br Effects of estrogens on bone Estrogens
Effects of estrogens on bone Estrogens play an important role in bone remodeling, as demonstrated by studies in mice in which the ER genes were deleted , . ERβ compensates for the Norfloxacin of ERα, and vice versa, but when both ERs are deleted a profound decrease in trabecular bone volume is observed. One of the first studies showing a positive effect of estrogens on bone was performed by Lindsay et al. . Young women who had been ovariectomized for various clinical reasons lost bone rapidly and this could be counteracted by estrogen treatment. In postmenopausal women, estrogens increased bone mass whilst placebo-treated women lost bone mass. The difference from placebo may be up to about 10%, the magnitude probably depending on the preparation (i.e. dose and type of estrogen) and route of administration. In general, the transdermal route (patch or gel) shows a less marked effect than oral preparations; the subcutaneous route is rarely used. The PEPI trial showed that the addition of medroxyprogesterone acetate (MPA) for 12 days per month had a stronger effect than CEE alone , whilst no such difference was found with a continuous combined regimen. One simple explanation is that a down-regulation of ERs occurs with continuous combined preparations, although this is not confirmed by other studies . It has also been shown that estrogen plus norethisterone acetate (NETA) results in a marked increase in bone mass  and this has been explained by the estrogenic properties of NETA. Unfortunately, head-to-head comparisons between different estrogen plus progestogen combinations have not been performed. Retrospective studies have indicated that estrogens prevent fractures , , , , although prospective studies have been lacking. Recently the Women’s Health Initiative (WHI) study showed prospectively that treatment of late postmenopausal women with CEE plus MPA for 5.2 years significantly reduced the risk of vertebral and hip fractures by approximately 40% .
Effects of SERMs on bone The positive effect of tamoxifen on bone mass in ovariectomized animals, but not in intact animals, initiated the development of similar types of compounds for the treatment of osteoporosis in postmenopausal women. There have even been reports that tamoxifen also improves bone quality . Turner et al. showed in preclinical studies that, after longer treatment with raloxifene, the effects on bone mass and bone strength were not different from those of estrogens . Clinical studies have shown that tamoxifen has a bone-sparing effect . Similarly, Delmas et al.  demonstrated a greater increase in bone mass with different doses of raloxifene than with placebo in postmenopausal women. Unfortunately, head-to-head comparisons investigating the effects of estrogens and SERMs on bone mineral density are rare. Heany and Draper  showed that the effect of raloxifene on bone remodeling repression was less than that of estrogens, thus suggesting that raloxifene may have a less marked effect on bone mineral density. Despite this, a significant reduction in vertebral fractures was shown in a long-term study with raloxifene in women with osteoporosis, although the effect on hip fractures was not significant .
Effects of tibolone on bone Tibolone has been shown to prevent bone loss due to inhibition of bone resorption in young rats and to dose dependently maintain both cortical and trabecular bone quality in mature rats to the same extent as estrogens , . The effects on bone were also evaluated in a monkey study primarily designed to investigate the effects of tibolone in comparison to CEE alone, and CEE plus MPA, on coronary artery atherosclerosis . The bone mineral density in the tibolone-treated groups was higher than in the CEE and CEE plus MPA-treated groups. The positive effects of tibolone on bone were first demonstrated in a clinical study performed by Lindsay et al. . Geussens et al. subsequently showed an increase of 8% in spinal bone mineral density after 2 years of tibolone treatment in women with osteoporosis . Two double-blind, placebo-controlled, dose-finding studies have confirmed the prevention of bone loss with tibolone treatment in early postmenopausal women , , and it may be concluded that a 1.25mg dose is as effective as a 2.5mg dose on both spine and femoral neck.