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Risedronate Prevents Bone Loss in Early Postmenopausal Women: a Prospective Randomized, Placebo-Controlled Trial

Posted on: Sunday, 18 September 2005, 03:00 CDT

ABSTRACT

Objectives To assess the efficacy and tolerability of risedronate, a pyridinyl bisphosphonate, in preventing loss of bone mineral density (BMD) of the lumbar spine and proximal femur in early postmenopausal women.

Methods A total of 383 patients were randomly assigned to receive risedronate 2.5 or 5 mg or placebo once daily for 24 months. All patients received 1 g elemental calcium daily. BMD was measured by dual X-ray absorptiometry at baseline and at 3, 6, 12, 18, and 24 months.

Results Risedronate 5 mg significantly increased BMD at the lumbar spine and femoral neck and trochanter in early postmenopausal women. Significant results were observed as early as 3 months. In the control calcium-supplemented group, BMD decreased steadily at each site throughout the study. The mean percentage change from baseline in BMD in the risedronate 5 mg group was significantly different from that in the control group at each determination at each site. At 24 months, the differences were 4.5 0.45% at the lumbar spine, 3.3 0.49% at the femoral neck, and 4.3 0.67% at the femoral trochanter. Risedronate 2.5 mg maintained BMD at each site, although the effect was less pronounced than that of risedronate 5 mg. Risedronate was well tolerated and was not associated with an increased incidence of overall or upper gastrointestinal adverse events.

Conclusions Risedronate 5 mg prevents bone loss in early postmenopausal women, is well tolerated, and represents an effective choice to maintain bone mass and prevent osteoporosis.

Key words: RISEDRONATE, OSTEOPOROSIS, MENOPAUSE, BONE MINERAL DENSITY, BISPHOSPHONATES

INTRODUCTION

Osteoporosis results from a loss of trabecular connectivity, which compromises the mechanical strength of bone1. Current evidence indicates each decrease of one standard deviation in age-adjusted bone mineral density (BMD) increases the risk of fracture two- to three-fold and that the risk of fracture is 8.5 times greater for older women in the lowest BMD quartile than for those in the highest quartile2-4. Because 20% of women who sustain a vertebral fracture will fracture again within 1 year5, it is important to reduce the risk of the first osteoporotic fracture. These findings underscore the benefits in the at-risk woman of preserving BMD and preventing destruction of bone microarchitecture during the period of rapid bone loss occurring immediately after the menopause.

Long-term hormone replacement is an effective therapy for preventing bone loss and reducing fracture risk6-9, but, since the publication of the findings from the Women's Health Initiative (WHI) trial9-11 and the Heart and Estrogen/ progestin Replacement Study Follow-up (HERS II)12,13, this therapy is advocated primarily for short-term relief of climacteric symptoms14. Further, many women discontinue hormone replacement therapy or refuse it altogether because of concern about its side-effects, especially monthly bleeding, and the fear of breast or endometrial cancer15. Selective estrogen receptor modulators (SERMs), such as raloxifene, possess both estrogen-antagonist and estrogen-agonist effects and have attracted interest because they may confer some of the benefits of estrogen without its adverse effects on breast and endometrial tissue16-19. However, in early postmenopausal women, the use of raloxifene may be limited by an increased occurrence of vasomotor symptoms and an increase in the absolute risk of thromboembolic events similar to that associated with hormone replacement therapy19- 21.

Bisphosphonates have been shown to significantly reduce the risk of osteoporotic fractures at both vertebral and non-vertebral sites22-24 and to increase bone mass in early postmenopausal women25- 30. In clinical trials, bisphosphonates have been found to be generally well tolerated22-24,30-34, but some bisphosphonates have been associated with upper gastrointestinal intolerance in clinical practice34-36.

There is considerable information showing that risedronate (Actonel, Procter & Gamble Pharmaceuticals, Cincinnati, OH and sanofi-aventis, Bridgewater, NJ, USA), a pyridinyl bisphosphonate, leads to significant reductions in vertebral and non-vertebral (including hip) fractures in older postmenopausal women with established osteoporosis22,23,32, and in patients with glucocorticoid-induced osteoporosis31. In a smaller, earlier study, daily or cyclical risedronate 5 mg prevented bone loss in early postmenopausal women with normal BMD26. The purpose of this larger study was to determine the efficacy and safety of risedronate at two different doses in the prevention of bone loss in the early postmenopausal period.

