine if bone is being broken down rapidly.79

Emphysema Emphysema is a condition in which the walls between the air sacs within the lungs lose their ability to stretch and recoil.81 The loss of elasticity of the lung tissue causes air to be trapped in the air sacs. Emphysema is a very important cause of loss of pulmonary vascularity, resulting in reduced exchange of oxygen and carbon dioxide. As the airway support is lost, obstruction of airflow occurs.81 Of the estimated 3.1 million Americans ever diagnosed with emphysema, 91% were 45 or older with the greater percentage of those affected, being male.81 Less than 5% of the cases of emphysema in the United States is caused by alpha1 antitrypsin deficiency-related (AAT) emphysema and is an inherited disorder.81 An estimated 100,000 Americans, primarily of northern European descent, have AAT deficiency emphysema with 25 million carrying a single deficient gene that causes the disease.81 Symptoms of emphysema include cough, shortness of breath and a limited exercise tolerance. Pulmonary function tests, along with the patient’s history, examination, and other tests are used to diagnosis emphysema.81 Pulmonary rehabilitation is used with COPD, bronchitis, and emphysema. Lung transplantation is being performed for people who suffer severe emphysema. Because glucocorticosteroids are used in the treatment and maintenance of COPD, asthma, bronchitis, emphysema and similarly related lung diseases, the long-term use of these drugs have been implicated in osteopenia and osteoporosis.

95 Part 12 Specialty Groups and Bone Loss

Osteoporosis in Men Osteoporosis has traditionally been considered a disease of women but men can also incur substantial bone loss with aging. Elderly men have age- specific hip fracture incidence rates and vertebral fracture prevalence rates that are at least half those in women.82 Although previously the etiology of osteoporosis in men was not clear, a research study funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have found new clues related to bone loss and the risk of fracture in older men. Analysis of data from the Osteoporotic Fractures in Men Study (MrOS) demonstrated that although hip bone loss in the 4,720 men over age 65 studied, was typically modest, it did increase with age.82 The researchers also learned that men with the lowest BMD at the beginning of the study were at greatest risk for subsequent bone loss. Also the data of the MrOS study include the following facts:  African American men (who comprised 4% of the cohort) had nearly 2% higher hipbone mineral density compared to Caucasian men. Race was the strongest factor influencing BMD levels in the analysis;  Increased body weight (by 22 pounds) was associated with a 4% increase in levels of BMD; and,  The use of selective serotonin re-uptake inhibitors, a class of antidepressants, was associated with a 4% decrease in BMD levels.83

Other factors positively related to low BMD in men includes diabetes, osteoarthritis, physical activity, grip strength, moderate alcohol intake and dietary calcium. A history of maternal or paternal fracture, chronic lung disease, prostate cancer and kidney stones was associated with reduced BMD in the analysis. The number of men expected to have osteoporosis is estimated to be over 17 million in 2010 and to well over 20 million in 2020.83,84 The number of men of all races and ethnic groups who are affected is significant. Approximately 1 in 2 women and 1 in 4 men over age 50 will have an osteoporosis-related fracture in their remaining lifetime.84 There is evidence that men and women do not have similar outcomes after fracture. For example it is estimated that hip

96 fracture mortality at one year is approximately 20% in women and 30% in men. Data shows that men with vertebral deformities have greater functional impairment compared to women and the institutionalization rate after fracture is higher in men than in women.85 Despite the large number of men affected, osteoporosis in men remains under diagnosed and under reported. Osteoporosis is more commonly diagnosed in women, and women are at greater risk than men. However, men really have only temporary protection against osteoporosis. The temporary protection is related to the size of men’s skeletons, which are generally larger than women’s. Men have larger, stronger bones than women, which means they have a greater reserve of bone mass to draw from as they age and their bone loss progresses more slowly. Also, men do not experience the same rapid bone loss that occurs in women during and after menopause. Because bone loss is delayed and osteoporosis does not have any symptoms, men do not usually know they have osteoporosis until a fracture occurs. Increasing awareness about the true frequency of osteoporosis in men is essential for prevention and long-term health. Even though bone loss in men usually occurs later in life compared with women, men can still be at high risk for osteoporosis. The risk factors for men are similar to those in women and these include chronic disease, use of certain medications, low levels of sex hormones, unhealthy lifestyle habits, and increasing age. By age 65, men catch up to women and lose bone mass at the same rate. Additional risk factors such as a small body frame, long-term corticosteroids, and other diseases, or low testosterone levels can increase the risk of osteoporosis in men. Hypogonadism refers to abnormally low levels of sex hormones and if present during peak bone mass development may lead to a reduction of bone mass later in life. In men, reduced levels of sex hormones may cause osteoporosis. Although it is natural for testosterone levels to decrease with age, there should not be as sudden a drop in this hormone as compared to the estrogen drop experienced by women at menopause. Low sex hormone levels are associated with bone loss and reduced bone mass, either when hypogonadism is present during purbertal bone mass development or when it develops in adult men and results in accelerated bone loss.86 Medications, such as, glucocorticoids, cancer treatments (especially for prostate cancer), and many

97 other factors can affect testosterone levels. Additional causes of hypogonadism include testicular disease, pituitary insufficiency, alcohol abuse, gonadal suppression or castration, and aging.86 Recent research suggests that estrogen deficiency may also be a cause of osteoporosis in men. For example, estrogen levels are low in men with hypogonadism and may play a part in bone loss. Osteoporosis has been found in some men who have rare disorders involving estrogen. The role of estrogen in men is under active research investigation. Men who are most likely to have osteoporosis are those who are over the age of 75, have a low body-mass index, have lost more than 5% of their body weight during the previous 4 years, currently smoke and are physically inactive. At least 50% of the causes of osteoporosis in men can be traced to other diseases or lifestyle choices. Men are more likely than women to have osteoporosis secondary to an underlying disease or metabolic related condition.83 Early detection of low bone mass or osteoporosis is the most important step for prevention and treatment. The bone mineral density (BMD) test results are compared to standards, or norms, determined from a large average population. One of the problems with measuring the BMD of men is that many of the standards used for comparison are from young women rather than men. The average bone mass in healthy young women are always lower than that observed in healthy young men. This means that a man may have low bone mass, but the comparison with the norm (from young women) will not show that they are at risk for osteoporosis. Consequently, few men are classified as osteoporotic based on the normal data from young women. If a man over the age of 50 has a T-score of –2.5 or lower, he can be diagnosed as having osteoporosis. The diagnosis of osteoporosis in healthy men under age 50 should not be made on the basis of densitometric criteria alone. The decision about which men should have BMD measurement comes from several national groups and includes the following indications:  Radiographic low bone mass (osteopenia) and/or vertebral deformity;  Loss of height or thoracic kyphosis;  Prior fracture;  Conditions/medications recognized to increase risk for bone loss and fracture;

98  Hypogonadism and/or prostate cancer; and,  Age 70 or older. Medical research on osteoporosis in men is limited. However, experts agree that all persons should take the following steps to preserve bone health:  Recognize and treat any underlying medical conditions that affect bone health;  Identify and monitor use of prescribed medications that are known to cause bone loss;  Eliminate any unhealthy lifestyle habits, such as smoking;  Participate in a regular exercise program; and,  Ensure recommended daily calcium and vitamin intake.

The FDA has approved 3 antiresorptive medications to treat osteoporosis in men. These are aldendronate (Foxamax®), risedronate (Actonel®), and zoledronic acid (Reclast®).84,85 Only one anabolic medication, teriparatide (Forteo®), has been approved to treat osteoporosis and it is also approved for use in men. Testosterone helps protect the bones of men and if osteoporosis is due to low testosterone levels, testosterone replacement therapy may be a treatment option.

Hispanic Women and Osteoporosis Several studies indicate a number of facts that highlight the risks Hispanic women face with regard to developing osteoporosis. These facts include:  Ten percent of Hispanic women aged 50 and older are estimated to have osteoporosis, and 49% are estimated to have bone mass that is low, but not low enough for them to be diagnosed with osteoporosis;  The incidence of hip fractures among some Hispanic women appears to be on the rise;  Studies have shown that Hispanic women consume less calcium than the recommended dietary allowance in all age groups; and,  Hispanic women are twice as likely to develop diabetes as white women, which may increase their risk for osteoporosis.1

99 The Very Elderly Osteoporosis becomes much more prevalent with increasing age, because bone is progressively lost through out adult life. Very elderly people who are mobile and in reasonable health need to be encouraged to improve bone health. Very elderly people who live in nursing homes and aged care facilities tend to be in poor health and may not be ambulatory. Many people in this group have low BMD or established osteoporosis and are at increased fracture risk. When osteoporosis is present, even minor trauma such as coughing, minor bumps or falls can lead to fractures. Older women and men have slower response times and more often fall to the side, suffering direct impacts to the hip. The falls are often unrelated to external obstacles, but many result from deterioration in gait and postural instability, decreased muscular performance, malnutrition, comorbidity (e.g., poor vision, cognitive impairment and medications). Regardless of age, bones and muscles need exercise to retain strength, so a special exercise program tailored to the very elderly who are institutionalized is very important. Improved balance, posture, coordination and muscle strength are the benefits that result from sustained weight-bearing exercise.

100

Part 13 Bone Fractures

Fractures are by far the biggest problem caused by bone disease.1 Annually, an estimated 1.5 million individuals suffer a fracture caused by bone disease. 1 Approximately one-third (500,000) of fracture patients are hospitalized, while many more suffer and do not require hospitalization.1 The risk of fracture increases dramatically with age in both sexes because bones become more fragile and the risk of falling increases.1 Roughly 1 in 4 (24%) women age 50 or older fall every year, compared to nearly half (48%) of women age 85 or older.1 Comparable figures for men are 16% and 35%.1 These falls can result in fractures, and when they do the fracture is almost always caused by low bone mass (osteopenia) or osteoporosis.1 Fracture incidence in the United States is usually highest for Caucasians and lower for other ethnic groups.1 The lower incidence of fractures among African-Americans has generally been explained by their greater bone mass.1 But differences in bone mass fail to explain the lower hip fracture rates observed in Hispanics and Asians.1 The FRAX® assessment tool was developed by the World Health Organization (WHO) as a tool to evaluate fracture risk of individual people. FRAX® algorithms give the 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture. Additional information about the FRAX® assessment tool will be provided later in this course.

Types of Fractures Some of the more common types of fractures resulting from bone loss include fatigue fractures, insufficiency fractures, and burst fractures. Each of these will be briefly described. A fatigue fracture results from repeated trauma to an otherwise normal healthy bone. The repeated stress to the bone promotes bone resorption, causing gradual dissolution at the site of strain that can later result in complete fracture. A fatigue fracture most commonly occurs in the metatarsals, but it can also occur in the pelvis, calcaneus, tibia, fibula, and femoral neck and shaft.87

101 An insufficiency fracture occurs when a normal stress breaks a bone that is abnormal and deficient of elasticity. These fractures should be distinguished from a fatigue fracture.87 A burst fracture occurs in the vertebral body and results from axial compression loading most frequently when the neck and lower back are in flexion.87 When vertical compression is applied, the vertical endplates of the vertebrae fracture and the nucleus of the disc is forced into the vertebral body, which “bursts”, into multiple fragments. The normal posterior margin of the vertebral body is straight or concave, but if it is convex, a burst fracture is probably present. There is usually widening of the interpediculate distance, and since at least 2 columns are involved these fractures are considered unstable.87 When morphometric studies are performed without reference to clinical presentation, the abnormalities found are usually referred to as deformities rather than fractures. Early methods to classify vertebral fractures have been replaced by morphometric measurements of vertebral height with fracture defined according to fixed cut-off values. Each vertebral body has unique dimensions. The most widely adopted thresholds for defining and grading fractures are:

 Grade 1 (moderate) deformities are those that fall between 3 or 4 standard deviations (SD) from the mean value specific to each vertebra.

 Grade 2 (severe) deformities are those that fall 4 SD or more from the mean.88

There are 3 categories of vertebral fracture, compression, wedge, and biconcave.88 Compression fractures, also referred to as crush fractures, results in loss of both anterior and posterior vertebral height. A wedge (i.e., partial) fracture results in loss of anterior height. When a biconcave or balloon fracture occurs there is a loss of contact with the bony tissue thus leading to concavity of both vertebral endplates.88 A fracture occurs when a bone is too fragile to resist relatively minor degrees of trauma that should not normally result in fracture. Generally, the occurrence of any fracture in an elderly person is often considered to be

102 osteoporotic, especially if it was related to a fall from no more than a standing height, or if there was little or no recognized trauma. Women with asymptomatic vertebral deformities are more likely to have a history of increased back pain and back disability. Asymptomatic vertebral deformities are often noted on routine chest radiography, with nearly three- fourths of vertebral deformities being asymptomatic. A symptomatic or asymptomatic vertebral fracture increases the risk of subsequent hip fracture by 2.3 fold and distal forearm (Colles) fracture by 1.6-fold during a 10 year period.88 High-trauma fractures in older men and women have been linked to osteoporosis. Researchers at the California Pacific Medical Center (CPMC) Research Institute are challenging a widely held belief that fractures resulting from major trauma, such as automobile accidents, are not related to osteoporosis.89 Those with osteoporosis experience fractures from a level of force that would not break a healthy bone. Although clinicians often recognize fractures resulting from minimal trauma as osteoporotic, those related to more substantial injury are rarely given the same consideration. It is thought that many clinicians pass on any follow-up of many fracture patients because it is assumed that the fracture is merely a result of the trauma.89 These missed opportunities can have a devastating impact on victims, who, without proper management, are at increased risk for subsequent fracture. The CPMC Study, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), analyzed data from 2 large prospective cohort studies the Osteoporotic Fractures (SOF) in women and the Osteoporotic Fractures in Men Study (MrOS).89 Study participants were contacted every 4 months to determine whether they experienced a fracture in the previous 4-month period. When a fracture was reported in a study candidate, clinical staff interviewed the participants to learn how their trauma occurred. Without knowledge of the participant’s BMD, staff classified each fracture as high-trauma or low-trauma. High-trauma fractures were defined as those caused by motor vehicle crashes and a fall from greater than standing height. Low- trauma fractures were defined as those resulting from falls from standing height and less severe trauma.89 The study researchers discovered that the relationship between BMD and fracture risk was similar for high-trauma and low- trauma fractures. They also found that women who experienced a high-trauma

103 fracture were at increased risk for future fractures.89 Researchers concluded that the evidence indicates that any fracture experienced by an older individual is worthy of an osteoporosis evaluation.89 The researchers further concluded that the study changes the definition of osteoporotic fracture and expands the number of fractures that should be considered as such.89 Osteoporosis is not only a major cause of fractures, it also ranks high among diseases that cause people to become bedridden with serious complications.90 In America and Europe, osteoporotic fracture accounts for 2.8 million disabilities, adjusted life years (DALYS) annually.90 This figure is more than that attributed to hypertension, breast and ovarian cancer, and prostate cancer but less than lung cancer, diabetes mellitus, and chronic obstructive pulmonary disease (COPD).90 Figure 8 shows the WHO estimated number of osteoporotic fractures in 2000, by site in men and women aged 50 years or more, in America and Europe.90

Hip Spine Proximal Forearm Humerus America 311 214 111 248 Europe 620 490 250 574 Fig. 8. Osteoporotic fractures by site in men and women aged 50 years or more in 2000 by WHO region.

Physical Examination During a physical examination of the patient, certain questions can be asked that may indicate the presence of fractures due to bone loss. Patient questions that may elicit information about the possibility of undiagnosed fractures includes:  Has there been a change in height;  Are there changes in existing kyphosis: and,  Has the patient had shortness of breath? 90

Vertebral fractures are associated with varying degrees of back pain. When a clinical vertebral fracture occurs, most report sudden onset of pain that follows a mechanical pattern (increasing by load and decreasing by rest) with varying frequency, severity, and duration.

104 Hyperkyphosis (dowager’s hump) can result. An occiput to wall distance of greater than 0 centimeters and a rib-pelvis distance less than 2 finger breaths have been associated with the presence of a thoracic fracture, Figure 9.90

Fig. 9. Loss of height and occiput to wall distance of greater than 0 centimeters and decreased rib to pelvis distance.

A simple questionnaire has been proposed to help identify patients who are more likely to have existing vertebral fracture and who may benefit from spinal imaging. The Prevalent Vertebral Fracture Index (PVFI) is calculated by adding points based on the following 5 variables.  History or diagnosis of a vertebral fracture;  History or diagnosis of a non-vertebral fracture;  Height loss since the age of 25;  History or diagnosis of osteoporosis, and;  Age.90

105 If a fracture is suspected, imaging of the total thoracic and lumbar spine is usually indicated. Currently there is no gold standard imaging modality for detection of vertebral fracture. Several methods have been developed to describe vertebral deformity and these include quantitative and semi-qualitative methods. Quantitative methods of vertebral morphometry include measurements of the anterior, middle, and posterior heights of vertebra but are generally only used in clinical trials. Semi-quantitative methods use the Genant Score. There is no generally accepted definition of a spine fracture, and estimates of overall prevalence of spine fractures in postmenopausal women vary widely depending on the definition used.1 Falls account for about one-fourth of the spine fractures that come to clinical attention.1 The majority of spine fractures result from excess stresses on the spine caused by everyday activities.127 The incidence of clinically recognized spine fractures increase rapidly with age in both sexes.1 Often, the physical changes that result from fractures make it hard to find clothing that fits properly. People with vertebral fractures lose height and develop a curved back and protruding abdomen. Modification of clothing to accommodate the physical changes can make getting dressed and undressed easier for the person with osteoporosis.

Clinical Signs of Vertebral Fracture Only 1 in 3 vertebral fractures come to clinical attention. Often the circumstances resulting in vertebral fracture are dismissed as trivial. In those with clinically diagnosed vertebral fracture, 14% followed severe trauma and 83% followed moderate or no trauma.75 Clinical vertebral fracture occurred after an in- home accident (fall or stumble in 13% of cases, after lifting a heavy load in 24% of cases, and without any cause in 44% of cases).75 Spontaneous restoration of normal spinal anatomy is not possible after a vertebral fracture.75 Vertebral fractures are associated with varying degrees of height loss, thoracic hyperkyphosis of the thoracic spine, and flattened lumbar lordosis in cases of lumbar vertebral fracture. Lung function progressively decreases with increasing hyperkyphosis. To fully appreciate the possible dire consequences of vertebral fractures, one must recognize the function and components of the vertebral column. The following is a review of the vertebral anatomy.

106 Overview of Vertebral Anatomy The vertebral column, commonly referred to as the backbone, indeed serves as our own personal lightning rod for the impacts and injuries inflicted during a lifetime of activity. The bony components provide a flexible support for the trunk and head and allow flexion, extension, rotary and lateral movement along its various articulations. Vertebral compression fractures (VCFs) are considered the most serious consequence of bone loss in the aging and at-risk population.91 Those with a VCF experience a decreased quality of life and also have increases in digestive and respiratory morbidity, anxiety, depression, and death.91 The most serious implication of VCFs is that these carry as much as a 5-fold increased risk of another fracture within 1 year of initial fracture.91 As many as two-thirds of VCFs are undiagnosed and even if diagnosed, many patients are treated only acutely and few are treated for future prevention of fracture. The spinal column is the center for control of posture and provides stability for the trunk of the body and the head. The vertebral column, which extends the weight of the trunk and upper body to the lower extremities, is situated in the midsagittal plane of the body. The spine allows flexibility of the torso and surrounds the spinal cord. The many bony structures of the spine and the spinal cord are very vulnerable to injury. Injuries can occur to the bones themselves, the ligaments that connect the bones, discs that separate each vertebral bone from one another, muscles that give movement to the spinal skeleton, and the spinal cord and nerve endings. The vertebral column consists of 26 bones in the adult and 33 bones in the child and includes the vertebrae, spinal canal, spinal cord, intervertebral discs, ligaments, muscles, and associated soft tissues, Figure 10.1 The term vertebra is used when referring to a singular bone and vertebrae when referring to more than one bone of the spinal column. The spinal column, also called the vertebral column, consists of:  7 cervical (neck) vertebrae;  12 thoracic (chest) vertebrae;  5 lumbar (back) vertebrae; and,  5 fused vertebra that makes up the sacrum and coccyx.

107 The vertebral column has a series of anterioposterior curves. The terms concave and convex are used to describe the curvatures. Concave refers to a rounded inward or depressed “cave-like” depression. Convex refers to a rounded outward or elevated surface. Looking at the curvatures from the posterior viewpoint, the cervical and lumbar regions have concave curvatures and are referred to as lordotic.

Fig. 10. Side view of the spine. Used with permission from National Institute of Arthritis and Musculoskeletal and Skin Diseases. Bethesda, MD. Retrieved from www.niams.nih.gov on December 2, 2011.

The thoracic and sacral regions have convex curvatures. The thoracic and sacral convex curves begin to develop soon after birth and are called primary curves. The first compensatory concave curve begins to develop as soon as the infant begins to raise their head and sit up. As the child learns to walk, the second compensatory concave lumbar curvature develops. Both primary and compensatory curvatures are normal and add strength and stability along the vertebral column.

108  Cervical lordosis (concave) curvature is the first primary compensatory curve;  Thoracic kyphosis (convex) curvature;  Lumbar lordosis (concave) curvature is the second compensatory curve; and,  Anterior sacral (convex) curvature.

These normal curvatures can become abnormal or exaggerated due to a number of causes. Terms used to describe these include lordosis, kyphosis, and scoliosis. Disorders associated with abnormal curvatures of the spine are commonly diagnosed in infancy. The symptoms of these may resemble other spinal conditions or deformities and may be congenital or from injury or infection. Disorders such as muscular dystrophy, developmental dysplasia of the hip or neuromuscular disorders may cause abnormal curvature of the spine. The term lordosis is used to describe the normal anterior concavity of the cervical and lumbar spine region; however, it also is used to refer to an abnormally increased curvature. Lordosis exists when there is evidence of an abnormally increased curvature of the spine in the lower back area, appearing as swayback, Figure 11.2 Kyphosis exists when there is evidence of an abnormal or exaggerated increased convexity of the thoracic region of the spine, appearing as a “humpback”, Figure 12.3

Fig. 11. Lordosis, an abnormal increase curvature of the spine. Courtesy drawing by DGMConsulting: 2011. Fig. 12. Kyphosis, an abnormal or exaggerated increase convexity of the thoracic region of the spine. Courtesy drawing by DGMConsulting: 2011.

109 Kyphosis can be congenital or due to acquired conditions that may include:  Metabolic and neuromuscular conditions;  Osteogenesis imperfecta;  Spina bifida; and,  Scheuermann’s disease.

Kyphosis is more common in females than males and symptoms of the condition may include:  Differences in shoulder height;  A forward bend of the head compared to the rest of the body;  Differences in scapula height or position;  The height of the upper back appears higher than normal, when bending forward; and,  Tight hamstring muscles.

Scoliosis or adolescent idiopathic scoliosis is the most common spinal curvature disorder.4 It is defined as a persistent lateral curvature of the spine of more than 10 degrees in the upright or standing position. When the spine is viewed from the anterior or posterior surface, the vertebral column is normally almost straight with minimal lateral curvature. If the curvature presents as a pronounced S-shaped lateral curvature, the thoracic cavity may be deformed and results in compromised respiratory functions. When scoliosis occurs in the lower vertebral column, the effect is more obvious and may create tilting of the pelvis, which may cause a limp or uneven gait.

The Cervical Spine The cervical spine is made up of 7 cervical vertebrae whose main function is to support the weight of the head, which is estimated to be 10-12 pounds. Of all the portions of the spine, the cervical spine has the greatest range of motion primarily due to specialized vertebrae that move with the skull. The cervical vertebrae are the smallest of the vertebrae. The first cervical vertebra is called the atlas and is significantly different from the other vertebrae. It has a ring-like shape with two large protrusions on the sides to support the weight of the head.

110 The second cervical vertebra is called the axis and is also unique in that it has a bony peg-like protrusion, called the dens or odontoid. On its upper surface, the odontoid fits within the ring of the atlas. The curve of the cervical spine is described as a “C” in reverse or a lordosis or lordotic curve. The cervical curve begins at the apex of the odontoid process and ends at the middle of the 2nd thoracic vertebrae. The first two cervical vertebrae are unique in their development. Three primary ossification sites form C1, known as the atlas, the anterior arch and two neural arches, which surround the anterior arch and fuse later in life to form the posterior arch. The anterior arch is ossified in only 20% of cases at birth and becomes visible as an ossification center by 1 year of age.26 Cartilaginous plates (i.e., epiphyseal plates) are found between the diaphysis and each epiphysis until skeletal growth is complete, usually at full maturity at about age 25. The 2nd cervical vertebra, the axis, has the most complex and unique development with four ossification centers present at birth. There is one center for each neural arch, one for the body and one for the odontoid process. The body of C2 fuses with the odontoid process by 3-6 years of age.

