Nutrition & The

® MAY 2006 MAY VOL. 32 NO. 5 continued on page 2 continued on page is intended for ® and prothrombin) Table 1. Physiologic Processes Dependent on Dependent Processes 1. Physiologic Table Calcium transduction (“second messenger”) Intracellular signal Neuronal transmission and contraction) excitation Muscle function (linking VII, for factors Blood coagulation (cofactor IX, X, Enzymatic cofactors integrity Cellular membrane and cytoskeletal Hormone secretion (e.g. insulin) Biomineralization In This Issue in the Calcium is the best-selling dietary supplement United States, of this intake adequate achieving but This month’s nutrient remains a challenge for many. the importance of maintaining lead article reviews proper calcium homeostasis through diet and not at the calcium. Related articles will look of skeletal expense at the most recent clinical trials of calcium and vitamin D supplementation, potentially as well as a rare but osteoporosis drug therapy. of debilitating side effect Why Are Calcium-Deficient? We Perspective...... 4A Paleolithic Supplementation and Bone Health: Interpreting the Latest Findings...... 5 Us Tell Study WHI What Does the D Status?Vitamin About ...... 6 Bone-Building Drugs Can Have Opposite Effect ...... 7 ionized calcium is physiologically significant and tightly ionized calcium is physiologically significant In response to a decrease in ionized calcium, regulated. occurs,rapid release of parathyroid hormone (PTH) which and bones in the kidneys mechanisms acts through several to restore eucalcemia. In the distal nephron, PTH mediates Nutrition & the M.D. The cal- 1 After reading this article,After reading the The continuing education activity in The continuing education activity

physicians and health care professionals with an interest in nutrition-related disorders. physicians and health care professionals with an interest in nutrition-related

analysis of calcium and vitamin D status. status may be increasing in prevalence. status may be increasing maintains calcium homeostasis.

the Professional Nutrition & the M.D. Nutrition the Professional by cium content of bone correlates directly with resistance to cium content of bone correlates directly as the areal bone fracture and can be clinically measured x-ray absorptiometry mineral density with dual-energy skeletal The presence of minor impurities makes (DEXA). salts soluble, hypocalcemia defense against an invaluable Consequently, intake. calcium during periods of low when calcium consumption is insufficient, bone is preferentially demineralized to meet systemic, func- calcium-dependent 1). Increased metabolic demands for calcium tions (Table to explain,are believed in part, loss of bone the frequency chronic inflammatory with aging and in various observed diseases. However, of calcium and intake with sufficient vitamin D and a functioning calcitropic hormonal axis, the body can maintain the proper balance between the metabolic and structural needs for calcium. Calcium Homeostasis calcium—complexed Of the three states of extracellular (10%), protein-bound (40%), and ionized (50%)—only Protect and Defend Protect 1 kg of calcium,The adult human body contains nearly of salts of the which 99% is found in the hydroxyapatite skeleton, it with strength and stiffness. endowing 3. laboratory that complicate Describe the factors 2. why poor calcium and vitamin D Cite the reasons Jordan L. Geller,Jordan MD at the Cedars-Sinai Geller is a practicing endocrinologist Dr. in endocrinology at Medical Center and a clinical instructor the UCLA School of Medicine,Angeles, Los CA. Learning Objectives: participant should be able to: the body which 1. through State the mechanisms Borrowing Against the Bones: Borrowing Eucalcemia in the The Price of State Calcium-Deficient The author has disclosed that he has no significant relationships with or financial pertaining to this educational activity. commercial organizations interests in any Lippincott CME Institute, Inc., conflicts all faculty has identified and resolved of interest. Written for 605899_NMD05_sw 5/25/06 2:19 PM Page 1 Page PM 2:19 5/25/06 605899_NMD05_sw

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2 May 2006 Nutrition & the M.D.