METHODS

The trial was a randomized, double-masked, placebo-controlled, parallel-group study conducted at 11 centers in Australia from September 1994 to April 1997. It was conducted in compliance with Good Clinical Practices and the Declaration of Helsinki, and the protocol underwent independent ethical review.

A total of 383 women were enrolled in the study. The protocol specified that all were to have been postmenopausal (as determined from their medical histories) for 6 to 36 months, with a serum follicle stimulating hormone concentration of at least 50 mIU/ml and a serum estradiol concentration of no more than 20 pg/ml. Menopause could be natural or surgical. Patients who had undergone hysterectomy without bilateral oophorectomy could be enrolled if they were 51-60 years of age. All patients were required to have a lumbar spine BMD T-score greater than - 2.5 (BMD greater than 0.76 g/ cm^sup 2^ when measured with a Hologic densitometer (Waltham, Massachusetts, USA) or greater than 0.87 g/cm^sup 2^ when measured with a Lunar densitometer (Madison, Wisconsin, USA)). All patients were in good health and had no history of hyperparathyroidism, hyperthyroidism, or osteomalacia, or of treatment with agents that were likely to affect bone metabolism. Patients were not excluded because of previous or active gastrointestinal disease (including dysphagia, esophagitis, and esophageal, gastric, and duodenal ulceration), need for antisecretory therapy, or concomitant use of medications with potential to irritate the gastrointestinal tract. Written, informed consent was obtained from all patients before entry to the study.

Patients who qualified for the study were randomly assigned in a 1:1:1 ratio to receive placebo or risedronate 2.5 or 5 mg/day, according to a computer-generated randomization schedule, which was held at the contract research organization. Patients received 2.5- or 5-mg film-coated risedronate tablets (the commercial dosage form) or matching placebo tablets. All study drugs were provided by Procter & Gamble Pharmaceuticals (Cincinnati, Ohio, USA). Patients were instructed to take one tablet of risedronate or placebo once daily with a large amount of water (240 ml) on an empty stomach at least 30 and not more than 60 min before breakfast. They were to take this medication only with water and not to lie down for 1 h after taking the tablet. Patients were also to take 1 g elemental calcium daily with their midday or evening meal. Treatment was continued for 2 years.

BMD at the lumbar spine (L1-L4) and proximal femur (neck and trochanter) was measured by dual energy X-ray absorptiometry with Hologic or Lunar instruments at baseline and after 3, 6, 12, 18, and 24 months of treatment. Phantom data were used to monitor instrument performance throughout the study37. Longitudinal correction factors were generated to compensate for variability in instrument performance. Standardized lumbar spine BMD values were calculated at baseline to correct for differences in instrumentation38,39. Femoral neck BMD values obtained using Lunar instruments were adjusted at baseline to make them comparable to those obtained using Hologic instruments38.

Lateral and anterior-posterior radiographs were taken of the thoracic and lumbar vertebrae (T4-L4) pretreatment, and lateral spinal radiographs were taken at 24 months or study exit. The prevalence and incidence of vertebral deformities were assessed by morphometric analysis. A vertebral body was considered to be deformed at baseline (prevalent deformity) if any of the vertebral height ratios fell below 3 standard deviations of the mean of the study population. An incident new vertebral fracture was defined as a loss of 15% or more in the anterior, posterior, or middle vertebral height in a vertebra that was normal at baseline. Incident deformities were confirmed by visual inspection40.

Biochemical markers of bone turnover, including osteocalcin (OsteoHunan, Nichols Diagnostic, San Diego, California, USA), serum bone-specific alkaline phosphatase (BSAP) (Ostase, Hybritech Inc., San Diego, California, USA), and urinary total pyridinoline (PYD) and deoxypyridinoline (DPD), were measured by HPLC after 1, 3, 6, 12, and 24 months. Urinary measurements were corrected for urinary creatinine concentrations (Cr). All assays were run in a central laboratory (Nichols Institute, Quest Diagnostics, San Juan Capistrano, CA, USA).

