Bone Densitometry and the Treatment of Osteoporosis

Transcription

1 Reference Section Bone Densitometry and the Treatment of steoporosis a report by Dr Glen Blake and Professor Ignac Fogelman Senior Lecturer, and Professor of Nuclear Medicine, Guy s, King s and St Thomas Hospitals Medical School 1 Dr Glen Blake Professor Ignac Fogelman Dr Glen Blake is Senior Lecturer in Guy s, King s and St Thomas Hospitals Medical School and, before that, Head of Nuclear Medicine Physics for Guy s and St Thomas NHS Trust. His research interests include the clinical application of all types of bone densitometry measurements and the development of new tracer tests of skeletal turnover using bone-seeking radiopharmaceuticals. Ignac Fogelman is Professor of Nuclear Medicine in the Division of Imaging Sciences at the Guy s, King s and St Thomas Hospitals Medical School and is Clinical Director of Nuclear Medicine for Guy s and St Thomas NHS Trust. His research interests include the diagnosis and treatment of osteoporosis and the use of bone-seeking radiopharmaceuticals in the investigation of metabolic bone disease. Introduction In many developed countries, osteoporosis is now recognised as one of the most serious problems in public health. 1,2 For a 50-year-old Caucasian woman, the lifetime risk of suffering a fragility fracture is estimated to be 30% to 40%, which compares with the figures for breast cancer and cardiovascular disease of 9% to 12% and 30% to 40%, respectively. 1 For men, the risk of a fracture is about one-third of that in women. 2 In the US in 1995, the total healthcare costs attributable to osteoporotic fractures exceeded US$13 billion, 3 a figure that is expected to rise to between US$30 and US$40 billion by The increased recognition of the impact of osteoporosis on the lives of elderly people and the costs of healthcare has led to a major effort by the pharmaceutical industry to develop new treatments that prevent fractures. Large trials aimed at demonstrating the effectiveness of these therapies in reducing the number of fractures have had an important role in their evaluation The new treatments include bisphosphonates (BPs), selective oestrogen receptor modulators (SERMs), calcium and vitamin D supplements and parathyroid hormone (PTH). At the same time, there have been improvements in the bone densitometry equipment used to identify patients at risk of fracture. 17 The technique associated most closely with the recent growth in bone densitometry is dual-energy X-ray absorptiometry (DXA) (see Figure 1). With its advantages of good precision, low radiation dose and stable calibration, DXA is well suited for its role in identifying those patients at risk of fracture and aiding decisions about their treatment. The Definition of steoporosis In the early 1990s, a consensus meeting defined osteoporosis as: A systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. 18 It should be noted that this definition does not require an individual to have sustained a fracture before a diagnosis of osteoporosis is made, but introduces the concept of low bone mass and its relationship to increased fracture risk. While it could be argued that it is wrong to define a disease on the basis of what is essentially a risk factor, i.e. low bone mineral density (BMD), there is nevertheless some logic to this, as fractures occur late in the disease process when skeletal integrity is already compromised. It is therefore desirable to identify those individuals at high risk with a view to instituting appropriate treatment. Today, scans to measure BMD are seen as having an essential role in the evaluation of patients at risk of fracture. 1 In 1994, a World Health rganization (WH) report recommended an epidemiological definition of osteoporosis based on a BMD measurement of the spine, hip or forearm expressed in standard deviation (SD) units called T-scores. 19 T-scores are calculated by taking the difference between the measured BMD and the mean BMD of healthy young adults matched for gender and ethnic group, and dividing by the young adult population SD. The WH report classified a patient as having osteoporosis if their T-score was less than or equal to -2.5 at the spine, hip or forearm (see Table 1). The WH study also proposed an intermediate state referred to as osteopaenia that was defined by a T-score between -2.5 and -1. A T-score greater than -1 was regarded as normal. The WH report definitions of osteoporosis, osteopaenia and normal are intended to identify patients with high, intermediate and low risk of fracture, respectively. However, an important limitation of these definitions is that they apply only to BMD measurements at the sites specified and cannot automatically be applied to other sites in the skeleton or to alternative measurement techniques such as quantitative computed tomography or quantitative ultrasound. 20 The rationale for the WH definition of osteoporosis is that it affects around 30% of postmenopausal women. 1 This figure was chosen because it BUSINESS BRIEFING: GLBAL SURGERY 2003