The Thoracic Spine The thoracic vertebrae are inferior to the cervical vertebrae, beginning after the 7th cervical vertebrae. There are 12 thoracic vertebrae with each side articulating on the posterior aspect with a rib. This arrangement forms a cage for which the primary function is to protect the organs of the chest. The thoracic spine has less mobility than the cervical and lumbar spine because of its rib attachments. The thoracic spine has a normal kyphosis, or “C” curve. The thoracic curve begins at the middle of the T2 and ends at the middle of the T12 vertebra. The most prominent point of the thoracic spine corresponds to the spinous process of the 7th thoracic vertebra. The thoracic and pelvic curves are termed primary curves, because they alone are present during fetal life.

111 The Lumbar Spine & Sacrum and Coccyx There are 5 lumbar vertebrae located between the thoracic and sacral segments of the vertebral spine. The lumbar vertebrae are the largest and strongest bones in the vertebral column and bear the greatest impacts of the body’s weight. The lumbar vertebrae are aligned in a reverse “C” like the cervical spine, creating a normal lumbar lordosis. The lumbar curve is more pronounced in the female than in the male and it begins at the middle of the last thoracic vertebra and ends at the sacrovertebral angle. The sacrum and coccyx are the distal portions of the vertebral spine. The sacral vertebrae begin immediately after the 5th lumbar vertebrae and are wedged between the ilium and contribute to the pelvic girdle. The sacroiliac joints (SI joints) are located where the sacrum meets the iliac bones on each side. The sacrum connects the spine to the pelvis and the lower half of the skeleton. Sacroiliac joints are classified as synovial joints and are enclosed in a fibrous articular capsule containing synovial fluid. Synovial joints are generally freely movable, or diarthrodial; however, the SI joints are a special type that permits little movement (i.e., amphiarthrodial). The SI joint surfaces are irregular and the bones fit together in an almost locking construction, allowing for only limited motion. The 5 sacral segments become fused into a single bone in the adult but can be seen as individual sacral bones in the newborn. The coccygeal vertebrae consist of a single fused bone in the adult but the newborn has 3 to 5 individual segments. Transitional vertebrae are frequently encountered developmental variants of the spine. They are found in approximately 20% of human skeletons and often involve the sacrococcygeal and lumbosacral junctions.92 The L5 vertebrae can be incorporated into the sacrum, or the S1 vertebrae can be incorporated into the lumbar spine. The transitional vertebra retains partial features of the segments above and below it so that the total number of vertebrae in the spinal column remains relatively constant. Transitional vertebrae are usually incidental findings during imaging examinations. The most important aspect of a transitional vertebrae is the potential for confusion over the labeling or assignment of vertebral levels during medical or surgical treatment planning.92

112 Basic Vertebral Structure Each individual vertebra has unique features depending on the region of the spine where it is located. A typical vertebra has two basic aspects, the body and the vertebral arch. The vertebral body is designed to bear weight and withstand compression or loading and as such is the focus of considerable anatomic change due to these impacts. It is composed of hard cortical bone on the outside and less dense cancellous bone on the inside. The superior and inferior surfaces are flat and rough and provide an attachment for the intervertebral discs. These surfaces of the vertebral body are called the endplates. The vertebral arch is a bony ring or arch that extends posteriorly from the body. The posterior surfaces of the vertebral body and the arch form a circular opening, the vertebral foramen, which contains the spinal cord. The pedicles are strong bony structures consisting of cortical bone on the outside and cancellous bone on the inside. The pedicles extend posteriorly from either side of the vertebral body forming most of the sides of the vertebral arch. Pedicles act as the lateral (side) walls of the bony spinal canal that protects the spinal cord and cauda equina, or nerve roots, in the lumbar region. The intervertebral foramen is created in the space between the facet joints and pedicles of each vertebra. The spinal nerves are located in the intervertebral foramen. Intevertebral discs are pads of cartilage located between each vertebral body and are attached to the endplates and serve as shock absorbers. Each vertebral body has a right and left superior articular process and a right and left inferior articular process. The articular processes allow for zygapophyseal joints that are unique to the vertebral column. These joints are often referred to as facet joints; however, this is a misuse of the term. The facet is only the articulating surface and not the entire superior and inferior articular process. Degenerative or traumatic changes in the discs and joints may be accompanied by changes in the endplates. Each vertebral body has two articular processes at the top and bottom where the lamina and pedicle meet. A zygapophyseal joint is located on each side of the vertebral body and usually lies behind the spinal nerves as they emerge from the central spinal canal. The surfaces of the joint are capped with cartilage and are contained in a capsule

113 lined by synovium. The two joints and the intervertebral disc at each level allow for motion between the vertebral bodies. Radiographic demonstration of the zygapophyseal joints and the intervertebral foramina provides critical diagnostic information concerning the relationship of consecutive vertebrae. The radiographic demonstration of these structures can be confusing to the radiographer because different positions and projections are required for each major section of the spine. Figure 13 provides an overview of the various positions and projections that will provide visualization of the zygapophyseal joints and the intervertebral foramina in each region of the spine. Cervical Spine Thoracic Spine Lumbar Spine Intervertebral Oblique position Lateral position Lateral position Foramina The patient’s head and body should be The patient should be in The patient should be in rotated 45 degrees for a right anterior a true 90-degree lateral. a true 90-degree lateral. oblique (RAO) and a left anterior oblique (LAO) with a 15 to 20 degree caudal x-ray tube angle.

This demonstrates the joint closest to the film.

A right posterior oblique (RPO) and a left posterior oblique (LPO) with a 15 to 20 degree cephalic x-ray tube angle.

This demonstrates the joint farthest or “side up” from the film.

RAO = right joint RPO = left joint LAO = left joint LPO = right joint Zygapophyseal Lateral position Oblique position Oblique position Joints The patient’s body The patient’s body and should be rotated 20 part should be at a 45- degrees from true degree rotation. lateral to form a 70 degree oblique.

RPO & LPO RPO & LPO This demonstrates the This demonstrates the joints on the up side or joint on the side down or farthest from the film. closest to the film.

RAO & LAO RAO & LAO

This demonstrates the This demonstrates the joints closest to the film joint on the up side or or the side down. farthest from the film. Fig. 13. Positions and projections providing visualization of the zygapophyseal joints and intervertebral foramina in each region of the spine.

114 The intervertebral discs are composed of fibrous layers, called the annulus fibrosus, surrounding a gel-like substance called the nucleus pulposus or nucleus. The annulus fibrosus consists of 15 to 25 layers of collagen, which allows the annulus to contain the nucleus pulposus under pressure, and to help hold the vertebral bodies in place. The annulus fibrosus is weakest at the back, on either side of the midline, which is often the location of disc herniations. The nucleus pulposus has a high water content, which allows it to act as a cushion and distribute loads onto the vertebral body endplates and to the annulus fibrosus. The water content of nucleus pulposus decreases with age, which can contribute to degenerative conditions, many of which will be presented later in this course. The posterior portion of the vertebral arch is formed by the laminae. The laminae are flat shingle-like plates of bone and are shorter than the vertebral body so that there is a gap between any two laminae, bridged by soft tissue called the ligamentum flavum. Together, the laminae and pedicles form the vertebral arch and posteriorly their junction forms the spinous process. The spinous process extends posteriorly at the midline junction of the two laminae. The spinous process of each vertebra can often be palpated along the posterior surface of the back and serves as positioning landmarks for the technologist.

Ligaments The typical vertebral body has two transverse processes, or lateral projections, one on each side. These projections serve as points of attachment for muscles and ligaments in the spine. In the cervical spine, the transverse processes each have a foramen or canal through which the vertebral artery and vein travel. The ligaments of the spine are fibrous tissues that keep the bones and joints in alignment.93 The intertransverse ligaments connects the transverse processes of the vertebrae on each side of the spinal column.93 The interspinous ligament runs between the spinous processes and the supraspinous ligament runs along the superior portion of the cervical spine region to the sacrum. The posterior longitudinal ligament connects all the vertebral bodies. It consists of a fibrous band that extends from the base of the skull to the sacrum.13 The anterior longitudinal ligament is a broad band on the front surface of the

115 vertebral bodies. The supraspinous ligament runs across the top of the spinous processes. The ligamentum flavum is a paired ligament that lies between adjacent lamina, and protects the neural structures beneath it. It is comprised of elastic fibers and has an opening in the middle between the two-paired halves. An understanding of the ligaments of the craniocervical junction is important for recognizing mechanisms of injury. The anterior and posterior atlanto-occipital membranes extend from the upper aspect of C1 to the anterior and posterior aspects of the foramen magnum. The anterior atlantoaxial ligament extends from the anterior midportion of the dens to the inferior aspect of the anterior arch of C1. The tectorial membrane is the superior extension of the posterior longitudinal ligament and attaches to the anteriolateral aspect of the foramen magnum. The transverse ligament extends from the tubercle on the inner aspect of one side of the atlas to the tubercle on the other side. The apical ligament lies between the superior longitudinal fasciculus of the cruciform ligament and the anterior atlanto-occipital membrane. The alar ligaments connect the lateral aspect of the dens and the medial inferior aspect of the occipital condyles. The main function of the alar ligaments is to limit rotation to the contralateral side. The ligamentum nuchae is a fibrous membrane in the neck extending from the external occipital protuberance and median nuchal line to the spinous process of the bottom of the cervical vertebra. These ligaments, when stressed beyond their range, can stretch or tear and this results in rotational instability. A partial or complete tear of a ligament is called a sprain.

The Spinal Cord The vertebral column creates a vertical tunnel, commonly referred to as the spinal or neural canal. The back of the vertebral bodies creates the front wall of the spinal canal; the sides are formed by the pedicles at each level; and the lamina forms the posterior wall. The spinal canal runs from the cervical region to the sacrum, and contains the spinal cord, which ends at the top of the lumbar region. At this level, it becomes the conus medullaris and then the cauda equina.94 A neural foramen is located on each side of the spinal canal at each level of the cervical, thoracic, and lumbar spine. These small canals allow passage for the paired spinal nerves. The foramen on each side is created by the space

116 between two pedicles, above and below, in addition to the side of the vertebral body and the facet joint. The spinal cord is composed of millions of nerve fibers, which forms the tube-like structure that extends from the brain to the area between the L1 and L2 vertebra in the upper lumbar region.95 The nerve fibers branch off from the spinal cord and form the nerve roots, which are paired at each spinal level for a total of 32 pairs. The nerve fibers are directed to various parts of the body. The end of the spinal cord is tapered and is called the conus medullaris from which a thread continues to the filum terminale. These structures are surrounded by the roots of the caudal spinal nerves and together are termed the cauda equina. The nerve roots each leave the vertebral canal through an intervertebral foramen and the nerve roots in the cauda equina diminish toward the farthest end of the spinal canal. The nerve roots in the cauda equina go to the lower extremities, bowel and bladder. Many disease processes and injuries present as bowel and/or bladder dysfunction and pain in the lower extremities. Spinal nerves have both motor and sensory fibers.95 The area of the skin innervated by the sensory fibers of a certain root is known as the dermatome. The dermatomes are named according to the spinal nerve, which supplies them. If there is a loss of nerve function, the skin, which it supplies, is not usually completely numb because adjacent spinal nerves also provide innervation to the area. The thecal sac is a protective membrane that covers the spinal cord and cauda equina and contains cerebrospinal fluid, which provides nutrients to the spinal cord.95 The membrane is composed of several layers: the outermost is the dura mater, the middle layer is the arachnoid mater and the inner layer is called the pia mater. The thecal sac is separated from the wall of the vertebral canal by the epidural space, which contains epidural fat.95

The Muscles The muscles and ligaments in the spine function to hold the spine upright and to allow forward bending (flexion) and backward bending (extension) as well as rotation from side to side and combinations of these movements.93 Muscles in the cervical spine area contribute to motion and stability of the neck.

117 The trapezius muscle covers the upper and back part of the neck and shoulders while the scalene muscles lie deeper in the neck serving to allow flexion and rotation of the cervical spine. The muscles of the lumbar spine region act in various combinations to allow flexion, extension, lateral flexion and rotation of the torso. The motion aspect of the spinal column results from a combination of both bony and soft tissue structures. The motion segment is composed of two adjacent vertebral bodies, the zygapophyseal joint created by their articular processes, the intervertebral disc between them and the associated soft tissue structures already mentioned.93 The intervertebral discs and the zygapophyseal joints allow for motion in flexion, extension, side bending and rotation at the level of the motion segment. The lower portion of the spine bears most of the body’s weight and allows the greatest amount of motion. The lumbar spine segment allows motion within a restrained range and provides stability. Lateral bending occurs mostly in the upper lumbar motion segment. As individuals age, flexibility of the spine is gradually lost. This is due primarily to the loss of water content and diminishing size of the nucleus pulposus. The load borne by the annulus fibrosus subsequently increases and is subject to weakening and tearing. Resistance to loading is diminished, and motion of the functional spinal unit changes. Disc degeneration is the term used to describe these changes, which includes decreased disc height, irregular bony endplates and osteophyte (bone spur) formation. Disc degeneration and the accompanying changes in soft tissues and bone results in increased instability of the vertebral column and decreased motion. Disc degeneration and disc space narrowing in the lumbar spine area forces the lumbar facet joints to bear increased loads and likely leads to early degenerative changes.

Developmental Changes to the Spine Abnormal vertebral configurations may be congenital or result from disease or trauma-specific actions on the spine. Figure 14, provides a brief list of the more common congenital and acquired abnormal changes to the body of a vertebra.

118 The body of a vertebra develops from the cells of the sclerotome, a derivative of the notochord.96 Development is complete by the 12th week of gestation and any deviation in the normal development of the body of a vertebra can lead to congenital anomalies.96 Developmental malformations of the body of a vertebra are often associated with congenital anomalies of the genitourinary, gastrointestinal, and central nervous systems.96 Examples of these include asomia, hemivertebra, coronal cleft, butterfly vertebra, block vertebra, and hypoplastic vertebra.

Asomia Abnormal size (small/enlarged) Hemivertebra Border Abnormalities  Anterior/posterior scalloping  Anterior border straightening  Endplate deformities Coronal cleft Vertebral tongues, spurs/beaks Butterfly vertebra Miscellaneous body shapes Block vertebra Hypoplasia

Fig. 14. Common Congenital and Acquired Abnormal Changes to the Body of a Vertebra. Adapted from The Vertebral Body: Radiographic Configurations in Various Congenital and Acquired Disorders. Kumar, R., Guinto, FC, Madewell, JE., et al. RadioGraphics Volume 8, Number 3. May 1988.

Asomia is the complete absence of the body of a vertebra due to failure of ossification centers to develop. In this anomaly, the posterior elements may still be present and may involve more than one vertebral segment. Among the congenital vertebral anomalies, hemivertebrae are the most likely to cause neurologic problems. Hemivertebrae are wedge shaped vertebrae, and therefore may cause kyphosis, scoliosis, and lordosis. When one-half of a vertebral body fails to ossify, a unilateral wedge vertebra, either right or left hemivertebra may occur. If the dorsal or ventral half of a vertebral body fails to ossify, a dorsal or ventral hemivertebrae may result. The most common location of dorsal hemivertebra is the midthoracic vertebrae, especially at thoracic 8. A coronal cleft results when fusion of the anterior and posterior ossification centers remains separated by a cartilage plate.96 The deformity is

119 more common in premature male infants and may occur in infants with congenital chondrodystrophic calcificans. Butterfly vertebra has a cleft through the body of the vertebrae and a funnel shape at the ends giving the appearance of a butterfly. It results when there is a failure in the fusion of the lateral halves of the vertebral body. This results in the persistence of notochordal tissue between them. Anterior spinal bifida, with or without anterior meningocele may be associated with a butterfly vertebra.96 A block vertebra can occur when there is improper segmentation of the vertebrae, leading to parts of or the entire vertebrae being fused. A failure in the process of segmentation during fetal life is thought to cause this condition, also referred to as a congenital vertebral fusion. In the congenital type, the fusion usually occurs in the lumbar and cervical portion of the spine. The intravertebral foramina of block vertebrae take on an ovoid and narrowed dimension. A hypoplastic vertebra is usually caused by vascular insufficiency during fetal development and may affect one or more vertebrae.96 Intraosseous notochord remnant is commonly an incidental imaging finding.96 The notochord is an embryologic structural organizer and inducer of chondrification and segmentation of the mesenchymal elements.96 This normally regresses during fetal development and contributes to the formation of the intervertebral disc nucleus pulposus; however, remnants can give rise to chordomas.96 Acquired vertebral body abnormalities can result from trauma, infection, and tumor. Various conditions also can cause radiographic variations in portions of the spine, with the vertebral body being the most affected. Small vertebral bodies are linked to radiation-induced vertebral hypoplasia often resulting from irradiation of the spine during early childhood.97 Osteoporosis and vertebral collapse in adults has been reported following radiation exposure to the vertebral spine.97 Small vertebrae are evident in juvenile rheumatoid arthritis and Gaucher’s disease (i.e., the most common of the lysosomal storage disorders).97 Flattened small vertebral bodies are also evident in a number of other diseases and conditions such as achondroplasia, mucopolysaccharidosis, osteopetrosis, neurofibromatosis, and osteogenesis imperfecta. An extreme flattening or hypoplastic vertebral body is seen in a thanatophoric dwarfism, which is a rare condition.97 Many of these conditions result in bone loss.

120 Enlarged vertebral bodies are commonly seen in Paget’s disease, which causes an enlargement in all dimensions. Gigantism and myositis ossificans progressiva is also associated with enlargement of the vertebral bodies. Abnormalities can affect any border of a vertebral body, including the endplates. Pulsatile pressure from an aortic aneurysm has been attributed to anterior border scalloping; however, many pathological conditions can cause these abnormalities. Neurofibromatosis, acromegaly, achondroplasia, and ependymoma are associated with marked scalloping of the posterior borders of the vertebral bodies. Any benign mass that lies in close proximity to either side of the vertebral column may cause indentations along the lateral borders of the vertebral bodies. Anterior border straightening produces a “square” or “box-like” vertebral abnormality.93 Straightening may be caused by bony erosions at the anterior corners of the body resulting in loss of the normal concavity of the anterior vertebral surface and is most easily seen in the lumbar spine. Endplate abnormalities occurs in many diseases and conditions and is seen as a compression of one or more vertebral bodies with decrease in vertebral height resulting in wedge-shaped, flat or biconcave vertebral bodies.93 The specific radiographic appearance of the vertebral body help identify certain disease processes. For example, in sickle cell disease spine images demonstrate a characteristic step-like central depression of the vertebral endplates. German pathologist Christian George Schmorl (1861-1932) was the first to describe protrusions into adjacent vertebral bodies associated with adolescent kyphosis. The term Schmorl’s nodes have since been applied to all such defects. A Schmorl’s node is a contour defect in the endplate of a vertebra resulting from central herniation of a portion of the disc into the adjacent vertebral body. The importance of abnormally persisting endplate deformities is that they promote early and advanced disc degeneration. There are different kinds of endplate deformities including:  Vascular channel defects (referred to as “limbus” vertebrae), are related to weaknesses left by a vascular channel;  Centrum abnormalities occur between the centrum and ring apophysis; and,

121  Notochord endplate defects, when prominent, impair diffusion and convection of nutrients to the disc across the endplate and thus promote disc degeneration.

A limbus vertebra is a distinct type of disc herniation in which there is intraosseous penetration of disc material at the junction of the endplate with the bony rim of a vertebral body. This most commonly occurs at the anteriosuperior corner of a single lumbar vertebra. A “ring” epiphysis appearing around the superior and inferior margins of a vertebral body is seen as small, step-like recesses at the corners of the anterior edges of vertebral bodies. Vertebral tongues, beaks, and spurs are bony projections that may occur along the vertebral margins and cause specific contour deviations in the vertebral bodies.96 For example, in Hurler’s syndrome, also referred to as gargoylism, Hunter’s syndrome, and Morquio’s disease the lower half of the kyphotic curve projects anteriorly in a tongue-like appearance affecting the body of thoracic 12, lumbar 1 or lumbar 2.96 Osteophytes, which result from reactive bone formation, can be visualized along the spine as beaks and spurs. Osteophytes occur when the outer annular (Sharpey’s) fibers are sheared and ruptured causing disc herniation. Osteophytes are most commonly seen along the anterior and lateral aspects of the vertebral bodies and rarely seen in the posterior aspect. A Rugger-Jersey appearance of the spine resembles a sandwich or hamburger and occurs when a zone of sclerosis alternates with a radiolucent band through the centers of the vertebral bodies and the radiolucent disc spaces. This results when sclerotic vertebral endplates alternate with the radiolucent regions of the disc spaces and the mid-portion of the vertebral bodies. An accordion or corduroy appearance of the spine results from thickening of the bony trabeculae in the vertebral body. A bone-within-bone appearance of vertebrae also known as ghost vertebra occurs following a stressful event during vertebral growth in childhood. An appearance of a “Napoleon” hat in the vertebral spine represents a grade IV spondylolisthesis of L5 and S1. A bamboo appearing spine represents bilateral symmetrical syndesmophytes that occur because of ossification of the annulus fibrosis.

122 A syndesmophyte is a bony growth originating inside a ligament in the spine and is pathologically similar to an osteophyte.

Radiation, as a curative, adjuvant, and palliative therapy is used for a wide range of malignant conditions; however, has the potential to render as much harm as benefit. Radiation-induced changes occur and are evident as bone growth disturbances in the immature axial or appendicular skeleton.97 Complications in the mature skeleton include osteoradionecrosis, pathologic fracture, and radiation-induced neoplasms.97 In osteoradionecrosis of the spine, elements of the marrow are replaced with fat. Radiation-induced osteochondromas are radiographically identical to those that arise spontaneously.97 Demonstrable radiation-induced changes in bone depend on the age of the patient, absorbed dose, size of the radiation field, beam energy, and fractionation.97 Radiation-induced growth disturbances are greater in younger patients for any given dose and its effects in both growing bone and mature bone and are dose dependent.20 With radiation doses of 2000 – 3000 centiGray (cGy), irreversible scalloping and irregularity of the vertebral endplate associated with decreased vertebral body height often occurs.97 Scoliosis convex to the side opposite the radiation port results from asymmetric vertebral growth changes and fibrosis of the adjacent muscle.20 Scoliotic changes are dose related and most severe in those irradiated before the age of 2 years.20 The spine is often irradiated for palliation in those with metastatic disease or myeloma and radiation-induced changes may not be visible on plain radiography.97 As early as two months after radiation therapy, bone changes manifest as sharp demarcation at the edge of the radiation port and may be best demonstrated with bone scanning and MRI.20 Pelvic irradiation is a common predisposing factor for sacral insufficiency fractures.97

Summary and Topographical Landmarks There are many important features that distinguish each segment of the vertebral column. A few of the more important distinctive characteristics are included in Figure 15.

123 Vertebra Important Feature C1, Atlas No body but has an anterior arch C2, Axis Contains the dens C1-C6 Has short spinous processes with bifid tips C7 Called the vertebra prominens because of its long spinous process T1-T10 Contain facets on the transverse processes or rib articulations T1-T9 Contain demifacets for rib articulations T10-T12 Contain a single facet for rib articulations Fig. 15. Important features of the vertebral column.

The technologist must often be guided by external or topographic landmarks to locate various internal structures of the vertebral column when positioning the patient for imaging examinations. A few of the most important topographic landmarks concerning the vertebral spine are listed in Figure 16.

Landmark Corresponding level in the Vertebral Column Mastoid tip C1 Gonion C3 (When the head is in a neutral position) Thyroid cartilage C5 Vertebra prominens C7 Jugular notch T2 and T3 Sternal angle T4-5 Xiphoid process T9-10 Inferior rib margin L2-3 ASIS S1-2 (anterior superior iliac spine) Greater trochanter Distal coccyx Fig. 16. Topographic landmarks and corresponding level in the vertebral column.

