In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague-Dawley rats by ormeloxifene, a selective estrogen receptor modulator

Antiosteoporotic activity of ormetoxifene, a multifunctional SERM, using inhibition in parathyroid hormone (PTH) induced resorption of Ca-45 from prelabeled chick and rat fetal limb bones in chase cultures and modulation of certain biochemical markers of bone turnover and bone mineral density (BMD) in ovariectomized adult female rats, was investigated. Ormeloxifene concentration-dependently inhibited PTH-induced resorption of Ca-45 from chick fetal femora with treated/control (T/C) ratio of 0.71, 0.32 and 0.20 at 50, 100 and 200 muM concentration, in comparison to 0.49,0.53 and 0.95 in case of CDRI-85/287 (a pure antiestrogen), tamoxifen and ethynylestradiol (100 muM), respectively. Using rat fetal limb bones, ormeloxifene (100 muM) exhibited T/C ratio of 0.67, in comparison to 1.43 with PTH alone. Heat-killed bones exhibited negligible resorption (2.9%; T/C: 0.098) in response to PTH, In adult female rats, ormeloxifene (1.25 and 12.5 mg/kg per day) inhibited ovariectomy-induced increase in serum total and bone-specific alkaline phosphatase and osteocalcin and urine calcium/creatinine ratio to almost intact control level. Ovariectomy was accompanied by marked decrease in bone mineral density of isolated femur and tibia, being maximum in femur neck (28.3%; P < 0.01) and midshaft (23.7%; P < 0.01), but only marginal (6.7%; P > 0.05) in region proximal to tibio-fibular separation point. Decrease in BMD based on T-/Z-score, too, was > 2.5 S.D. than mean value of normal young adult/age-matched females. This was prevented by ormeloxifene and the effect, though apparently more in females supplemented with higher dose of ormeloxifene, was not always significantly different and clear dose-response was not evident until BMD data was evaluated on T-/Z-score basis. The analysis also demonstrated much higher threshold level of tibia than femur and more so for their mid-shafts. Increase in BMD of isolated bones was also observed in ormeloxifene-treated intact females, without significantly altering biochemical markers of bone turnover or uterine weight. Findings suggest potential of ormeloxifene in management of post-menopausal osteoporosis and beneficial effect on BMD in women taking this SERM for contraception or any hormone-related clinical disorder. (C) 2004 Elsevier Ltd. All rights reserved.