2 Bone Densitometry and the Treatment of steoporosis approximates to the lifetime risk of fracture for a 50- year-old Caucasian woman. 19 In comparison, it can be argued that the WH definition of osteopaenia captures too high a percentage of women to be clinically useful and, nowadays, this term is being used less often, particularly in the context of making therapeutic decisions. In contrast, the WH definition of osteoporosis has had a major influence on clinical practice, to the extent that, if the issue is whether or not a patient has osteoporosis, it is now regarded as a T-score issue. Figure 1: A DXA Scanner for Measuring Spine and Hip BMD DXA Measurements of Bone Density DXA equipment for the assessment of the central skeleton (see Figure 1) is used for BMD measurements of the spine and hip. BMD measurements are useful because they are known to be predictive of fracture risk with every singlepopulation SD reduction in BMD, equating to an approximate twofold increase in the likelihood of fracture. 21 The hip and spine are regarded as the most important measurement sites because they are sites of frequently occurring fractures that cause substantial impairment of quality of life, morbidity and mortality. A measurement of hip BMD is known to be the most reliable way of evaluating the risk of hip fracture. 21 Also, because of the metabolically active trabecular bone in the vertebral bodies, the spine is the best site for monitoring response to treatment. 22 DXA scanning of the central skeleton has become the most widely used bone densitometry technique because of its ability to measure spine and hip BMD with high precision and to identify patients with osteoporosis on the basis of the WH definition. 23 Despite the widespread popularity of spine and hip DXA, there is continuing interest in new peripheral DXA (pdxa) devices for assessing sites such as the forearm, heel or hand. The advantages of pdxa systems include their small size and low cost. However, epidemiological studies show that the discriminatory ability of peripheral BMD measurements to predict hip fractures is poorer than when hip BMD is used. 21 Also, these types of measurement are unsuitable for patient follow-up studies. 24 The New Treatments for steoporosis Ten years ago, the only treatment available for osteoporosis was hormone replacement therapy (HRT). However, although oestrogen is effective in preventing osteoporosis and relieving menopausal symptoms, there is increasing concern about the risk of breast and other types of cancer after long-duration HRT Recent trials have also cast doubt on the findings of earlier observational studies that HRT is effective in the prevention of cardiovascular disease 28,29 and dementia. 30 Consequently, much effort has been n modern machines it takes only 10 seconds to perform a scan. Table 1: WH Definitions of steoporosis and steopaenia The WH study group recommendations for the definitions of osteoporosis and osteopenia: 19 Terminology Normal T -1.0 Figure 2: Chemical Structures of Pyrophosphate and Three BPs Investigated for the Treatment of Postmenopausal steoporosis =P P= Pyrophosphate CH 3 =P C P= H Etidronate =P C P= H Alendronate =P C P= H Risedronate Later-generation BPs such as alendronate and risedronate are much more potent inhibitors of bone resorption than etidronate. devoted to developing alternative treatments for osteoporosis and showing that these are safe and effective. Among the new treatments, the BPs are increasingly recognised as the agent of choice. BPs are chemical analogues of pyrophosphate in which the phosphorus-oxygen-phosphorous (P--P) bond is replaced by a phosphorus-carbon-phosphorous (P-C- P) bond (see Figure 2). The P-C-P bond is extremely NH 2 ( CH 2 ) N CH 2 T-Score Definition steopaenia -2.5 < T < -1.0 steoporosis T -2.5 Established osteoporosis T -2.5 in the presence of one or more fragility fractures 3 2 BUSINESS BRIEFING: GLBAL SURGERY 2003