At every visit, each patient was asked if she had experienced any medically related changes in her well-being since the last visit. Particular attention was paid to reports of v\ertebral and non- vertebral fractures and upper gastrointestinal events.

Approximately 385 patients were expected to be enrolled in this study. Assuming a 25% dropout rate at the end of 2 years, 288 patients would complete 24 months of study (96 patients per treatment group). The sample size of 96 patients per group would provide at least 90% power to detect a between-group difference of 3% or greater in mean percentage change from baseline in lumbar spine BMD at month 24, assuming a two-sided, 5% significance level and a standard deviation of 5% in percentage change from baseline in lumbar spine BMD. Efficacy and tolerability data were analyzed on an intentionto-treat basis. The analyses included all patients who received at least one dose of the study medication.

The groups were evaluated for differences at baseline by a two- way analysis of variance (ANOVA) with treatment and investigator as factors. The principal efficacy measure was the percentage change from baseline in lumbar spine BMD at 24 months. Within treatment groups, the mean percentage changes from baseline in lumbar spine BMD were evaluated by a paired t test. A two-way analysis of covariance (ANCOVA) model, with treatment group and investigator as factors and years since menopause as a covariate, was used to evaluate overall treatment effect and pairwise treatment differences of percentage change from baseline in lumbar spine BMD at each visit.

Secondary efficacy measures included the mean percentage changes from baseline in the BMD of the femoral neck and trochanter and the mean percentage change from baseline in serum BSAP, osteocalcin, and urinary pyridinoline and deoxypyridinoline; these changes were analyzed using the methods described for spinal BMD.

Safety was assessed primarily on the basis of the occurrence of adverse events and vertebral and non-vertebral fractures. The incidences of vertebral fractures in the three groups were compared by the Cochran-Armitage test of trend41; paired comparisons between the risedronate and control groups were performed using Fisher's exact test.

RESULTS

Of the 383 randomized patients, 126 were assigned to receive placebo, 128 to receive risedronate 2.5 mg, and 129 to receive risedronate 5 mg. Two patients were not treated, one because she withdrew her consent and the second because she was randomized in error. The three groups were well balanced, except that the number of smokers was significantly (p ≤ 0.05) lower in the risedronate 2.5 mg group than in the control group (Table 1). Ninety- eight percent of the patients in each group were Caucasian. The average age of the study population was 53 years (range, 42-63 years). The groups were similar with respect to baseline BMD (Table 2). The groups were also similar with respect to the numbers of patients who discontinued treatment and the reasons for discontinuation (Figure 1).

Table 1 Baseline demographic data. Data are presented either as mean standard deviation or as number (percentage) of patients

Table 2 Baseline bone mineral density, lumbar spine T-scores, and bone turnover markers. Data are presented as mean (standard error)

Figure 1 Progress of patients during randomization and during the trial

Treatment with risedronate 5 mg led to significant increases from baseline in BMD at the lumbar spine, femoral neck, and femoral trochanter, beginning at 3 months and persisting throughout the study (Figures 2, 3, and 4). At 24 months, mean BMD in the risedronate 5 mg group had increased by 2.0% at the lumbar spine, 0.8% at the femoral neck, and 2.5% at the femoral trochanter. At 24 months, compared with the control group, mean BMD in the risedronate 5 mg group increased by 4.5% at the lumbar spine, 3.3% at the femoral neck, and 4.3% at the femoral trochanter. Treatment with risedronate 2.5 mg also led to preservation of BMD at each site, although the effect was smaller than that of risedronate 5 mg. There was a well-defined dose response at each measured site and timepoint. The BMD of patients in the control group decreased from baseline at each site at each timepoint. The losses were significant, beginning at 12 months for the lumbar spine, at each determination for the femoral neck, and at all but the 3- and 12- month determinations for the femoral trochanter.

Mean serum BSAP levels increased transiently 8-10% from baseline at 1 month in all treatment groups, and then decreased sharply at 3 months in both risedronate groups and remained below the baseline and control levels for the duration of the study (Table 3). Changes in median BSAP values were very similar (data not shown). In the control group, mean BSAP was significantly greater than at baseline at 3 months and at each subsequent timepoint except 24 months. The changes in the risedronate 2.5 mg group were in the same direction, but smaller than those in the 5 mg group, except at 1 month. In all three groups, mean values for serum BSAP remained within normal limits throughout the study. Similar trends were observed in osteocalcin.

