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Maby • Prevention and treatment of osteoporosis JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 • S9 Hormone therapy was long consid-ered the best medical therapy for osteoporosis. If it is prescribed for bone health, however, it is no longer the drug of choice in view of its side effect profile. This loss leaves a tremendous thera-peutic gap. Indeed, osteoporosis is a large and growing problem in the United States. Approximately 10 mil-lion American women have osteo-porosis; it has been diagnosed in only 29%, and only 14% of women with diag-nosed osteoporosis are receiving therapy.1 With life span increasing, a woman today can expect to live to the age of 85 years, living one third of her life in the postmenopausal period, and thus subject to diseases associated with estrogen deficiency, such as osteo-porosis. 2 Osteoporosis leaves bones fragile and prone to fracture. Fractures, partic-ularly certain types of fractures, are asso-ciated with significant morbidity and mortality in elderly patients. After a hip fracture, for instance, 24% of patients die within 1 year,3 50% will be permanently incapacitated,4 and 20% will require long-term nursing home care.5 Vertebral frac-tures are equally devastating, leading to acute and chronic back pain, lung dis-ease, gastrointestinal problems, depres-sion, and a 5% to 10% increase in mor-tality. Preventing osteoporosis is a lifelong goal. Teenagers should be educated on how to achieve adequate peak bone mass; adults, on how to maintain that bone mass; and seniors, on how to slow bone loss and reduce the risk of falls. Patients also need to understand the appropriate use of supplements, partic-ularly calcium and vitamin D, and agents available for the prevention and treat-ment of osteoporosis, especially in light of recent findings of the Women’s Health Initiative (WHI) hormone replacement trial.6 The Physician’s Guide to Prevention and Treatment of Osteoporosis1 identifies universal recommendations for all patients to maximize and preserve bone mass: adequate intake of calcium and vitamin D, regular weight- bearing exercise, avoidance of tobacco, avoidance of alcohol, and treatment of fracture risk factors, such as impaired vision. Definition of osteoporosis Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture.4 A unit of measure called the T score was developed by the World Health Orga-nization to compare a patient’s bone mass with the mean value for young, healthy individuals, expressed as a stan-dard deviation score. A T score of 2.5 or lower is consistent with a diagnosis of osteoporosis. Preventive approaches to the postmenopausal patient Reducing the risk of falls for at-risk patients is critical. Intrinsic risk factors associated with an increased risk of hip fracture are included in Figure 1. Age is progressively associated with increased risk of falls.7 Calcium Calcium is a critical part of any prevention program, both for women and men. Rec-ommended daily calcium intake changes during a patient’s lifetime. It is actually highest during the adolescent years, when young people are building toward peak bone mass (Figure 2).8 For those who do not have adequate calcium in their diet, Dr Maby is medical director of Cobohill Health Center, Brooklyn, NY, where she serves as director of the osteoporosis program and its bone den-sity laboratory. Dr Maby has received past grant support from Merck & Co, and she is a consultant to Eli Lilly and Company, Novartis, and Procter & Gamble. She is also on the speakers bureau of Eli Lilly and Com-pany and Novartis. Correspondence to Jan I. Maby, DO, 1000 Dahill Rd, Brooklyn, NY 11204. E-mail: docmaby@msn.com Prevention and treatment of osteoporosis: Where are we today? Jan I. Maby, DO Impaired vision Low body weight Use of long-acting benzodiazepines Inability to rise from a chair without using one’s arms Smoking Less than 4 hours per day on the feet History of postmenopausal fracture PROGRAM PROCEEDINGS HIGHLIGHTS Checklist Figure 1. Intrinsic risk factors associated with increased risk for falls. (Source: Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332:767-773.) S10 • JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 Maby • Prevention and treatment of osteoporosis supplements are necessary, and physi-cians should educate patients with regard to the nuances of calcium pills. Supple-ments come in two general types: Calcium carbonate: cost-effective, higher percentage of calcium per tablet, should be taken with food, may cause constipation and gas. Calcium citrate: lower percentage of calcium per tablet, easily absorbed, taken without regard to food. Key to the absorption of calcium is vitamin D. Natural sources of vitamin D include liver, cod liver oil, egg yolks, for-tified milk, and sunshine. For the majority of people who do not find suf-ficient vitamin D in their diet, supple-ments should be recommended (400 IU for adults, 800 IU for seniors). Bone mineral density testing Testing for bone mineral density (BMD) is important to any assessment of patients