BoneKEy-Osteovision | Commentary
Anti-fracture efficacy of hormone replacement therapy
DOI:10.1138/2001035
The pivotal role played by the menopause in the genesis of postmenopausal bone loss, and thus postmenopausal osteoporotic fractures, has led to hormone replacement therapy (HRT) being regarded as the logical intervention for both the prevention and treatment of postmenopausal bone loss. These theoretical considerations have been supported by a large number of randomized controlled trials, which demonstrate beneficial effects of hormone replacement therapy on bone density throughout the skeleton in both early and late postmenopausal women. Thus, hormone replacement therapy became established as the gold standard for osteoporosis management during the 1980s, at a time when bone density was regarded as an adequate surrogate endpoint. As a consequence, the large-scale randomized controlled trials that are now regarded as being necessary to demonstrate anti-fracture efficacy were not undertaken.
The absence of definitive trials demonstrating anti-fracture efficacy has recently led to a questioning of the value of HRT in the treatment of osteoporosis, and to the FDA no longer licensing HRT preparations for this indication. In this context, the recent meta-analysis of the effect of HRT on non-vertebral fracture incidence reported by Torgerson and Bell-Syer () is especially welcome. They collected 22 randomized controlled trials of at least one year's duration, in which HRT was compared with either placebo, no treatment, calcium, or vitamin D. Many of these did not report fracture data but this has been obtained from the authors of the original studies. In the pooled analysis, the relative risk of fracture in women randomized to HRT was 0.73 (95% CI, 0.56-0.94, P=0.02). For hip and wrist fractures alone, the relative risk was 0.60 (95% CI, 0.40-0.91, P=0.02). The effects appeared to be greater in women under the age of 60, but this finding is heavily dependent on the inclusion of the HERS study, which involved a relatively obese population of older women with cardiovascular disease in whom no anti-fracture efficacy of HRT was demonstrable ().
The positive findings of Torgerson and Bell-Syer complement a number of other bodies of evidence. Thus, hormone replacement therapy consistently has positive effects on bone density of both animals and humans (); there is a large body of observational data suggesting that the use of HRT is associated with a lower incidence of fractures (); and there is evidence from two randomized controlled trials that HRT also reduces the incidence of vertebral fractures - in both early postmenopausal women (in whom height loss is also reduced) (), and in those with established osteoporosis (). The latter study has been criticized for using numbers of fractures rather than numbers of patients with fractures as the endpoint. When reanalysed using patients with fractures, the result is no longer statistically significant because this reanalysis reduces the study's statistical power. However the trend towards fracture reduction remains, strongly suggesting that this is a real finding.
The case for the use of HRT is also supported by comparisons with other agents of established anti-fracture efficacy. Whether assessed by bone mineral density or biochemical measures of bone resorption, HRT is at least as effective as bisphosphonates (), and rather more so than raloxifene () or salmon calcitonin (). Since all of these agents primarily act as inhibitors of bone resorption, it is unlikely that an agent which decreases bone resorption and increases bone mass to the extent seen with HRT, is going to be without anti-fracture efficacy.
Do the positive results of the Torgerson and Bell-Syer meta-analysis remove the need for a definitive randomized controlled trial of HRT in the treatment of osteoporotic fractures? They will re-assure many doctors that their long-term practice of using HRT in this context is reasonable, but they may not cause all regulators to accept this as a proven therapeutic option. A positive result from an appropriately designed trial would remove any remaining uncertainty, and the Women's Health Initiative and the WISDOM trial may meet this need to some extent, albeit in non-osteoporotic populations. However, concerns regarding the non-bone safety of HRT and the satisfactory efficacy and tolerability data with bisphosphonates have both diminished the incentive to use HRT in women with established osteoporosis, and thus reduced the commercial and scientific imperatives to carry out a definitive anti-fracture study with this treatment. Therefore, for the foreseeable future, doctors will need to advise their patients in the absence of this information. The fact that this trial has not been done should not blind us to the substantial efficacy data that do exist for HRT, nor to the fact that this therapy is much less expensive than the potent bisphosphonates, and therefore much more widely available. Based on current evidence and now supported by the valuable meta-analysis of Torgerson and Bell-Syer, HRT remains an important therapeutic modality in postmenopausal osteoporosis, particularly in the cost-conscious prescribing environments which exist in most parts of the world.
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