A research program is proposed to continue and to advance investigations focusing on evolution of histopathological and serum-biochemical changes associated with loss of ovarian function. Loss of ovarian function represents a major contributing factor in the development of postmenopausal osteoporosis. The sequelae of osteoporosis constitute one of the greatest challenge to health and longevity, exceeding cardiovascular-renal diseases and cancer in prevalence. In preliminary studies, an in vivo dog model for bone loss associated with cessation of ovarian function was established in our laboratory. This model allows to perform much needed controlled prospective studies which are not feasible in patients, but closely related and directly applicable to the bone loss occurring in humans. Abnormalities in static and dynamic parameters of bone structure and bone cells occurring during six months after induction of gonadal deficiency will be unravelled by sequential bone biopsies, mineralized bone histology and histomorphometry in ovariohysterectomized dogs. The hormonal derangements will be elucidated by monthly determinations of sex hormones including estradiol, progesterone, luteinizing hormone, follicle stimulating hormone, prolactin and parameters of bone metabolism such as serum concentrations of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, bone-Gla-protein, 1.25 Vitamin D3 and urinary hydroxyproline. The predictive value of these biochemical parameters for bone changes associated with loss of ovarian function will be studied. The contribution of skeletal mass and total body weight at time of loss of ovarian function to the rate of bone loss and the amount of bone remaining after long term ovarian insufficiency will also be studied. Cancellous and cortical bone will be separately evaluated to unravel possible differences in rates or degree of bone loss. In addition, the role of estrogen deficiency versus other hormonal derangements in the bone abnormalities developing after loss of ovarian function will be studied in separate groups of animals subjected to ovariectomy and subsequent estrogen replacement. The studies will fill a most important gap currently existing in the understanding of evolution of bone loss and the role of estrogen in the bone abnormalities associated with ovarian insufficiency.