A non-vertebral fracture is also a major risk factor for vertebral and new nonvertebral fracture. Measurements that have been shown to enhance the predictive value over and above BMD are age, family history of fracture, markers of bone resorption, hip geometry, fall risks, quantitative ultrasonographic findings, self-reported poor health, and poor mobility. Although fractures of the upper arm, pelvis, and some other sites are more common in the elderly, the fractures most closely associated with bone disease are those of the hip (proximal femur), spine (vertebrae), and wrist (distal forearm).1 The annual incidence of hip fractures increases dramatically with age, from just 2 fractures per 100,000 among Caucasian women under age 35 to over 3,000 fractures per 100,000 among Caucasian women age 85 and older.1

124 Hip Fractures The lower limb is comprised of the foot, leg, femur and bones of the hip. The femur is the longest and strongest bone in the entire body. The entire weight of the body is transferred through this bone and the associated joints at each end. These joints are a frequent source of pathology when trauma occurs and are also commonly affected by bone loss diseases. Each hipbone is comprised of three divisions: (1) ilium, (2) ischium, and (3) pubis. In a child, these 3 divisions are separate bones, but they fuse into one bone during the middle teens. The fusion occurs in the area of the acetabulum, a deep, cup-shaped cavity that accepts the head of the femur to form the hip joint. The ilium is the largest of the 3 divisions and is located superior to the acetabulum. The ischium is inferior and posterior to the acetabulum, while the pubis is inferior and anterior. Fracture of long bones generally occurs due to substantial trauma, and males are more frequently affected than females.98 In these cases, it is the magnitude of trauma rather than deficient bone strength. In the elderly, low bone mass is the critical factor, with most fractures occurring with minimal force. There are also age-related increases in fractures of other bones, such as the humerus, pelvis, and ribs. The majority of deaths after hip fracture are due to pre-existing comorbidity, such as ischemic heart disease, with the majority a direct result of complications or management of the fracture itself.98 There is an exponential increase in hip fracture with aging due to age- related increase in the risk of falling and reduction in bone strength.98 The majority of hip fractures occur after a fall from standing height or lower. Hip fractures are more frequent among Caucasians than among non-Caucasians and is explained by the higher bone mass observed in African Americans compared to Caucasians.75 Hip fractures are seasonal, occurring more frequently in both sexes during the winter in temperate countries. Falls occurring indoors is the major cause of hip fractures. The age-adjusted male to female incidence ratio for hip fracture is about 1:2.75 Women have an expected longer lifetime longevity and approximately 80% of hip fractures occur in women.31 Men; however, especially older men are subject to hip fracture. Approximately 20% of the total health care costs of osteoporosis can be attributed to fracture in men.

125 The lifetime risk of sustaining a nontraumatic fracture in a 60-year-old male is approximately 25%.31 The greatest incidence of osteoporotic fracture in men occur in the elderly, with the average age of hip fracture being about 80 years.31 There is a rapid increase in vertebral and hip fracture in men beginning at about age 65-70 years.31 Two-thirds of men presenting with osteoprosis fracture will have identifiable causes of metabolic bone disease with one-third being idiopathic. The common causes of secondary osteoporsis in men are glucocorticoid treatment, alcohol excess, and hypogonadism. Life expectancy is increasing around the globe and the number of elderly individuals is rising in every geographical region. The world population is expected to rise from its current 323 million individuals aged 65 years and older to 1555 million by the year 2050.75 These demographic changes alone can be expected to increase the number of hip fractures occurring. The total number of hip fractures is expected to rise three-fold by 2050 as Americans over age 65 increases to 69 million in 2050.75

Fractures of the Acetabulum Imaging analysis of trauma to the hip and pelvic area now routinely includes computed tomography (CT) and frequently 2-dimensional CT and multiplanar reformatting. CT provides information regarding the extent of the injury and is complementary to conventional radiography for determining the spatial arrangement of fracture fragments. The goal of imaging is the precise preoperative understanding of the fracture pattern and the locations of the resultant fragments. This information helps in planning the surgical approach and ultimate treatment. The Judet and Letournel system is the most widely accepted method for acetabular fractures. The system is based on multiple plain radiographs that provide interrelation with clinical management to define a particular surgical approach. The Judet and Letournel system divides acetabular fractures into 2 broad categories, elementary and associated. Elementary fractures consist of injuries to one structural component of the acetabulum or it’s supporting structures. The second major category called “associated” fractures represents combinations of the elementary types. The frequency of acetabular fractures is listed in Figure 17.

126 Elementary Fractures  27% Posterior wall  9% Transverse anterior  5% Posterior column  2% Anterior wall

Associated Fractures 20% Transverse & posterior wall 19% Both columns 6% T shaped 5% Anterior wall & posterior hemi-transverse 3% Posterior column & posterior wall

Fig. 17. Judet and Letournel classification and frequency of elementary and associated fractures.

Adult chronic hip pain may elude clinicians both clinically and radiographically.100 Subtle radiographic signs have been documented that indicate traumatic, infectious, arthritic, neoplastic, congenital, or other causes. For example, stress fractures appear as a lucent line surrounded by sclerosis or as subtle lucency.100 Subtle femoral neck angulation, trabecular angulation, or a subcapital impaction line indicates an insufficiency fracture.100 Apophyseal avulsion fractures appear as a subtle, disk-shaped opacity. Effusion, cartilage loss, and cortical bone destruction are diagnostic of a septic hip.100 Transient osteoporosis manifests as osteoporosis and effusion.100 Subtle osteophytes or erosive change is indicative of arthropathy. Rheumatoid arthritis may manifest as classic osteopenia, uniform cartilage loss, and erosive change. Osteoarthritis may result in cyst formation, small osteophytes or buttressing of the femoral neck. Transient osteoporosis is a process in which peri-articular osteoporosis occurs, with cartilage remaining intact. Transient osteoporosis manifests on a bone scan as increased uptake and abnormal signal intensity on MR images.100 Magnetic resonance imaging (MRI) has been used to evaluate a variety of hip disorders, particularly the evaluation of avascular necrosis.101 Glucocorticoid therapy can cause aseptic (avacsular) necrosis, most commonly in the femoral neck, distal femur, and proximal humerus and is dose dependent. It also has an effect on muscle tissue. MRI is valuable in the evaluation of hip disorders because it provides assessment of articular structures, extra-articular soft tissues, and the osseous structures that can be affected by hip disease.101 Individual patient clinical findings help determine the examination protocol. Some of the issues determining MR imaging protocol include:

127  Distribution of disease (unilateral or bilateral);  Location of the disease (intra-or extra-articular); and,  Type of disorder suspected )i.e., infection, neoplastic).101

The MRI protocols options that should be considered in imaging each patient for hip examination include:  Receiver coil selection;  Pulse sequence selection (spin-echo);  Gradient-echo;  Inversion-recovery techniques;  Image acquisition planes; and  Need for intravenous administration of contrast material. 101

The usual protocol for MRI of the adult hip is a T1-weighted SE coronal image with a body coil to assess both hips and to serve as a guide for subsequent sequences.101 This method may also be useful in those with bilateral abnormalities or when contralateral comparisons may be required. A surface coil or a small field-of-view body coil may be indicated when unilateral or intra- articular abnormalities are suspected.101 There are several indications and limitations of the various MR imaging planes. The true coronal and axial planes provide the benefit of symmetric, bilateral images, which can be helpful when evaluating both hips.101 The intertrochanteric region is best demonstrated on images acquired in the coronal plane.101 Axial MR images provide good image detail of the articular space, hip musculature, and supporting ligaments. One disadvantage is that the oblique orientation of the femur at the level of the hip in the orthogonal coronal, axial, and sagittal planes, do not depict the femoral neck and the relationship of the femoral head and neck.101 Insufficiency fractures occur when a normal stress breaks a bone that is abnormal and deficient of elasticity. Some causes of reduced bone elasticity include bone diseases, metabolic disorders, and inflammatory conditions. Insufficiency fractures are considered a subgroup of stress fractures. Stress fractures are defined as fractures produced as a result of repetitive, prolonged

128 muscular action on bone that has not accommodated itself to such action. Unlike fatigue fractures, (another subgroup of stress fractures), which occur when normal bone is subjected to excessive repetitive stress, insufficiency fractures may occur from the effects of normal or physiologic stress on abnormally weakened bone. Insufficiency fractures frequently occur in the calcaneus, tibia, fibula, and thoracic vertebra. Insufficiency fractures of the pelvis are being increasing recognized as a major cause of low back pain in elderly women with osteoporosis.102 Insufficiency fractures of the pelvis have been increasingly recognized as a major cause of low back, buttock, and groin pain in elderly patients.102 The most common cause of insufficiency fractures is osteoporosis with the majority of those affected being elderly women with post-menopausal osteopenia.102 Additional reported risk factors include rheumatoid arthritis, fibrous dysplasia, Paget disease, osteogenesis imperfecta, osteopetrosis, metabolic bone disease (i.e., osteomalacia and hyperparathroidism).102 Prolonged corticosteroid treatment and pelvic irradiation have also been indicated as addition risk factors for insufficiency fractures of the pelvis.102 The clinical presenting symptoms of pelvic insufficiency fractures include severe low back, buttock or groin pain. Most of those affected do not recall a major traumatic event but report pain so severe as to interfere with walking. The sacral ala, parasymphyseal region of the os pubis, pubic rami, supar-acetabular region, and the superomedial portions of the ilium are the most frequently reported sites of pelvic insufficiency fractures. Parasymphyseal and pubic rim fracture may occur in isolation or in combination with sacral insufficiency fracture.102 Clinically, pelvic insufficiency fractures are often difficult to diagnosis. On conventional radiography, pelvic insufficiency fractures are classified as either occult or aggressive. Occult fractures are those that occur in the sacrum and less commonly in the supra-acetabulum or ilium.102 These occult fractures may radiographically be seen as sclerotic bands, cortical disruptions, or even fracture lines.102 Conventional radiography often fails to disclose pelvic insufficiency fractures because of overshadowing structures.102 The radiographic appearance of aggressive pelvic insufficiency fractures depends on the stage of fracture at the time imaging is performed and the healing progress or delay in healing.102

129 When healing is prolonged or delayed increased lysis and bone fragments may be present. Often multiple imaging modalities must be used to adequately diagnose both occult and aggressive pelvic insufficiency fractures.102 Bone scintigraphy is the most sensitive imaging modality for the detection of occult pelvic insufficiency fractures. Computed tomography (CT) may be helpful in confirming the presence of fractures in cases with atypical scintigraphic patterns. CT has also demonstrated value in illustrating parasymphyseal and pubic rami abnormalities and fractures. CT is the most accurate imaging modality for detecting sacral insufficiency fractures especially vertical fractures of the sacrum. Axial CT, with use of both bone and soft-tissue windows with maximum 10 mm-section thickness of contiguous 10 mm intervals is performed through the sacrum or os pubic. Sacral insufficiency fractures are demonstrated on CT images as sclerotic bands, linear fracture lines, or a combination of both within the sacral alae. MR imaging demonstrates insufficiency fractures of the sacrum as bands of decreased signal intensity on T1-weighted images. On T2- weighted and short inversion time inversion recovery (STIR) images, edema can be seen as areas of increased signal intensity that surrounds the fracture.

Wrist Fractures Wrist fractures tend to occur among younger individuals with osteoporosis, but these patients are at increased risk of a hip fracture later in life.1 The incidence of wrist fracture rises little with age among men, with most distal forearm fractures occurring in women.1 Fractures of the carpal bones are common, with an annual incidence of 159 per 100,000 in the United States.103 Scaphoid fractures account for 50% to 80% of all carpal bone fractures and is more common in young men. Because of the complexity of the carpal anatomy and the limitations of conventional radiography, many carpal fractures are not detected on initial interpretation.103 If a fracture is overlooked, often treatment is delayed, and this can lead to dysfunction in the mobility of the wrist. Computed tomography is frequently being used to find radiographically occult carpal fractures.103 The normal wrist anatomy consists of 8 carpal bones, which intricately articulate to form the carpus. The 8 carpal bones and their corresponding

130 ligaments are seen as 2 horizontal rows. The proximal carpal row consists of the scaphoid, lunate, and triquetrum. The pisiform does not belong to the proximal row but may act indirectly on the triquetrum. The proximal carpal row is located between the radius and the distal carpal row. The proximal carpal row is important in maintaining wrist stability by coordinating the movement and controlling forces transmitted from the hand to the forearm. The distal carpal row consists of the trapezium, trapezoid, capitate, and hamate. The distal carpal bones form a rigid transverse arch that is more stable than the proximal row. The blood supply to the carpal bones enters the distal half of the bones thus the increased risk for avascular necrosis if the bone suffers a fracture with disruption of blood flow. In the proximal carpal row the scaphoid bone is the most commonly fractured and is most frequently initially overlooked on conventional radiography.103 The scaphoid is the largest bone of the proximal carpal row resembling the shape of a boat (scaphion is Greek for boat). The scaphoid bone is a critical link between the proximal and distal carpal rows and acts as an intercalated segment between the lunate proximally and the trapezium and trapezoid distally. About 80% of the scaphoid surfaces are articular facets covered in articular cartilage.103 Because the surfaces of the scaphoid are covered in articular cartilage there is an increased risk of delayed union and nonunion of fractures. Avascular necrosis occurs in 13% to 50% of scaphoid fractures.103 The scaphoid is typically injured due to hyperextension which may result in complications such as progressive fragment displacement, avascular necrosis, malunion, delayed union, and nonunion.103 When fractures of the scaphoid bone are misdiagnosed, chronic wrist pain, loss of full mobility and early degenerative changes may occur. CT has an increasing role in the evaluation of suspected scaphoid fractures when conventional radiographs are negative. CT sensitivities and specificities for detecting scaphoid fractures are reported at 89%-97% and 85%-100%, respectively.103 A high negative predictive value of CT (96.8%-99%) makes it very useful for excluding a fracture.103 The lunate carpal bone is moon-shaped when viewed on a lateral radiographic image. It serves as the foundation of the proximal carpal row, sitting in the central position of the carpus. Fractures of the lunate bone usually occur

131 from direct axial compression from the head of the capitate driven into the lunate. Such fractures may result in carpal instability, nonunion, and avascular necrosis, if not promptly recognized and treated. Radiographically, an isolated lunate fracture is often obscure because of the overlapping of other carpal bones on lateral radiographs. CT has proven useful in illustrating lunate fractures and its associated injuries. Kienböck disease can occur when a lunate fracture fails to unite. Kienböck disease is an avascular necrosis of the lunate bone, occurring primarily in young adults. The precise etiology of Kienböck disease is unknown, but it has been linked to a traumatic event. Triquetral fractures are the second most common carpal bone fractured with a prevalence of 18.4%.103 A triquetral fracture usually results from impingement of the ulnar styloid process against the dorsal surface of the triquetrum during wrist hyperextension and ulnar deviation. Pisiform fractures are uncommon, accounting for 1.3% of all carpal fractures.103 The pisiform is a sesamoid bone enclosed within the flexor carpi ulnaris tendon and articulates with the triquetrum dorsally. Most pisiform fractures result from a fall on an outstretched hand, causing a direct blow to the pisiform. Pisiform fractures may be linear, comminuted, or chip-type with or without associated pisiform dislocation.103 Due to its close proximity to the ulnar nerve, fractures of the pisiform may cause ulnar nerve injury. In the distal carpal row, trapezium fractures account for 3%-5% of all carpal fractures.103 The trapezium is the most mobile bone of the distal carpal row. Trapezial ridge fractures may result from a direct blow to the volar surface of the trapezium or an avulsion injury. Conventional radiography carpal tunnel views may be helpful in detecting a trapezium fracture. CT may also be useful in identifying a fracture of the trapezium. The trapezoid is the least commonly fractured carpal bone.103 A trapezoid fracture is usually caused by a high-energy axial blow to the second metacarpal bone. Trapezoid fractures are most commonly associated with other carpal bone fractures. Conventional radiography of the wrist may demonstrate trapezoid fractures however CT may illustrate the degree of displacement and fractures of adjacent bones. The capitate is the largest of the carpal bones in the distal carpal row. The capitate bone has a rounded head that articulates with the scaphoid and

132 lunate bone and partially articulates with the hamate. Because the head of the capitate is covered almost completely with articular cartilage and has a limited vascular blood supply, it is at increased risk of prolonged healing and avascular necrosis. It is supported by palmar ligments and injuries to the capitate are usually due to a high-energy hyperextension blow. In the distal carpal row, fractures of the hamate bone account for 1.7% of all carpal bone fractures. 103 The hamate bone has a hook that is a prominent rounded projection at the palmar nonarticular surface. The hamate hook is a frequent site of fracture, mostly occuring in athletes participating in racket type sports. Hamate hook fractures generally result from direct compression of the handle of the racket against the protruding hook. The tip of the hamate hook serves as an attachment site for several flexor tendons, muscles, and ligaments and displacement of these due to trauma may result in delayed healing or nonhealing. Radiographic signs of a hamate hook fracture include absence of the hook in an acute displaced fracture or sclerosis in the area near the hook. A low energy fracture of the proximal humerus indicates osteoporosis and it is important to direct treatment to this group of patients who are at high risk for future fracture.104 It has been suggested that BMD measurement taken at the hip or lumbar spine may misrepresent the BMD in the upper limb. 104 Underestimation of BMD in the upper limb leads to osteoporosis and subsequent risk of fracture in the upper limb.

Rib Fractures Simple rib fractures are the most common injury sustained following blunt chest trauma, accounting for more than half of thoracic injuries from nonpenetrating trauma.105 The position of simple rib fractures in the thorax helps identify potential injury to underlying organs.8 Fracture of the left lower ribs is associated with splenic injuries, and fracture of the right lower ribs is associated with liver injuries.105 Fracture of the floating ribs (ribs, 11, 12) is often associated with renal injuries.105 First rib fractures were once thought to be an indicator of severe trauma, since the first rib is very well protected by the shoulder, lower neck, musculature, and clavicle, and was thought to require a much higher impact force to fracture than other ribs.105 This assumption is now in question; however, first rib fracture should raise suspicion of significant chest trauma.105

133 Tenderness on palpitation, crepitus, and chest wall deformity are common findings of rib fracture.105 Population studies suggest that rib fractures are associated with a reduction in bone mass.106 There is substantial evidence about the predictive risk of hip, spine, and distal forearm fracture or the risk of future fracture; however, little is known about the increased risk associated with rib fracture.106 The purpose of a select study of participants in the European Prospective Osteoporosis study (n= 6,344 men, with a mean age of 64.2 years, and 6,788 women, with a mean age of 64.6 years), was to establish data about the predictive risk of future fracture based on rib fracture.106 After adjustment for prevalent vertebral deformity and previous (non-rib) low trauma fractures, the data showed slightly reduced strength between the association of rib fracture and subsequent limb fracture.106 In men, after adjustment of the data, there was a small though non-significant association between recalled history of rib fracture and future fracture. The study data however highlighted the importance of rib fracture as a marker of bone fragility in women.106

134 Part 14 Imaging Modalities

Today, the availability of various imaging modalities provides excellent assistance in the identification of abnormalities and bone loss disease processes. Often several imaging modalities are used on the same patient during the assessment of BMD, detection of fractures, and depiction of skeletal structural deterioration. These modalities include dual energy x-ray absorptiometry (DXA), conventional radiography, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, and interventional and diagnostic procedures. DXA is considered the “gold standard” for BMD measurements. Conventional radiography, without contrast, is helpful for initial screening and diagnostic evaluation. CT is useful in identifying bony injury (i.e., fracture), extent of fracture, status of posterior elements, and the spinal canal. MRI is superior for the evaluation of the spinal cord and other soft tissues, muscles, and ligaments. Fluoroscopy, bone scintigraphy, and image guided interventional and diagnostic procedures are also useful in determining the presence of spine disease and injury and in the treatment of these. Bone densitometry, which will be addressed in Part 15, includes the use of:  Radiographic absorptiometry (RA);  Single-energy photon absorptiometry (SPA);  Dual-energy photon absorptiometry (DPA);  Single-energy x-ray absorptiometry (SXA);  Dual-energy x-ray absorptiometry (DXA);  Quantitative computed tomography (QCT); and,  Quantitative ultrasound (QUS).

Currently DXA, QCT, and QUS are the more commonly used imaging modalities. The SPA and DPA imaging modalities, which use radioactive sources instead of a x-ray tube, are no longer in clinical use.

The Medical Record and Documentation Results from clinical examinations, imaging procedures and prescribed treatment for bone loss diseases requires accurate documentation and often inter-communication between several medical specialties. The medical record,

135 health record, or medical chart is a systematic documentation of a patient’s medical history and care.107 Medical records are uniquely personal documents and there are many ethical and legal issues surrounding them, such as who has access to them and the proper storage and disposal of the records.108 The medical record allows communication among health care providers, and contains critical evidence of the type and quality of care provided to the patient.74 The 3 most recognized reasons for the medical record are:  To document the diagnosis, treatment and progress of the patient;  For business purposes; and,  To use as legal documents.

According to a recent article in Mayo Clinic Women’s HealthSource, electronic personal health records are likely to replace handwritten notes. During his presidency, Barack Obama has stated that he will make electronic medical records a priority.110 One of the major roadblocks is finding the right technology to handle the transition to paperless medical records. Among the many challenges are the storing, accessing, and updating of records so that the patient’s privacy is maintained yet the information is accessible across a wide network of medical providers. The medical record serves as the basis of the quality and timeliness of the care provided to the patient. The record also serves as a legal document and is often cited in malpractice litigation. In the first two-thirds of the 20th century, the most common reasons for malpractice were negligent acts of commission (i.e., physicians did something wrong).111 Medical care providers were often charged with the failure to order radiologic studies in a timely manner. The litigation involves what is referred to as “omission of care.” Defensive medicine, in which medical care providers ordered tests and procedures that were not indicated medically, but if absent might render the physician vulnerable in malpractice litigation, became the norm.111 The annual cost to the nation for defensive medicine has been estimated to range from $25 billion to $126 billion.111 Radiologists are subject to litigation for “failure to diagnose” and “failure to follow-up” or failure to obtain additional diagnostic studies to clarify or confirm the impression, when appropriate.111 It is anticipated that as the sophistication of

136 radiologic and nonradiologic procedures and tests continues to expand, the errors caused by physicians’ omission in ordering or using this technology will increase.111 Radiologists can expect to be increasingly sued not only for failure to recommend imaging tests, but for failure to recommend other diagnostic procedures as well.111 One may also speculate that in the not-so-distant future, radiologists will likely be subject to litigation for errors in omitting the use of technology that is not yet the standard of care, such as computer-assisted detection (CAD) and teleradiology to obtain expert consultations.111 Conscientious review of the patient’s medical history and clinical findings in conjunction with the radiography request is a first step in providing quality patient care, and hopefully reducing future litigation. The technologist plays a critical role in reviewing the patient’s medical history and clinical symptoms prior to performing an imaging examination. The technologist documents information in the patient’s medical record and is the liaison between the patient and the radiologist. Radiologists have a duty to acquaint themselves with the pertinent clinical information concerning patients whose images they will be interpreting. In many imaging centers, it is the technologist who questions the patient and completes a preprinted questionnaire form.112 If this is the procedure used, the technologist should have the patient or their advocate review, sign, and date the questionnaire form. Risk management experts recommend that a written form on which the patient must provide (i.e., write) pertinent clinical information is the most reliable source document.111,112 Although it is acceptable practice for the technologist to complete the information on the questionnaire form, there may be less likelihood of misunderstanding if the patient herself/himself fills out the form.111 The technologist can then go over the completed form and obtain additional verbal confirmation from the patient. If the patient fills out the form, the technologist should document that the completed questionnaire was reviewed and the answers confirmed by the patient. Such notations in the record should be signed and dated. A system that ensures that every patient undergoing imaging procedures provides a complete medical history, possible symptoms, and clinical signs is critical to obtaining high quality images. Risk management experts also suggest that the questionnaire form have a question about the patient’s understanding of

137 why she/he is having the imaging procedure. By asking these pertinent questions, the technologist will be able to determine if the imaging request properly matches the patient’s clinical signs and symptom. When taking the patient’s medical history or confirming what the patient has written, the technologist should be able to use the information about risk factors, and the “red-flag” indicators of disease processes previously covered in this course, to further question the patient.

