Is HRT still indicated for the primary prevention of osteoporosis?

In most European countries, the actual guideline on the evaluation of new medicinal products in the treatment of primary osteoporosis is incomplete in that, unlike the previous Note for Guidance on Postmenopausal Osteoporosis in Women (EMEA 2001 Guidance), it fails to address the prevention of osteoporosis indication. Early prevention of osteoporosis is essential because the majority of fractures occur in the nonosteoporotic population. Furthermore, it is well known that individuals who had one osteoporotic fracture approximately double their risk to have another. Although treatment of osteoporosis can reduce the risk for a subsequent fracture, it cannot eliminate the excess risk. It is therefore essential to maintain bone architecture and quality as early as in the periand early post-menopause. Gynecological endocrinologists are therefore greatly astonished that EMEA did not maintain the prevention of osteoporosis by estrogens as a first-line medical intervention in women with an increased risk of osteoporosis and bone fractures in its latest recommendations. It is well known that the first 5–10 years after menopause are associated with an accelerated rate of bone loss. Primary prevention of osteoporosis is directed at women identified as being at increased risk for the disease but without established disease. Hormone replacement therapy (HRT) has been shown to reduce post-menopausal bone loss and reduce fracture incidence in several RCT studies, including the PEPI [1] and the HOPE trial [2] trial. More recently, the WHI trial, using a fixed combination of conjugated equine estrogens 0.625 mg and medroxyprogesterone acetate 2.5 mg, has shown that the resulting loss of bone architecture and quality preventable with hormone therapy and confirmed the fracture reduction efficacy of HRT, including hip and spine fractures [3,4]. The WHI trial was of women aged between 50 and 80 years, who were not known to have increased fracture risk and who were supposed to be in general good health. In addition, the Women’s Health Initiative [3] has demonstrated fracture prevention with hormone therapy in a non-osteoporotic population, too. This preventive effect is maintained: the PERF study [5] demonstrated that administration of hormone therapy in early post-menopause offers a long-lasting benefit for the prevention of postmenopausal bone loss and osteoporotic fracture. Lower doses than previously thought necessary are now proving effective [2,6–8], and a very low dose estrogen product has recently been licensed for osteoporosis prevention by the US Food and Drugs Administration. HRT is an effective treatment for the prevention of osteoporotic fractures in women without established disease. These women tend to be younger, as older women have an increasing prevalence of osteoporosis as defined by bone density criteria [9]. Are younger women with osteopenia, rather than osteoporosis, at increased fracture risk? In the age group of 50–80 years, around 36% of classical osteoporotic fractures occur in those below age 65 years [10,11]. In the UK, this amounts to more than 100,000 fractures per year in women aged 50– 65 years, over 9000 of which are hip fractures [10,11; www.uk2u. net]. There is no doubting the efficacy of HRT for the primary prevention of osteoporosis in post-menopausal women. Its current role in prevention of fractures seems best suited to those younger postmenopausal women with an increased risk. In such a population, HRT use for osteoporosis prevention would be cost-effective [12].