Markers of bone resorption were also indicative of significant reductions in bone turnover. In the risedronate 5 mg group, the mean (standard error) percentage decreases from baseline in DPD/Cr values were significant at 1 month (-15% (5.1)) and at 3 (-28% (2.8)), 6 (- 22% (3.4)), 12 (-9% (4.9)), and 24 (-24% (3.7)) months. These changes were also significantly greater than those in the placebo group at each timepoint. In the placebo group, mean DPD/Cr values increased from baseline at each determination except month 3. The results in the risedronate 2.5 mg group were similar to those in the 5 mg group, except at 3 months when the difference from placebo was not significant and at 12 months when the change from baseline was not significant. Similar trends were seen for PYD.

Overall, risedronate was well tolerated. The percentages of patients reporting adverse events and the nature of events reported were similar in the three treatment groups (Table 4). Adverse events were the reason for discontinuation in eight (6%) patients in the control group, 12 (9%) in the risedronate 2.5 mg group, and seven (5%) in the risedronate 5 mg group. Overall, the percentage of patients who had serious adverse events was greater in the control group than in the risedronate groups.

Figure 2 Mean ( standard error) percentage changes from baseline (month 0) to 24 months in bone mineral density of the lumbar spine in patients treated with risedronate 2.5 mg (square), risedronate 5 mg (triangle), or placebo (diamond). #p ≤ 0.05 vs. control (two-way analysis of covariance); *p ≤ 0.05 vs. baseline (one- sample t test)

Upper gastrointestinal adverse events were reported by 16% of the patients in the control group, 21% in the risedronate 2.5 mg group, and 19% in the risedronate 5 mg group (Table 4). The majority of upper gastrointestinal events were mild and did not lead to discontinuation of treatment. Abdominal pain was reported more frequently in the risedronate groups than in the control group but occurred with similar frequency in the risedronate 2.5 and 5 mg groups. The frequency of esophagitis was low and similar between the control and risedronate 5 mg groups, but more patients experienced an esophageal ulcer in the control group than in the active treatment groups. Upper gastrointestinal events assessed by the investigator as causally related led to withdrawal of two patients in the control group, three in the risedronate 2.5 mg group, and one in the risedronate 5 mg group. The gastrointestinal adverse event profiles of patients with previous or active gastrointestinal illness and users of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin were similar across treatment groups.

Figure 3 Mean ( standard error) percentage changes from baseline (month 0) to 24 months in bone mineral density of the femoral neck in patients treated with risedronate 2.5 mg (square), risedronate 5 mg (triangle), or placebo (diamond). #p ≤ 0.05 vs. control (two-way analysis of covariance); *p ≤ 0.05 vs. baseline (one- sample t test)

Vertebral and non-vertebral fractures were monitored as adverse events. There was no significant difference between the groups in the percentage of patients with incident vertebral fractures at 24 months (control, 8.3%; risedronate 2.5 mg, 8.7%; and risedronate 5 mg, 7.7%). Also, the percentages of patients with one or more incident non-vertebral fractures were similar among the three groups (control, 4.8%; risedronate 2.5 mg, 2.4%; risedronate 5 mg, 3.9%). With the exception of the expected pharmacological effects of risedronate (e.g. changes in markers of bone metabolism, serum phosphorus, and serum calcium), no consistent and clinically significant changes in clinical chemistry or hematology were observed.

DISCUSSION

Risedronate 5 mg daily led to sustained increases in BMD of the lumbar spine, femoral neck, and femoral trochanter of early postmenopausal women. At 3 months, the first timepoint evaluated, the change from baseline in BMD in the risedronate 5 mg group was significant at all three measured sites, and this significant effect persisted throughout the 24-month study. These changes were significantly greater than those in the placebo group at all timepoints. Early postmenopausal women in the risedronate 2.5 mg group maintained BMD at all three sites, but the effect was less pronounced than that of the 5 mg dose. Similar findings were found in previous studies of risedronate in early postmenopausal women25,26. Consistent with the observed changes in BMD, in our study, risedronate therapy was associated with dose-related reductions in bone turnover, as reflected by BSAP levels and DPD/Cr ratios, as early as 1 month.