Editors Borrowing continued from page 1 Peter Pressman, MD, MS, FACN* Cedars-Sinai Medical Center, Los Angeles, CA Sunlight Roger Clemens, DrPH, CNS, FACN† University of Southern California, Los Angeles, CA UVB Editorial Administrative Support Debra K.W. Topham, MS, CNS OTC Knowledge Bank, Huntington Beach, CA Diet Vitamin D3 Vitamins Staff Writer Kevin Lomangino Vitamin D South Portland, ME 25-hydroxylase Editorial Board – Lilla Aftergood, PhD Liver University of California, Los Angeles, CA Judith Ashley, PhD, RD University of Nevada, Reno, NV 25(OH)D3 Brent A. Bauer, MD Mayo Clinic College of Medicine, Rochester, MN α P1 and other 25(OH)D-1 – Michael A. Bush, MD factors hydroxylase Cedars-Sinai Medical Center, Los Angeles, CA Dennis W. Cope, MD, FACP +/– Kidney University of California, Los Angeles, CA 1,25(OH )D 1,25(OH )D Ellen DiGiampaolo RD 2 3 2 3 Inglewood, CA David S. Gray MD – Sonoma Developmental Center, Eldridge, CA Clare M. Hasler, PhD, MBA PTH University of California, Davis, CA Penny M. Kris-Etherton, PhD, RD Bone PTH Penn State University, University Park, PA Denise B. Schwartz, MS, RD, FADFA, CNSD Intestine Providence St. Joseph Medical Center, Studio City, CA Linda Strause, PhD Parathyroid Strategic Research Management Consultant, Del Mar, CA glands

Randy K. Ward, MD 2 2- 2 2- Medical College of Wisconsin, Milwaukee, WI Ca +HPO4 Ca +HPO4 *Dr. Pressman has disclosed that he is/was a member of the speakers bureau for Pfizer. Calcification Blood † Dr. Clemens has disclosed that he has no significant relationships with or financial inter- calcium ests in any commercial organizations pertaining to this educational activity. Nutrition & the MD® (ISSN 0732-0167) is published monthly Figure 1. The calcitropic hormonal axis. OTC, over-the- by Lippincott Williams & Wilkins, Inc., 16522 Hunters Green Park- way, Hagerstown, MD 21740-2116. Customer Service Manager, counter; PTH, parathyroid hormone; UVB, ultraviolet B. Audrey Dyson: Phone (800) 787-8981 or (410) 528-8572. 24-Hour Reprinted with permission from http://geneticslab. Fax (410) 528-4105 or Email [email protected]. Visit our website at LWW.com. Publisher, Daniel E. Schwartz: Phone (410) 528-4020, topcities.com/VitaminD%20homeostasis.jpg. Fax (410) 528-4105. Copyright © 2006 Lippincott Williams & Wilkins, Inc. All rights reserved. Periodicals avid reabsorption of filtered calcium, whereas in the proxi- Postage paid at Hagerstown, MD, and at additional mailing offices. POSTMASTER: Send address changes to Nutrition & the MD®, Subscription Dept., Lippincott Williams & mal tubule, it promotes generation of the active vitamin D Wilkins, P.O. Box 1600, 16522 Hunters Green Parkway, Hagerstown, MD 21740-2116. metabolite, 1,25-dihydroxyvitamin D. A steroid hormone, Publisher: Daniel E. Schwartz vitamin D regulates the synthesis of calcium channels and PAID SUBSCRIBERS: Current issue and archives (from 1999) are now available FREE online at www.lwwnewsletters.com. transport proteins in the intestines essential for the absorp- Subscription rates: Personal: $107 US, $141 Foreign. Institutional: $177 US, $211 tion of calcium (Figure 1). Without adequate vitamin D or Foreign. Resident: $67 US, $71 Foreign. GST Registration Number: 1380876246. Send calcium, sustained secondary hyperparathyroidism will bulk pricing requests to Publisher. Single copies: $15. COPYING: Contents of Nutri- tion & the MD® are protected by copyright. Reproduction, photocopying, and storage indirectly stimulate osteoclastic bone resorption to release or transmission by magnetic or electronic means are strictly prohibited. Violation of calcium from bone. Although secondary hyperpara- copyright will result in legal action, including civil and/or criminal penalties. Permis- sion to reproduce in any way must be secured in writing from: Permissions Dept., Lip- thyroidism can maintain serum calcium during transient pincott Williams & Wilkins, 351 W. Camden Street, Baltimore, MD 21201; Fax (410) shortages, it is clearly maladaptive in the modern setting of 528-8550; E-mail: [email protected]. For commercial reprints, contact Kimberly Chek at (410) 528-4556 or [email protected]. sustained insufficiency of calcium and vitamin D. Nutrition & the MD® is independent and not affiliated with any organization, vendor, or company. Opinions expressed do not necessarily reflect the views of the Calcium and Vitamin D Requirements Publisher, Editor, or Editorial Board. A mention of products or services does not constitute endorsement. All comments are for general guidance only; professional Despite the critical importance of calcium, humans are counsel should be sought for specific situations. ill-adapted to conserve dietary calcium, as illustrated by

