Three studies were carried out. First, the effects of aging on the maturation of the female skeleton were assessed. Second, the hypothesis that has linked ovarian hormone deficiency bone loss to hypercalcemic suppression of the parathyroids leading to a decrease in 1,25-dihydroxyvitamin D synthesis and gut absorption of calcium was examined. Third, the effects of ovariectomy and a combination of ovarian hormone deficiency and low dietary calcium on bone and the calcium-regulating hormones were evaluated. After 6 months, ovariectomy and a low calcium diet independently decreased the density of the ilium, the femur, and the fourth lumbar vertebra as well as the calcium content of the latter two. The effects of the two treatment regimens were additive and more marked in the vertebral bone. Ovariectomy lowered serum calcitonin only in animals fed a normal diet and had no effect on serum PTH and vitamin D metabolites, while a low calcium diet caused a significant increase in serum 1,25-dihydroxyvitamin D. In both dietary regimens ovariectomy resulted in about a 30% decrease in intestinal calcium absorption. A low calcium diet increased morphometric indices of bone formation and bone resorption as did ovariectomy, with resorption exceeding formation. The discussion of our findings led to the conclusion that the aged rat model of ovarian hormone deficiency bone loss qualifies for serious consideration as a practical convenient cost-effective animal model for exploring aspects of the pathogenesis and treatment of postmenopausal bone loss.

A group of 3-month-old Sprague-Dawley rats were sham operated or ovariectomized and given daily injections of human PTH-(1-34) (8 or 16 micrograms per 100 g body weight) for 5 weeks. At the termination of the study histomorphometric techniques were used to examine changes in cortical and cancellous bone in the diaphysis and proximal metaphysis of the tibia. Ovariectomy resulted in a 50% decrease in cancellous bone that was accompanied by a 41 and 120% increase in osteoclasts and osteoblasts, respectively. In contrast, in the ovariectomized animals treated with PTH, the metaphyseal cancellous bone increased by over 300% to a level in excess of that present in the sham-operated control animals. The increase in cancellous bone induced by PTH was associated with an over 70% increase in osteoblasts and tetracycline-labeled area and an unexpected decrease in trabecular osteoclasts. In the tibial diaphysis PTH also decreased endosteal osteoclasts and at the same time increased osteoblast size and number as well as endosteal and periosteal bone formation; ovariectomy increased only periosteal bone formation. Our findings demonstrate that intermittent administration of PTH prevents ovariectomy-induced bone loss and augments cancellous and cortical bone formation in sexually mature ovariectomized rats. Although the basis of the bone anabolic action of PTH remains elusive, our data indicate that it may involve the uncoupling of bone formation and resorption such that the latter is inhibited as bone formation is enhanced. Our findings are also compatible with the view that intermittent administration of PTH increases bone mass, in part by stimulating the proliferation and differentiation of osteoblast progenitors while inhibiting osteoclast proliferation.