Conventional hormone replacement therapy preserves bone mass predominantly by reducing bone turnover but does not exert significant anabolic skeletal effects. In contrast, high doses of estrogen have been shown to increase bone formation in animals and we have recently reported high bone mineral density values in women treated long-term with estradiol implant therapy. The aim of this study was to investigate the mechanisms by which high doses of estrogen may increase bone mass in postmenopausal women. Iliac crest biopsies were obtained from 12 women who had received long-term treatment with estradiol implants (at least 14 years), on demand, following hysterectomy and bilateral salpingo-oophorectomy. Indices of bone turnover, remodeling balance and cancellous bone structure were assessed by image analysis and compared with those of premenopausal women. Mean wall width was significantly higher in women treated with estradiol therapy than in premenopausal women (44. 8 +/- 4.8 vs 38.8 +/- 2.8 mm; mean +/- SD; p = 0.001) and eroded cavity area was significantly lower in the implant-treated women (3612 +/- 956 vs 5418 +/- 1404 mm(2); p = 0.001). Bone formation rate at tissue level and activation frequency were lower in the women treated with implants, although the differences were not statistically significant. Indices of cancellous bone structure were generally similar between the two groups. These results provide the first direct evidence that high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women and indicate that these are achieved by stimulation of osteoblastic activity.
Twelve women who had received oestradiol implantation on demand for at least 15 years following hysterectomy with bilateral oophorectomy, underwent bone densitometry of hip and spine. Bone mass of hip and spine was significantly elevated above that of both the age matched mean to a degree hitherto undocumented. This suggests that oestrogen in high doses or over a long period may produce a true anabolic effect on bone mass.Osteoporosis remains a formidable challenge to medicine, with the prevalence of fracture being augmented by the ageing of the population and the absence of an effective treatment. Future advances are likely to come from the fields of screening and prevention. The principal therapeutic means to retard bone loss in postmenopausal women is oestrogen, although serious doubts remain as to the optimal mode and duration of delivery. Oestrogen decreases the rate of bone resorption, principally by cytokine-mediated inhibition of osteoclastic activity. This leads to the correction of the imbalance between bone resorption and bone formation at bone remodelling sites.Non-oral oestrogens avoid the first pass effect on the liver and allow direct delivery into the systemic circulation'. Transdermal oestrogen can cause skin reactions and compliance is not guaranteed. Percutaneous oestrogen implants which guarantee compliance and are relatively cheap have been used in the prevention and treatment of osteoporosis. There is, however, disagreement as to whether this form of therapy simply arrests bone loss, or whether it also causes a prolonged gain in bone mineral density. Oestradiol has been shown to increase spinal and femoral neck bone mineral density when given in a dose of 75 mg every six months for one year to women with a bone mineral density below the 50th centile2.The use of oestrogen replacement therapy following abdominal hysterectomy and bilateral salpingo-
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