Nutrition & the M.D. May 2006 3

the fact that the fractional intestinal absorption of to 1,25-dihydroxyvitamin D.6 Calcium requirements can calcium is only 10%, half of which is then excreted in be met through various foods (many of which do not the urine!2 This disregard for dietary calcium is a rem- contain lactose) and supplements and should always be nant of the environment in which we evolved, one that accompanied with sufficient vitamin D (Table 2). was replete in calcium and other minerals (see the side- Current recommendations for vitamin D are 400 IU bar on page 4). Certainly, from a survival standpoint, per day for those aged 50–70, and 600 IU per day for lugging around excess calcium in a calcium-rich envi- those over age 70, although many experts believe the ronment would have been disadvantageous, just as is true requirement should be 800–1000 IU per day. For the case today with adipose tissue. Unlike dietary fat, children and younger adults, it’s 200 IU per day. These however, current calcium intake is poor while the meta- amounts are readily attainable with moderate sunlight bolic demands for it have perhaps never been greater. exposure of 5% of the body surface two or three times a Although the Institute of Medicine and the National week for approximately 10 minutes.7 However, accord- Academy of Sciences recommend intakes of 1000 mg/day ing to the National Health and Nutrition Examination of calcium for adults between the ages of 19 and 50, and Survey (NHANES III), over 70% of women ages 51 to 1200 mg/day for adults over 50 years old, the average 70 and nearly 90% of those over 70 are not getting the American adult consumes less than 800 mg/day.3 recommended adequate intake of vitamin D.8 In Low calcium intake is thought to be due to decreased addition, many adolescents are deficient in vitamin D consumption of dairy products, in part due to the preva- during the critical years when they are reaching peak lence of lactose intolerance, which is found in 15% to bone mass. Increased prevalence of vitamin D 90% of Americans, depending on ethnicity.4 It is not insufficiency is believed to be caused by decreased out- surprising, therefore, that lactose intolerance has been door activity; increased use of sun block; and, in the case demonstrated to be associated with low bone mass and of elderly persons, diminished synthesis of vitamin D increased risk of fracture.5 Elderly individuals also may due to thinning of the epidermis. By limiting the absorp- have a component of functional calcium deficiency tion of calcium, vitamin D insufficiency leads to caused by a decreased responsiveness of the intestines continued on page 4

Table 2. Calcium and Vitamin D Content of Various Foods Serving Size Calcium Content (mg) Calcium-fortified orange juice 1 c 308–344 Sardines 3 oz 270 Canned salmon (with bones) 3 oz 205 Soymilk, fortified 1 c 200 Broccoli (raw) 1 c 90 Orange 1 medium 50 Yogurt, plain, low-fat 1 c 415 Milk, reduced-fat, fortified 1 c 295 Swiss cheese 1 oz 270 Cottage cheese 1/2 c 75 Serving Size Vitamin D Content (IU) Milk, reduced-fat, fortified 1 c 98 Baked herring 3 oz 1775 Baked salmon 3 oz 238 Canned tuna 3 oz 136 Sardines 1 oz 77

Adapted from Bone Health and Osteoporosis: A Report of the Surgeon General, Chapter 7: Lifestyle approaches to promote bone health, available at www.surgeongeneral.gov/library/bonehealth/content.html.

