droloxifene and Osteoporosis

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Topics: Adult; Anastrozole; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Estrogen Antagonists; Female; Forecasting; Humans; Indoles; Letrozole; Middle Aged; Neoplasm Metastasis; Nitriles; Osteoporosis; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Triazoles

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Bone and Bones; Breast Neoplasms; Cholesterol; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Organ Size; Osteoporosis; Ovariectomy; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Reference Values; Tamoxifen; Toremifene; Transplantation, Heterologous; Tumor Cells, Cultured; Uterus

Droloxifene (DRO) is a selective estrogen receptor modulator that prevents bone loss by inhibition of bone turnover associated with estrogen deficiency in both growing and aged female rats. The purposes of this study were to test: (a) whether DRO can maintain prostaglandin E2 (PGE2)-restored bone after discontinuation of PGE2 in aged, ovariectomized (ovx) rats; (b) if an inhibition of bone turnover by DRO reduces bone anabolic effects of PGE2; and (c) whether bone mass restored by PGE2 plus DRO can be maintained after discontinuation of both agents. Female rats at 12 months of age were sham-operated (sham) or ovx. Three months postsurgery, ovx rats were treated with either PGE2 (3 mg/kg per day, subcutaneously [s.c.]) alone, or PGE2 plus DRO (10 mg/kg per day, per os [p.o.]) for 2 months. Thereafter, the PGE2 or PGE2 plus DRO treatment was withdrawn and the rats were then treated with either vehicle or DRO for another 1.5 months. Using dual-energy X-ray absorptiometry (DXA), total lumbar vertebral bone mineral density (LV-BMD) was determined in vivo at months 0, 3, 5, and 6.5. At the end of the study, the rats were autopsied, and BMD of total femur, femoral shaft, distal femoral metaphysis, and proximal femur was determined ex vivo by DXA. Standard static and dynamic bone histomorphometric parameters were determined on the fourth lumbar vertebral body (L-4). At 3, 5, or 6.5 months postsurgery, LV-BMD decreased significantly (-15%, -19%, and -19%, respectively) in the vehicle-treated ovx rats compared with sham. Beginning at 3 months post-ovx, PGE2 alone or in combination with DRO for 2 months completely restored LV-BMD back to the sham level. There was no difference in LV-BMD in PGE2 alone or PGE2 plus DRO. Upon cessation of PGE2 treatment, a significant decrease in LV-BMD was observed in the PGE2-alone group (-12%). On the other hand, when DRO treatment was given after discontinuation of PGE2, the PGE2-restored LV-BMD was completely maintained. In the PGE2 plus DRO group, no loss in LV-BMD was observed after cessation of either PGE2 alone or both PGE2 and DRO. However, treatment with DRO following 2 months of PGE2 plus DRO further increased LV-BMD (+10%). At the end of the study, ex vivo femoral BMD data confirmed the observation in lumbar vertebrae. Histomorphometric results of L-4 indicated that loss in bone mass after cessation of PGE2 in PGE2 alone group was associated with increased bone turnover. Treatment with DRO in the maintenance phase inhibite

Topics: Absorptiometry, Photon; Aging; Animals; Bone Density; Dinoprostone; Disease Models, Animal; Drug Therapy, Combination; Estrogen Antagonists; Female; Femur; Image Processing, Computer-Assisted; Lumbar Vertebrae; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Tamoxifen

The purpose of this study was to determine the effects of droloxifene (DRO), a new estrogen antagonist/agonist, on bone turnover, bone mass, total serum cholesterol, and uterine weight in rats made estrogen deficient by ovariectomy. Sprague-Dawley female rats were ovariectomized (OVX) or sham operated (sham) at 5 months of age and treated with 17 beta-estradiol (E2) at 30 micrograms/kg, sc, daily or with DRO at 5, 10, or 20 mg/kg.day, orally, for 4 weeks. At the time of death, body weight gain, uterine weight, and total serum cholesterol were measured. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora, distal femoral metaphyses, femoral shaft, and proximal femora were determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometric analysis of proximal tibial metaphyses was performed in double fluorescent labeled, undecalcified, 4- and 10-microns longitudinal sections. Body weight gain in E2-treated OVX rats was significantly reduced compared to that in OVX controls, but was not different from that in sham controls. Body weight gain in DRO-treated OVX rats was decreased significantly compared to that in both sham and OVX controls. In OVX rats, uterine weight was completely preserved by treatment with E2. Uterine weight in DRO-treated OVX rats was slightly, but significantly, increased from the vehicle-treated control value, and was significantly lower than that in sham controls and E2-treated OVX rats. Treatment with sc injection of E2 in OVX rats had no effect on total serum cholesterol, whereas OVX rats orally treated with DRO at 5-20 mg/kg.day decreased total serum cholesterol by 33-46% compared to levels in sham and OVX controls. Compared to sham controls, OVX decreased BMC and BMD of distal femoral metaphyses, increased BMD of the femoral shaft, and had no effect on BMC and BMD of whole femora and proximal femora. Treatment with either E2 or DRO prevented these changes induced by OVX. Proximal tibial metaphyseal trabecular bone volume and trabecular number were increased, and trabecular separation, percent osteoclast perimeter, osteoclast number, percent mineralizing perimeter, mineral apposition rate, bone formation rate, and bone turnover rate were decreased in 5, 10, or 20 mg/kg.day DRO-treated OVX rats compared to OVX controls. These cancellous bone histomorphometric indexes in DRO treated OVX rats did not differ from those in E2-treated OVX rats or sham controls,

Topics: Animals; Bone Density; Bone Resorption; Estradiol; Estrogen Antagonists; Estrogens; Female; Organ Size; Osteogenesis; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Tamoxifen; Uterus