Pharmacological and hormonal effects on bone with emphasis on osteoporosis : experimental studies in the rat

Abstract

In this thesis influences of some hormones (17beta-estradiol and human parathyroid hormone) and drugs (risedronate and verapamil) on bone were investigated.

The effects of verapamil, a phenylalkylamine calcium channel blocker, on bone mass in female and male rats on a low calcium diet were evaluated. Six female and six male rats each were given verapamil at a concentration of 0.75, 0.075 and 0 mg/ml respectively. After 12 weeks, bone effects were evaluated by measuring tibial wet, dry and ash weight, and volume. Verapamil decreased tibial ash/volume and increased tibial volume in female rats in a doseresponse manner. The effect of verapamil on male rats was the opposite.

The effect of systemic verapamil treatment on the bone response to in vivo mechanical loading was evaluated. Seventy-two intact, female rats were divided into six groups. Half were verapamil treated for 12 weeks. After 8 weeks of treatment, the right tibia was intermittently loaded (40, 30, or 0 N) with a four-point bending device for four weeks. Tibial cortical bone formation and femoral bone mineral density (BMD) were evaluated. Loading uniformly increased bone formation in loaded tibiae of verapamil and control rats.

The bone effects of human parathyroid hormone (1-84) (hPTH) followed by maintenance administration of 17beta-estradiol (E2), risedronate (Ris), or a reduced dose hPTH (LowPTH) in ovariectomized (OVX) rats were evaluated. Eight groups of OVX (n=219) and one group of intact female rats (n=48) were left untreated for 11 weeks. For the following 12 weeks, four OVX groups received hPTH and four groups received vehicle. Treatments were then changed to E2, Ris, LowPTH or vehicle for 36 weeks. Bone tissue was collected every twelve weeks and analyzed by densitometry (distal and diaphyseal femur, and vertebral body), histomorphometry (proximal and diaphyseal tibia), and mechanical tests (vertebral body).

After ovariectomy, osteopenia developed in all sites. hPTH treatment for 12 weeks increased bone formation resulting in an increase in bone mass at all sites and vertebral strength above OVX rats' level. After withdrawal of hPTH bone mass and strength were at the OVX levels within 12-24 weeks. In groups on maintenance treatment with LowPTH, bone mass at measured sites and vertebral strength remained above the OVX levels during the 36 week follow-up. Treatment with E2, in the dose given, resulted in bone mass and vertebral strength at the OVX levels at the end of the maintenance period, even though bone turnover was decreased. In groups on Ris maintenance treatment, bone mass remained above the OVX levels during the follow-up period, due to decreased bone turnover. Bone strength did not differ from either intact or OVX at the end of the study.

In conclusion, verapamil cause osteopenia in female rats, but had the opposite effect on male rats on a low calcium diet. Verapamil did not effect the bone cellular response to altered mechanical stress in mature female rats. By increasing bone formation, hPTH(1 -84) increased cancellous and cortical bone mass, and vertebral strength, in osteopenic rats. The study indicated that treatment with LowPTH was the most effective treatment regimen for maintaining bone mass and strength for up to 36 weeks. Ris was not as effective as LowPTH, but fully maintained bone mass and partially maintained bone strength. E2, in the dose given, did not maintain either bone mass or vertebral strength.