4 May 2006 Nutrition & the M.D.

Why Are We Calcium-Deﬁcient? A Paleolithic Perspective

Humans evolved over several million years on a hunter-gatherer diet rich in leafy greens, nuts, roots, tubers, and other foods that are very high in calcium. In fact, this diet was so calcium rich that the body appears to have developed defensive strategies—including very poor absorption and little or no systemic conservation of calcium—to prevent toxicity associated with excess calcium consumption. But this adaptation, well-suited to a nomadic existence in East Africa, may have become a liability in the modern era. With the switch to an agricul- tural economy just 10,000 years ago, relatively low-calcium grains became a dietary staple, and intake of calcium plummeted. This drop probably is exacerbated today by high intakes of protein and sodium, both of which increase calcium excretion. So while our bodies remain genetically programmed to process the calcium- rich diet of a hunter-gatherer, our current menu looks much different than that of our predecessors in the Paleolithic era. The differences between our present and prehistoric diets may help explain the high rates of osteoporosis observed in modern society.

Reference Heaney RP, The roles of calcium and vitamin D in skeletal health: An evolutionary perspective. Food and Agricul- ture Organization of the United Nations website; www.fao.org/docrep/W7336T/w7336t03.htm#TopOfPage.

Borrowing continued from page 3 and adjust the measurement for serum albumin using a published nomogram to obtain the “corrected calcium.” secondary hyperparathyroidism, which, even in its mildest Laboratory issues aside, obtaining a result of measured forms, can cause bone loss and increased fracture risk. Vit- calcium that falls within the reference range does not amin D insufficiency is a common cause of sustained bone absolve the physician of further inquiry. Because the loss in patients taking osteoporosis medications, highly human body is so efficient at “borrowing from the prevalent in osteoporotic patients hospitalized with hip bones,” it is not possible to discern whether the source of fracture, and associated with proximal muscle weakness normal serum calcium is adequate vitamin D and calcium 9–11 and falls—both of which compound the risk of fracture. intake or PTH-mediated skeletal reabsorption. Therefore, Sunlight exposure is not recommended as a supplemental I would argue that periodic measurement of calcium source of vitamin D in deficient patients, though should always include a measured intact PTH and requirements can be easily met through various foods and 25-hydroxyvitamin D to exclude eucalcemia from supplements (Table 2). secondary hyperparathyroidism. In regard to assessing vitamin D status, one must remain cognizant of the fact Measuring Calcium and Vitamin D: that only the 25-hydroxyvitamin D metabolite reflects vit- Question Normality amin D stores. Moreover, most experts agree that Measurement of calcium and vitamin D may be plagued “normal” reference ranges are not necessarily optimal ref- by various sources of preanalytical and analytical variabil- erence ranges, based on the fact that as the 25-hydroxvita- ity, respectively. Preanalytical factors such as specimen col- min D levels drops below 30 ng/mL, calcium absorption lection, specimen handling, and interfering substances are is impaired, and the PTH level begins to rise.13 common causes of inaccurate calcium measurements.12 Serum calcium should be collected in the morning fasting Conclusion state in anaerobic containers, with the patient in a supine Humans developed remarkable homeostatic mechanisms position. Calcium binding to protein is exquisitely pH- to maintain calcium during transient deficiencies. How- dependent, and an increase or decrease in the sample pH ever, we no longer live in the same calcium-replete envi- will raise or lower, respectively, the bound fraction. ronment from which we evolved; and consequently, Furthermore, heparinized blood or the presence of what was intended as a temporary response has instead ethylenediaminetetraacetic acid (EDTA) also may lower become the norm. Eucalcemia should always be main- the measured ionized calcium artificially. Lastly, serum tained through proper intake of calcium and vitamin D protein concentrations may change the total calcium with- and never at the expense of our skeleton. With a basic out affecting the physiologically relevant ionized calcium. understanding of calcium homeostasis, we can enable If the measured total calcium is markedly abnormal in an patients to maintain systemic calcium demands while asymptomatic patient, consider protein binding as a factor preserving skeletal integrity. ❍