3 Reference Section Figure 4: Results for Antifracture Efficacy of Alendronate as Reported in the Fracture Intervention Trial 1 Study Figure 3: Results From a Study of the Changes in Biochemical Markers of Bone Resorption and Bone Formation in Elderly Women Receiving BP Treatment for steoporosis Bone Marker T-Score NTX Bone ALP Bone Resorption Marker Time (months) Bone Formation Marker Key: BSAP: bone-specific alkaline phosphatase; NTx: N-telopetide of collagen crosslinks. Results are expressed in standard deviation units (T-scores) with respect to the mean and population SD in premenopausal women. Note that bone resorption returns to normal within one month and bone formation within six months of patients starting treatment. Source: P Garnero, et al. 31 between the rates of bone resorption and bone formation that existed before the menopause (see Figure 3). 31 The earliest BP studied for the prevention of osteoporosis was etidronate. 32 Subsequently, the newer and more potent BPs alendronate and risedronate were evaluated and shown to reduce the incidence of fragility fractures by up to 50%. 7,8,10,11,13 ther classes of antiresorptive agents evaluated for the treatment of osteoporosis include calcitonin-12 and SERMs. SERMs are compounds that mimic the beneficial effects of oestrogen on bone while antagonising the effects on the breast and uterus. 9,16,33 Interest has mainly centred on raloxifene, which has been shown to reduce the incidence of vertebral fractures 9,16 and breast cancer. 34 It is widely recognised that different types of treatment might be appropriate in the case of elderly patients in whom bone loss is often associated with secondary hyperparathyroidism resulting from vitamin D deficiency and low calcium intake. Studies of calcium and vitamin D supplementation in elderly women living in nursing homes have confirmed its effectiveness in reducing the risk of hip fracture. 5,6 While most established treatments for osteoporosis are antiresorptive agents that work by preventing further bone loss, the ideal therapeutic agent for osteoporosis would be one that stimulated bone formation and could therefore restore bone mass in patients in whom substantial loss had already occurred. Currently, there is a great deal of interest in the use of PTH for this purpose and two recent trials have examined the use of the aminoterminal fragment of human PTH (hpth) (1-34). 15,35 Although requiring daily self-injection, large increases in bone mass are seen over periods of two or three years, after which time it is probable that the gains can be maintained by continuing treatment with an antiresorptive agent. Do Treatments for steoporosis Prevent Fractures? The bar chart shows the relative risk for different types of fractures. Error bars show the 95% confidence intervals. The study was designed to show a significant reduction in the number of vertebral fractures reported on spinal radiographs (vertebral fracture). However, the reduction in fracture risk was also statistically significant for clinically presenting vertebral fractures, any clinically presenting fracture, hip fracture and wrist fractures. Source: J D M Black, et al. 7 3 stable and, unlike pyrophosphate, these compounds are not metabolised in vivo. The bone loss that occurs in older women is associated with the state of increased bone turnover that develops after the menopause. BPs are antiresorptive agents that work by inhibiting bone resorption and so restoring the balance The need to demonstrate that treatments for osteoporosis are effective in preventing fractures has been the primary objective of some of the largest trials conducted in this area of clinical research Such studies are regarded as particularly important in view of previous experience with sodium fluoride (NaF) treatment for osteoporosis. 36 Like PTH, NaF has an anabolic effect on bone and promotes bone formation, especially at the spine. However, a series of studies showed that treatment with NaF did not prevent fractures. 37 More recently, however, studies of alendronate, 7,8,13 raloxifene, 9,16 risedronate, 10,11,14 calcitonin-12 and PTH-15 have confirmed the antifracture efficacy of these agents (see Figure 4). BUSINESS BRIEFING: GLBAL SURGERY 2003