at risk for osteoporosis. In fact, in September 2002, the National Osteo-porosis Foundation (NOF) applauded the US Preventive Services Task Force recommendation that all women aged 65 years and older be screened for osteo-porosis. The NOF recommends BMD testing for all women older than 65 years, regardless of other risk factors.9 The NOF also recommends testing for: postmenopausal women younger than 65 years with one or more addi-tional risk factors for osteoporosis (besides menopause); postmenopausal women who have had one or more fractures; women who have received hormone replacement therapy for a prolonged period; and women considering therapy for osteo-porosis and for whom BMD test results influence this decision. It is also important to test for BMD in patients starting long-term corticoste-roid therapy, defined as greater than 7.5 mg of steroids daily for more than 6 months.10 Management of osteoporosis The management of osteoporosis has been dynamic during the past few years. Several classes of agents are available for the prevention or treatment of osteo-porosis, including hormone therapy, cal-citonin, bisphosphonates, and selective estrogen receptor modulators (SERMs). Until recently, hormone therapy was the mainstay of preventive treatment. The WHI hormone replacement trial showed a decreased risk of hip fractures with estrogen plus progestin treatment.6 How-ever, since the cessation of the WHI estrogen plus progestin study, recom-mendations for the use of hormone therapy suggest consideration of alter-native treatment modalities for osteo-porosis. Indeed, the label changes on estrogen plus progestin formulations con-firm this statement. Calcitonin Calcitonin is approved for the treatment (ie, reduction in fracture risk), but not prevention (increasing bone density) of osteoporosis. Although calcitonin has been available since 1984, it was not widely used because of its high cost and RECOMMENDED CALCIUM INTAKE Infants aged 6 to 12 mo Children and adolescents 270 mg/d Aged 1 to 3 y Aged 4 to 8 y Aged 9 to 18 y 500 mg/d 800 mg/d Aged 18 y Aged 19 to 50 y 1300 mg/d 1000 mg/d Aged 19 to 50 y Aged 50 y 1000 mg/d 1200 mg/d 1300 mg/d Adults Pregnant and lactating women Figure 2. Recommended calcium intake for strong bones. (Source: National Academy of Sci-ences. Dietary reference intake for calcium. Arch Intern Med. 1997;4:39.) Maby • Prevention and treatment of osteoporosis JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 • S11 patients’ discomfort with the injectable formulation. The nasal spray approved by the Food and Drug Administration (FDA) in 1995 allowed it to be more widely used clinically. Efficacy studies indicated a statistically significant increase in bone density for patients receiving calcitonin therapy for 1 and 2 years. Furthermore, 200 IU of calcitonin delivered by nasal spray was associated with a 33% reduction in risk of vertebral fracture compared with placebo in a clin-ical trial.11 Calcitonin also has an excellent long-term safety record. Bisphosphonates Bisphosphonates, as a class, are currently the most potent antiresorptive agents available. Although many bisphospho-nates are on the market today, comments here are limited to the two that are approved by the FDA for the prevention and treatment of osteoporosis: alen-dronate sodium and risedronate sodium. Both medications are available in once-daily and once-weekly formulations. Each has a role in reducing hip fracture in selected patients. The once-weekly dosing has been shown to increase bone density, yet no clinical trials have yet been conducted to show a decrease in hip fracture, though it is anticipated that bisphosphonates will have such an effect. Finally, both agents have gastrointestinal side effects and dosing requirements, which consist of taking the tablets on an empty stomach with water only. To date, eight trials have been con-ducted with bisphosphonates; only two—the Fracture Intervention Trial (FIT II)12 and the Risedronate Hip Study13— will be discussed here. The FIT II trial examined the effect of alendronate on reduction of hip fractures as a secondary outcome. (The primary outcomes included risk of radiographically evident vertebral fractures, which decreased by 44% overall with alendronate treatment.) In women with femoral neck T scores of less than 2.5, alendronate significantly reduced the risk of hip fracture by 56%.12 However, this effect was not seen in women with osteopenia (T score between 1.0 and 2.5). More than 9000 women aged 70 years and older were enrolled in the rise-dronate hip fracture study, the first study to look at hip fracture as the primary end point.13 Patients were enrolled in two groups: those aged 70 to 79 years with low bone density (group 1), and those older than 80 years with more than one risk factor for fracture (group 2). McClung et al13 reported that risedronate significantly reduced the risk of hip frac-ture for patients in group 1, but not for those in group 2 (Table). In group 1, the risk reduction was limited to patients who had a previous vertebral fracture; other patients