Routine of the Imaging Examination Following a routine procedure can help prevent unnecessary mistakes or omissions that may require a retake examination. Each technologist often adapts the routine procedure to fit individual patient circumstances, however, the following lists the basic routine steps in an imaging examination.  Request is received for the examination.  The request is reviewed to determine accuracy of information.  Patient arrives and is greeted and given necessary instructions.  The technologist prepares the examination room. -Reviews the request for examination. -Reviews prior imaging examinations, if applicable. -Determines the site to be scanned for BMD examinations of the anatomic area or part for other imaging modalities.  The technologist prepares the patient. -Confirms the patient’s identity. -Reviews the clinical history. -Explains the procedure to the patient. -Asks the patient to disrobe, if applicable. -Determines if the patient has followed imaging preparation instructions, if applicable.  Positions the patient. -Performs a scout image, if applicable to the imaging modality. -Conducts the scan or obtains the image. -Observes radiation protection procedures.  Assesses the image. -Image contains the patient’s identification.

138 -Image contains no artifacts or motion. -Determines if the scan or image must be repeated.  Dismisses the patient according to facility protocol.  Prints examination report, if applicable.

Conventional Radiography Imaging assessment is important to the prompt and accurate diagnosis of diseases and traumatic injuries related to bone loss and fractures. Often, the clinician selects a particular imaging modality based on the suspected disease process or injuries. Radiography, without contrast provides noninvasive imaging examinations and is usually the first choice in initial examinations for non-trauma cases. Image quality on conventional radiographs often suffers if the patient is overweight or obese due to limited penetrability and attenuation of the primary radiation beam. Excessive scatter radiation, which degrades the image, is also of primary concern. Inadequate image quality radiographs may also be compromised in those who are obtund (i.e., less than full mental capacity, as a result of a medical condition or trauma), uncooperative, unconscious and those receiving life support. Decisions regarding the appropriate selection of imaging modalities for trauma patients with possible spine injuries are quite controversial. Currently, the debate centers on the question of whether CT should be an integral part of the initial imaging examination of trauma victims. The greater detectability of fractures in spine trauma with the use of CT compared with conventional radiography has been well documented. Decisions regarding the choice of which imaging modality to use in general diagnosis of bone loss diseases and trauma care are often dictated by institutional polices and often restricted by availability of various equipment and the patient status, etc. In any case, radiographic examinations of the individuals with bone loss conditions and fractures should demonstrate the portion(s) or the area of clinical interest requested and should be repeated if the image quality is insufficient. Any prior imaging studies including CT, MRI, or nuclear medicine should be obtained, if possible, to provide additional correlation information for the radiologist.26 The American College of Radiology (ACR) provides guidelines to assist practitioners in providing appropriate radiologic care for patients; however, states

139 that “…the ultimate judgment regarding the propriety of any specific procedure or course of action must be made by the physician in light of all the circumstances presented”.26 According to the ACR, indications for conventional radiographs include, but are not limited to, the evaluation of:  Pain or limitation of motion;  Trauma (symptomatic or at risk patients);  Surgical planning;  Previous surgery;  Suspected malignancy;  Congenital anomalies;  Previously detected abnormality; and,  Alignment abnormalities.26

The ACR along with a panel of experts have published recommendations regarding appropriateness of imaging examinations of the various areas of the body based on several specific chief complaints. The complete ACR Appropriateness Criteria® is available from the National Guideline Clearinghouse’s website www.guideline.gov. In this guideline various radiologic examination procedures for specific chief complaints are given an appropriateness rating from 1 to 9 with 1 being least appropriate and 9 being most appropriate for the specific condition. These guidelines will be covered in greater detail concerning the appropriate imaging modalities to use when the clinical indication is osteoporosis or bone density.

Technical Considerations in Conventional Radiography: An Overview Conventional radiography has demonstrated value in the diagnosis and treatment of bone loss disease conditions and trauma and its consequences. The ultimate goal of any radiography examination is to provide diagnostic quality images for prompt and accurate interpretation. The following provides a review of the factors related to optimum image quality in conventional radiography. Radiographs provide images of specific anatomic areas of interest. To accomplish this goal, the selection of technical factors must provide proper penetration of the anatomic area. Penetrability refers to the ability of the x-ray beam to pass through tissues; whereas, attenuation is the reduction in x-ray

140 intensity that results from absorption and scattering of the x-rays. Attenuation is the product of absorption and occurs as x-rays travel through matter and interact resulting in scatter (i.e. Compton and photoelectric absorption). Each anatomic area of the body as well as its condition (i.e., disease and injury status) has unique characteristics that affect penetration and attenuation of the x-rays. The patient’s overall body size and musculature must be considered in the selection of technical factors. Overweight and obese patients have increased body thickness, which generally requires adaptation of the x-ray exposure factors. Also patients suffering trauma, pain, and altered states of consciousness may require modifications in technical factors. Increasing the current (milliamperage) and exposure time can improve image quality but also increases the overall radiation exposure to the patient and staff. Longer exposure times may allow patient motion (voluntary and involuntary). Any degree of patient motion, whether voluntary or involuntary causes artifacts and distortion of the image quality. The newest generation of x-ray systems offers boosted kilovoltage (kVp) and milliamperage (mA) needed to penetrate thicker layers of tissue without compromising fast exposure times. The following factors control the quantity and quality of the x-ray beam and the photographic and geometric properties of a diagnostic radiograph. The primary x-ray beam, also referred to as useful radiation and primary radiation, consists of the radiation emerging from the x-ray tube that has not interacted with an object. As the primary x-ray beam passes through anatomic tissue, it will lose some of its energy. This reduction in the energy of the primary x-ray beam is known as attenuation. When the primary x-ray beam interacts with anatomic tissues; absorption, scattering, and transmission occur. Less than 5% of the primary x-ray beam interacting with the anatomic tissue actually reaches the cassette or image receptor (IR). The central ray (CR) is representative of the radiation emerging off of the x-ray tube target at a right angle. The CR is intended to be projected perpendicular to both the anatomical part and the IR. Whenever the CR is not perpendicular, some degree of shape distortion will be evident on the radiographic image. Scatter radiation occurs during attenuation of the x-ray beam. Some of the photons in the primary x-ray beam are not absorbed, but instead they lose

141 energy during interactions with atoms in the anatomic tissue. This process is simply referred to as “scatter”. Scattered radiation provides no useful diagnostic information and needlessly increases the radiation exposure of both patient and staff and places an undesirable fog over the radiographic image. Scatter radiation can be minimized by limiting the primary x-ray beam field size to the size of the film; thus reducing the amount of tissue with which the x-rays interact, producing fewer scattered x-rays. Leakage radiation refers to x-rays that escape from the protective x-ray tube housing. The amount of permissible leakage radiation is usually dictated by state law and is a parameter that is measured during equipment safety inspections. X-Ray tube construction factors such as beam filtration, line focus principle, and anode heel effect also have an impact on the quantity and quality of the x-ray beam. Filtration affects both quality and the quantity of radiation in the primary x-ray beam. The x-rays that exit the x-ray tube are heterogenous or polyenergetic, consisting of low, medium, and high energy x-rays. The low x-ray energies are not strong enough to penetrate the anatomic part and are not useful in forming the image. These low energy x-rays only contribute to the patient radiation dose. Filtration installed within the x-ray tube attenuates or absorbs the low energy x-rays. Additional filtration may be added to increase the attenuation and absorption. Various components within the x-ray tube assembly (i.e., metal housing, oil insulation, etc.) also contribute to the attenuation of low-energy x- rays. The amount of total filtration that must be present in a diagnostic radiography tube is set by the United States government to ensure that patients receive minimum doses of radiation. Special filters, called compensating filters, can be added to the primary x-ray beam to alter its intensity. Such filters are usually employed when imaging anatomic areas that are non-uniform in composition and/or size. For example, a compensating filter may be useful in obtaining uniform density along the vertebral column. Line focus principle describes the relationship between the actual and effective focal spots in the x-ray tube. The actual focal spot size refers to the size of the area on the anode target that is struck by the electrons from the tube current. The actual focal spot is determined by the size of the filament producing the tube current (i.e., electron stream). The effective focal spot size refers to focal spot size as measured directly under the anode target. A large focal spot

142 has the advantage over a small focal spot by being able to withstand the heat generated by higher x-ray exposure ranges. However, a small focal spot produces an image that has the greatest geometric sharpness. To overcome this disadvantage, manufacturers have developed x-ray tubes having specific anode angle, typically ranging from 6 to 20 degrees. Based on the line focus principle, the amount of anode angle determines the size of the effective focal spot. Also based on the line focus principle, the smaller the anode angle, the smaller the effective focal spot; thus greater geometric sharpness in the image. Anode heel effect is a phenomenon that occurs because of the angle of the x-ray tube target. Because the target of the x-ray tube is angled, the emerging x-ray beam has greater intensity (number of x-rays) on the cathode side of the x-ray tube, with the intensity diminishing toward the anode side of the x-ray tube. The anode heel effect has a practical application when imaging anatomic areas that present different ranges in centimeter thickness. One such application is the thoracic spine, which has small vertebrae at the top and larger vertebrae at the lower or distal portion. The patient should be positioned with their head under the anode end of the x-ray tube so the more intense radiation (from cathode end of the x-ray tube) will be directed toward the larger sized areas of the vertebral spine. Diagnostic quality radiographs exhibit adequate photographic and geometric properties. The photographic properties of a radiograph are radiographic density and contrast and the geometric properties are recorded detail and distortion. The correct balance of these properties determines visibility of detail on the recorded image and overall image quality. The following is a brief review of these properties. Radiographic density is the amount of overall image blackness after processing. The controlling factors of density are milliamperage (mA) and exposure time. Milliamperage and exposure time control the quantity of radiation reaching the image receptor. There are many influencing factors and these include kilovoltage, distance, grids, film-screen speed, collimation, anatomic part, anode heel effect, reciprocity law, generator output, filtration, and film processing. Milliamperage (mA) is the unit of measurement for x-ray tube current. Tube current is the number of electrons flowing per unit of time between the cathode and anode. The quantity of electrons in the tube current is directly

143 proportional to the mA. If the mA increases, the quantity of electrons and the quantity of x-rays increase proportionally. The mA does not affect the quality, or energy of the x-rays produced. Selection of the mA exposure factor is under the direct control of the technologist. The quantity of radiation is proportional to the mA. For example, if the mA is doubled, then the quantity of radiation is doubled or increased by a factor of two. Exposure time determines the length of time that the x-ray tube produces x-rays. The exposure time determines the length of time that the tube current is allowed to flow from the cathode to anode. Selection of the exposure time is under the direct control of the technologist. Milliamperage and time when multiplied results in the factor referred to as milliamperage-seconds (mAs). Higher mAs result in more electrons flowing in the x-ray tube current from cathode to anode. The more electrons in the tube current, the more x-rays produced. The mAs affect only the quantity of x-rays produced. The mAs have no affect on the quality of the x-rays produced. Radiographic contrast is a major factor affecting visibility of recorded detail. Contrast is the degree of difference between adjacent densities and can be classified as either high or low. High contrast means that in the visible image there are few densities but great differences or shades among them. High contrast is also referred to as short-scale contrast. Low contrast means that in the visible image there are a large number of densities but little differences among them. Low contrast is also referred to as long-scale contrast. The controlling factor of contrast is kilovoltage. There are many influencing factors affecting contrast and these include grids, collimation, object-to image-receptor distance (OID), anatomic part, contrast media, and processing. A grid is a device that is placed between the patient and the cassette or image receptor (IR) to absorb scatter radiation exiting from the patient. A collimator is used to limit the primary x-ray beam to the area of clinical interest. Collimation of the primary radiation field size ultimately reduces the amount of scatter radiation. Whenever the quantity of scatter radiation can be reduced, the quality of the radiographic image improves. Scatter radiation is detrimental to the radiographic image quality. Excessive scatter radiation results in additional unwanted density and reduces contrast (brightness). By using a grid to absorb scatter radiation before it reaches the cassette or IR, its affects on image quality

144 can be minimized. The amount of scatter that exits from the patient increases as kVp increases. Restriction of the primary x-ray beam limits the size of the area exposed and ultimately reduces the amount of scatter radiation produced. Kilovoltage (kVp) is under the direct control of the technologist. The penetrability and quality of the primary x-ray beam is controlled by the selection of the kVp range. The higher the kVp, the greater the penetrating ability of the primary x-ray beam. The primary x-ray beam intensity is directly proportional to the kVp. If the kVp is doubled, the intensity increases by a factor of four. This means that by increasing the kVp, the quantity of radiation can be increased. Increasing kVp by 15% (i.e., the 15% rule), is comparable to doubling the mAs and may be used as a guideline when kVp adjustments are required. Higher kVp ranges result in a decrease in the patient’s radiation dose. Source to image distance (SID) is under the direct control of the technologist. The quantity of radiation is affected by the inverse square law, which states that the intensity (quantity) is inversely proportional to the square of the distance. SID has an affect on both photographic and geometric properties. The ultimate goal of any radiographic procedure is to produce a diagnostic radiograph, which accurately projects the anatomy on the image. Geometric properties are those factors that affect recorded detail and distortion. Recorded detail refers to the sharpness of the structural lines that make up the recorded detail. During the x-ray exposure, any motion of the x-ray tube, patient, part, or image receptor decreases recorded detail. Factors controlling recorded detail include penumbra (geometric unsharpness), image receptor system speed, and motion unsharpness. Factors influencing recorded detail include focal spot size, SID, OID, screen phosphor crystal size and phosphor layer thickness, screen reflective layer, film emulsion crystal size, crossover, screen-film contact and motion. Distortion refers to the radiographic misrepresentation of either the size (magnification) or shape of the anatomic part. When the image is distorted, recorded detail is also reduced. As SID increases, size distortion (magnification) decreases; as SID decreases, size distortion increases. Elongation and foreshortening are shape distortions, which can be minimized by the proper central ray (CR) alignment (i.e., x-ray tube, part, image receptor, and CR entry or exit point).

145 Digital Radiography “Increasingly, medical imaging and patient information are being managed utilizing digital data during acquisition, transmission, storage, display, interpretation, and consultation. The management of these data during each of these operations may have an impact on the quality of patient care.”37 The American College of Radiology in the ACR Practice Guideline for Digital Radiography lists motivations for using digital radiography and several of these can be used to advantage in imaging the vertebral column.37 The ACR list of motivations includes:  Significantly larger range of x-ray intensities that can be imaged by digital receptors compared to analog systems;  Independence of displayed contrast from kVp setting through adjustment of the display window width;  Independence of displayed brightness from mAs setting through adjustment of the display window level;  The availability of image processing and computer aided detection (CAD) and diagnosis algorithms for image enhancement and analysis;  Easier and more reliable generation of accurately labeled and identified image data;  The ability to electronically transmit data to an appropriate storage medium from which it can be electronically retrieved for display for formal interpretation, review, and consultation; and,  The ability to transmit data to remote sites for consultation, review, or formal interpretation.37

The ACR states that the components necessary for the performance of high-quality digital radiography should include, but are not limited to:  Development of validated imaging protocols so that consistency of image quality and radiation dose can be established and maintained between rooms and between sites;  Utilization of appropriate compression of image data to facilitate transmission or storage, without loss of clinically significant information;  Archiving of data to maintain accurate patient medical records in a form that may be retrieved in a timely fashion;

146  The ability to retrieve data from available prior imaging studies to be displayed for comparison with a current study;  The ability to apply image processing for better display of acquired information;  Adherence to applicable facility, state, and federal regulations;  Maintenance of patient confidentiality;  Minimization of the occurrence of poor image quality;  Minimization of the delivery of inappropriate ionizing radiation dose to the patient; and,  Promotion of clinical efficiency and continuous quality improvement.37

The greatest advantage of digital radiography is that the steps of recording, displaying, and archiving an image are decoupled, providing the radiologist and radiographer the opportunity to optimize each task independently. In addition, the ability to display, archive, and transmit digital images may facilitate:  Teleradiology: Transmission of digital images to remote sites for purposes of off-site monitoring of diagnostic work-ups, interpretation, consultation, and conferencing;  Computer-aided detection and diagnostic assistance to radiologists;  Reduction in the number of repeats for technical reasons;  More efficient storage and retrieval of images; and,  Interventional techniques.

Teleradiology Teleradiology consists of one or more digital imaging units linked by a network or common line to one or more remote display workstations. Provisions such as data encryption and authentication must be provided to ensure confidentiality. Transmission time can be reduced by image compression and may not be the only bottleneck in the teleradiology system. Teleradiology has been credited with allowing interpretation of images by radiologists with the greatest expertise to be conducted. This is an especially important benefit of teleradiology particularly in under served rural areas where an experienced radiologist may be not available. The process has also proven

147 beneficial when a second reader opinion is required on certain cases. Consultation on difficult cases with experts anywhere in the world or within an organization allows improved and efficient communication among radiologists, surgeons, and oncologists. There are dramatic differences among digital systems in the areas of imaging performance, patient radiation dose, workflow and long-term costs. These and other advantages have been promoted as being superior in comparison to screen film imaging. Digital imaging has overcome the negative criticism of early skeptics and may prove to be a powerful tool in the battle to provide early diagnosis and treatment of diseases. As with any new technology, the advantages and disadvantages and any shortcomings will have to be considered and addressed before imaging facilities transition to digital imaging

Computer Aided Diagnosis (CAD) Early and accurate evaluation of bone loss conditions and related fractures is important for optimizing therapy and improving prognosis.51 Computer aided diagnosis (CAD) or second reader is currently available in applications such as CT and conventional radiography; however development of CAD for MRI has proven to be a more complicated process than that of CT because of intensity in-homogeneity problems and higher noise levels. CAD is defined as a diagnosis made by a radiologist who considers the output of a computer analysis of the image when making an interpretation. With CAD, radiologists use the computer output as a “second opinion” but make the final decision.51,52,53 CAD is a concept established by taking into account equally the roles of physicians, whereas automated computer diagnosis is a concept based on computer algorithms only.53 CAD is a technical method for the automated detection of lesions and various pathologies. With CAD, the performance by computers does not have to be comparable to or better than that by physicians, but needs to be complementary to that by physicians.53 The radiologist interprets and analyzes the image findings and if necessary the patient is recalled for further work-up or the findings may be dismissed as insignificant.25 Suboptimal quality images result in poor CAD output. CAD has the potential to increase detection of cancer; however, it is the radiologist’s knowledge and interpretive skill that determines the final decision.53

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Computed Tomography The use of computed tomography (CT) in the detection of spine fractures has been well documented and is considered the “gold standard” of imaging modalities when multi-trauma victims must be evaluated in life-threatening situations.113 For the initial evaluation of spinal disorders, depending on the nature of the disorder, CT may be the primary modality used or it may complement other modalities such as conventional radiography, MRI, or bone scintigraphy.113 CT scanning provides exacting bone detail and may be performed with a sequential single-slice technique or with single or multidetector helical protocol.113 For CT of the spine, contiguous or overlapping axial slices with an optimal slice thickness, depending on the spinal segment of interest, are preferred.113 CT examinations of the spine may include a series of mulitplanar reformations; such as sagittal and coronal reformations, which are extremely helpful in assessment of the spine.113

History of CT Computed tomography originally known as computed axial tomography employs tomography and digital geometry processing to generate 3-dimensional images of the internals of an object. The final images are created from a large series of images by a single axis of rotation. The discovery of CT is considered to be the greatest innovation in the field of radiology since the discovery of x-rays. CT provides ultimate clinical information in the detection and differentiation of disease. In the examination a volume of data is produced, which can be manipulated, through a process known as windowing, in order to demonstrate various structures based on their ability to attenuate x-rays. In 1979, Godfrey Newbold Hounsfield and Allan McLeod Cormack were awarded the Nobel Prize in medicine for the invention of CT. Hounsfield conceived the first commercially viable CT scanner in Hayes, England (1967) at Thorn EMI Central Research Laboratories while Cormack was also independently working on the concept at Tufts University. The first scanner was installed at the Mayo Clinic in the United States CT provides excellent visualization of anatomic details even in the most obese patients.114 CT does have some limitations, including increased noise due

149 to inadequate beam penetration, limited field of view, which can result in beam- hardening artifacts in areas where the patient’s body exceeds the size of the field of view; and image quality limitations because of image cropping.114 After a CT study is acquired, the technologist may crop the images to focus on internal organ structures at the expense of subcutaneous tissues. Due to the availability of several different types of CT scanners from different manufacturers, as well as the rapid evolution of the technology, the ACR recommends that technologists use the manufacturer’s recommendations with respect to image acquisition in order to optimize spatial and contrast resolution. The ACR provides minimal recommendations in regard to CT imaging of the spine to include.  Cervical spine evaluation of the craniocervical junction and cervical spine requires thin sections for definitive diagnosis. The effective slice thickness should be no greater than 3 mm; and,  Thoracic and lumbar spine evaluation requires effective slice thickness of no greater than 3 mm. Diagnostic reformation can be made from these images. The field of view should always be as small as appropriate to improve geometric resolution. For evaluating spine fusion, 1-2 mm contiguous slices of the suspected spinal segment will allow a greater degree of certainty in detecting pseudoarthrosis. Reformations may be helpful for detecting solid or failed fusion.58

Magnetic Resonance Imaging Felix Bloch of Stanford University and Edward Purcell of Harvard University made the first successful nuclear magnetic resonance experiment to study chemical compounds in 1956. Dr Bloch and Dr. Purcell were awarded the Nobel Prize for Physics in 1964. In the early 1980s, the first “human” magnetic resonance imaging scanners became available, producing images of the inside of the body. Current MRI scanners produce highly detailed 2-dimensional and 3- dimensional images of the human anatomy. Magnetic resonance imaging (MRI) is primarily used in medical imaging to visualize the structure and function of the body.67 It provides detailed images of the body in any plane and has much greater soft tissue contrast than CT making it especially useful in neurological, musculoskeletal, cardiovascular, and

150 oncological imaging.68 As late as the early 1980s, the best way to evaluate the spine for disorders was with the use of invasive myelography. This procedure poses many severe risks including reactions to contrast agents, infection from the injection site, and radiation exposure. MR images provide high soft-tissue contrast and the multiplanar capabilities are superior to images acquired with myelography or myelographic CT examinations.67,68 MR imaging is one of the most useful imaging techniques to characterize spine infection, with documented sensitivity of 96%, and 92% specificity, making it more accurate than both plain radiographs and bone scans.67,68 MR imaging has standard protocols regarding pulse sequence parameters and imaging options based on the spinal anatomy and suspected abnormalities. Like other imaging procedures, MRI requires more than one set of images to provide necessary diagnostic information. MR images may be acquired in the sagittal, axial, coronal, or oblique planes. Images are generally acquired in the sagittal and axial planes to demonstrate the soft tissues of the neck. 67,68 The basic types of pulse sequences are: proton (spin) density, T1 relaxation time and T2 relaxation time.67,68 Each type of pulse sequence demonstrates the anatomy differently and helps differentiate between normal and abnormal structures. For a complete diagnostic evaluation, a combination of these pulse sequences is usually required.67,68 A proton-density-weighted image uses long repetition time (TR) and shorter echo time (TE) values to produce images based on the concentration of hydrogen protons in the tissue.67,68 The brighter the area on the image, the greater the concentration of hydrogen protons. The darker the area on the image, the fewer the number of hydrogen protons. A T1-weighted pulse sequence uses short TR and short TE values to produce a high or bright signal in substances such as fat, acute hemorrhage, and slow-flowing blood.67,68 A T2- weighted pulse sequence uses long TR and long TE values to obtain a high signal in substances such as cerebrospinal fluid, simple cysts, edema, and tumors.67,68 Generally, both T1-weighted images (with and without contrast) are obtained of the spinal area under evaluation.67,68 T1-weighted images are used primarily to evaluate spinal anatomy since they provide a high signal-to-noise ratio (SNR) and T2-weighted images are used to evaluate pathologic conditions due to high intrinsic contrast.67,68 T1- and T2- and contrast enhanced sequences