4 Bone Densitometry and the Treatment of steoporosis Large numbers of subjects (often several thousand) are required for trials to achieve statistically significant results within a short period. The findings are presented as the relative risk by dividing the incidence of new fractures in the group on treatment by the fracture incidence in the placebo group. Most studies have been powered to demonstrate efficacy in the prevention of vertebral fractures monitored with annual radiographs, 7 13 since such studies are less demanding in terms of patient numbers. However, a recent study of the BP risedronate specifically addressed the issue of the prevention of hip fractures. 14 The results of this study showed that, although it was possible to demonstrate fracture prevention in patients selected because of a low femoral neck BMD (T-score -3) at enrolment, there was no benefit in patients who were enrolled on the basis of having one or more non-skeletal risk factors for hip fracture but in whom BMD was not measured. This interesting and potentially important result is consistent with the findings of the Fracture Intervention Trial (FIT) study, 8,13,38 in which prevention of clinically presenting fractures at any site in the skeleton was shown only in patients with a femoral neck T-score -2.5 (see Figure 5). Thus, the WH definition of osteoporosis may have an important bearing on identifying those patients in whom treatment is likely to prove effective. Figure 5: Results for Antifracture Efficacy of Alendronate as Reported in the Fracture Intervention Trial 2 Study The bar chart shows the relative risk of any clinically presenting fracture (left) (source: J S R Cummings, et al. 8 ); and vertebral fracture only (right) (source: D Black, et al. 38 ). Results are shown plotted as a function of femoral neck BMD T-score. Error bars show the 95% confidence intervals. In the case of all clinical fractures, only patients who fulfil the WH definition of osteoporosis with a T-score -2.5 show a statistically significant response to treatment. Figure 6: Relative Risk of a New Vertebral Fracture for Patients Receiving Active Treatment Compared With Patients Receiving Placebo Plotted Against the Change in Spine BMD After Three Years Treatment Do Changes in BMD Explain the Reduction in Fracture Risk? Several reports have examined the issue of whether the measured changes in BMD in clinical trials can explain the observed reductions in fracture risk When relative risk values for prevention of vertebral fractures are plotted against the three-year changes in BMD, the reduction in fracture risk is too significant to be explained by the changes in BMD alone (see Figure 6). In reality, the disparity between BMD changes and fracture risk reduction is even greater than implied in Figure 6. This is because, although most studies report that the full benefit in antifracture efficacy is seen as early as six to 12 months after commencing treatment, 13 generally BMD is still increasing at this time. However, changes in biochemical markers of bone turnover show an immediate response to treatment (see Figure 3) and detailed studies show that the changes in bone markers explain more of the variance in fracture risk than the BMD changes. 41,42 The reasons for this strong relationship between antifracture efficacy and changes in the bone turnover markers are unclear, but possible explanations include that the early response to treatment reflects the filling in of sites of bone remodelling, and this may decrease the incidence of microfractures that represent points of weakness in bone. 42 Data points are for osteoporotic postmenopausal women treated with: (1) nasal spray salmon calcitonin (100IU, 200IU and 400IU per day) (data from C H Chesnut, et al. 12 ; (2) raloxifene (60mg and 120mg per day) (data from J B Ettinger, et al. 9 ); (3) risedronate (5mg per day) (data from North American (J S T Harris, et al 10 ) and International (J-Y Reginster, et al. 11 ) studies); (4) alendronate (5mg per day) (data from FIT1 (D M Black, et al. 7 ) and FIT2 (S R Cummings, et al. 8 ) studies); (5) parathyroid hormone [rhpth(1-34)] (20mg and 40mg per day) (data from R M Neer, et al. 15 ). Error bars show the 95% confidence intervals. The solid line shows the predicted relationship if the relative risk decreases by a factor of two for each single SD increase in BMD. (data from D Marshall, et al. 21 ). In practice, treatments are consistently more effective in preventing fractures than expected from the measured changes in BMD. Conclusions In recent years, the range of treatments available for patients with osteoporosis has increased greatly. A decade ago, the only proven therapy was oestrogen, 4 BUSINESS BRIEFING: GLBAL SURGERY 2003