had no significant reduc-tion. These findings raise several key points. First, a previous fracture predicts a second fracture. Women who have suf-fered any kind of postmenopausal frac-ture— hip, forearm, vertebrae—are more likely to have a subsequent fracture. And, according to this clinical study, rise-dronate will help to prevent a second fracture. Second, and perhaps more important, medication alone is not suffi-cient therapy for women who are at risk of fracture based on clinical signs when bone density is unknown. Selective estrogen receptor modulators The last class of antiresorptive agents are the SERMs, which are not estrogens; they act as estrogen receptor agonists in some tissues (bone and heart) and antagonists in other tissues (breast and uterus). Ralox-ifene hydrochloride is a SERM that cur-rently is approved both for the preven-tion and treatment of osteoporosis. Intriguing recent data also suggest that raloxifene may reduce the risk of breast cancer,14 as well as cardiovascular events in high-risk women,15 as opposed to estrogen plus progestin, which appears to increase the risks for breast cancer and cardiovascular events. Like hormone therapy, however, raloxifene does appear to increase the incidence of venous thromboembolism. Some women also have reported increased incidence of hot flashes. The Multiple Outcomes of Ralox-ifene Evaluation (MORE) trial examined the use of raloxifene in postmenopausal women.16 Compared with placebo, ralox-ifene significantly increased BMD in both the spine and the femoral neck. Further-more, raloxifene decreased the risk of vertebral fracture both in women with and without prevalent fractures. In women with a previous fracture, the rel- Effect of Risedronate Sodium on Incidence of Hip Fracture in Elderly Women* Incidence of hip fracture, % Group Risedronate† Placebo P value Group 1 (aged 70 to 79 years with low bone density‡) Overall 1.9 3.2 .009 With vertebral fracture 2.3 5.7 .003 No vertebral factures at baseline 1.0 1.6 .14 Group 2 (aged 80 years and older with more than one risk factor for fracture) 4.2 5.1 .35 *Source: McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-340. †All patients assigned to risedronate: relative risk, 0.70; 95% confidence interval, 0.6 to 0.9; P .02 ‡Hip T score 4. S12 • JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 Maby • Prevention and treatment of osteoporosis ative risk reduction was 0.66 (95% confi-dence interval [CI] 0.55 to 0.81). In women without a prevalent fracture the relative risk reduction was 0.51 (95% CI 0.35 to 0.73). The MORE trial also reported an impressive finding, though it was not a primary outcome of the study: there was a 72% reduction in the risk of invasive breast cancer in women receiving raloxifene for 4 years (P .001).14 Future trends Although a number of options are avail-able to replace hormones in the preven-tion and treatment of osteoporosis, many more agents are currently under investi-gation and in development. These pos-sibilities include long-acting bisphos-phonates and new SERMs, as well as parathyroid hormone, statins, and even soy. Agents that are currently available act only by decreasing bone resorption. The eventual goal, however, is not only to prevent bone loss, but also to enhance bone formation. Comment Until this year, hormone therapy was largely regarded as being safe for short-and long-term use, suitable for a range of maladies from hot flashes to osteoporosis. Cessation of the estrogen plus progestin arm of the WHI hormone replacement trial and the confirmed association with cardiovascular events and breast cancer radically change this concept of hormone use. It is now recommended that the estrogen plus progestin combination not be used for the prevention of cardiovas-cular disease or osteoporosis, but only for the short-term amelioration of symp-toms associated with menopause. A number of nonhormonal prod-ucts are available for the treatment of osteoporosis, including calcitonin, bis-phosphonates, and SERMs. Certain of these, such as the SERM raloxifene, have shown other benefits as well: raloxifene appears to reduce the risk of invasive breast cancer and cardiovascular disease (among high-risk patients). At the least, it appears that these agents do not suffer from the significant drawbacks associ-ated with hormone therapy and may fill the gap in the management of osteo-porosis left by the elimination of hor-mone therapy. Addendum In December 2002, the FDA approved a new medication for the treatment of osteoporosis. This new agent, teri-paratide, or parathyroid hormone, shows great promise in reversing bone loss. Pre-viously, all modes of therapy for osteo-porosis were inhibitors of bone resorp-tion. Teriparatide is the first agent available to directly stimulate bone for-mation by increasing the number and action of osteoblasts. In the clinical trials on which the FDA based its approval, men and women with osteoporosis treated with teriparatide, calcium, and vitamin D had a significant increase in bone density of the hip and spine. The data demonstrated that teriparatide reduced the relative risk of spine frac-tures by 65% and lowered risk of non-spinal fractures by 53% compared with placebo. Teriparatide represents an important new advance in the therapy for osteoporosis. References 1. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteo-porosis. Washington, DC: National Osteoporosis Foundation; 1998. 2. Campbell S. The Management of the Menopause and Post-Menopausal Years: The Proceedings of the International Symposium Held in London 24–26 November, 1975. Baltimore, Md: University Park Press; 1976; p 33. 3. Ray NF, Chan JK, Thamer M, Melton LJ III. Med-ical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;12:24-35. 4. Consensus Development Conference. Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94:646-650. 5. Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime osteoporosis impact. Arch Intern Med. 1991;151:2026-2032. 6. Writing Group for the Women’s Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288:321-333. 7. O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S. Inci-dence of and risk factors for falls and injurious falls among the community-dwelling elderly. Am J Epidemiol. 1993;137:342-354. 8. National Academy of Sciences. Dietary refer-ence intake for calcium. Arch Intern Med. 1997;4:39. 9. National Osteoporosis Foundation. Bone Mass Measurement. Available at: http://www.nof. org/osteoporosis/bonemass.htm. Accessed: January 27, 2003. 10. American College of Rheumatology. Recom-mendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Com-mittee on Glucocoritcoid-Induced Osteoporosis. Arthritis Rheum. 2001;44:1496-1503. 11. Chesnut CH III, Silverman S, Andriano K, Genant H, Gimona A, Harris S, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures (PROOF) study group. Am J Med. 2000;109:267-276. 12. Cummings SR, Black DM, Thompson DE, Apple-gate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral frac-tures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082. 13. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-340. 14. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie D, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Breast Cancer Res Treat. 2001;65:125- 134. 15. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al. Ralox-ifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Eval-uation) randomized trial. JAMA. 2002;287:847-857. 16. Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87:3609-3617.
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Title | Prevention and treatment of osteoporosis: where are we today? [review; review, tutorial] |
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Transcript | Maby • Prevention and treatment of osteoporosis JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 • S9 Hormone therapy was long consid-ered the best medical therapy for osteoporosis. If it is prescribed for bone health, however, it is no longer the drug of choice in view of its side effect profile. This loss leaves a tremendous thera-peutic gap. Indeed, osteoporosis is a large and growing problem in the United States. Approximately 10 mil-lion American women have osteo-porosis; it has been diagnosed in only 29%, and only 14% of women with diag-nosed osteoporosis are receiving therapy.1 With life span increasing, a woman today can expect to live to the age of 85 years, living one third of her life in the postmenopausal period, and thus subject to diseases associated with estrogen deficiency, such as osteo-porosis. 2 Osteoporosis leaves bones fragile and prone to fracture. Fractures, partic-ularly certain types of fractures, are asso-ciated with significant morbidity and mortality in elderly patients. After a hip fracture, for instance, 24% of patients die within 1 year,3 50% will be permanently incapacitated,4 and 20% will require long-term nursing home care.5 Vertebral frac-tures are equally devastating, leading to acute and chronic back pain, lung dis-ease, gastrointestinal problems, depres-sion, and a 5% to 10% increase in mor-tality. Preventing osteoporosis is a lifelong goal. Teenagers should be educated on how to achieve adequate peak bone mass; adults, on how to maintain that bone mass; and seniors, on how to slow bone loss and reduce the risk of falls. Patients also need to understand the appropriate use of supplements, partic-ularly calcium and vitamin D, and agents available for the prevention and treat-ment of osteoporosis, especially in light of recent findings of the Women’s Health Initiative (WHI) hormone replacement trial.6 The Physician’s Guide to Prevention and Treatment of Osteoporosis1 identifies universal recommendations for all patients to maximize and preserve bone mass: adequate intake of calcium and vitamin D, regular weight- bearing exercise, avoidance of tobacco, avoidance of alcohol, and treatment of fracture risk factors, such as impaired vision. Definition of osteoporosis Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture.4 A unit of measure called the T score was developed by the World Health Orga-nization to compare a patient’s bone mass with the mean value for