151 are generally acquired for spine studies. Motion artifacts on MR images are commonly due to swallowing, pulsatile flow motion, and respiration and can be minimized by instructing the patient to not swallow during image acquisition. Pulsatile flow motion artifacts can be minimized by using saturation pulses and can be applied to inferior and superior images.67,68 MR image quality is least affected by obesity although increased body habitus introduces noise and the large field of view needed decreases the in- plane resolution of the images. The main limitations of MRI are the size of the bore and the table weight limits, which prevent imaging of large individuals. To compound problems associated with MRI bore size and table weight restrictions for overweight and obese patients, there is always the concern about claustrophobia. Due to the construction of closed MRI scanners, they are potentially unpleasant for someone who cannot bear the feeling of being closed within a structure. Those who are claustrophobic may require high doses of weight-based sedative medications, which may put certain individuals at risk for respiratory depression.65,66 Traditionally, open-bore MRI magnets use lower field strengths, often 0.2 Tesla (T) to 0.5T, but newer model have increased the open-bore capability to handle 1.0T and 1.5T field strength, making it possible to obtain better-quality images as well as perform newer applications. To image the extremely obese patient a high field strength magnet is needed. Strengths of 0.2 to 0.5T do not provide adequate signal to noise and sometimes render it impossible to perform the examination even with a longer acquisition time.1 The 1.5T magnet is a new standard and may prove helpful in imaging overweight and obese patients.65 The higher strength magnets and improved software techniques, such as fat saturation may improve the MRI procedures used in imaging obese patients. Atraumatic vertebral compression fractures in the thoracic or lumbar spine are a common clinical problem, particularly in elderly patients.116 Osteoporosis is the most common cause of compression fractures in this age group however, the spine is a common site of metastatic disease and accounts for up to 39% of all bone metastases.116 Chronic benign compression fractures can be easily detected due to absence of abnormal signal intensity in a compression vertebra. Acute osteoporotic compression fractures can be difficult to differentiate from malignant compression fractures.116 Collapsed vertebrae are

152 considered to be acute if there is a recent history of back pain of less than 3 months duration that is located at the same spinal level.116 The malignant nature of fractures can be established by progressive deterioration of a fractured vertebra or newly developed other spinal metastases at follow up. MR imaging, CT, bone scintigraphy, or conventional radiography may be used to monitor the disease. After an examination, if the findings of follow up imaging studies did not show signs of progression in a patient without a clinical history of malignancy, the fracture can be considered to be a benign compression fracture. MR imaging findings suggestive of acute osteoporotic compression fracture is bandlike low signal intensity on T1 – and T2- weighted images.116 Spared normal bone marrow signal intensity of the vertebral body is also highly suggestive of acute osteoporotic compression fracture.116 Most vertebral metastases do not result in compression fractures until the entire body is infiltrated by tumor, causing structural bone weakening from destruction of the trabeculae, the cortex, or both. In osteoporosis the collapse is due to bone softening but the bone marrow of the vertebral body remains relatively intact. 116 MR imaging has been proven to demonstrate unsuspected fractures of the tibial plateau, femoral condyles, pelvis, hip and proximal humerus during investigation of other conditions.117 Such fractures were either radiographically not apparent or demonstrated very subtle abnormalities that were not seen on the initial interpretation of the images.117 Also it has been noted that in a large number of patients, images demonstrate evidence of intraosseous trabecular disruption or edema and hemorrhage of medullary bone, or stress type injuries that are occult with conventional radiography.117 MR imaging requires that all personnel adhere to strict safety protocols. Before entering a high magnetic field, all individuals should be screened for contraindications including biomedical devices/implants or a device that is electronically, magnetically, or mechanically activated such as pacemakers, cochlear implant, certain intracranial aneurysm clips, and orbital metallic foreign bodies. These devices may move or undergo a torque effect in the magnetic field, overheat, produce an artifact on the image or become damaged or functionally altered. Most MRI magnets are superconductive and the magnetic

153 field is always on. Any ferromagnetic material, oxygen tank, wheelchair, scissors, etc., may become a projectile object. In summary, MR imaging has the following advantages and disadvantages. The advantages are that MR imaging:  Acquires patient information without the use of ionizing radiation;  Produces excellent soft tissue contrast;  Can acquire images in the transverse (axial), sagittal, coronal, and oblique planes; and,  The quality of the images is not affected by bone.67,68

The disadvantages to MR imaging includes:  Any contraindication that would present a detrimental effect to the patient or health care personnel;  Long scan time compared to CT; and,  Cost.67,68

Bone Scintigraphy Bone scintigraphy is an imaging examination using pharmaceuticals that have been labeled with radionuclides. Prior to obtaining the image, the patient receives the radionuclides (i.e., ingests or is injected).118 The scintigraphic image is obtained using a gamma camera or a positron emission tomography (PET) unit. The scintigraphic image represents the distribution of the radioactive nuclide and provides a physiologic map of the organ or system being examined. Bone scintigraphy differs from most other imaging modalities because it primarily shows the physiological function of the system being investigated as opposed to traditional anatomical imaging such as CT or MRI. The physiologic mapped image allows skeletal changes to be detected earlier than conventional radiography. Abnormal images illustrate “hot spots” produced by an increase in uptake of the radionuclide that is directly proportional to the emission of gamma radiation; or, “cold spots” reflecting a decrease in uptake of the radionuclide. Bone scintigraphy uses a form of technetium 99-m injected intravenously. Tc-99-m is absorbed by bone and provides a survey study of the skeletal system for evaluation of abnormal musculoskeletal conditions such as stress fracture, injuries, and metastases.

154 Skeletal scintigraphy has a resolution of about 5-mm in the best conditions.118 In a normal skeletal scintigram, the radioactive tracer uptake is fairly uniform and symmetric. Uptake is greater in the axial skeleton (pelvis and spine) than in the appendicular skeleton (skull and extremities). The ability of a scintigram to demonstrate trauma precedes conventional radiography detection of fracture healing by approximately 10 days.118 Bone dysplasia often shows an increase in uptake on the scanned images. Paget disease of bone, fibrous dysplasia, and many other benign and malignant bone conditions are detected by bone scintigraphy. Two of the many indications for bone scintigraphy are to detect bone lesions and impacts of metabolic diseases on the skeleton. On bone scintigraphy images, osteomalacia is usually demonstrated as a random distribution of intense activity with looser zones and pseudofratures. Looser zones also called looser lines are areas of insufficiency fracture with incomplete healing due to mineral deficiency in the bone. The pathology of looser zones relates to areas of unmineralized woven bone occurring at sites of mechanical stress. Looser zones are frequently associated with osteomalacia, Paget disease, osteogenesis imperfecta tarda, fibrous dysplasia, renal disease, congenital hypophasphatasia, vitamin D malabsorption, and neurofibromatosis. Common locations of looser zones are the scapula, medial femoral neck, femoral shaft, pubic and ischial rami, ribs, lesser trochanter and the proximal 1/3rd of the ulna, and the distal 1/3rd of the radius. Looser zones are generally visualized as a 2-3 mm stripe of lucency located at a right angle to the cortex of the bone.

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Part 15 Bone Densitometry

Bone loss is often a silent disease, and signs and symptoms may not be evident in the early stages, so a bone density test may be used to determine bone mass. Assessment of BMD is one of the most important predictors of future bone fracture in postmenopausal women without a history of previous fracture. BMD measurements can be useful in the diagnosis and treatment of bone loss conditions as well as in tracking how successful the prescribed treatments are in curbing additional bone loss. Bone densitometry is the only technology available for accurately measuring bone mass or predicting fracture risk.119 The accuracy of bone densitometry to predict fracture risks makes it an ideal tool for disease prevention.119 Prior to the widespread availability of the DXA imaging technology, the diagnosis of low bone mass or frank osteoporosis depended on the presence of a fragility fracture.119 DXA provides an areal measurement of bone, which provides a 2- dimensional representation of the structure. Bone strength is directly related to its 3-dimensional properties (microarchitecture) and the number and strength of trabecular bone. The thinner or fewer the trabecular, the weaker the bone, the higher the risk for fracture. DXA does not provide a volumetric or 3-dimensional image of bone and for this reason, clinicians may use several diagnostic tools to arrive at an accurate assessment of bone density. According to the Clinician’s Guide to Prevention and Treatment of Osteoporosis, the following statements are provided regarding BMD testing. “BMD testing is a vital component in the diagnosis and management of osteoporosis. In postmenopausal women and men age 50 years and older, the WHO diagnostic T-score critera (normal, low bone mass and osteoporosis) are applied to BMD measurement by central DXA at the lumbar spine and femoral neck. BMD measured by DXA at the one-third (33%) radius site can be used for diagnosing osteoporosis when the hip and spine cannot be measured. In premenopausal women, men less than 50 years of age and children, the WHO BMD diagnostic classification should not be applied. In these groups, the diagnosis of osteoporosis should not be made on the basis of densitometric criteria alone.”5

156 The shortcomings of DXA are often overcome by using a combination of tests including, DXA results, laboratory tests for measurement of markers of bone turnover, clinical history, evaluation of risk factors, and application of the FRAX® assessment tool. Additional imaging modalities such as conventional radiography, quantitative ultrasound, bone scintigraphy and magnetic resonance imaging are also used to diagnose and monitor bone loss diseases.

Biochemical Markers Bone remodeling, the process of removing old bone and forming new bone tissue, produces byproducts that are released into the bloodstream and urine. Clinicians may request that the patient undergo blood and urine tests to detect these markers and provide information about the rate of bone removal and formation. Biochemical marker laboratory tests help to determine if bone is being lost at a faster rate than normal. The tests may also be able to determine whether bone is responding to bone loss drug therapy within several months of starting that therapy. Laboratory bone marker tests do not detect low bone density, cannot diagnose osteoporosis, and are not a substitute for BMD testing, but are considered an important tool in the diagnostic arsenal.

Risk Assessment During routine medical visits or health screening examinations, clinicians can take a risk assessment questionnaire that may be used to identify potential victims of osteoporosis, (Figure 18).5 The following questionnaire may be used for both men and women. For premenopausal women it is vitally important for them to know how much bone mass they have prior to menopause. These results can then be used as a baseline reference in the future for the early detection of bone loss. The premenopausal BMD results are then compared to establish scores and used as a future reference point for ongoing medical surveillance.

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Question Risk Value Are you white or Asian, or do you have a small thin body frame? 2 Have you or family members broken a bone as an adult? 3 Are you a postmenopausal female? 2 Did you have an early or surgically induced menopause? 3

Have you (or do you now) take thyroid medication, 1 long-term steroid therapy, or antiseizure medication?

Do you have a diet low in dairy products or other calcium sources? 2 Do you have a sedentary lifestyle? 1 Do you smoke cigarettes or drink alcohol in excess? 1 Scoring: 0-1 point =low risk 3-4 points = medium risk 5-6 points = high risk 7-8 points = very high risk Fig. 18. Risk Assessment Questionnaire.5

FRAX® Assessment Tool FRAX® was developed by the World Health Organization (WHO) as a tool to evaluate fracture risk of individual people.120 It is based on individual patient models that integrate the risks associated with clinical risk factors as well as bone mineral density at the femoral neck. The FRAX® models have been developed from studying population-based cohorts from Europe, North America, Asia, and Australia. FRAX® is a computer-driven tool and is available at http://www.shef.ac.uk/FRAX/120 Simplified paper versions based on several risk factors are also available and can be downloaded for clinical use. FRAX® algorithms give the 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, hip or shoulder fracture). This information is very valuable in making clinical treatment decisions that relate to fracture risk assessment, fracture risk reporting, intervention thresholds, treatment decisions, and follow-up. By including information provided by FRAX®, clinicians have yet another tool to use when talking with individual patients about their personal risk of fracture within the next 10-year period.120 The WHO and other national and international groups have validated risk factors for the prediction of future fractures. These factors are considered within the FRAX® assessment and include:  Femoral neck BMD;  Demographic information such as age, sex, height, weight, ethnicity (i.e., for the United States only to include Caucasian, African-American, Hispanic, and Asian); and,

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 Seven clinical risk factors: -Previous low trauma fracture; -Current cigarette smoking; -Rheumatoid arthritis; -Secondary osteoporosis; -High alcohol intake (3 or more units/day); -Parental history of hip fracture; and, -Systemic glucocorticoid use.120

The FRAX® assessment report provides a 10-year probability of osteoporotic fracture.120 The following example using two people with a hip T- score of –2.5 illustrates differences based on just one demographic variant (i.e., age).120 All other factors being the same, a person 80 years old will have a 19.4%, 10-year relative risk of fracture compared to a person 50 years old with a 1.9% 10-year relative risk of fracture using the FRAX® assessment tool. The FRAX® model accepts ages between 40 and 90 years. Clinicians are advised to use clinical judgement to interpret the risk when using the model for patients under age 50. If, when entering the age data, the age is below 50 or above 90, the program will compute probabilities at 40 and 90 years of age, respectively. Age is just one of the variant factors within the FRAX® assessment model.120 For assessments within the United States, the FRAX® questionnaire gives 4 ethnicity options and also allows customization for specific machines.120 The individual’s weight in kilograms and height in centimeters are entered into the questionnaire. The model uses these factors to calculate the body mass index and fracture prediction. Low body mass index is a risk factor for hip fracture but obesity is not protective against hip fracture.120 A very important factor used in predicting future fracture risk is prior history of fracture.120 A question in the model asks about previous fracture in adult life occurring spontaneously, or a fracture arising from trauma which, in a healthy individual, would not have resulted in a fracture. Also the model asks about parental hip fracture since a family history of fragility fracture is a significant risk factor that is largely independent of BMD. A family history of hip fracture is a stronger risk factor than any other bone fractures.

159 Current smoking and alcohol intake are important considerations in the prediction of fracture and the FRAX® poses questions about these habits in the form of a yes answer. For an answer of “yes” to the smoking question, the model computation assumes an average exposure and does not account for dose effect. The alcohol intake question is also a “yes” or “no” type question. The response should be “yes” for those who take 3 or more units (i.e., 8-10 grams of alcohol) daily. An alcohol intake of 8-10 grams of alcohol is equivalent to a standard glass of beer (285 ml), a single dose of spirits (30 ml), a medium-sized glass of wine (120 ml), or 1 measure of an aperitif (60 ml).120 Lower daily intake of alcohol may reduce fracture risk but the model does not account for dose effect.120 Another “yes” or “no” type question concerns risk factors that are strongly associated with osteoporosis. These include type 1 (insulin dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (<45 years), chronic malnutrition, or malabsorption and chronic liver disease.120 Glucocorticoid use is strongly associated with fracture risk and is an important cause of osteoporosis. A “yes” answer should be entered if the individual has current or prior exposure to oral glucocorticoids for more than 3 months at a dose of prednisone 5-mg daily or more (or equivalent). The model does not account for dose effect.120 A patient who has a confirmed diagnosis of rheumatoid arthritis is at increased risk of fracture. Rheumatoid arthritis increases fracture risk independently of BMD and the use of glucocorticoids. The model does not account for dose effect due to severity or duration of the disease.120 The benefits of using the FRAX® assessment includes:  Quantitative assessment of fracture risk rather than qualitative;  Fracture probability that provides greater clinical utility than relative risk;  Application beyond postmenopausal Caucasian women; and,  It can be used with cost-utility analysis to determine cost-effective intervention thresholds.120 The NOF has issued intervention thresholds, which are based on fracture probability where treatment is considered cost-effective. The following NOF treatment guidelines are based on postmenopausal women and men age 50 and older:

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Low Bone Mass, Low Bone Density, or Osteopenia T-score between –1.0 and –2.5 at the femoral neck or lumbar spine; and,

FRAX® 10-year probability of hip fracture ≥3% or major osteoporotic fractures ≥20%.121

Osteoporosis T-score –2.5 or less at the femoral neck or lumbar spine after evaluation for secondary causes; or,

Hip or vertebral (clinical or morphometric) fracture.121

The NOF intervention thresholds are calibrated to United States data on fracture incidence, morbidity, and mortality.120,121 The thresholds are also base- case assumptions of a 35% fracture risk reduction with treatment costing $600 a year for 5 years with a 5-year offset to effect.120,121 Also, the thresholds are based on societal willingness to pay up to $60,000 per quality of life gained and serves only as a guideline for making clinical decisions and is not a mandate to treat or not to treat.120,121 A few of the benefits of the NOF guidelines include improved selection of patients most likely to benefit from therapy, better use of limited healthcare resources, and application beyond postmenopausal Caucasian women. A few of the risks associated with the new NOF guidelines are that the cost-effectiveness may be used to determine pharmacy benefits and that the cost-effectiveness may be irrelevant if the drug cost is extremely small. Additional risks include possible limitations of treatment options, treatment recommendations that may be conflicting, if the FRAX® model is used inappropriately, and physicians may have less control of clinical decisions.120,121 If an individual is found to be at risk, preventive measures may be taken to reduce bone loss and to conserve current bone mass. Those who have several high risk factors may wish to have a bone density scan at age 45 to be assured that they have not already lost more bone mass than is normal. It is recommended that an osteoporosis risk assessment become part of routine

161 medical care. One expert compares lack of risk assessment for low bone density to waiting for someone to have a stroke before treating the high blood pressure.120,121 The first NOF guidelines issued in 1998 were updated in 2008. The current guidelines address postmenopausal women and men age 50 and older, secondary causes of osteoporosis, and universal recommendations for osteoporosis prevention. The guidelines recommend that all postmenopausal women and men age 50 and older should be evaluated clinically for osteoporosis risk to determine the need for BMD testing. Further, NOF recommends BMD testing of all women age 65 and older and men age 70 and older. NOF does not recommend BMD testing for children or adolescents, healthy young men, or premenopausal women.

Guidelines for Bone Density Measurements  Postmenopausal women age 65 and older and men 70 and older, regardless of clinical risk factors;  Younger postmenopausal women and men age 50-69 with clinical risk factors;  Women in the menopausal transition if there is a specific risk factor;  Adults who have a fracture after age 50;  Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥ 5 mg prednisone or equivalent for ≥ than 3 months) associated with low bone mass or bone loss;  Anyone being considered for pharmacological therapy for osteoporosis;  Anyone being treated for osteoporosis, to monitor treatment effect;  Anyone not receiving therapy in whom evidence of bone loss would lead to treatment; and,  Postmenopausal women discontinuing estrogen should be considered for bone density testing.121

The Bone Mass Measurement Act of 1997 was announced in the Federal Register 42 CFR Part 410; Vol.63, no.121, June 24, 1998. As of July 1, 1998, this federal law mandated that Medicare pay for bone density tests. Payment coverage by other medical insurers varies from company to company.

162 Medicare payment covers BMD testing for many individuals age 65 and older, including but not limited to:  Estrogen deficient women at clinical risk for osteoporosis;  Individuals with vertebral abnormalities;  Individuals receiving, or planning to receive, long-term glucocorticoid therapy in a daily dose ≥ 5 mg prednisone or equivalent for ≥ 3 months;  Individuals with primary hyperparathyroidism; and,  Individuals being monitored to assess the response or efficacy of an approved osteoporosis drug.120,121

Physicians may consider women on estrogen replacement therapy to be at risk because the estrogen dosage may not be sufficient to protect their bones. Frequency standards were also included in the 1997 Bone Mass Measurement Act. The standards were set as guidelines for the frequency of BMD testing, and state that at least 23 months must have passed since the month the last measurement was performed except…  For monitoring patients on long-term glucocorticoid therapy.  For capturing a baseline measurement to permit future monitoring, if the initial test was performed with a technique that is different from the proposed monitoring method.

Indications for DXA Bone mineral density measurements are used to determine current bone loss status, to forecast risk of future risk, and to determine appropriate interventions that can reduce fracture risk. The 10-year fracture probability is the most current tool for reporting fracture risk and depends upon individual clinical risk factors and BMD, as previously mentioned. The ACR recognizes DXA as a clinically proven method of measuring bone mineral density (BMD) in the lumbar spine, proximal femur, forearm, and whole body; and, provides guidelines to assist practitioners in providing appropriate radiological care for patients. The ACR indications for DXA are similar to those established by other bone health advocates such as the Surgeon General of the United States, National Osteoporosis Foundation (NOF), American Academy of Endocrinologists, and the International Society of Clinical

163 Densitometry (ISCD). The ACR practice guideline states that there are no absolute contraindications to performing DXA. The ACR has issued specific guidance in the ACR Appropriateness Criteria®, as well as relative radiation levels (RRL) associated with specific imaging modalities.122 The ACR provides guidance about the appropriateness of the use of various imaging modalities as they relate to the clinical condition of osteoporosis and bone mineral density. Accordingly, the criteria ranks imaging modalities from 1 to 9, with 1 being the least appropriate for the clinical situation to 9 being the most appropriate based on individual variants.122 Examples from the ACR Appropriateness Criteria® based on the clinical condition of osteoporosis and bone mineral density include the following:  Variant 1: For identification of low bone density and fracture risk in postmenopausal females, greater than 50 years old and males greater than 50 years old with risk of fracture, in all races, the recommendation includes the following: -The imaging protocols that received a 9 rating are DXA of the posterior- anterior (PA) spine, DXA of the proximal femur, and femoral neck and total hip, each having a minimal relative radiation level (RRL). When DXA imaging is not available or cannot be performed quantitative computed tomography of the spine is recommended as the next best imaging modality; however has a higher RRL value than does DXA.  Variant 2: For follow-up of patients demonstrated to have risk for fracture or low bone density a DXA of the PA spine or DXA of the proximal femur and femoral neck, and total hip is recommended.  Variant 3: For premenopausal females with risk factors and males 20-50 years of age with risk factors, all races, a DXA of the PA spine is recommended or a DXA proximal femur and femoral neck and total hip.119  Variant 4: Follow-up to low BMD for premenopausal females and males 20- 50 years old with risk factors, all races, a DXA of the PA spine and DXA proximal femur and femoral neck and total hip.  Variant 5: For diagnosis of osteoporosis and BMD in both males and females greater than 50 years old with advanced degenerative changes of the spine, with or without scoliosis, a DXA proximal femur and femoral neck and total hip. When a PA spine cannot be assessed, hip/hip (bilateral) scans should

164 be performed. If only one hip is available for assessment, hip and forearm measurement can be used. The spine cannot be used with more than 2 compression fractures and a minimum of 2 vertebral bodies is required for adequate assessment of BMD.  Variant 6: Low BMD in those less than 20 years old with risk of fracture. DXA total body calcium.  Variant 7: Follow-up patient less than 20 years old with risk of fracture. DXA total body calcium. QCT is given a rating of 7 and may be used in this demographic population due to increasing size of bone.  Variant 8: Suspected fracture of a vertebral body based on clinical history, height loss, or steroid therapy, DXA and VFA is given a 9 rating and radiography of the thoracic and lumbar spine is given an 8 rating.

Assessment of and indications for performing BMD examinations in children differ significantly from those in adults.122 The measurement and the issue of the rapidly growing skeleton often complicates interpretation of BMD in children. Studies have shown that DXA is unable to take into account large changes in body and skeletal size during growth, limiting its use in longitudinal studies in children. In children, DXA examination usually consists of an examination of the lumbar spine and/or whole body; evaluation of other anatomic regions in children may be performed, but is not routine or standardized. The reference population to which the child is compared must be noted, as well as adjustment for height, radiographic bone age, and stage of sexual maturity, weight or other factors if used. The relationship of BMD to fracture risk in children is not clearly established.

General Information about Bone Mass Measurement Technologies The first documented use of bone densitometry was in the field of dentistry. Over 100 years ago, dentists used crude instruments to measure the density of the mandible. According to Dr. John Cameron, an early bone densitometry pioneer, “…medical care providers were not interested in bone density technology until pharmacology agents became available to treat osteoporosis.”123

165 The United States space exploration program was the most important influence on the clinical acceptance of bone density technology. It was found that space travel and weightlessness accelerated bone loss. Currently, with the space program planning longer space missions to the International Space Station (ISS) and Mars, bone loss from weightlessness pose questions that scientists must consider for the health of space travelers. Researchers estimate that on average, hip strength declines by 2.5% for each month of space flight.123 Living tissue is constantly regenerating in response to the stresses placed on it, but in zero gravity, no stress is placed on the bones. In zero gravity, the formation of new bone-forming cells slows, while bone-destroying cells continue to remove bone from the skeleton.123 When humans lose bone density, much of what they lose is trabecular bone. Trabecular bone can be found next to the joints at the ends of long bones, thus any major bone loss in these areas significantly increases the risk of fracture.123 In the late 1980s, the dual energy x-ray absorptiometry (DXA) technology was introduced, and was applied to the measurement of bone mass. The introduction of new technologies to measure bone mass was critical, since ordinary x-ray techniques could not detect anything less than a 30% loss in bone mass.123 Using bone mass measurement technologies, a change in bone mass as small as 1% is detectable. Tests for bone mass density are classified as either central or peripheral tests. A central test is used to quantify BMD in the spine and proximal femur. A peripheral test is used to quantify BMD in the heel, radius, and ulna. Bone densitometry has four major applications in clinical practice: quantification of bone mass or density, assessment of fracture risk, skeletal morphology, and body-composition analysis. Bone mass testing may be performed to:  Confirm suspected bone loss.  Diagnose osteoporosis.  Document or follow the effect of a disease process that causes changes in bone mineral content or density.  Monitor response to therapy over time.