Nutrition & the M.D. May 2006 5

References 11. Bischoff-Ferrari HA et al., Higher 25-hydroxyvitamin D concentrations are associated with better lower- 1. Bringhurst FR. Regulation of calcium and phosphate extremity function in both active and inactive persons homeostasis. In Degroot LJ, Jameson JL (eds). aged > or = 60 y, Am J Clin Nutr, 2004; 80;752. Endocrinology, 4th ed. Philadelphia: WB Saunders, 12. Portale AA. Blood calcium, phosphorus and magne- 2001, pp 1029–1105. sium. In Favus MJ (ed). Primer on the Metabolic 2. Heaney RP, Weaver CM, Calcium and vitamin D, Bone Diseases and Disorders of Mineral Metabolism, Endocrinol Metab Clin North Am, 2003; 32:181. 5th ed. Washington, DC: American Society for Bone 3. Calcium supplements, Med Lett Drugs Ther, 2000; and Mineral Research, 2003, pp 151–154. 42:29. 13. Heaney RP et al., Calcium absorption varies within 4. Jackson KA and Savaiano DA, Lactose maldiges- the reference range for serum 25-hydroxyvitamin D, tion, calcium intake and osteoporosis in African-, J Am Coll Nutr, 2003; 22:142. Asian-, and Hispanic-Americans, J Am Coll Nutr, 2001; 20:198S. 5. Obermayer-Pietsch BM et al., Genetic predisposi- tion for adult lactose intolerance and relation to Supplementation and Bone diet, bone density, and bone fractures, J Bone Health: Interpreting the Latest Miner Res, 2004; 19:42. 6. Heaney RP et al., Calcium absorption in women: Findings Relationships to calcium intake, estrogen status, and age, J Bone Miner Res, 1989; 4:469. Kevin Lomangino 7. Standing Committee on the Scientific Evaluation Staff Writer, South Portland, ME Dietary Reference of Dietary Reference Intake. Mr. Lomangino has disclosed that he has no significant relationships with or finan- Intakes: Calcium, Phosphorus, Magnesium, Vita- cial interests in any commercial organizations pertaining to this educational activity. min D, and Fluoride. Washington, DC: National Learning Objective: After reading this article, the Academy Press, 1997. participant should be able to state the findings of the 8. Moore C et al., Vitamin D intake in the United Women’s Health Initiative supplementation trial and States, J Am Diet Assoc, 2004; 104:980. describe why the findings may have differed from 9. Dawson-Hughes B, 3 Perspectives on Vitamin D’s those of other recent trials. Role as a Hormone, Endocrine News, 2005; Aug/Sept:13. Should postmenopausal women supplement with cal- 10. LeBoff MS et al., Occult vitamin D deficiency in cium and vitamin D to prevent fractures? Considering the nearly $1 billion in U.S. sales that calcium supple- postmenopausal US women with acute hip ments racked up in 2004, many consumers clearly fracture, JAMA, 1999; 28:1505. have answered “yes” to this question. Nevertheless, the results from recent studies have raised doubts. Although a meta-analysis of randomized controlled tri- Attention Continuing als reported a reduction in hip and nonvertebral fractures Education Participants: associated with vitamin D supplementation, new findings from the Women’s Health Initiative (WHI) trial As the 2005–2006 continuing education program suggest that vitamin D plus calcium supplementation closes, we’d like to remind all participants of the has no effect on the incidence of hip fractures. upcoming deadline for returning tests for scoring. What are we to make of these conflicting results? Please return all completed tests to Lippincott One reasonable conclusion is that vitamin D and CME Institute, Inc., for scoring by June 30, calcium have a more limited impact on fracture risk 2006, in order to receive credit for the program than is widely perceived. Despite being tested in a year from June 1, 2005, through May 31, 2006. number of large and well-conducted studies, these We are also accepting renewals for the next CE interventions have not been shown consistently to have program, which will run from June 1, 2006, clinically important effects on bone health. However, it through May 31, 2007. To renew, please call our does not necessarily follow—as a number of commen- customer service department at (800) 787-8981. tators have concluded—that these interventions are of Thank you for your participation in the CE program no clinical benefit at all. While the WHI regimen may this year and best wishes for your continued success! not have had much impact in a general population of continued on page 6