young, healthy individuals, expressed as a stan-dard deviation score. A T score of 2.5 or lower is consistent with a diagnosis of osteoporosis. Preventive approaches to the postmenopausal patient Reducing the risk of falls for at-risk patients is critical. Intrinsic risk factors associated with an increased risk of hip fracture are included in Figure 1. Age is progressively associated with increased risk of falls.7 Calcium Calcium is a critical part of any prevention program, both for women and men. Rec-ommended daily calcium intake changes during a patient’s lifetime. It is actually highest during the adolescent years, when young people are building toward peak bone mass (Figure 2).8 For those who do not have adequate calcium in their diet, Dr Maby is medical director of Cobohill Health Center, Brooklyn, NY, where she serves as director of the osteoporosis program and its bone den-sity laboratory. Dr Maby has received past grant support from Merck & Co, and she is a consultant to Eli Lilly and Company, Novartis, and Procter & Gamble. She is also on the speakers bureau of Eli Lilly and Com-pany and Novartis. Correspondence to Jan I. Maby, DO, 1000 Dahill Rd, Brooklyn, NY 11204. E-mail: docmaby@msn.com Prevention and treatment of osteoporosis: Where are we today? Jan I. Maby, DO Impaired vision Low body weight Use of long-acting benzodiazepines Inability to rise from a chair without using one’s arms Smoking Less than 4 hours per day on the feet History of postmenopausal fracture PROGRAM PROCEEDINGS HIGHLIGHTS Checklist Figure 1. Intrinsic risk factors associated with increased risk for falls. (Source: Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332:767-773.) S10 • JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 Maby • Prevention and treatment of osteoporosis supplements are necessary, and physi-cians should educate patients with regard to the nuances of calcium pills. Supple-ments come in two general types: Calcium carbonate: cost-effective, higher percentage of calcium per tablet, should be taken with food, may cause constipation and gas. Calcium citrate: lower percentage of calcium per tablet, easily absorbed, taken without regard to food. Key to the absorption of calcium is vitamin D. Natural sources of vitamin D include liver, cod liver oil, egg yolks, for-tified milk, and sunshine. For the majority of people who do not find suf-ficient vitamin D in their diet, supple-ments should be recommended (400 IU for adults, 800 IU for seniors). Bone mineral density testing Testing for bone mineral density (BMD) is important to any assessment of patients at risk for osteoporosis. In fact, in September 2002, the National Osteo-porosis Foundation (NOF) applauded the US Preventive Services Task Force recommendation that all women aged 65 years and older be screened for osteo-porosis. The NOF recommends BMD testing for all women older than 65 years, regardless of other risk factors.9 The NOF also recommends testing for: postmenopausal women younger than 65 years with one or more addi-tional risk factors for osteoporosis (besides menopause); postmenopausal women who have had one or more fractures; women who have received hormone replacement therapy for a prolonged period; and women considering therapy for osteo-porosis and for whom BMD test results influence this decision. It is also important to test for BMD in patients starting long-term corticoste-roid therapy, defined as greater than 7.5 mg of steroids daily for more than 6 months.10 Management of osteoporosis The management of osteoporosis has been dynamic during the past few years. Several classes of agents are available for the prevention or treatment of osteo-porosis, including hormone therapy, cal-citonin, bisphosphonates, and selective estrogen receptor modulators (SERMs). Until recently, hormone therapy was the mainstay of preventive treatment. The WHI hormone replacement trial showed a decreased risk of hip fractures with estrogen plus progestin treatment.6 How-ever, since the cessation of the WHI estrogen plus progestin study, recom-mendations for the use of hormone therapy suggest consideration of alter-native treatment modalities for osteo-porosis. Indeed, the label changes on estrogen plus progestin formulations con-firm this statement. Calcitonin Calcitonin is approved for the treatment (ie, reduction in fracture risk), but not prevention (increasing bone density) of osteoporosis. Although calcitonin has been available since 1984, it was not widely used because of its high cost and RECOMMENDED CALCIUM INTAKE Infants aged 6 to 12 mo Children and adolescents 270 mg/d Aged 1 to 3 y Aged 4 to 8 y Aged 9 to 18 y 500 mg/d 800 mg/d Aged 18 y Aged 19 to 50 y 1300 mg/d 1000 mg/d Aged 19 to 50 y Aged 50 y 1000 mg/d 1200 mg/d 1300 mg/d Adults Pregnant and lactating women Figure 2. Recommended calcium intake for strong bones. (Source: National Academy of Sci-ences. Dietary reference intake for calcium. Arch Intern Med. 1997;4:39.) Maby • Prevention and treatment of osteoporosis JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 • S11 patients’ discomfort