Current bone measurement devices do not actually measure BMD; rather, they provide information about bone mineral content (BMC) and the

166 length or area of bone. The information, provided as a BMD score, is useful when related to a comparative score. The method used to develop the reference data with which the score is compared has a great impact on the estimation of the peak bone mass of young, normal women, and on the estimation of population-standard deviations. Additional information about BMD test results will be covered later in this course. When bone densitometry is used to quantify the BMD for the purpose of diagnosing osteopenia and osteoporosis, or for predicting fracture risk, it is critical that the measurement be accurate. When bone densitometry is used to follow changes in bone density over time, precision is critical, since any change between measurements is a key factor in monitoring progression of the disease and responsiveness to treatment. Precision of BMD studies is dependent on the technical skill and competency level of the technologist performing the examination. Although equipment manufacturers provide precision values expressed as a percent coefficient of variation (%CV), each facility must establish its own %CV value.119 Technologists and physicians involved in BMD testing must be familiar with testing objectives, diagnosis, and treatment protocols. Technologists must also be proficient in machine operation and calibration. Generally, when a facility purchases a BMD machine, the manufacturer provides initial hands-on staff training on the application and use of the BMD equipment.119 Approximately two-thirds of the states have licensing laws governing those who operate equipment that generates x-radiation. Bone mineral density testing equipment generates small amounts of ionizing radiation, and as such, these laws may regulate its use. Persons who wish to perform BMD tests are usually required to meet existing state laws concerning the operation of ionizing x-ray machines (i.e. for diagnostic purposes). Also, they may be required to pass an examination covering the following topics: osteoporosis and bone health, equipment operation and quality control, patient preparation and safety, and DXA scanning of the lumbar spine, proximal femur, and forearm. Persons who have already attained certification by the American Registry of Radiologic Technologists (ARRT) in the supporting categories of either radiography, nuclear medicine technology, or radiation therapy, can take the ARRT post-primary examination in bone densitometry. Post-primary candidates must document

167 clinical experience in BMD testing to be eligible for the examination. The ARRT may be contacted at (651) 687-0048 or at www.ARRT.ORG. For those who do not have ARRT certification and are not eligible to take the ARRT-administered post-primary bone densitometry examination, they may obtain training by supervised on-the-job training and from DXA equipment manufacturers. The ISCD certification course, which is offered throughout the world, provides comprehensive training session with separate tracks for physicians and technologists. The ISCD may be contacted at (860) 586-7563 or at www.ISCD.ORG. Additionally, some states may have a contractual agreement with the ARRT to administer a bone densitometry examination to those not eligible to take the ARRT post-primary densitometry examination. Successful passage of this examination is not intended to lead to ARRT certification; rather, it is used by certain states as a requirement for state certification in bone densitometry. For specific state agency information, contact the Conference of Radiation Control Program Directors (CRCPD) at (502) 227-4543 or at www.CRCPD.ORG. Certification in bone densitometry recognizes skill and documents proficiency in bone densitometry. Continuing education is essential to both technologists and physicians who perform BMD testing, since innovations in measurement technology and new approaches to prevention and treatment of osteoporosis (and other bone loss diseases) are occurring at a rapid rate.

Bone Densitometry Equipment Types Bone densitometry equipment available in the United States for clinical use is generally listed by type, which refers to the technology application of the equipment. The types that will be discussed in this course include single and dual photon absorptiometry, dual-energy x-ray absorptiometry, peripheral dual energy absorptiometry, quantitative computed tomography, and quantitative ultrasound. A discussion of computer-enhanced absorptiometry is not included in this course; however, machines approved by the United States Food and Drug Administration (FDA) are available for these applications. Also, radiogrammetry, the measurement of the dimensions of the bones using skeletal radiographs, is not included in this course.

168 Today most bone densitometry applications are controlled by a computer system. The computers that control the operation of x-ray densitometers are often considered by the FDA to be the x-ray controllers. As such, the computer systems used to operate x-ray bone densitometers are sold as part of a package with the densitometer. Using a computer which does not come from a densitometry manufacturer to operate an x-ray densitometry system may be a violation of FDA regulations. Technologists who perform BMD testing must have a thorough understanding of basic computer applications. They must also be proficient in using the computer system applications that have been installed on the equipment, and in recognizing the importance of installing manufacture software upgrades according to instructions.

Single Photon Absorptiometry (SPA) Single photon absorptiometry (SPA) was introduced in 1963 as a new method for determining bone density. The SPA units were portable, and allowed technologists to carry the measurement test device to off-site locations, thus making the technology more accessible and convenient to the public. SPA was used for bone density measurements of skeletal sites, such as the calcaneus and ulna. SPA units have a single energy source and the size and shape of the energy source is restricted through collimation. The SPA method requires careful positioning of the bone site and use of a uniform thickness surrounding the bone. The anatomic part being measured is submerged in a water bath or a gel solution to compensate for the variable soft tissue thickness. The use of SPA equipment was replaced by dual photon absorptiometry (DPA) equipment. Today, however, SPA and DPA bone densitometry technology have both been replaced by dual-energy x-ray absorptiometry (DXA), which is considered the “gold-standard” in BMD testing. DXA is also referred to a pencil-beam or fan- array scanner. All bone densitometry equipment provides measurements based on the same basic concept, which is attenuation of the beam of energy by bone and soft tissue. Attenuation of the machine’s energy beam allows for quantification of the bone density in skeletal areas surrounded by large or irregular soft tissue (spine, proximal femur). Thus, the greater the amount of bone mass, the greater the absorption, or attenuation, of the energy beams. Consequently, as bone mass

169 decreases, attenuation of the energy beam decreases. The major differences between the earlier SPA and DPA units and the DXA units are the type and direction of the energy source. A major disadvantage to using radioactive isotopes as the photon energy source is that the energy level of the isotopes constantly changes due to the natural process of radioactive decay. A disadvantage of DPA study is that it is a time-consuming procedure, taking approximately 30 minutes to scan the spine, 30-45 minutes to scan proximal femur and 1 hour to scan the total body. The skin radiation dose during spine or proximal femur studies is 15 millirem (mrem). The most significant clinical improvement with the use of DXA compared to DPA is the marked improvement in precision. Also, DXA study times are shorter for the spine, and in the case of the proximal femur a study that requires less than one minute. Radiation exposure for all types of DXA scans during a posterior-anterior (PA) lumbar spine or proximal femur study is only 2 - 5 mrem expressed as skin dose. Thus, with the introduction of the x-ray tube as the energy source, a consistency of the energy was established.

Peripheral Dual Energy X-ray Absorptiometry (pDXA) Peripheral dual energy x-ray absorptiometry, also referred to as peripheral DXA or pDXA, is best used for single event measurements to determine a patient’s bone mass relative to normative BMD values. The pDXA unit is small, portable, inexpensive, and easy to use in off-site locations. The usefulness of pDXA is limited because the peripheral bones are slow to respond to drug therapy.

Quantitative Computed Tomography (QCT) Quantitative computed tomography is a photon absorptiometric method. It is the only method that provides a 3-dimensional, or volumetric, measurement of bone density. Because QCT can assess both volume and density of bone in the axial and appendicular skeleton without influence from body or skeletal size, it may be more useful than DXA in children. QCT technology has been used in preterm infants, as well as adolescents in whom increases in DXA areal BMD are more likely a reflection of vertebral size than actual changes in density.

170 Caution must be used in making the diagnosis of osteoporosis based on nonvolumetric measurements. Therefore, QCT may be a better method for measuring changes in bone density resulting from various pathologic processes that may affect children and their growing skeletons. This includes patients who have been treated with radiation or chemotherapy for malignancies; patients who have been treated for bone disorders such as primary or secondary hyperparathryodism, osteogenesis imperfecta, or osteopetrosis; and patients who have been treated for growth hormone deficiency, inflammatory bowel disease, or HIV. QCT may also demonstrate the effect of race and gender on the developing skeleton more than DXA. In children, QCT examination usually consists of an examination of the lumbar spine. Evaluation of other anatomic regions in children can be performed, but is not routine or standardized. A QCT study of the spine requires about 30 minutes with a radiation skin dose of 100-300 mrem. Accuracy of QCT for spine BMD measurements can be affected by the presence of marrow fat. Since bone marrow fat increases with age, the accuracy of spine QCT decreases in older patients. Accuracy of QCT may range from 5-15% depending on the percentage of bone marrow fat and the age of the patient. QCT has some advantages over DXA. The BMD values provided by DXA may be biased significantly by severe degenerative changes of the hip or spine, vascular calcifications, oral contrast agents, and foods or dietary supplements containing significant quantities of calcium or other heavier minerals or elements. DXA results are more likely to be affected by body habitus and in the extremely obese or individuals having a low body mass index. The goal of QCT is to measure BMD accurately and reproducibly, and to compare that measurement to reference population standards and/or to an individual’s previous bone densitometry examinations. QCT may be indicated in the diagnosis, staging, and follow-up of individuals with conditions that result in pathologically increased BMD, such as osteopetrosis or prolonged exposure to fluoride. QCT is generally contraindicated for patients who are pregnant or who may be pregnant. According to the ACR there are certain conditions that may influence the accuracy and/or precision of QCT bone mass measurements. Such conditions

171 may be suitable for a general assessment of bone density, but degradation of measurement accuracy and/or precision under these conditions may limit the utility of such measurements for detecting significant change in BMD via serial study comparisons.125 These conditions include:  Recent administration of IV contrast;  Severe fracture deformity in the measurement area;  Radiopaque implants in the measurement area, most commonly at the spine or hip;  Patient’s inability to attain correct position and/or remain motionless for the measurement; and,  Extreme obesity resulting in an inability to position a patient completely within the scan field-of-view of the CT scanner.125

Prior to the QCT procedure, a scout image is obtained to localize the area to be evaluated. An 8-10 millimeter slice is obtained through 4 separate vertebral bodies, or 20 to 30 continuous 5-mm slices are obtained over 2-3 vertebral bodies between thoracic-12 and lumbar-5. A calibration standard is scanned at the same time for correlation with image analysis software averages for the values from all the bones. A QCT spine examination should include a lateral localizer image of the lumbar spine. The localizer should be reviewed by the technologist to determine if specific sites within the lumbar spine should be excluded from analysis. The lateral localizer should also document the spine region scanned and should span the entire lumbar spine with sufficient resolution for assessing biochemical integrity. Positioning and soft-tissue equivalent devices issued by the manufacturer should be used consistently and properly. Comfort devices, such as pillows under the head or knees, should not interfere with proper positioning and should never appear in the scan field. Anatomic areas of prior surgery or known prior fracture and all fractured vertebrae should be excluded from measurement. If a vertebra is anatomically intact and review of the images confirms the absence of a lytic or blastic process, it may be included in the scanned area. If there is significant unexplained discordance between 2 measured areas, additional QCT acquisitions should be performed. Comparisons should

172 be reported as T-scores for QCT hip measurements. Comparisons of QCT spine measurements may or may not be reported as T-scores, but QCT spine T-scores generally should not be used to assign a diagnostic category using WHO (DXA) guidelines. Volumetric QCT spine BMD measurements are used to characterize only trabecular bone, while hip area-density measurements obtained using either QCT or DXA predominantly characterize cortical mineral. It has been established that QCT spine BMD measurements provide a significant indication of hip fracture risk and they provide a more sensitive indication of spine fracture risk. Assigning a WHO diagnostic category based on QCT spine T-score may result in overstating a patient’s risk of hip fracture. Consequently, it is advised that a WHO diagnostic category is assigned based on consideration of only the QCT hip T-score in a standard QCT study. Comparison should be made to any prior comparable QCT examination of the same site. The precision error and calculated least significant change of the specific scanner(s) should be checked to determine if measured changes are statistically significant.

QCT Equipment Specifications The 3 methods used to perform QCT include:  Acquisition of volumetric CT data with simultaneous scanning of the patient and a calibration device;  Acquisition of single axial images through a vertebral body or peripheral site, with simultaneous scanning of a calibration device; and,  Acquisition of single axial images through a vertebral body or peripheral site, with separate scanning of a calibration device.125

The 3 methods provide accurate BMD determinations suitable for assessing bone status. There are some differences in the precision of each method, resulting in different sensitivities in detecting significant change in BMD through serial measurement comparisons. Precision is at its greatest when the patient and the calibration standard are imaged simultaneously, and volumetric QCT units often have better precision because of reduced dependence on operator skills such as patient positioning and data processing. 125

173 Measurement precision is influenced by CT scanner model, QCT method, and the skill of the technologist.125 The ACR suggests that facilities should not rely on the precision data provided by the QCT manufacturer but should perform precision testing to determine its precision error and calculate its least significant change (LSC). Estimation of LSC based on a 95% confidence interval is suggested.125 In facilities where several technologists are operating the QCT machinery, the data should represent an average of pooled data from all technologists. The LSC should be recalculated in the following instances:  The CT scanner or the CT x-ray tube is replaced;  The CT scanner is recalibrated;  CT scanner software revisions are made; and/or  Modifications to the QCT accessory components are made. 125

There are various designs of QCT equipment currently available that can accurately and precisely measure bone density and the ACR recommends that these should include or provide the following:  Software with normal young adult and age and sex-matched control population standards specific to the equipment;  A phantom or other calibration standard to evaluate the accuracy and precision of BMD measurement;  Labeled images of the anatomic site measured and relevant measurements for permanent patient records; and  Precision error of measurements of the phantom or standard that do not exceed the specifications or recommendations of the manufacturer and are less than 1%.125

Peripheral quantitative CT (pCT) is used to obtain BMD measurements in the peripheral skeleton, primarily in the distal radius. Most peripheral quantitative CT scanners incorporate a multi-section data acquisition capability that covers a larger volume of bone than does the commonly used single-section technique. The advantages of pCT are its ease of use and the capability of assessing trabecular and cortical bone compartments separately.

174 Quantitative Ultrasound (QUS) Quantitative ultrasound (QUS) provides a quantitative ultrasound index (QUI) or measurement of bone stiffness based on the transmission of high- energy sound waves through bone. The speed with which sound passes through bone is related not only to the density of the bone, but also to the quality of the bone. Quantitative ultrasound has been used for the evaluation of BMD since the 1990s. It is a non-ionizing technique used to assess BMD in peripheral sites. QUS measurements include attenuation, velocity, and a derived parameter, “stiffness”. The attenuation and velocity of a sound wave passing though bones are related to the biomechanical properties, geometry, and density of the bone. With QUS, the more complex the anatomic structure, the greater the attenuation and velocity. Normal bone demonstrates higher attenuation and is associated with greater sound velocity than osteoporotic bone. Stiffness does not reflect a biomechanical property of bone; rather, it is an algorithm derived from the attenuation and velocity of the sound wave. Quantification of bone density and structure can be achieved by analyzing the attenuation or velocity of US in bone. Healthy bone permits both higher speeds of sound (SOS) and broadband ultrasound attenuation (BUM). QUS measurement procedures do not expose patients to radiation; however, the QUS values are not easily related to the WHO bone mineral density standards. QUS is a quick and simple BMD measurement and does not use ionizing radiation. The most common site scanned with QUS is the heel. In fact, data from a multicenter study released in 2008 has found that QUS of the heel can be used to predict fractures due to osteoporosis. A “predicative rule” was developed to determine the risk for fractures using heel ultrasound and other factors, such as age or recent fall. QUS allows BMD analysis of those who are unable to be scanned because of excessive weight or unable to be scanned with a conventional table C-arm or computed tomography method.

DXA Precision and Accuracy DXA incorporates the use of both a high and a low energy beam to measure the amount of bone embedded in soft tissue. A pulsing energy or rare earth system provides high-low energy beams filters. The pulsing energy system delivers a specific high and low kilovoltage, which are further, attenuated by the

175 filters used. New generation DXA equipment consists of a fan-beam construction with an array of detectors or a C-arm. Precision or reproducibility is the ability of a DXA system to obtain consistent BMD values on repeated measurements of the same patient. Precision determines the least significant change (LSC) on BMD that can be statistically recognized as a real change in BMD that is not due to random errors of measurement. Clinical DXA precision is influenced by the factors of short-term variability of the scanner, patient motion during scanning, body habitus, and operator- related factors such as patient positioning and placement of the regions of interest being analyzed. Patient operator related sources of variability are more important than scanner variability itself. Operator factors have the greatest influence on overall precision of DXA measurements. The precision of DXA is different for various clinical measurement sites. DXA precision is usually documented to be 1% for the total hip, 1.5% to 2.5% for the spine, a 2%-3% for the femoral neck.119 The least significant changes in BMD that can be recognized with 95% confidence is 2.8 multiplied by the coefficient of the variation.119 Thus, if a DXA scanner and an operator with combined precision is 1% are used to scan a patient 2 times at 1 year apart, the difference between the 2 readings must exceed 2.8% for the referring physician to be confident that a change in BMD from the baseline measurement has actually occurred.119 If precision were 2%, a change of greater than 5.6% would have to have occurred (2.8 times 2 = 5.6). Thus the poorer the precision, the larger the change in BMD required for the change to be recognized as real.119 Accurate measurement precision is critical for detecting changes in BMD because the rate of change of bone in normal individuals or those being treated are small. To achieve consistent precision, the technologist must perform scanning in a methodical routine manner as well as consistently following standard operating procedures for analyzing the scan and performing instrument quality control tests in accordance with the manufacturer’s recommendations. Accuracy is defined as how well the measured value reflects the true or actual value of the object measured. Accuracy is the difference between true and measured values compared with the true value of the quantity measured, expressed in percentage points.

176 Generally the accuracy of a DXA unit is better than 10% and is recognized as adequate for the clinical assessment of fracture risk and the diagnosis of osteoporosis.119 It is important that individuals being followed for therapeutic progress be evaluated on the same scanner because different manufacturer scanners are calibrated differently. The calibration difference between scanners may vary by as much as 15%, depending on the skeletal site scanned.119 Calibration even in identical type and model scanners may vary by several percentage points. If the only objective is to monitor BMD longitudinally, follow-up scans should be done with the same scanners. A common situation is the comparison of 2 readings of the same individual made at different times with the same DXA unit and in this situation precision is more important than accuracy.

DXA Equipment DXA equipment quality control is extremely important for long-term monitoring of the effectiveness of therapy or progression of disease. Each imaging facility should have documented polices and procedures for monitoring and evaluating the effective management, safety, and operation of imaging equipment.119 At installation, a qualified medical physicist should conduct an environmental radiation safety survey. A survey should include any additional evaluation as required by state regulations.119 Quality control procedures should be performed and permanently recorded by a trained technologist. These procedures are generally required at least 3 days a week and always before the first patient measurement of the day.119 They should be interpreted immediately upon completion according to the guidelines provided by the manufacturer to ensure proper system performance. If a problem is detected according to manufacturer guidelines, the service representative should be notified and patients should not be examined until the equipment has been cleared for use. Each facility should determine its precision error and calculate least significant change (LSC).119 If a facility has more than one technologist, these values should represent an average of pooled data from all

177 technologists.119 If a new technologist joins the facility, he/she should do a precision study and those results, if acceptable, should be pooled with the precision data for the facility.119 While methods of evaluating DXA devices are not yet fully developed, traditional phantoms for evaluating radiological devices are still relevant. This includes line pair phantoms for measuring the resolution and contrast/detail phantoms. Resolution, while not critical for BMD measurements, is important for vertebral fracture assessment (VFA), aortic aneurysm calcification (AAC) detection, and measurements of bone structure and strength. In addition to image quality, long-term stability of the BMD measurements should be provided since it is required to detect very small changes. It is recommended by the ISCD that quality control phantoms (different than a calibration phantom) be scanned at least weekly to monitor the stability of the BMD of the device.

The DXA Procedure: Patient Preparation, History and Positioning The ACR recommends that a written or electronic request for DXA or other imaging examination should provide sufficient information to demonstrate the medical necessity of the examination and allow for its proper performance and interpretation.119 Documentation that satisfies medical necessity includes 1) signs and symptoms and/or 2) relevant history (including known diagnoses). A history should be obtained from the patient regarding risk factors (previously listed), including family history, prior fragility fractures, and prior bone trauma/fractures or surgery that could potentially affect the accuracy of measurements.119 If prior radiographs of these anatomic areas are available, they should be reviewed to determine if specific sites should not be analyzed. The ACR states that the standard DXA examination in adults should consist of a PA scan of the lumbar spine and a scan of either or both proximal femurs. The WHO classification of osteoporosis is based on a measurement of the PA spine, proximal femur, or total femur.119 In cases where these measurements are not possible, alternate sites can be used for evaluating the patient, including the lateral lumbar spine, forearm, and total body. In some cases (extensive abdominal aortic calcification, degenerative disease of the lumbar spine or hip, scoliosis, fractures, orthopedic implants), the nondominant

178 forearm or whole body may be used. DXA of the nondominant forearm may be useful when DXA of the spine or hip cannot be performed or accurately interpreted, in very obese individuals who exceed the weight limit of the DXA table, and in individuals with hyperparathyroidism. Positioning and soft-tissue-equivalent devices issued by the manufacturer must be used consistently and properly. Comfort devices, such as pillows under the head or knees, must not interfere with proper positioning and must never appear in the scan field. Anatomic areas of known fracture or surgery should be excluded from the measurement. For the lumbar spine, vertebrae should be excluded if other abnormalities result in a T-score difference of more than 1.0 compared to the adjacent vertebrae. If significant discordance is present between 2 areas measured with no evident explanation from the patient’s history, DXA images or radiographic correlation, additional DXA acquisition (e.g., opposite proximal femur or nondominant forearm) should be considered. Comparison should be made to any prior comparable DXA examinations of the same skeletal site, region or interest, and area size. For all examinations the report should indicate whether artifacts or other technical issues might have influenced the reported measurements of BMD. A statement comparing the current study to prior available comparable studies should include an assessment of whether any changes in measured BMD are statistically significant. Recommendations that relate to the timing of a follow-up DXA scan may also be included.119 No special preparations are required prior to a bone density examination other than refraining from taking calcium and vitamin supplements the day of the examination. Some special considerations include the following:  If there is any possibility of pregnancy, the bone density study should not be done until the pregnancy is ruled out.  Patients who have had diagnostic testing that included contrast material or radioisotopes (nuclear medicine testing) must wait at least 7 days before undergoing a bone density study.  There may be weight restrictions on table equipment; certain tables may have a maximum weight limitation noted for example, “Capacity is 300 pounds”.

179 Patients may wear their street clothes during the bone density procedure. Metal objects such as zippers, belt buckles, and snaps should be removed from the area being scanned. The technologist should evaluate each patient to determine if he/she requires assistance in sitting or lying down, or especially in regaining equilibrium after the examination. Questionnaires are useful in gathering relevant patient information that may assist in bone density measurement. Most importantly, patient history questionnaires provide consistency so that every patient is asked the same questions. The technologist should review all available patient records and the physician’s request to confirm the anatomic site to be scanned. In the case of ongoing BMD measurements, the patient’s record should also be reviewed to confirm positioning and exact placement of the region of interest (ROI) prior to the scan.

Vertebral Spine DXA Procedure BMD vertebral spine studies are usually acquired by the movement of x- ray energy from the posterior location in an anterior direction (posterior-anterior PA spine study). In this examination, the patient is supine, with the energy source beneath. The beam direction in a DXA study of the spine has minimal influence on the image appearance, and has no influence on the BMD. Lateral spine DXA studies may also be performed while the patient is supine or in a left lateral decubitus position. The patient is placed in a supine position with the midsagittal plane aligned with the midline of the table. The technologist should place a support beneath the patient’s legs to position them at a 60-90 degrees angle to the trunk in order to reduce the lordotic curve. The spine should be straight and aligned with the scan field. Any abnormal vertebral body is not considered in the assessment of BMD because this could cause false BMD measurements. The scanned image should be free of artifacts from the thoracic 12 to the iliac crest. The average BMD for 3 or 4 contiguous vertebrae (L1-L4 region) is the preferred measurement. This value has been shown to have greater accuracy and precision than the BMD for a single vertebra. For example, it is an accepted practice in densitometry to refer to the L1-L4 BMD and the L2-L4 BMD as the

180 average BMD value, although this is not the average of the BMD at each vertebra. Structural changes or artifacts may detract from either the accuracy or precision (or both) of the BMD measurement of the lumbar spine. A vertebral fracture, osteophytes, facet sclerosis, and aortic calcification will cause an increase in BMD at the site. Other artifacts that may occur in BMD testing in the lumbar spine area include gallstones, renal and pancreatic calcifications, and ingested calcium tablets. Despite this issue, the BMD measurement of the lumbar spine is extremely important in predicting fracture risks, following disease progression, and drug therapy.