6 May 2006 Nutrition & the M.D.

Supplementation continued from page 5 group but was unchanged compared with placebo at other sites. Women in the supplement group had 17% healthy women, there is still considerable evidence that higher risk of kidney stones. supplementation is beneficial in higher doses and in While the calcium dose used in the WHI appears suf- certain subgroups of patients. ficient to ensure optimal intake for this mineral, data from other recent studies suggest that the vitamin D WHI vs. Other Trials dose may not have been adequate to produce a benefit. Comparing the WHI findings to those of other recent In a meta-analysis examining the effects of vitamin D investigations can help identify patients who may be supplementation on fracture risk, investigators pooled most likely to benefit from supplementation. In the WHI data from five studies of hip fracture risk (n = 9294) and trial, 18,176 healthy, community-living postmenopausal seven studies of fracture risk at a nonvertebral site women ages 50 to 79 (mean age 62; 83% Caucasian) (n = 9820).2 They found no fracture-prevention benefit were randomized to either calcium (1000 mg daily of in the two studies that used 400 IU/d of vitamin D—the elemental calcium as calcium carbonate) and vitamin D same dose administered in the WHI. However, in stud- (400 IU daily) in two divided doses, while 18,106 ies that used a higher vitamin D dose of 700 to 800 received placebo.1 The primary outcomes were changes IU/d, supplemented patients had a 26% reduction in the in bone mineral density (BMD), fracture risk, and risk of relative risk of hip fracture and a 23% reduction in the colorectal cancer after a mean follow-up of seven years. relative risk of any nonvertebral fracture. Intention-to-treat analysis showed no effect for the Other evidence tends to support the hypothesis that regimen on fracture risk or risk of colorectal cancer. that the WHI participants were under-supplemented Hip bone density increased by 1.06% in the supplement with vitamin D. Although the intervention raised

Comment:What Does the WHI Study Tell Us About Vitamin D Status? Researchers for the Women’s Health Initiative (WHI) Dietary Modification and Hormone Therapy trial recently reported on the effects of supplementation with calcium and vitamin D on bone mineral density, fractures, and adverse effects. In essence, the results showed an improvement in hip bone mineral density but no significant reduction in fractures.1 Many people have interpreted these findings to indicate there is no real clinical benefit to taking calcium and vitamin D. However, a closer look at the study design and findings is warranted before mak- ing any such conclusions. This study design was inherently flawed in that the two groups were poorly matched. To begin with, participants in both the treatment and control groups were permitted to take personal supplementation of up to 1000 mg of elemental calcium and 600 IU vitamin D daily. Moreover, even the so-called “treatment arm” was grossly under-supplemented with current RDA of 400 IU of vitamin D. Where did this RDA originate? In the early 20th century, it was recognized that this was the amount of vitamin D in a teaspoon of cod-liver oil, sufficient to prevent rickets in sun-deprived dogs. It is no longer appropriate to define vitamin D insufficiency by the absence of rickets, which is the end result of a continuum of pathology, beginning with calcium malabsorption, followed by osteopenia, ultimately leading to osteoporosis. To define vitamin D insufficiency by the absence of rickets is analogous to claiming the success of anti-hypertensive therapy is the absence of myocardial infarction. Although the interventional findings of the WHI were of limited usefulness, some valuable observations were made in this study. The mean baseline serum 25-hydroxyvitamin D (25-OHD) in both groups was less than 20 ng/mL, a level that is now recognized as vitamin D-insufficient. Moreover, although subjects who were randomized to receive 400 IU of vitamin D per day demonstrated a 28% increase in their mean levels of 25-OHD, they still remained below 30 ng/mL, which is the level of vitamin D at which serum parathyroid hormone starts to rise. These findings not only reaffirm the high prevalence of vitamin D insufficiency in this country, but underscore the fact that more vigorous vitamin D supplementation (i.e. above the current RDA of 400 IU) will be required in order to maintain serum 25-OHD levels above 30 ng/mL year-round. —Jordan Geller, MD Reference 1. Jackson RD, et al. Calcium plus vitamin D supplementation and the risk of fractures, N Engl J Med, 2006; 354:669.