Figure 4 Mean (plusmn; standard error) percentage changes from baseline (month 0) to 24 months in bone mineral density of the femoral trochanter in patients treated with risedronate 2.5 mg (\square), risedronate 5 mg (triangle), or placebo (diamond). #p ≤ 0.05 vs. control (two-way analysis of covariance); *p ≤ 0.05 vs. baseline (one-sample t test)

Our observations in the control group confirm that early postmenopausal women lose bone significantly at all measured sites despite calcium supplementation, and underscore the need for early intervention to prevent bone loss. This is particularly important in women with the lowest premenopausal BMD. At 24 months, BMD at the lumbar spine in the control group had decreased 2.5% from the baseline value, consistent with expected losses in this group of early postmenopausal women receiving calcium supplementation42. Similar decreases were noted at the femoral neck and trochanter.

Our findings that risedronate prevents bone loss at both cortical and trabecular sites are clinically important because of the morbidity and mortality associated with fractures at these sites. In this study, we observed no significant difference in fracture incidence between the treatment groups, as would be expected in this population of early postmenopausal women. Nevertheless, the preservation of bone density associated with risedronate treatment would be expected to protect against future fracture since the risk of fracture increases sharply with decreases in BMD1-3.

Table 3 Mean (standard error) percentage change from baseline in bone-specific alkaline phosphatase

Table 4 Summary of adverse event findings and number (%) of patients with upper gastrointestinal adverse events occurring in ≥ 1% of patients

In this study, we observed overall baseline prevalences of vertebral deformities of 16-20%. These figures were higher than would have been expected in early postmenopausal women with Tscores greater than -2.5 standard deviations and may be related to the methods used to identify prevalent deformities and differences in the reference populations. In our study, a vertebral body was considered to be deformed at baseline (prevalent deformity) if any of the vertebral height ratios fell below 3 standard deviations of the mean of this specific study population. In other studies, the presence of vertebral deformities at baseline was also determined by comparing each woman's baseline vertebral height ratios with those of a reference group, but different reference groups were used43. Although there are numerous published reports of the efficacy of osteoporosis treatments in early postmenopausal women, few, if any, of these reports include information on the prevalence of vertebral deformities at baseline in these younger patients26,27,30,44. Moreover, many of these studies excluded patients with prevalent deformities26,30,44. As a result, there is relatively little information on the percentage of early postmenopausal women with prevalent deformities. It is possible that the prevalence is higher than currently estimated.

In this study, risedronate was shown to have a favorable safety profile, with gastrointestinal events comparable to placebo. The studies in the risedronate clinical program were designed to include patients with underlying gastrointestinal disorders (e.g. those taking H2-receptor antagonists or proton-pump inhibitors) or patients at risk of incurring gastrointestinal injury through use of concomitant medications (e.g. those taking NSAIDs or aspirin) to more closely emulate the anticipated in-market clinical experience. The gastrointestinal effects reported in this study, consistent with those from an analysis of over 10 000 patients from other risedronate studies45, generally were mild and did not lead to discontinuation of treatment. The use of aspirin or NSAIDs and previous or active gastrointestinal illness were not associated with an increased frequency of upper gastrointestinal adverse events. Regardless of the presence of risk factors for upper gastrointestinal symptoms, the proportion of patients who experienced new symptoms was not greater in the risedronate groups than in the placebo group.

The decision of whether or not to administer therapy to prevent osteoporosis remains a clinical and pharmacoeconomic challenge. Osteoporosis is a silent, progressive disease. Definitively identifying which women will ultimately sustain fractures is not yet possible. Nevertheless, some early postmenopausal women will be at risk for osteoporosis due to a combination of factors such as an early age at menopause, a low peak bone mass, and a high rate of bone turnover. It is important for clinicians to know that antiresorptive therapies like risedronate are both effective and well tolerated in this population and represent an alternative to reduce bone turnover and to maintain bone mass.