Lateral DXA Imaging

Most vertebral fractures are not clinically recognized, and can accumulate silently. While BMD is widely used in patient evaluation, radiologic assessment of vertebral fracture is commonly not performed, or if performed, is inadequately standardized and interpreted.127 Radiologists and clinicians generally analyze lateral radiographs of the thoracolumbar spine quantitatively to identify vertebral fractures in individuals whose clinical indications suggest trauma, osteoporosis, malignancy, or acute back pain. The decision can be aided by additional radiographic projections or by complementary examinations, such as bone scintigraphy, CT, and MRI. Scans of the lateral spine, called instant vertebral assessment (IVA) or lateral vertebral assessment (LVA) can help detect fractures before the disease can destroy the integrity of the bony vertebra.128 The use of either IVA or LVA reduces patient radiation exposure risk and can be performed at the same time as the BMD measurement, depending on particular capacity of the machinery. The fan-beam scanning geometry of the DXA system overcomes distortions caused in conventional radiography of vertebral bodies. Using the DXA system, the vertebral disc space is parallel to the x-ray beam and detector, providing images of both fractures and vertebral height. Dual-energy techniques in DXA equipment allow for compensation between soft tissue difference of the lungs and abdomen thus providing an image of the entire spine in a single image. Newer fan-beam DXA systems can detect vertebral fractures with fast, low dose lateral scans of the vertebra from T4 to L4. In modern fan-beam DXA devices that are capable of

181 performing VFA there is one-fiftieth of the radiation dose of a conventional radiograph of the spine. Some DXA devices are equipped with a rotating C-arm so that the lateral examination can be performed without moving the patient from the supine position. By combining VFA with BMD, the two strongest risk factors for future fracture can be obtained on the same device without little additional examination time. Lateral spine images obtained with fan-beam DXA systems are alternative to radiographs for vertebral fracture diagnosis.124 Several clinical studies have shown the feasibility of visual evaluation of lateral DXA spine images. These studies reported that the DXA images permitted visual assessment of 95% of all vertebrae.124 Among the vertebra that could be visualized, there was 92% sensitivity and 96% specificity for detection of moderate to severe fracture.124 However, caution should be observed when using lateral DXA images for assessment of vertebral fracture. Some fracture seen on DXA should be confirmed with standard radiographs to exclude the possibility of pathology fracture. Also those with indeterminate DXA images, which is common in the upper thoracic spine, should potentially be referred for radiography.

Hip DXA Procedure DXA of the hip is the most valuable for predicting future hip fracture. If the hip is measured, the patient should be in the supine position with the midsagittal plane aligned with the midline of the table. The patient’s legs should be extended, with the shoes removed. The hip selected should be free of prior fracture or congenital diseases of the hip. The legs should be positioned in a true AP with the legs rotated internally approximately 15 to 20 degrees to place the femoral necks parallel to the imaging surface. Immobilization devices may be used to help provide correct positioning. The proximal femur should be midline of the femoral body parallel to the lateral edge of the scan. Additional skeletal sites for BMD measurements include the metacarpals, phalanges, and calcaneus. These sites are commonly used today with the use of computerized radiographic absorptiometry, computerized radiogrammetry, pDXA, and ultrasound equipment. A BMD study of the calcaneus, which

182 contains a high percentage of trabecular bone, and of the phalanges is useful sites in the prediction of future fracture risk.

DXA as a measure of body composition Medicare now classifies obesity as a disease. Body mass index (BMI) formulas and waist circumference measurements are not adequate to accurately define obesity. DXA has long been considered the gold standard in the precise measurement of a person’s percent body fat. There has been however a lack of accurate reference data from which to define healthful levels of percent body fat and muscle mass. The United States Center for Disease Control’s National Health and Nutrition Examination survey has taken on the task of collecting accurate body composition (% fat and % lean) in the United States. This reference data, collected from whole body DXA examinations on a single manufacturer’s equipment, should provide information for the accurate diagnosis of obesity with DXA.125

Interpretation of DXA Results A physician is responsible for issuing the request for a DXA examination. The technologist is responsible for ensuring that the measurement is made of the region requested, and that patient positioning is correct. When serial DXA examinations are conducted to monitor therapy, evaluate bone-loss, and follow patients who are not being treated but are at risk, consistent positioning in subsequent examinations is critical. A notation should be included in the patient’s chart regarding exact positioning, unique patient considerations, and the presence of artifacts that may have been noted. The technologist’s competency skill level and knowledge of the procedural applications are important, because accuracy and precision in BMD measurements determine ongoing patient monitoring and treatment. It is important for the technologist performing DXA scans and the interpreting physician to establish routine procedural and interpretation protocols. The physician bears the ultimate responsibility for the interpretation of DXA examination results. The technologist, however, must have an understanding of how the BMD values are interpreted, and what the scores imply. Additionally, because of the time spent with the patient during the DXA examination, the

183 technologist should be able to respond to questions and concerns that the patient might express. The technologist should be able to determine which of these to answer and which should be referred to the physician. The technologist may be directed by the interpreting physician to provide information about the test results (and what they represent) to the referring physician. Also, the technologist may be asked to provide community education about osteopenia, osteoporosis, and topics related to bone health, such as nutrition, exercise, and fall prevention, drug therapies, and healthy lifestyle choices. Most x-ray densitometry machines provide a paper copy image of the region of interest (ROI) being studied. Although these images are not FDA approved for making a structural diagnosis, the technologist should review the image. The technologist should closely review the scan image to determine if artifacts that may interfere with interpretation are present. If artifacts are present in the ROI requested by the physician, the technologist should refer to the supervising physician in selecting an alternate site. The technologist should note on the paper copy the presence of any structural artifacts or abnormalities, and this information should be provided to the interpreting physician. The technologist performing the BMD scan is responsible for establishing a copy of the scan for the patient’s permanent record. Information provided by the BMD scan is part of the patient’s medical record, a legal document, and as such is subject to the provisions of the Patient Privacy Act. Physicians use BMD values to predict the patient’s likelihood of future fracture risk. A doubling of fracture risk for each standard deviation (SD) decline in bone density is used for global fracture predictions. For site-specific fracture predictions, the predicative value depends on the anatomic site where the measurement is obtained. The standardized BMD information is reported in milligrams per square centimeter, and is not used for diagnosis, fracture risk assessment, or serial monitoring. Typically, after a bone densitometry test, a woman will receive one of four diagnoses: normal, osteopenia or osteoporosis.  Normal-the BMD is within 1 SD of a “young normal” adult (T-score at 1.0 and above).  Low bone mass (osteopenia)- The BMD is between 1.0 and 2.5 SD below that of a “young normal” adult (T-score between –1.0 and –2.5).

184  Osteoporosis- the BMD is 2.5 SD or more below that of a “young normal” adult (T-score at or below -2.5).  Severe or “established” osteoporosis.

185 Part 16 Radiation Safety

Benefit versus Risk

“Medical imaging has transformed medicine … and is the standard of modern medical care for diagnosis of most conditions and diseases. While imaging was once thought of primarily as a diagnostic tool, today it is used on the front line of treating, managing, and even predicting disease. The ability of medical imaging to provide physicians with this new information and new vision inside the human body has created dramatic improvements in the quality and length of lives. At the same time…the use of radiation exposure from medical imaging brings potential risk…”130

A new report on population exposure released March 3, 2009, by the National Council on Radiation Protection and Measurements (NCRP) noted that in 2006, Americans were exposed to more than 7 times as much ionizing radiation from medical procedures as was the case in the early 1980s.130 In 2006, medical exposure constituted nearly half of the total radiation exposure of the United States population from all sources.130 According to the NCRP report, the increase was due mostly to the higher utilization of CT and nuclear medicine imaging.130 These imaging modalities alone contributed 36% of the total radiation exposure and 75% of the medical radiation exposure of the United States population.131 The number of CT scans and nuclear medicine procedures performed in the United States during 2006 was estimated to be 67 million and 18 million, respectively.131 The growth of CT is widespread with more than 60 million examinations performed in 2008 compared with 3 million performed in 1980.131 Emergency room departments have an extreme increase in the use of pediatric CT imaging with an estimated 400% increase for some examinations such as chest and cervical spine.131 The use of CT in adults and children has increased about 8-fold since 1980, with annual growth estimated at about 10% per year.133 This increased use of CT is due to its utility in common diseases as well as technical improvements.133

186 According to the FDA and other federal agencies, benefits from the use of radiation in medical diagnostic imaging and for therapy purposes normally outweigh the small potential risks posed by such radiation.133 Despite this statement, the agencies expect referring physicians and radiologists to use prudent judgement when evaluating the risks versus the benefits when requesting medical imaging procedures. It is expected that the benefits and cost- effectiveness of the medical imaging procedure relative to the particular patient’s condition guide the decision.133 Physicians licensed in the healing arts bear the responsibility of using their knowledge and judgment to determine the benefits versus the risks of using ionizing radiation for each patient’s particular situation. The physician is responsible for determining the diagnostic efficacy of a x-ray procedure.133

Diagnostic efficacy is the degree to which a diagnostic study accurately reveals the presence or absence of disease in a patient.

It is recognized that some referring physicians and non-physician health care providers (i.e., physician assistants and nurse practitioners) are very knowledgeable about radiation safety issues and incorporate such decisions in their requests for imaging examinations. However, others have had minimal radiation safety training and do not consider radiation exposure factors when ordering imaging examinations.133 Furthermore, in many clinical situations, non- radiologists perform interventional procedures using fluoroscopy and CT. Although these individuals have credentials and are capable of performing the procedures, they may lack sufficient information about radiation protection and exposure dose factors. “At a recent international conference, the executive director of NCRP, cited self-referral, the process by which nonradiologist providers buy imaging equipment and refer patients to these in-office scanners as a primary, preventable driver of the dramatic increase in radiation exposure.”134 Furthermore, several concerned groups have recommended to the Centers for Medicare and Medicaid Services (CMS) that imaging services provided from such centers be removed from the list of providers.134 Many of these procedures are currently protected under the "in-office ancillary exception” to federal law

187 which allows providers to directly profit financially from referring patients to MRI, CT, and PET scanners which they own.134 A Government Accountability Office (GAO) report in June 2008, and peer-reviewed medical studies indicate that in- office CT, MRI, and nuclear medicine exams charged to Medicare from 1998 through 2005 grew at three times the rate of the same examinations performed in hospitals and independent diagnostic testing facilities. Studies by private payers such as the Blue Cross and Blue Shield organization indicate that nearly half of self-referred imaging is unnecessary.134 The ACR as well as others concerned about the publics’ increasing radiation exposure during medical procedures brought together a group of qualified experts to address the issues. The ACR Blue Ribbon Panel on Radiation Dose in Medicine was convened to assess the current situation and to develop an action plan for the ACR that would further protect patients and inform the public about the risks and benefits of medical imaging procedures using ionizing radiation. The committee released the American College of Radiology White Paper on Radiation Dose in Medicine in 2007, which made the following recommendations:  The ACR should work to convince the Liaison Committee on Medical Education and the Association of American Medical Colleges of the need for a standard methodology of introducing medical students to radiation exposure in medical imaging and offer to prepare learning materials in support of this initiative;  The ACR should work with the American Medical Association to ensure the wide dissemination and enactment of its Council Report on Diagnostic Radiation Exposure;  The ACR should request that the Council of Medical Specialty Societies (CMSS) address the critical issue of radiation exposure during medical imaging with its member societies;  The ACR should add relative radiation dose levels to its Appropriateness Criteria® and work to ensure that the Appropriateness Criteria® can be integrated into physician order entry systems for real-time guidance in ordering imaging examinations; and,

188  The ACR should sponsor a summit meeting with leaders from emergency medicine to discuss developing consensus guidelines for imaging common conditions for which computed tomography may be over-utilized.133

Once the decision has been made to perform a diagnostic imaging procedure, the physician, radiologist, and the technologist further accept the responsibility for protecting the patient from unnecessary and excessive radiation exposure. This concept of responsibility is known as ALARA, which is an acronym for As Low As Reasonably Achievable. ALARA encompasses all radiation safety measures, which as a whole minimize radiation dose. The ACR White Paper on Radiation Dose in Medicine (2007) made specific recommendations concerning the radiologist, radiographer, and medical physicist.134 The following is a brief overview of a few, but not all, of these recommendations:  The ACR should support the current multiorganizational effort to improve radiology resident training in medical physics;  The ACR should develop and implement maximum radiation dose estimate pass/fail criteria for the ACR CT Accreditation Program; and,  The ACR should encourage radiology practices to record all fluoroscopy times.132

In regard to the radiologic technologist The ACR White Paper on Radiation Dose in Medicine recommends:  The ACR should encourage radiology practices to provide in-service training on radiation safety issues for their technologists on a regular basis;  The ACR should phase in the requirement that at least one technologist per accredited CT site hold the American Registry of Radiologic Technologists advance registry in computed tomography and that at least one technologist per accredited nuclear medicine site hold the advanced registry in nuclear medicine or certification by the Nuclear Medicine Technology Certification Board; and,  The ACR should continue to support the Consistency, Accuracy, Responsibility, and Excellence in Medical Imaging and Radiation Therapy Act (i.e., CARE bill).132

189

An effective radiation safety program begins with staff commitment to safety. Most medical facilities providing imaging services must have an effective radiation safety program to ensure adequate safety of patients, staff, and the public. For any program to be successful it must have the financial and philosophical support of the administration, which generally confer actual responsibility and implementation to a radiation safety committee (RSC). Radiography staff bears responsibility for their own personal safety in:  Awareness of potential radiation hazards, exposure levels and ALARA safety controls;  ALARA operating policies and procedures; and,  Compliance with wearing personnel radiation monitoring badges and ensuring it’s return for the proper exchange frequency.

The technologist is “…typically the first, and may be the only, health care professional to interact with a patient presenting for an imaging procedure, and as such should be able to respond to patients’ imaging-related questions.”132 Technologists should be familiar with all imaging procedures within their realm of responsibility including the technical aspects and radiation dose and risk. Technologists are further responsible for reviewing the examination request and alerting a supervisor in cases where the patient may be subject to a duplicate or questionable imaging procedure. One of the most significant recommendations made by the Blue Ribbon Panel concerns adding relative radiation level (RRL) designations to the imaging procedures listed in the ACR Appropriateness Criteria®.136 “By prominently displaying the relative radiation exposure level for a particular examination during order entry, a clinician may be steered toward an imaging regimen that minimizes radiation.”136 These designations indicate the amount of radiation exposure that patients receive and the relative magnitude of that exposure. The RRL designations are based on the effective dose range of a particular imaging procedure. Effective dose is a quantity equal to the weighted sum of the doses to various body organs and tissues in which the weighting factors depend on the relative sensitivity to radiation-induced cancer or hereditary effects for those organs or tissues. According to the ACR relative radiation levels for DXA, QCT,

190 and DXA/VFA the examinations received a rating of minimal or low radiation exposure. In the United States, two primary agencies provide radiation protection standards, the Nuclear Regulatory Commission (NRC) and the National Council on Radiation Protection and Measurements (NCRP). The NRC, a federal agency, is charged with licensing facilities and controlling the use of radioactive materials. The NCRP, an advisory group, makes recommendations for radiation protection. In 1993, NCRP Report No. 116 Limitation of Exposure to Ionizing Radiation gave recommended values for occupational and public dose limits.137 These guidelines recommend that exposure to radiation should be “as low as reasonably achievable” (ALARA). The ALARA concept applies to bone densitometry patients, facility personnel, technologists, and the general public.137 The energy source in DXA equipment originates from a x-ray tube which, when activated, produces radiation. Although the quantity of radiation generated during BMD procedures is extremely low in comparison to the amount of radiation produced during medical diagnostic radiography procedures, the principles of ALARA must be used. For practical purposes, radiation protection guidelines are divided into 2 classifications for: the general public and occupational workers. The public group includes people who do not work in an occupation that uses radiation. For the public, radiation exposure, exclusive of any exposure received as the result of medical procedures, is limited to 1/10th (0.5 rem) of the effective dose limit for occupational workers. The annual effective dose limit for occupational workers is 5 rem (NCRP Report No. 116).137 The concept of ALARA is accomplished by the application of three basic principles:  Reduction of time spent in the area of the operational radiation source.  Distance between the radiation source and the individual to be protected.  Shielding between the radiation source and the individual to be protected.137

The technologist is responsible for radiation protection of the general public, patient, and staff, as well as for himself/herself. The technologist may accomplish this by several actions that include the following:

191  Prior to the examination, the technologist should ask if the patient has had a previous bone density study, and if so, when and where it was performed, and what kind of machine was used. This can reduce unnecessary radiation exposure, since patients should attempt to obtain bone density studies at facilities having compatible equipment.  The technologist should maintain quality control procedures prior to, during, and after the examination.  The technologist should correctly position the patient, and follow through with proper data acquisition. By avoiding restarting and/or repeating the scan, the technologist can decrease the patient’s radiation dose.  Patient motion during the scan may interfere with the diagnostic quality of the BMD measurement; resulting in a repeat scan and additional radiation exposure. The technologist should explain to the patient the importance of not moving during the scan, and should continually encourage the patient to remain still.

The frequency of bone density measurements also contributes to the patient’s radiation dose. Frequency standards were addressed in the 1997 Bone Mass Measurement Act; however, the ISCD 2007 Official Positions & Pediatric Official Positions quoted below from the 2007 ISCD Official Position Brochure (www.iscd.org) suggests the following reasons for serial BMD testing:  To determine whether treatment should be started on untreated patients, because significant bone loss may be an indication for treatment;  To monitor response to therapy by finding an increase or stability of bone density;  To evaluate individuals for non-response by finding loss of bone density, suggesting the need for reevaluation of treatment and evaluation for secondary causes of osteoporosis; and  To follow-up BMD testing when the expected change in BMD equals or exceeds the least significant change (LSC).

NOF recommends that repeating BMD examinations should agree with Medicare guidelines of every 2 years, but recognizes that BMD testing more frequently may be warranted in certain clinical situations.5 Environmental design

192 features may also be used to minimize radiation exposure to the public. These include posting a radiation-warning sign on the entrance door to the scan room, and limiting access to the examination room during scanning. A radiation- warning sign posted on the entrance door to the scan room serves as a warning to the public and staff that they should not enter when the door is shut. Also, many facilities post a sign regarding pregnancy that reads “Please tell the technologist if you are pregnant or suspect you may be pregnant”. During operation of the bone densitometry scanner, only the patient and technologist should be in the examination area. All entrance doors to the scan room should be kept closed during the operation of the scanner.

Radiation Protection for the Technologist The ALARA principles apply to radiation protection for the technologist performing bone densitometry. The three cardinal principles of ALARA are time, distance, and shielding. The length of scan times dictates not only the amount of radiation received by the patient, but also how long the technologist may be exposed to leakage and scatter radiation. The shortest possible scan time should be used to reduce the amount of radiation exposure to both the patient and the technologist. Distance from the source of radiation and the amount of shielding from the radiation source are also ALARA principles. Leakage and scatter radiation are low to nonexistent for fan-beam DXA devices, so the technologist should stand or sit at a distance of 3 feet or more from the x-ray tube. In the case of central DXA equipment, the x-ray tube moves during patient scanning, so the technologist should be positioned as far away from the energized x-ray source as possible. The technologist may also wear a radiation-monitoring device to track radiation exposure. Wearing one of these monitors is voluntary unless the anticipated radiation dose that an individual may receive is more than 1/4th of the effective dose limit.116 The 2 most common types of personnel radiation monitoring devices are the film badge and thermoluminescence dosimeter (TLD). A TLD is more sensitive to low doses of radiation than the film badge. The important thing to

193 remember when using either type of device is that they are for monitoring radiation exposure, and are not protective devices. One special concern is radiation exposure during pregnancy. The National Academy of Sciences/National Research Council Committee on the Biologic Effects of Ionizing Radiation (BEIR) recently published studies in the BEIR V report that suggest the fetus may be particularly radiosensitive during the period of 8-15 weeks post-conception.138 Observing all radiation protection guidelines to reduce radiation exposure is extremely important to anyone who is pregnant, including pregnant (or potentially pregnant) patients and personnel. The National Council on Radiation Protection (NCRP) guidelines currently recommend that the monthly equivalent dose limit (excluding medically necessary exposure) for the embryo not exceed 0.05 rem (0.5 mSv) once the pregnancy becomes known.138,139 It is highly unlikely that the technologist would approach this level of radiation exposure, but the ALARA concept should always be applied during bone densitometry procedures.

194

Part 17 Treatment

Treatment Many people think that there is nothing that can be done after a diagnosis of osteoporosis has been made. The good news is that the Federal Drug Administration (FDA) has approved bone-rebuilding drugs; however, more potentially effective drugs are always being developed.5 Current FDA approved drugs for the prevention and/or treatment of postmenopausal osteoporosis include bisphosphonates (alendronate, alendronate plus D, ibandronate, risedronate, risedronate with 500 mg of calcium carbonate and zoledronic acid), calcitonin, estrogens (estrogen and/or hormone therapy, estrogen agnoist/antigonist (raloxifene) and parathyroid hormone (PTH [1-34] teriparatide). Additional information about use and dosage levels may be found in the NOF’s Clinican’s Guide to Prevention and Treatment of Osteoporosis. After osteoporosis has been diagnosed, a physician prepares a treatment plan designed to help maintain the patient’s current bone mass and prevent additional bone loss. Treatment usually involves a long-term program that includes medication, diet, exercise, and regular serial BMD monitoring. It is important that the serial BMD measurements used to monitor a patient’s response to treatment be precise and accurate in order to detect small changes in BMD. Of the drugs the FDA has approved for the treatment of osteoporosis, hormone replacement therapy (HRT) has traditionally been an inexpensive choice for the prevention and treatment of osteoporosis in postmenopausal women. However, recent findings linking HRT to increased incidence of heart attacks, deep vein thrombosis, strokes, and breast cancer have caused physicians to reconsider its use. The Woman’s Health Initiative (WHI) study recently confirmed that one type of estrogen plus progestin (HT), Prempro®, reduced the risk of hip and other fractures, as well as colon cancer, but increased a woman’s risk of breast cancer, strokes, heart attacks, and venous blood clots. Upon analysis of the WHI results, the FDA made the following recommendations for all estrogen therapy (ET) and HT preparations:  Prescribe the lowest possible doses of ET and HT for the shortest period of time to manage symptoms of menopause; and,

195  Discuss alternative osteoporosis medications for women at risk for, or diagnosed with, osteoporosis.5

Bisphosphonates slow the rate of bone loss. The FDA has approved these drugs for both the prevention and treatment of osteoporosis, and for treatment of bone loss due to long-term glucocorticoid treatment.5 Patients taking bisphosphonate drugs report gastrointestinal disturbances with some severe digestive reactions, such as irritation, inflammation, or ulceration of the esophagus. Because of the possibility of such reactions, patients must take bisphosphonate drugs with 6 to 8 ounces of plain water and stay fully upright for at least 30 minutes after taking the drug. The pharmacological action of bisphosphonate drugs causes a reduction in the activity of the cells that cause bone loss, decreasing the rate of bone loss and increasing the amount of bone development. The use of bisphosphonate drugs is contraindicated in those with certain disorders of the esophagus, severe kidney disease, low blood calcium levels, or allergy to the drugs. Raloxifene, an estrogen agonist/antagonist, formerly known as selective estrogen-receptor modulators (SERMS) is FDA approved for both prevention and treatment of osteoporosis in postmenopausal women. Clinical evidence demonstrates that raloxifene (i.e., brand name Evista®) reduces the risk of vertebral fractures by about 30% in women with a prior vertebral fracture and by about 55% in those without a prior vertebral fracture over 3 years. Calcitonin is a non-sex hormone that regulates blood calcium levels and bone metabolism. It adjusts calcium blood levels by inhibiting osteoclasts and stimulating osteoblasts. Calcitonin is used to treat disorders of increased bone remodeling, such as Paget disease, and to treat osteoporosis in women who are at least 5 years past menopause. Calcitonin may be taken by mouth or via a nasal spray and oral calcitonin is FDA approved for treatment of osteoporosis (i.e., women who are at least 5 years postmenopausal).