Nutrition & the M.D. May 2006 7

serum 25-hydroxyvitamin D (25-OHD) levels signifi- diet and, if necessary, through supplementation. Others, cantly from baseline, the level of 25-OHD in subjects noting the increased risk of renal calculi associated with still did not reach the levels now considered sufficient supplementation, are recommending supplements only to for optimal bone health. (See the sidebar on page 6 for women at high risk and those who do not achieve recom- more discussion of this point.) mended intakes through diet. ❍ Population Characteristics References Age is another factor that may help explain the 1. Jackson RD et al., Calcium plus vitamin D supple- discrepant findings observed in the WHI vs. other stud- mentation and the risk of fractures, N Engl J Med, ies. With a mean age of 62, the WHI population was 2006; 354:669. significantly younger than that in many of the studies 2. Bischoff-Ferrari HA et al., Fracture prevention with that have reported a benefit for calcium plus vitamin D vitamin D supplementation: A meta-analysis of ran- supplementation. Supporting the notion that supplemen- domized controlled trials, JAMA, 2005; 293:2257. tation is more effective in elderly patients, a subgroup 3. Chapuy M et al., Vitamin D3 and calcium to analysis of the WHI showed a reduction in hip fracture prevent hip fractures in elderly women, N Engl J risk in women 60 years of age or older. Med, 1992; 327:1637. The WHI did not report on the sunlight exposure of 4. Grant AM et al., Oral vitamin D3 and calcium for participants, but this is a related consideration that may secondary prevention of low-trauma fractures in have a bearing upon the results. Elderly patients—and in elderly people (Randomised Evaluation of Calcium particular those who are institutionalized—tend to spend Or vitamin D, RECORD): A randomised placebo- less time outdoors and therefore have less endogenous vit- controlled trial, Lancet, 2005; 365:1621. amin D production than younger individuals. Accordingly, 5. Porthouse J et al., Randomised controlled trial of a population of very old institutionalized patients would calcium and supplementation with cholecalciferol be expected to have reduced exposure to sunlight and a (vitamin D3) for prevention of fractures in primary higher risk of vitamin D deficiency. Such patients might care, BMJ, 2005; 330:1003. respond better to supplementation than the younger, community-dwelling population enrolled in the WHI. Similarly, it is possible that baseline BMD and other frac- Bone-Building Drugs Can Have ture risk factors predict response to supplementation. To help make their findings applicable to all postmenopausal Opposite Effect women, the WHI did not enroll subjects on the basis of their fracture risk. However, it can be argued that the women most Kevin Lomangino likely to benefit from supplementation are those who have Staff Writer, South Portland, ME already suffered a fracture or have been diagnosed with Mr. Lomangino has disclosed that he has no significant relationships with or finan- osteoporosis. That said, there is no consistent pattern in the cial interests in any commercial organizations pertaining to this educational activity. results of primary vs. secondary prevention trials in this area; Learning Objective: After reading this article, the par- some primary prevention trials (i.e. trials to prevent a first ticipant should be able to cite the risk factors for osteoporosis-related fracture) have reported a benefit to sup- bisphosphonate-induced osteonecrosis of the jaw, as plementation,3 while several recent secondary prevention well as recommended strategies to prevent it. studies (i.e. trials designed to prevent a second fracture) have For many patients with osteoporosis, bisphosphonate 4,5 reported negative findings. drugs are an important treatment to help maintain bone Recommendations mass and reduce the risk of fractures. But according to recent reports, these drugs may also impair bone’s The WHI was designed to provide definitive answers ability to heal following trauma and may, in rare cases, regarding the effects of calcium and vitamin D supple- lead to osteonecrosis, or “bone death.” mentation on fracture risk. While its results suggest Salvatore Ruggiero, MD, DMD, an oral surgeon at Long that any benefit from supplements is likely to be mod- Island Jewish Medical Center, and colleagues reported the est, it has not conclusively ruled out a benefit for association after noticing a cluster of patients with necrotic higher doses of vitamin D or for women who, for vari- jaw lesions following tooth extractions.1 They performed a ous reasons, are at increased risk for fractures. retrospective chart review at their clinic, and found 63 With these uncertainties in mind, many experts continue patients during a two-year period who had a diagnosis of to recommend that postmenopausal women achieve the osteomyelitis and a history of bisphosphonate use. recommended intake of calcium and vitamin D through continued on page 8

