ChAptER 50 and

Laura M. Borgelt and Danielle R. Fixen

The United States and Initiative, as part attention to screening patients, provide education, of the Global Alliance for Musculoskeletal Health, perform research, and work to help ensure proper is the U.S. National Action Network of the Global management and follow- up of patients diagnosed Bone and Joint Decade.1 It is a group of patient with these and related disorders as a way to help and healthcare professional organizations, medical prevent the devastating consequences of fracture schools, government agencies, health- system pro- and its potential complications of , dis- viders, and industry established to improve preven- ability, and death.1 This includes evaluation of med- tion of bone and joint disorders and the quality of life ications that may cause musculoskeletal conditions for those affected by these conditions. The primary such as osteoporosis and osteomalacia. goal of this initiative is to advance care and reduce Deterioration of bone mass not associated with the burden of disease for individuals with various other chronic illness is referred to as primary osteo- musculoskeletal conditions. Other goals include porosis and is related to aging and decreased gonadal increasing awareness and educating the world on function. Secondary osteoporosis can be viewed as the increasing societal impact of musculoskeletal low density or increased risk of fragil- injuries and disorders, empowering patients to par- ity fracture caused by any factor other than aging or ticipate in decisions about their care and treatment, postmenopausal status, such as medical disorders or increase global funding for prevention activities exposures.2 Differentiating between pri- and treatment research, and continually seeking mary osteoporosis and the various causes of second- and promoting cost-effective prevention and treat- ary osteoporosis can be challenging due to the many ment of musculoskeletal injuries and disorders. disease states and drugs that may be involved. Indi- Although many musculoskeletal conditions are viduals with secondary osteoporosis experience bone incorporated into its aims, osteoporosis is recog- loss greater than that caused by aging and meno- nized as a significant contributor to the healthcare pause in primary osteoporosis, and it is especially burden worldwide. The spirit of this initiative sug- important, therefore, to identify, accurately evaluate, gests that all healthcare providers should increase and appropriately treat these patients.2

1119 1120 DRUG-INDUCED DISEASES: Prevention, Detection, and Management

Osteomalacia is a softening of the , typi- incidence are not available. More than two thirds cally due to deficiency and less commonly of men, more than half of premenopausal women, due to hypophosphatemia or hypocalcemia. In chil- and approximately one third of postmenopausal dren, this condition is called . Osteomalacia women with osteoporosis have a disease state or can cause fatigue, , muscle weakness, drug therapy contributing to their bone loss.65 The and difficulty and result in .3 incidence of drug-­­induced bone loss or increased Drugs that may affect vitamin D metabolism should bone fragility is difficult to quantify, as be cautiously prescribed in patients at risk for the usually contribute to an increased risk of osteopo- development of osteomalacia. rosis rather than represent its sole cause. Table 50-1 provides information regarding the risks for bone CAUSATIVE AGENTS loss and fractures with drug use. is one of the most com- Medications commonly associated with osteoporo- mon secondary causes for bone loss and fractures, sis or osteomalacia are listed in Table 50-1.4-59 The especially in the elderly. Prolonged, severe vitamin D impact of each of the medications on bone mineral deficiency can to poor bone mineralization density (BMD) or fracture incidence (or both) is and osteomalacia. The overall incidence of vitamin presented where data are available. D–induced osteomalacia is not precisely known, are the most common cause of but it appears to be lower in the United States than drug-in­­ duced osteoporosis, and their effects appear in many other countries because of fortification of to be dose- and duration-­­dependent.2,45 An increased milk with vitamin D. risk of fracture has been reported for patients tak- ing 2.5 mg or more daily; national rec- MECHANISMS ommendations indicate prednisone >5 mg/day (or equivalent exposure to other glucocorticoids) for The process through which bone undergoes repair >3 months may result in low bone mass or bone and readjustment is called , and loss.60 Approximately 30–50% of patients receiving there are three main cells involved in this process: long-t­­erm therapy will experience a , osetocytes, and . Osteoblasts fracture.47,48 are derived from a mesenchymal stem precursor and are responsible for synthesizing the organic bone matrix () and mineralizing the bone. EPIDEMIOLOGY , which are retired osteoblasts trapped in It is estimated that over 200 million people world- bone, are considered the communication cells and wide suffer from osteoporosis.61 Approximately 10 help coordinate the remodeling cycle at a particu- million Americans have osteoporosis and an addi- lar site. Osteoclasts are derived from hematopoietic tional 43 million have low bone mass or osteope- precursors of the monocyte–macrophage lineage nia as defined by the World Health Organization and are responsible for . (WHO).60,62 This accounts for approximately 55% of The remodeling process begins when the people age 50 years and older in the United States. receptor activator of nuclear factor kappa-B ligand More than 2 million fractures were attributed to (RANKL), which is secreted from the pre- osteoporosis in 2005 and this number is expected cursor cells, binds to its receptor activator of nuclear to exceed 3 million by 2025.63 Fracture rates in other factor kappa-B (RANK) on the surface of the osteo- countries tend to vary. For example, and clast precursor cells. This to the differentiation fracture in the United Kingdom occurs at a rate and activation of mature osteoclasts, which in turn about 30% lower than that in the United States and resorb bone through the degradation of the incidence differs among various Asian matrix and demineralization. Once bone resorption countries.64 Although secondary osteoporosis is is complete at that site, cytokines and growth factors known to be common, precise data regarding its that are involved in chemotaxis, proliferation, and