Bone Remodeling and Structure in Postmenopausal Women Treated with Long-Term, High-Dose Estrogen Therapy

Abstract

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.

Characterization of Osteocrin Expression in Human Bone

“…Sections from the estrogen-treated women showed more intense and extensive Ostn staining than those from the untreated women, particularly at sites of bone formation. Previously, we have demonstrated anabolic skeletal effects in this estrogen-treated group (Vedi et al 1999;Bord et al 2001), with increased osteoblastic activity.…”

Increased Bone Morphogenetic Protein-6 Expression in Mouse Long Bones After Estrogen Administration

“…Estrogen is also thought to stimulate osteoblast function in humans (5,6) and other mammals. (53)(54)(55) In view of our findings, it is tempting to speculate that BMP-6 is involved in mediating stimulatory effects of estrogen on osteoblast function in other species.…”

“…(3,4) In addition, recent evidence suggests that estrogen therapy stimulates osteoblast function in postmenopausal women, particularly when administered at a relatively high dose. (5,6) Though estrogen also stimulates osteoblasts in vitro, this action is restricted to certain experimental conditions, (7,8) and the physiological relevance of these observations is unclear. Animal models also exist for studying the stimulatory action of estrogen on bone formation, of which the mouse has been used most widely.…”

Estrogen Added Intermittently, but Not Continuously, Stimulates Differentiation and Bone Formation in SaOS-2 Cells

“…This stimulatory effect of E 2 provides strong in vitro evidence that a direct effect of E 2 on human osteoblasts via ERa maybe one of the mechanisms involved in its stimulatory effect on bone formation in vivo, seen both in lower species [7][8][9][10][11] and in postmenopausal women. [12][13][14][15] Furthermore, our data demonstrating the formation of mineralized bone-like structures in long-term cultures of SaOS-2 cells in the presence of dexamethasone, ascorbic acid and bglycerophosphate make the SaOS-2 cell culture a valid human cell system for quantitative study of estrogen action on bone formation in vitro.…”

“…It is thought that the major effect of estrogen in vivo is inhibition of resorption, 6) but effects on bone formation have been reported in lower species. [7][8][9][10][11] More recently, studies 12,13) showing a sustained stimulation of osteoblast function in postmenopausal women who were exposed for prolonged period to relatively high doses of estrogen, may suggest that estrogen also has an effect on bone formation in humans. 6,14,15) Others still view the anabolic effect of estrogen as being controversial.…”