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Bone-Building Drugs continued from page 7 Prevention and Treatment An expert panel convened in 2004 developed a number In most of the cases, patients had received infusions of recommendations for preventing ONJ in patients of bisphosphonates as part of their cancer treatment. who are due to begin bisphosphonate infusion Intravenous bisphophonates often are prescribed for therapy.4 These include: hypercalcemia, bone pain, and skeletal complications • Conducting a routine dental examination, resulting from therapy for metastatic breast cancer or including x-rays, to identify potential infections multiple myeloma. In about 10% of cases, however, before therapy begins; the patients were receiving long-term oral bisphosphonate therapy for osteoporosis. • Performing extractions or other surgeries before initiation of bisphosphonate therapy; and Review Finds More Cases • Avoiding any elective procedures that will require The findings reported by Ruggerio and others have the jaw to heal. prompted a more comprehensive analysis of the osteo- The panel also developed recommendations for reducing necrosis risk in bisphosphonate users undergoing cancer ONJ risk in patients already undergoing bisphosphonate treatment. In a preliminary review of 963 patient charts at therapy. These include: M.D. Anderson Cancer Center, investigators found osteonecrosis of the jaw (ONJ) in 18 cancer patients • Managing dental infections nonsurgically with (1.8%) treated with the bisphosphonates pamidronate and root canal treatment instead of tooth extractions zoledronic acid.2 The study confirmed that having dental whenever possible; work increased the risk of developing the condition. How- • Adjusting removable dentures to avoid potential ever, some cases have occurred spontaneously. soft tissue injury, especially areas over bone; and The pathophysiology of bisphosphonate-related, • Maintaining excellent oral hygiene, including reg- osteonecrosis is not well understood. According to ular cleanings, to avoid infection. Care should be Ruggiero, “It is hypothesized that the profound inhibition taken to avoid soft tissue injury. ❍ of osteoclast function impairs bone remodeling and bone healing to the extent that simple bone wounds (extraction References sites) do not heal.”3 Likewise, the risks faced by users of oral bisphopho- 1. Ruggiero SL et al., Osteonecrosis of the jaws asso- nates not undergoing cancer treatment have not been well ciated with the use of bisphosphonates: A review characterized. Merck, maker of the oral bisphosphonate of 63 cases, J Oral Maxillofac Surg, 2004; 62:527. Fosamax (alendronate sodium), notes that in controlled 2. Novartis Corporation, Background Information for clinical trials involving 17,000 patients, it has not received FDA Oncologic Drugs Advisory Committee Meet- any reports of ONJ in patients taking their drug. And at ing, March 4, 2005. this time, post-approval surveillance has detected only a 3. Ruggiero S,Bisphosphonate-induced osteonecro- very small number of cases—perhaps several dozen—of sis: OMS perspective, J Oral Maxillofac Surg, ONJ in oral bisphosphonate users in the United States. 2005; 63(suppl 1):16. Although more cases probably will emerge as awareness 4. American Dental Association, Expert panel recom- of the problem increases, this is still likely to represent just mendations for the prevention, diagnosis, and a tiny fraction of oral bisphosphonate users, which number treatment of osteonecrosis of the jaws, www.ada. in the millions. org/prof/resources/topics/topics_osteonecrosis_ That is fortunate, because ONJ is a debilitating condi- whitepaper.pdf. tion that can be very challenging to manage. Surgical removal of necrotic bone has not proved beneficial, as the surgical sites do not heal and often become Coming in June reinfected. Management of ONJ therefore prioritizes nonsurgical approaches, including protection of exposed Our lead article next month will be “How to Maxi- bone with dental appliances and aggressive antibiotic mize the Role of Non-Drug Interventions in Lipid therapy. Bisphosphonates are metabolized slowly and Management: A Call to Action,” by Kevin C. Maki, can remain in bone for years; consequently, it is believed PhD, President of Provident Clinical Research, in that stopping therapy prior to surgical procedures will Bloomington, IN. not protect against the development of ONJ.