Interventional Treatments Treatments for bone loss diseases and vertebral conditions, and injuries range from those that are conservative in nature (i.e., non-steroidal anti- inflammatory drug (NSAID) therapy, lifestyle modification, etc.), medicinal

196 approaches for relief of pain (i.e., patient controlled analgesia pump), to surgical intervention. Conservative treatment and lifestyle modifications have been mentioned throughout this course where applicable to the particular ailment. The information provided in this section will focus on image guided surgical interventions and treatments of spinal injuries and diseases. Acute and chronic back pain that does not respond to conservative treatment can diminish the patients’ quality of life and ability to be a productive member of society.140,141 As a reminder, pain that continues for more than 7 – 12 weeks despite conservative therapy is considered chronic.140 Before more aggressive pain management therapy is initiated, the patient’s medical history, physical examination, and prior imaging studies must be reviewed. Additional diagnostic imaging examinations and adjunctive tests may be used to reveal common causes of chronic pain such as fracture, malignancy, visceral or metabolic abnormality, deformity, inflammation, and infection.88

Radicular pain is most often associated with spinal nerve root irritation due to compression and inflammation.

Nonradicular pain is most often caused by abnormalities in the facet joints, sacroiliac joints and intervertebral discs.

The purpose of surgical interventions is to provide improvements (i.e., relief of pain and increased mobility), however the procedure may not achieve the expected results. The most important outcome of diagnostic spinal injections is the relief of pain; however, success cannot be guaranteed. The ACR and others recommend that informed consent must be obtained prior to such procedures.143,144 Informed consent requires that all risks should be made known and that the potential need for immediate surgical intervention should be discussed.144 Further, informed consent during spinal interventions must include information about the possibility that the patient may not experience significant pain relief.144 The success of such procedures as percutaneous vertebroplasty is measured against established indicator thresholds based on individual patient circumstances.144 For example, when percutaneous vertebroplasty is performed

197 for osteoporosis, the ACR suggests that procedure outcomes can be defined using the criteria established by Holder et. al., with patients categorized as worse, same, better, or pain/disability gone. When percutaneous vertebroplasty is performed for tumor or metastatic involvement, success is defined as achievement of significant pain relief and/or improved mobility.144 The overall procedure threshold for all complications resulting from percutaneous vertebroplasty performed for osteoporosis is 2%, and when performed for neoplastic conditions is 10%.144 In many cases, although exhaustive testing has been conducted to determine the cause of chronic back pain, the exact source of pain may not be found. In such cases, image guided diagnostic spinal injections may be performed to locate the source of pain.142 Fluoroscopy, CT, or MR imaging is used to monitor needle insertion and locations during the testing procedure. Indications for diagnostic spinal injections in those with chronic low back pain include:  Multilevel spinal involvement;  Uncertainty between the location of imaging pathology and clinical symptoms;  Lack of or inconclusive imaging information about potential abnormalities to corroborate clinical symptoms; and,  Clinical needs for presurgical testing.142

During diagnostic spinal injections, the physician uses controlled and comparative injections to identify the source of pain. The spinal structures that have been identified as a possible source of chronic back pain include:  An innervated structure;  A structure that is susceptible to pathologic changes that are known to be painful; and,  A structure that has been proven to be a source of pain in diagnostic studies conducted on healthy volunteers.145

During the diagnostic phase of testing, a minimal amount of diluted contrast agent is injected with the anesthetic into the targeted spinal structure. Placement of the needle tip and distribution of the solution can be monitored with imaging. To ensure reliability of a positive test result, physicians may use various

198 methods to confirm accuracy of the procedure and to reduce false-positive test results. Once the validity of the diagnostic spinal injection has been confirmed, a therapeutic spinal injection may be administered to relieve pain. A fundamental difference between diagnostic and therapeutic spinal injections is the volume and type (i.e., short acting versus long acting) anesthetic.146 When used for back pain relief, spinal injections contain corticosteroids to reduce inflammation, local anesthetics to relieve pain, or a combination of cortiocosteroids and anesthetics.146 Spinal injections can be more effective than oral medication because the injected medication is concentrated in the affected spinal structure. This procedure is especially helpful to those with surgical contraindications or inoperable conditions. Image guided therapeutic injections are also used to relieve pain after spinal surgery when other pain relief methods are either contraindicated or ineffective. Additional indications for therapeutic spinal injections include:  Adjunctive therapy to conservative management of pain;  Contraindications to oral or systemic pain medication or discontinuation of pain medication due to adverse effect; and,  Presence of adjacent structural deterioration after spinal fusion surgery.142

Diagnostic and therapeutic spinal injections are also performed on the lumbar facet joints, sacroiliac joints, and selected nerve roots. Since there are no standardized references upon which to base specificity and sensitivity of diagnostic spinal testing, the measure of success is determined by short-term and long-term effects of pain relief. Pain relief of 50% to 80% is regarded as an indication that the targeted spinal structure was a significant source of pain.146 Furthermore, test accuracy and reduction of complications with spinal injections is accomplished when performed with image guidance. Fluoroscopy and CT are both widely used and provide comparable results; however, fluoroscopy is generally more cost-effective. CT is often preferred for injection guidance procedures of the sacroiliac joints and in spinal structures compromised by osteophytes and in structures near the spinal cord. MR imaging is also effective in injection guidance procedures and does so without ionizing radiation, which is particularly important when imaging children and those who undergo serial therapeutic injections.

199 Discography is another image-guided tool used to diagnose sources of back pain. It is the only functional test for the assessment of disc back pain and allows for individual testing of intervertebral discs to determine the level of pain generation. The examination also allows assessment of the intervertebral disc architecture. Fluoroscopy, CT, and MR imaging have been used to perform discography.67,68 The procedure is similar to that described for diagnostic spinal injections and the procedure may be used for both diagnosis and treatment.

Surgical Intervention Surgical spine procedures are performed to relieve pressure on the spinal cord or the nerve roots, to stabilize and fuse spinal structures, and to augment vertebral structures through kyphoplasty and vertebroplasty. Laminectomy, also commonly referred to as spinal decompression, can be performed on all regions of the spinal column to relieve pressure on the spinal cord or the nerve roots.147 A laminectomy is a procedure in which the lamina or bony roof of the spinal canal is removed. Once removed, the size of the spinal canal is increased, providing more room for the spinal cord or nerve roots. Narrowing or spinal stenosis is caused by a variety of diseases and conditions that cause pressure on the nerve roots and/or spinal cord. Decompression helps relieve pain and associated symptoms of spinal cord stenosis. Currently, depending on the patient’s status, minimally invasive image-guided surgical procedures are used to perform laminectomy. Prior to laminectomy, appropriate diagnostic imaging procedures are performed and usually during the post-operative period MR imaging is used to evaluate the spinal cord. Stabilization and fusion of the spine may be performed using various anterior and posterior surgical techniques and a wide range of devices, including screws, spinal wires, artificial ligaments, vertebral cages, and artificial discs.168 Both pre-operative and post-operative radiography is used to evaluate the spine. CT and MR imaging are valuable alternatives; however, MR imaging of the postoperative spine may not be possible due to metal-induced image artifacts. Spinal stabilization and fusion with instrumentation was first described in 1911 as a method for treatment of Pott disease. Since that time, a variety of spine instrumentation has become available. Examples of spinal hardware that the radiographer may encounter on spine images include:

200  Plates or rods with pedicle screws;  Translaminar or facet screws; and,  Hartshill rectangles.148

Radiographs of spinal hardware may be viewed at http://radiographics.rsnajnls.org.168 The choice of instrumentation and surgical approach depends on the clinical condition, the anatomic location, and the surgeon’s preference. Posterior surgical approaches are generally used when posterior decompression is required in addition to fusion. Anterior surgical approaches are used when pain is primarily discogenic and posterior decompression is not required.148 Today a vertebral body may be replaced after resection due to tumor, infection, or trauma and a total disc replacement is possible for those whose pain originates mainly from disc degeneration without nerve root involvement. Instrumentation is not intended to replace the bony structures of the spine but rather to stabilize them during the fusion process. Dynamic stabilization is a possible alternative to fusion in certain patients with low back pain originating from chronic degeneration of the lumbar spine. A stabilization intervention helps to reduce the stress load placed on a particular segment of the spine. The procedure also provides control of abnormal motion of the spine, which may prevent progressive degeneration.148 Postoperative imaging is used to:  Assess the progress of the bony fusion;  Confirm correct positioning and integrity of the instrumentation;  Detect suspected complications; and,  Detect new disease or disease progression.148

Percutaneous vertebral augmentation is a minimally invasive procedure to supplement a vertebra that has fractured because of osteoporosis or injury to the spine. There are two types of percutaneous vertebral augmentation, vertebroplasty and kyphoplasty.

201 Vertebroplasty and Kyphoplasty Vertebroplasty was originally developed in France in 1986 and has since been further refined and available in the United States since 1991.149 Kyphoplasty is a newer treatment and is used for those who are immobilized by painful vertebral body compression fractures associated with osteoporosis. Indications for vertebroplasty are osteolytic vertebral metastasis, myeloma, vertebral hemangioma, and vertebral collapse due to osteoporosis or other bone loss diseases. Contraindications to both vertebroplasty and kyphoplasty are coagulation disorders and extensive vertebral destruction (i.e., vertebra reduced to less than one-third of its original height). Absolute contraindications are published in the ACR Practice Guideline for the Performance of Percutaneous Vertebroplasty that include:  Asymptomatic vertebral body compression fractures;  Patients who are improving on medical therapy;  Nonfractured vertebral levels;  Prophylaxis in osteoporotic patients (unless being performed as part of a research protocol);  Osteomyelitis of the target vertebra;  Myelopathy originating at the fracture level;  Uncorrectable coagulopathy; and,  Allergy to bone cement or opacification agent.144

Both vertebroplasty and kyphoplasty utilize an orthopedic cement-like material that is injected directly into the fractured bone. Often the injection material, polymethyl methacrylate (PMMA), is combined with a contrast agent to allow imaging of the material distribution, and an antibiotic to reduce the risk of infection. A major advantage of kyphoplasty is that the injection is able to restore height to the spine structure thus reducing the deformity.144 Kyphoplasty is a two- part process in which the first step consists of inserting a balloon device into the compacted vertebrae to attempt to restore the vertebrae to a more normal shape. The cement material is then injected into the space created by the balloon device in an attempt to retain the height correction and restore the vertebra to a more normal size and shape.

202 Fluoroscopy and CT imaging are used during vertebroplasty and kyphoplasty in guidance and proper placement of the injection needle and administration of the stabilization cement material. Once injected the cement hardens quickly, providing strength and stability to the vertebra. During vertebroplasty and kyphoplasty procedures a technologist and nursing staff are in attendance and responsible for patient comfort. According to ACR guidelines, the examination suite should have adequate resources for observing patients during and after the procedure. This includes equipment for monitoring blood pressure, pulse oximetry, electrocardiography, and cardiopulmonary resuscitation equipment.144 Further the ACR recommends adherence to the Joint Commission’s Universal Protocol for Preventing Wrong Site, Wrong Procedure, Wrong Person Surgery™, which is required for procedures in non-operating room settings including bedside procedures. This protocol requires a “Time out” conducted in the location where the procedure will be performed and just before starting the procedure.144 The “Time out”:  Involves the entire operative team;  Uses active communication; and  Documents on a checklist the following information -Correct patient identity -Correct side and site -Agreement on the procedure to be done -Correct patient position -Availability of correct implants and any special equipment or special requirements.144

There should be standard protocols in place for reconciling differences in staff responses during “Time out”. Side effects and complications during and immediately following augmentation procedures include worsening of pain and fever and complications associated with leakage of the cement material. The ACR guideline recommends that facilities performing vertebroplasty and kyphoplasty have immediate access to CT and rapid (within 30 minute or 45 minutes) access to MR imaging to evaluate potential complications.144

203 Part 18 Prevention of Bone Loss

Prevention of osteoporosis requires a lifetime of many healthy living activities that include good nutrition, adequate intake of calcium, vitamins, and minerals, daily weight-bearing exercise, and avoidance of smoking and alcohol. Achieving recommended levels of intake for calcium, vitamin D, and other nutrients during infancy, childhood, and adolescence is critical to maintaining healthy bones throughout life. Adequate calcium in the diet is essential for strong healthy bones and requirements are based on age and reproductive stage. Adequate calcium intake is critical for infants, children, and adolescents. Nutrition is important to bone health even before birth. The largest influx of calcium into the fetal skeleton occurs during the last trimester of human pregnancy. Most newborns will receive adequate levels of calcium from their mothers during full-term pregnancies, and from breast milk, formula, and/or solid foods during the first year of life. Infants who are born prematurely “miss out” on some calcium before they are born and will likely have lower bone mass at birth than will a full-term infant. While breastfeeding provides important advantages to premature infants, it may not provide for all of their needs. As a result, health care professionals should encourage parents of premature infants who are being breast fed to use supplements that provide added nutrients, particularly calcium, vitamin D, phosphorus, and protein. Health care professionals should advise the parents of premature infants who are not being breast fed about the importance of using infant formulas that are designed to provide calcium and phosphorus intakes similar to those that occur in utero during the last trimester of normal human pregnancy. Even when premature infants use such formulas, it can take up to 5 years for their bone mass to catch up with that of full-term newborns. Children between 1 and 3 years old should get 500 mg per day of calcium, and those between 4 and 8 years old should consume 800 mg per day.1,5 Milk and foods derived from milk (e.g., cheese, and yogurt) serve as the major food sources for calcium throughout childhood and adolescence. Any type of milk (whole, lowfat, or nonfat) provides the same level of calcium, but low-fat milk is the best choice for children over age 2. Additional sources include foods supplemented with calcium, such as fruit juices, fortified soy beverage, breads, and other breakfast foods, which can help to boost overall dietary calcium intake

204 levels towards the recommended values. Since foods that contain calcium also have many other important nutrients, health care professionals should encourage parents and their children to strive for recommended levels of calcium intake through diet alone. The second most rapid bone mass gains occur with the onset of puberty, which also marks the time that calcium intake, needs become greatest. Children 9 to 18 years old should consume 1,300 mg per day of calcium. 1,5 Puberty is also the time that ethnic and gender differences in bone mass are first seen. Bone mass tends to be higher in African-Americans than in Caucasians, and higher in males than in females. Girls and boys experience their most rapid rate of bone growth during puberty, and by the end of puberty they have almost achieved peak mass. Hence, the teenage years are especially critical to maximizing skeletal growth. Girls and, to a greater extent, boys also accumulate bone mass during and after puberty, with some additional mass being gained even in the third decade of life. Finally, it is worth noting that a delayed onset of puberty is associated with a reduction in peak bone mass attainment. Few adolescents consume recommended levels of dietary calcium. Based in the National Health and Nutrition Examination Surveys (NHANWS), children up to age 9 consume the recommended amount of calcium.1,5 Consumption begins to decline slightly just as the calcium requirements to sustain pubertal growth goes up. Health care professionals should inquire specifically about calcium intake during check-ups. It is useful to remember that while fluid milk consumption decreases as children progress to adolescents, both children and adolescents consume mixed foods such as pizza that contain considerable amounts of calcium through cheese. It is important to recognize that even in the context of obesity and other chronic disease prevention, low-fat and nonfat, calcium-rich dairy foods can be emphasized as a way to promote bone health without having a negative impact on efforts to manage weight. Calcium supplements may be used for those individuals who would otherwise have a chronic, sub-optimal intake of calcium and are unable to meet the requirement for calcium through diet alone. Calcium intake should be 1,000 mg per day during early and middle adulthood.1,5 A quick assessment of calcium intake can be made by estimating that a diet without dairy products contains approximately 250-300 mg per day of

205 calcium.1,5 Calcium supplements can be critical for those persons who cannot meet calcium requirements through food alone. In the absence of gastrointestinal disease, all major forms of calcium supplements are absorbed equally when taken with meals. The citrated salts may be more readily absolved in individuals with gastrointestinal disease or decreased stomach acid production. Since different types of supplements may contain different amounts of elemental calcium, it is important to check the label and to determine the exact amount of calcium in the supplement, in order to achieve the targeted level of calcium intake. Calcium supplements should be ingested no less than 4 hours before or after taking iron or thyroid medications, since calcium may decrease the absorption of these other medications. The efficiency of calcium absorption from supplements is greatest when calcium is taken in doses of 500 mg or less. 1,5 Calcium intake, be it through food and/or supplements, should be spread throughout the day, and the daily requirement should not be consumed at a single setting. NOF supports the National Academy of Science (NAS) recommendation that women older than age 50 consume at least 1,200 mg per day of elemental calcium. The calcium dose must be divided (500 mg) and taken twice a day. 1,5 Intakes in excess of 1,200 to 1,500 mg per day have limited potential benefits. 1,5 Men and women age 50 and older usually only consume about 600 to 700 mg per day of calcium in their diets so increasing daily dietary intake of calcium is a first approach. Calcium can be obtained by increasing dietary servings of calcium-rich foods such as milk, yogurt, cheese, and fortified foods or juices. It is important for health care providers to emphasize to patients that the upper tolerable level for calcium intake recommended by the Institute of Medicine is 3,500 mg per day. 1,5 In some individuals, this limit should be even lower, since those who are susceptible can become hypercalciuric with calcium intakes as low as 1,500 mg per day. 1,5 Health care professionals should ask their patients if they regularly take antacids, since many of them may not know that common antacids contain high levels of calcium. As a result, those individuals who take antacids regularly may be consuming calcium at the higher-than-recommended levels. Vitamin D deficiency rickets is being recognized with increased frequency in the United States and other western nations, particularly among breastfed babies, children with dark skin, older individuals, and individuals with unusual

206 diets (e.g., vegans) or insufficient sunlight exposure.18 Rickets is most likely to occur during growth spurts, when requirements for calcium and phosphate are elevated. 1,5 Rickets is uncommon in newborns but may be seen in children as young as 6 months of age. The most significant risk factor for nutritional rickets in young children is unsupplemented breastfeeding for more than 6 months.18 The American Academy of Pediatrics recommends administration of 200 international units (IU) of vitamin D per day to all breastfed infants after 4-5 weeks of age.1,5 Clinical manifestations of osteomalacia and rickets include fatigue, malaise and bone pain. 1,5 Treatment of rickets, in general, consists of regular daily supplementation of vitamin D and calcium, if simple vitamin D deficiency is the cause. Some people may benefit from a single injection of vitamin D. Radiographically, bone affected by osteomalacia and rickets appears with an overall reduction in bone mineral density. Bone protein content (osteoid) is composed primarily of type I collagen. When there is insufficient mineral or osteoblast function, the osteoid tissue does not mineralize properly, and it accumulates. When the newly formed bone of the growth plate does not mineralize, the growth plate becomes thick, wide, and irregular. 1,5 Areas of reduced bone mineral density are referred to as looser’s zones and appear as short, lucent lines. Looser’s zones are particularly seen at the lateral margin of the scapula and the medial femoral neck. Vertebral collapse may be seen as well as transverse fractures at these locations of reduced bone mineral density. 1,5 Vitamin D is an important factor in calcium absorption, bone health, muscle performance, and balance. As with calcium, adequate levels of vitamin D are critical to forming and maintaining healthy bones throughout infancy, childhood, and adolescence. Full-term infants who are fed human breast milk appear to mineralize the skeleton similarly to infants fed commercial formulas, including soy-based formulas for infants with an intolerance to cow’s milk. However, infants who are exclusively breastfed and who have limited exposure to sunlight are at increased risk of developing vitamin D deficiency. Severe vitamin D deficiency can lead to rickets. The American Academy of Pediatrics has suggested that all infants who are exclusively breastfed receive 200 IU of vitamin D daily to lessen the likelihood of developing rickets. 1,5

207 Vitamin D requirements during childhood are 200 IU daily, which is the amount contained in two glasses of fortified milk or in most children’s multi- vitamins. 1,5 There are also rare cases of rickets in children who have congenital disorders of vitamin D or phosphorus metabolism and health care professionals should be alert to this possibility. The recommended diet for optimal bone health is consistent with diets recommended for the prevention of other diseases. NOF recommends that individuals who are age 50 and older should have a daily intake of 800 to 1,000 international units (IU) of vitamin D. 1,5 Those who are housebound, chronically ill and have limited sun exposure may require higher doses of vitamin D to bring the blood serum level to 25 (OH)D or higher. 1,5 In 1997, the safe upper limit for vitamin D intake for the general population was set at 2,000 IU per day but current evidence indicates that higher intakes are safe and that some elderly patients may need at least this amount to maintain optimal levels. 1,5 There has been some concern that the high intakes of protein, salt, and phosphorus by children and adolescents who eat high-calorie, low-nutrient foods and drink soda can impair bone growth and mineralization. This may be true if these intakes are at the expense of calcium-rich foods, but studies in adolescents have shown that intake of the recommended levels of calcium intake can compensate for high levels of protein, salt, and phosphorus. Sodium chloride intake increases urine calcium excretion, and excessive intake of salt may increase bone resorption in postmenopausal women, although this effect may be offset by adequate calcium intake. The Institute of Medicine recommends an intake of no more than 2,400 mg per day of sodium. 1,5 Individuals can reduce their intake by avoiding canned, jarred, cured, and processed foods in home cooking. The nutritional guidance provided for young and middle-aged adults also applies to older individuals and the elderly. Calcium and vitamin D absorption decreases with aging and older individuals with limited mobility tend to receive less sunlight, leading to rates of vitamin D deficiency of up to 57% in this population. As a result, recommended levels of both calcium and vitamin D increase in this population.

208 Exercise, Clothing, and Fall Protection Tips Bones require regular weight-bearing exercise to maintain peak mass and agility. Daily exercise throughout one’s lifetime, as well as intake of adequate calcium and vitamin D, may slow the bone mineral density decline associated with aging.1,5 A person with low bone density should practice good posture and safe movements. Examples of unsafe movements include exercises that involve twisting the spine, bending over from the waist with straight legs, or doing stomach crunches, or toe touches. Often, the physical changes that result from fractures make it hard to find clothing that fits properly. People with vertebral fractures lose height, and develop a curved back and protruding abdomen. Modification of clothing to accommodate the physical changes can make getting dressed and undressed easier for the person with osteoporosis. Additionally, the technologist may need to provide help to the patient in dressing prior to and after the DXA examination. Preventing falls is important for anyone with osteoporosis. Each year about one-third of all persons over age 65 experience a fall, which may result in a bone fracture, most often of the hip or wrist. The following are just a few indoor safety tips that can be used to fall-proof the inside and outside environment:  Keep floors free of clutter. Remove all loose wires and cords that are in a high-trafficked area.  Use non-skid mats or rugs on the floor, and clean up spills immediately.  Install grab bars on the bathroom walls beside the tub, shower, and toilet. Use a non-skid rubber mat in the shower or tub.  Wearing a personal emergency response system, if living alone.  Cover porch steps with gritty, weatherproof paint.  Slow down because accidents are more likely to happen to those who do things in haste.  Wear supportive, rubber-soled, low-heeled shoes.

209 Part 19 Course Conclusion

Major advances in bone health have been made over the past decade. The knowledge base needed for clinical decision-making has grown substantially, resulting in a much better understanding of the risk factors for poor bone health outcomes and strategies and interventions for reducing that risk. Measurement of bone density has become more widely available as the equipment for BMD testing has become less expensive. New and well-tolerated drugs have been introduced that are effective in increasing BMD and preventing fractures. Fall prevention programs have been developed and demonstrated to be effective. For those individuals who are at extremely high risk of fracture, rigorously tested hip protectors can significantly reduce fracture from a fall. Some payment decisions (e.g., Medicare'’ decision to cover BMD testing) have facilitated identification of those who need specific treatment to help prevent fracture. Finally, there has been increased public awareness of the importance of bone health and the potential consequences of osteoporosis. Clinicians, technologists, and health care providers all play a crucial role in the delivery of care and the ongoing need to diagnose, treat, and monitor bone loss diseases.

210 Bone Loss Diseses & Imaging Considerations (2012-2014)

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