This study shows that treatment with risedronate 5 mg led to sustained increases in BMD at the lumbar spine and proximal femur in early postmenopausal women. The limitations of hormone replacement therapy and other treatments available for the prevention and treatment of osteoporosis and risedronate's favorable gastrointestinal safety profile make risedronate an important option for early postmenopausal women at risk for osteoporosis.

ACKNOWLEDGEMENTS

The authors acknowledge Ian Barton for performing statistical analyses, David J. Valent for review and advice on the manuscript, and Mary G. Royer for help in preparing the manuscript.

Conflict of interest Dr Hooper has received honoraria and/or research funding from Aventis Pharma, Eli Lilly and Company, Merck, Sharp & Dohme, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi and Wyeth. Dr Ebeling has received honoraria from Aventis and Eli Lilly and Company, and research funding from Procter & Gamble, Merck, Sharp & Dohme, Roche and Amgen. Dr Roberts has received consultancy fees and research funding from Aventis Pharma, Eli Lilly and Company, and Merck, Sharp & Dohme, and research funding from Procter & Gamble, Novartis, and Wyeth. Dr Graham has received consulting fees from Aventis Pharma and Merck, and research funding from Aventis Pharma, Procter & Gamble, Merck, Sharp & Dohme, Pfizer, Eli Lilly and Company, Sevier Laboratories, Novartis, and Amgen. Dr Nicholson has received honoraria and travel grants from Aventis Pharma, Merck, Sharp & Dohme Australia, and Eli Lilly Australia. Dr D'Emden has no potential conflicts of interest. Drs Ernst and Wenderoth are employees of Procter & Gamble Pharmaceuticals.

Source of funding This study was supported by a grant from Procter & Gamble Pharmaceuticals, Cincinnati, Ohio and sanofi- aventis, Bridgewater, New Jersey, USA.

References

1. Dempster DW, Shane E, Herbert W, Lindsay R. A simple method for correlative light and scanning electron microscopy of human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects. J Bone Miner Res 1986;1:15-21

2. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991;114:919-23

3. Melton LJ 3d, Atkinson EJ, O'Fallon WM, Warmer HW, Riggs BL. Long-term fracture prediction by bone mineral assessed at different skeletal sites. J Bone Miner Res 1993;8:1227-33

4. Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fractures. Lancet 1993;341:72-5

5. Lindsay R, Silverman SL, Cooper C, et al. . Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320-3

6. Jacobs S, Hillard TC. Hormone replacement therapy in the aged: a state of the art review. Drugs Aging 1996;3:193-213

7. Reid IR. Pharmacological management of osteoporosis in postmenopausal women: a comparative review. Drugs Aging 1999;15:349- 63

8. Komulainen MH, Kroger H, Tuppurainen MT, et al. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women: a 5 year randomized trial. Maturitas 1998;31:4554

9. Rossouw JE, Anderson GL, Prentice RL, et al. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33

10. Shumaker SA, Legault C, Rapp SR, et al., for the WHIMS Investigators. 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. JAMA 2003;289:2651-62

11. Hays J, Ockene JK, Brunner RL, et al., Women's Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839-54

12. Hulley S, Furberg C, Barrett-Connor E, et al., for the HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66

13. Grady D, Herrington D, Bittner V, et al., for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57

14. Grady D. Postmenopausal hormones - therapy for symptoms only. N Engl J Med 2003;348:1835-7

15. Hahn RG. Compliance considerations with estrogen replacement: withdrawal bleeding and other factors. Am J Obstet Gynecol 1989;161:1854-8

16. Lufkin EG, Whitaker MD, Nickelsen T, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 1998;13:1747-54

17. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7

18. Ettinger B, Black DM, Mitlak BH, et al., for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical t\rial. JAMA 1999;282:637-45

19. Jolly EE, Bjarnason NH, Neven P, et al. Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause 2003;10:337-44

20. Balfour JA, Goa KL. Raloxifene. Drugs Aging 1998;12:335-41

21. Davies GC, Huster WJ, Lu Y, Plouffe L Jr, Lakshmanan M. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 1999;93:558-65

22. Harris ST, Watts NB, Genant HK, et al., for the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. A randomized controlled trial. JAMA 1999-282:1344-52

