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Chair, Scientific Advisory Council, Osteoporosis Society of Canada, Toronto, Ont.
Although raloxifene has been shown to have positive effects on bone mineral density1 and in the prevention of vertebral fracture2 in postmenopausal women with osteoporosis (with or without pre-existing vertebral fracture), there are as yet no data demonstrating efficacy for the prevention of hip fractures in this population. Furthermore, alendronate and risedronate have been shown to prevent hip fractures only in elderly postmenopausal women with severe osteoporosis (with pre-existing vertebral fracture).3,4 No adequately powered trial has yet been completed to address the impact of raloxifene on hip fracture. As stated in the 2002 guidelines,5 "a recommendation that a specific therapy be used as ‘first-line’ therapy for osteoporosis relies on Level 1 evidence for prevention of fragility fracture (mainly vertebral fracture)," and raloxifene fulfills this criterion.
In the MORE study,2 the administration of raloxifene (60 mg/day) in postmenopausal women increased the risk of venous thromboembolic events from 1.44 to 3.32 events per 1000 woman-years (change in absolute risk from 0.5% to 1.1%; attributable risk 0.6%) over 40 months (relative risk compared with placebo 3.1%, 95% confidence interval 1.5% to 6.2%). Edmund Yendt's clinical experience (2 cases of venous thromboembolism among 200 patients given raloxifene) is compatible with these data, but one must be wary of reporting clinical data when obtained from a small sample of patients, since the smaller the sample size, the greater the chance of drawing an incorrect conclusion. In the trial by Johnston and others,6 cited by Yendt, the rates of venous thromboembolism and pulmonary embolism were not expressly reported; rather, only the rates of deep vein thrombosis were given. Therefore, it is impossible to compare these findings with those of the MORE study2 (which reported both deep vein thrombosis and pulmonary embolism as venous thromboembolism). As stated in the 2002 guidelines,5 venous thromboembolism constitutes a serious side effect associated with raloxifene, although it is reported infrequently and the magnitude of the risk is similar to that observed for both hormone replacement therapy and tamoxifen. We agree that this risk should not be taken lightly, but it does not outweigh the benefits of raloxifene as a first-line treatment for postmenopausal women with osteoporosis.
Andreas Laupacis has cited 2 serious deficiencies in the guidelines: the lack of mention of absolute risks and the lack of cost-effectiveness analyses. We agree that discussion of absolute risk, absolute risk reduction and its reciprocal, the number needed to treat, could have made the guidelines stronger. However, the data from most of the prospective trials evaluating efficacy of therapy in preventing fracture are provided as relative risks in populations with high absolute risk at baseline; therefore, the absolute risk would not provide stronger antifracture evidence than that supplied by the relative risk in these known high-risk populations. Furthermore, evidence-based guidelines are not review articles or meta-analyses and do not pretend to compare various drug therapies in terms of a specific outcome, such as antifracture efficacy. This type of comparison can only be achieved in head-to-head randomized controlled trials.
With regard to the cost-effectiveness of therapies, it was decided in 1998, when development of the 2002 guidelines5 began, not to include cost-effectiveness questions. This decision was based on a number of factors, including lack of available high-quality economic impact data for all therapies (especially from Canada), the number of questions already being posed for the guidelines and the perceived priority of the need to determine the most effective therapies, irrespective of cost. As Laupacis has pointed out, the adoption of many of these therapies by third-party payers may require positive cost-effectiveness data, but our goal was to provide a true evidence-based guide to clinical efficacy. We hope that some of Canada's excellent health economists will pick up where we left off and supply this important cost-effectiveness information.
Jacques P. Brown Chair, Scientific Advisory Council Osteoporosis Society of Canada Toronto, Ont.
References
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Copyright 1995-2003, Canadian Medical Association. All rights reserved. ISSN 1488-2329
(e) 0820-3946 (p)
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association. |
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