with the injectable formulation. The nasal spray approved by the Food and Drug Administration (FDA) in 1995 allowed it to be more widely used clinically. Efficacy studies indicated a statistically significant increase in bone density for patients receiving calcitonin therapy for 1 and 2 years. Furthermore, 200 IU of calcitonin delivered by nasal spray was associated with a 33% reduction in risk of vertebral fracture compared with placebo in a clin-ical trial.11 Calcitonin also has an excellent long-term safety record. Bisphosphonates Bisphosphonates, as a class, are currently the most potent antiresorptive agents available. Although many bisphospho-nates are on the market today, comments here are limited to the two that are approved by the FDA for the prevention and treatment of osteoporosis: alen-dronate sodium and risedronate sodium. Both medications are available in once-daily and once-weekly formulations. Each has a role in reducing hip fracture in selected patients. The once-weekly dosing has been shown to increase bone density, yet no clinical trials have yet been conducted to show a decrease in hip fracture, though it is anticipated that bisphosphonates will have such an effect. Finally, both agents have gastrointestinal side effects and dosing requirements, which consist of taking the tablets on an empty stomach with water only. To date, eight trials have been con-ducted with bisphosphonates; only two—the Fracture Intervention Trial (FIT II)12 and the Risedronate Hip Study13— will be discussed here. The FIT II trial examined the effect of alendronate on reduction of hip fractures as a secondary outcome. (The primary outcomes included risk of radiographically evident vertebral fractures, which decreased by 44% overall with alendronate treatment.) In women with femoral neck T scores of less than 2.5, alendronate significantly reduced the risk of hip fracture by 56%.12 However, this effect was not seen in women with osteopenia (T score between 1.0 and 2.5). More than 9000 women aged 70 years and older were enrolled in the rise-dronate hip fracture study, the first study to look at hip fracture as the primary end point.13 Patients were enrolled in two groups: those aged 70 to 79 years with low bone density (group 1), and those older than 80 years with more than one risk factor for fracture (group 2). McClung et al13 reported that risedronate significantly reduced the risk of hip frac-ture for patients in group 1, but not for those in group 2 (Table). In group 1, the risk reduction was limited to patients who had a previous vertebral fracture; other patients had no significant reduc-tion. These findings raise several key points. First, a previous fracture predicts a second fracture. Women who have suf-fered any kind of postmenopausal frac-ture— hip, forearm, vertebrae—are more likely to have a subsequent fracture. And, according to this clinical study, rise-dronate will help to prevent a second fracture. Second, and perhaps more important, medication alone is not suffi-cient therapy for women who are at risk of fracture based on clinical signs when bone density is unknown. Selective estrogen receptor modulators The last class of antiresorptive agents are the SERMs, which are not estrogens; they act as estrogen receptor agonists in some tissues (bone and heart) and antagonists in other tissues (breast and uterus). Ralox-ifene hydrochloride is a SERM that cur-rently is approved both for the preven-tion and treatment of osteoporosis. Intriguing recent data also suggest that raloxifene may reduce the risk of breast cancer,14 as well as cardiovascular events in high-risk women,15 as opposed to estrogen plus progestin, which appears to increase the risks for breast cancer and cardiovascular events. Like hormone therapy, however, raloxifene does appear to increase the incidence of venous thromboembolism. Some women also have reported increased incidence of hot flashes. The Multiple Outcomes of Ralox-ifene Evaluation (MORE) trial examined the use of raloxifene in postmenopausal women.16 Compared with placebo, ralox-ifene significantly increased BMD in both the spine and the femoral neck. Further-more, raloxifene decreased the risk of vertebral fracture both in women with and without prevalent fractures. In women with a previous fracture, the rel- Effect of Risedronate Sodium on Incidence of Hip Fracture in Elderly Women* Incidence of hip fracture, % Group Risedronate† Placebo P value Group 1 (aged 70 to 79 years with low bone density‡) Overall 1.9 3.2 .009 With vertebral fracture 2.3 5.7 .003 No vertebral factures at baseline 1.0 1.6 .14 Group 2 (aged 80 years and older with more than one risk factor for fracture) 4.2 5.1 .35 *Source: McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-340. †All patients assigned to risedronate: relative risk, 0.70; 95% confidence interval, 0.6 to 0.9; P .02 ‡Hip T score 4. S12 • JAOA • Supplement 2 • Vol 103 • No 2 • February 2003 Maby • Prevention and treatment of osteoporosis ative risk reduction was 0.66 (95% confi-dence interval [CI] 0.55 to 0.81). In women without a