Despite recent advances in the awareness of osteoporosis as a major health problem causing a great societal economic burden of increasing proportions, little is known about the histological mechanisms leading to decreased bone mass after cessation of ovarian function. Our previous NIH funded studies identified an initial phase of rapid bone loss that occurs during the first four weeks after ovariohysterectomy followed by a maintenance phase of low bone mass during the months thereafter. The initiation phase appears to be related to hyperresorption, whereas, the maintenance phase is clearly dues to insufficient bone formation. The proposed in vivo studies will employ our established animal model for bone loss occurring after cessation of ovarian function since the histologic changes seen in this model mirror the histologic findings in postmenopausal women with high turnover osteoporosis. The specific objectives are to determine: (1) whether the initial phase of rapid bone loss after cessation of ovarian function is related to hyperresorption; (2) whether calcitonin can be used to prevent bone loss occurring soon after cessation of ovarian function; (3) whether intestinal 1,25 vitamin D receptors are altered in the initiation and maintenance phase of bone loss; (4) whether there are changes in growth factors and crystal size and perfection associated with bone loss occurring after cessation of ovarian function; and, (5) whether calcitonin can positively affect the maintenance phase of bone loss by exerting an effect on bone formation. To achieve these goals, Beagle dogs will be ovariohysterectomized or sham- operated, and then sequential bone biopsies, blood tests for calciotropic hormones, BGP, IGF-I, IGF-II, and other biochemical parameters will be examined at regular intervals. Half of the dogs will receive calcitonin, the others will serve as controls. Intestinal 1,25D receptors will be studied soon after ovariohysterectomy (initiation phase) and four months after cessation of ovarian function. Bone will be studied at the organ level (compressive strength), at the tissue and cellular level (static and dynamic histomorphometry) and at the crystal level (density fractionation and infrared spectroscopy). Results of these studies will provide new and relevant information on mechanisms associated with bone loss after cessation of ovarian function and the therapeutic value of calcitonin in preventing, arresting and/or reversing these changes.