5 Reference Section while, today, the choice includes BPs, SERMs, PTH and calcium and vitamin D supplements. Treatments can therefore be better tailored to the needs of individual patients. Bone densitometry measurements using DXA have an essential role in identifying patients at risk of a fragility fracture and the targeting of appropriate treatment. The efficacy of treatments has been examined in large trials powered to show reductions in fracture risk. Interestingly, these demonstrate that the reductions in fracture incidence observed are largely restricted to the patients with the lowest BMD values, in particular those who fulfil the WH definition of osteoporosis of a BMD T-score It appears that the changes in BMD during treatment explain only part of the observed antifracture efficacy of treatments, and that the normalisation of the rate of bone turnover may be the principal factor in the success of therapies. References 5 1. J A Kanis, P Delmas, P Burckhardt, C Cooper, D Torgerson, on behalf of the European Foundation for steoporosis and Bone Disease, Guidelines for Diagnosis and Treatment of steoporosis, steoporosis International, 7 (1997), pp J C Cooper, G Campion and L J Melton, Hip Fractures in the Elderly: A World-wide Projection, ibid., 2 (1992), pp J N F Ray, J K Chan, M Thamer and L J Melton, Medical Expenditures for the Treatment of steoporotic Fractures in the United States in 1995: Report from the National steoporosis Foundation, Journal of Bone and Mineral Research, 12 (1997), pp J E Chrischilles, T Shireman and R Wallace, Costs and Health Effects of steoporotic Fractures, Bone, 15 (1994), pp J M C Chapuy, M E Arlot, F Duboeuf, et al., Vitamin D3 and Calcium to Prevent Fractures in Elderly Women, New England Journal of Medicine, 327 (1992), pp. 1,637 1, J M C Chapuy, M E Arlot, P D Delmas, et al., Effect of Calcium and Cholecalciferol Treatment for Three Years on Hip Fractures in Elderly Women, British Medical Journal, 308 (1994), pp. 1,081 1, J D M Black, S R Cummings, D B Karpf, et al., Randomised Trial of the Effect of Alendronate on Risk of Fracture in Women with Existing Vertebral Fractures, Lancet, 348 (1996), pp. 1,535 1, J S R Cummings, D M Black, D E Thompson, et al., Effect of Alendronate on Risk of Fracture in Women with Low Bone Density but Without Vertebral Fracture: Results from the Fracture Intervention Trial, Journal of the American Medical Association, 280 (1998), pp. 2,077 2, J B Ettinger, D M Black, B H Mitlak, et al., Reduction of Vertebral Fracture Risk in Postmenopausal Women with steoporosis Treated with Raloxifene: Results from a 3-year Randomized Clinical Trial, ibid., 282 (1999), pp J S T Harris, N B Watts, H K Genant, et al., Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women with Postmenopausal steoporosis, ibid., pp. 1,344 1, J-Y Reginster, H W Minne, H Sorensen, et al., Randomised Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal steoporosis, steoporosis International, 11 (2000), pp C H Chesnut, S Silverman, K Andriano, et al., A Randomized Trial of Nasal Spray Salmon Calcitonin in Postmenopausal Women with Established steoporosis: The Prevent Recurrence of steoporotic Fractures Study, American Journal of Medicine, 109 (2000), pp D M Black, D E Thompson, D C Bauer, et al., Fracture Risk Reduction with Alendronate in Women with steoporosis: The Fracture Intervention Trial, Journal of Clinical Endocrinology and Metabolism, 85 (2000), pp. 4,118 4, M R McClung, P Geusens, P D Miller, et al., Effect of Risedronate on the Risk of Hip Fracture in Elderly Women, New England Journal of Medicine, 344 (2001), pp R M Neer, C D Arnaud, J R Zanchetta, et al., Effect of Recombinant Human Parathyroid Hormone (1-34) Fragment on Spine and Non-spine Fractures and Bone Mineral Density in Postmenopausal steoporosis, ibid., pp. 1,434 1, P D Delmas, K E Ensrud, J D Adachi, et al., Efficacy of Raloxifene on Vertebral Fracture Risk in Postmenopausal Women with steoporosis: Four-year Results from a Randomized Clinical Trial, Journal of Clinical Endocrinology and Metabolism, 87 (2001), pp. 3,609 3, H K Genant, K Engelke, T Fuerst, et al., Noninvasive Assessment of Bone Mineral and Structure: State of the Art, Journal of Bone and Mineral Research, 11 (1996), pp Consensus Development Conference, Diagnosis, Prophylaxis and Treatment of steoporosis, American Journal of Medicine, 94 (1993), pp Assessment of Fracture Risk and its Application to Screening for Postmenopausal steoporosis, WH Technical Report Series 843, Geneva: World Health rganization, BUSINESS BRIEFING: GLBAL SURGERY 2003