prevalent fracture the relative risk reduction was 0.51 (95% CI 0.35 to 0.73). The MORE trial also reported an impressive finding, though it was not a primary outcome of the study: there was a 72% reduction in the risk of invasive breast cancer in women receiving raloxifene for 4 years (P .001).14 Future trends Although a number of options are avail-able to replace hormones in the preven-tion and treatment of osteoporosis, many more agents are currently under investi-gation and in development. These pos-sibilities include long-acting bisphos-phonates and new SERMs, as well as parathyroid hormone, statins, and even soy. Agents that are currently available act only by decreasing bone resorption. The eventual goal, however, is not only to prevent bone loss, but also to enhance bone formation. Comment Until this year, hormone therapy was largely regarded as being safe for short-and long-term use, suitable for a range of maladies from hot flashes to osteoporosis. Cessation of the estrogen plus progestin arm of the WHI hormone replacement trial and the confirmed association with cardiovascular events and breast cancer radically change this concept of hormone use. It is now recommended that the estrogen plus progestin combination not be used for the prevention of cardiovas-cular disease or osteoporosis, but only for the short-term amelioration of symp-toms associated with menopause. A number of nonhormonal prod-ucts are available for the treatment of osteoporosis, including calcitonin, bis-phosphonates, and SERMs. Certain of these, such as the SERM raloxifene, have shown other benefits as well: raloxifene appears to reduce the risk of invasive breast cancer and cardiovascular disease (among high-risk patients). At the least, it appears that these agents do not suffer from the significant drawbacks associ-ated with hormone therapy and may fill the gap in the management of osteo-porosis left by the elimination of hor-mone therapy. Addendum In December 2002, the FDA approved a new medication for the treatment of osteoporosis. This new agent, teri-paratide, or parathyroid hormone, shows great promise in reversing bone loss. Pre-viously, all modes of therapy for osteo-porosis were inhibitors of bone resorp-tion. Teriparatide is the first agent available to directly stimulate bone for-mation by increasing the number and action of osteoblasts. In the clinical trials on which the FDA based its approval, men and women with osteoporosis treated with teriparatide, calcium, and vitamin D had a significant increase in bone density of the hip and spine. The data demonstrated that teriparatide reduced the relative risk of spine frac-tures by 65% and lowered risk of non-spinal fractures by 53% compared with placebo. Teriparatide represents an important new advance in the therapy for osteoporosis. References 1. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteo-porosis. Washington, DC: National Osteoporosis Foundation; 1998. 2. Campbell S. The Management of the Menopause and Post-Menopausal Years: The Proceedings of the International Symposium Held in London 24–26 November, 1975. Baltimore, Md: University Park Press; 1976; p 33. 3. Ray NF, Chan JK, Thamer M, Melton LJ III. Med-ical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;12:24-35. 4. Consensus Development Conference. Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94:646-650. 5. Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime osteoporosis impact. Arch Intern Med. 1991;151:2026-2032. 6. Writing Group for the Women’s Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288:321-333. 7. O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S. Inci-dence of and risk factors for falls and injurious falls among the community-dwelling elderly. Am J Epidemiol. 1993;137:342-354. 8. National Academy of Sciences. Dietary refer-ence intake for calcium. Arch Intern Med. 1997;4:39. 9. National Osteoporosis Foundation. Bone Mass Measurement. Available at: http://www.nof. org/osteoporosis/bonemass.htm. Accessed: January 27, 2003. 10. American College of Rheumatology. Recom-mendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Com-mittee on Glucocoritcoid-Induced Osteoporosis. Arthritis Rheum. 2001;44:1496-1503. 11. Chesnut CH III, Silverman S, Andriano K, Genant H, Gimona A, Harris S, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures (PROOF) study group. Am J Med. 2000;109:267-276. 12. Cummings SR, Black DM, Thompson DE, Apple-gate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral frac-tures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082. 13. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333-340. 14. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie D, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Breast Cancer Res Treat. 2001;65:125- 134. 15. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al. Ralox-ifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Eval-uation) randomized trial. JAMA. 2002;287:847-857. 16. Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87:3609-3617. |
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