23. Reginster J-Y, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 2000;11:83- 91

24. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-41

25. Delmas PD, Balena R, Confravreux E, Hardouin C, Hardy P, Bremond A. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebocontrolled study. J Clin Oncol 1997;15:95562

26. Mortensen L, Charles P, Bekker PJ, DiGennaro J, Johnston CC Jr. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. J Clin Endocrinol Metab 1998;83:396-402

27. Hosking D, Chilvers CED, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 1998;338:485-92

28. Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Delmas PD, Balena R. Prevention of early postmenopausal bone loss with cyclical etidronate therapy (a double-blind, placebo-controlled study and 1- year follow-up). J Clin Endocrinol Metab 1997;82:2784-91

29. Herd RJ, Balena R, Blake GM, Ryan PJ, Fogelman I. The prevention of early postmenopausal bone loss by cyclical etidronate therapy: a 2-year, double-blind, placebo-controlled study. Am J Med 1997;103:92-9

30. McClung M, Clemmesen B, Daifotis A, et al., for the Alendronate Osteoporosis Prevention Study Group. Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Ann Intern Med 1998;128:253-61

31. Wallach S, Cohen S, Reid DM, et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 2000;67:277-85

32. McClung MR, Geusens P, Miller PD, et al., for the Hip Intervention Program Study Group. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:33340

33. Liberman UA, Weiss SR, Broil J, Minne HW, Quan H, Bell NH. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-43

34. Colina RE, Smith M, Kikendall JW, Wong RK. A new probable increasing cause of esophageal ulceration: alendronate. Am J Gastroenterol 1997;92:704-6

35. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996;335:1016- 21

36. Maconi G, Porro GB. Multiple ulcerative esophagitis caused by alendronate. Am J Gastroenterol 1995;90:1889-90

37. Faulkner KG, McClung MR. Quality control of DXA instruments in multicenter trials. Osteoporos Int 1995;5:218-27

38. Genant HK, Grampp S, Gluer CC, et al. Universal standardization for dual x-ray absorptiometry: patient and phantom cross-calibration results. J Bone Miner Res 1994;9:1503-14

39. Steiger P. Standardization of postero-anterior (PA) spine BMD measurements by DXA. Committee for Standards in DXA. Bone 1995;17:435

40. National Osteoporosis Foundation Working Group on Vertebral Fractures. Assessing vertebral fractures. J Bone Miner Res 1995;10:518-23

41. Armitage P. Tests for linear trends in proportions and frequencies. Biometrics 1955;11:37586

42. Genant HK, Lucas J, Weiss S, et al., for the Estratab/ Osteoporosis Study Group. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med 1997;157:2609-15

43. Liberman UA, Weiss SR, Broil J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 1995;333:1437-43

44. Gallagher JC, Baylink DJ, Freeman R, McClung M. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dosefinding studies. J Clin Endocrinol Metab 2001;86:4717-26

45. Taggart H, Bolognese MA, Lindsay R, et al. Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials. Mayo Clin Proc 2002;77:262-70

M. J. Hooper, P. R. Ebeling*, A. P. Roberts[dagger], J. J. Graham[double dagger], G. C. Nicholson**, M. D'Emden[dagger][dagger], T. F. Ernst[double dagger][double dagger] and D. Wenderoth[double dagger]

The University of Sydney and the Department of Endocrinology an[double dagger]d Metabolism, Central Sydney Area Health Service, New South Wales, Australia; * Departments of Diabetes and Endocrinology, and Medicine, The University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia; [dagger] Ashford Specialist Centre, Ashford, South Australia, Australia; [double dagger] Ashford International Research Centre, Ashford Specialist Centre, Ashford, South Australia, Australia; ** The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health, Geelong, Victoria, Australia; [dagger][dagger] Department of Endocrinology, Royal Brisbane Hospital, Brisbane, Queensland, Australia; [double dagger][double dagger] Procter & Gamble Pharmaceuticals, Cincinnati, Ohio, USA

Correspondence: Professor M. J. Hooper, The University of Sydney, Endocrinology and Metabolism, C64, Level 6, Concord Hospital Medical Centre, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia

Received 21-07-04

Revised 3-03-05

Accepted 4-03-05

Copyright CRC Press Sep 2005

Source: Climacteric

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