6 Bone Densitometry and the Treatment of steoporosis 20. K G Faulkner, E Von Stetton, P Miller, Discordance in Patient Classification Using T-scores, Journal of Clinical Densitometry, 2 (1999), pp D Marshall, Johnell, H Wedel, Meta-analysis of how well Measures of Bone Mineral Density Predict ccurrence of steoporotic Fractures, British Medical Journal, 312 (1996), pp. 1,254 1, R Eastell, Treatment of Postmenopausal steoporosis, New England Journal of Medicine, 338 (1998), pp Royal College of Physicians (RCP), steoporosis: Clinical Guidelines for Prevention and Treatment: Update on Pharmacological Interventions and an Algorithm for Management, London: RCP, M L Bouxsein, R A Parker and S L Greenspan, Forearm Bone Mineral Densitometry Cannot be Used to Monitor Response to Alendronate Therapy in Postmenopausal Women, steoporosis International, 10 (1999), pp Collaborative Group on Hormonal Factors in Breast Cancer, Breast Cancer and Hormone Replacement Therapy: Collaborative Reanalysis of Data from 51 Epidemiological Studies of 52,705 Women with Breast Cancer and 108,411 Women Without Breast Cancer, Lancet, 350 (1997), pp. 1,047 1, C Rodriguez, A V Patel, E E Calle, et al., Estrogen Replacement Therapy and varian Cancer Mortality in a Large Prospective Study of US Women, Journal of the American Medical Association, 285 (2001), pp. 1,460 1, R T Chlebowski, S L Hendrix, R D Langer, et al., Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: The Women s Health Initiative Randomized Trial, ibid., 289 (2003), pp. 3,243 3, S Hulley, D Grady, T Bush, et al., Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women, ibid., 280 (1998), pp A D Pradhan, J E Manson, Jacques E. Rossouw, et al., Inflammatory Biomarkers, Hormone Replacement Therapy, and Incident Coronary Heart Disease: Prospective Analysis from the Women s Health Initiative bservational Study, ibid., 288 (2002), pp S A Shumaker, C Legault, S R Rapp, et al., Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women. The Women s Health Initiative Memory Study: A Randomized Controlled Trial, ibid., 289 (2003), pp. 2,651 2, P Garnero, J S Weichung, E Gineyts, et al., Comparison of New Biochemical Markers of Bone Turnover in Late Postmenopausal steoporotic Women in Response to Alendronate Treatment, Journal of Clinical Endocrinology and Metabolism, 79 (1994), pp. 1,693 1, T Storm, G Thamsborg, T Steiniche, et al., Effect of Intermittent Cyclical Etidronate Therapy on Bone Mass and Fracture Rate in Women with Postmenopausal steoporosis, New England Journal of Medicine, 322 (1990), pp. 1,265 1, P D Delmas, N H Bjarnason, B H Mitlak, et al., Effects of Raloxifine on Bone Mineral Density, Serum Cholesterol Concentrations and Uterine Endometrium in Postmenopausal Women, ibid., 337 (1997), pp. 1,641 1, S R Cummings, S Eckert, K A Krueger, et al., The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results from the MRE Randomised Trial, Journal of the American Medical Association, 281 (1999), pp. 2,189 2, R Lindsay, J Nieves, C Formica, et al., Randomised Controlled Study of Effect of Parathyroid Hormone on Vertebral-bone Mass and Fracture Incidence Among Postmenopausal Women on estrogen with steoporosis, Lancet, 350 (1997), pp P J Meunier, J L Sebert, J-Y Reginster, et al., Fluoride Salts are No Better at Preventing New Vertebral Fractures than Calcium-Vitamin D in Postmenopausal steoporosis: The FAVS Study, steoporosis International, 8 (1998), pp D Haguenauer, V Welch, B Shea, et al., Fluoride for the Treatment of Postmenopausal steoporotic Fractures: A Meta-analysis, ibid., 11 (2000), pp D Black, D Thompson, S Quandt, et al., Alendronate Reduces Risk of Vertebral Fracture in Women with BMD T-Scores Above -2.5: Results from the Fracture Intervention Trial (FIT), ibid., 13 (2002) Suppl. 1, p. S27, abstract. 39. M C Hochberg, P D Ross, D Black, et al., Larger Increases in Bone Mineral Density During Alendronate Therapy are Associated with a Lower Risk of New Vertebral Fractures in Women with Postmenopausal steoporosis, Arthritis and Rheumatism, 42 (1999), pp. 1,246 1, R D Wasnich, P D Miller, Antifracture Efficacy of Antiresorptive Drugs are Related to Changes in Bone Density, Journal of Clinical Endocrinology and Metabolism, 85 (2000), pp S Sarkar, B H Mitlak, M Wong, et al., Relationships Between Bone Mineral Density and Incident Vertebral Fracture Risk with Raloxifene Therapy, Journal of Bone and Mineral Research, 17 (2002), pp R Eastell, I Barton, R A Hannon, et al., Relationship of Early Changes in Bone Resorption to the Reduction in Fracture Risk with Risedronate, ibid., 18 (2003), pp. 1,051 1, BUSINESS BRIEFING: GLBAL SURGERY 2003