Project Summary The healthy skeleton continuously renews itself throughout the lifespan via closely coupled bone resorption and remodeling-based bone formation (RBF). In contrast, modeling-based bone formation (MBF), i.e., de novo bone formation without prior activation of bone resorption, is less commonly found in adults. However, MBF has been identified as an important mechanism by which anabolic agents for osteoporosis, e.g., intermittent parathyroid hormone (PTH) and PTH related peptide (PTHrP), and sclerostin antibody (Scl-Ab), rapidly elicit new bone formation. Despite the potent effect of anabolic agents on increasing bone mass, their treatment benefit can be reversed upon discontinuation. Nevertheless, osteoporosis is a life-long chronic condition and there is a pressing need for novel therapeutic regimens to enhance and maintain treatment efficacy and extend the treatment duration. Our recent investigation unexpectedly discovered that intact female and estrogen- deficient female rats had distinct responses to the discontinuation of PTH treatment. No adverse effect was observed in intact female rats, which sustained treatment benefit long after discontinuation, in contrast to the significant bone loss and bone microarchitecture deterioration observed in estrogen-deficient rats and pre- pubertal male rats after PTH discontinuation. These motivate the new objectives proposed in this supplement to further elucidate the influence of sex and gonadal function on the cellular mechanisms of MBF and RBF, which have been demonstrated to play important roles in determining skeletal responses to anabolic treatment and discontinuation. This critical knowledge will then be used to guide the novel design of a cyclic administration regimen of anabolic agents with and without intervening anti-resorptive agents to achieve the greatest treatment benefit by considering patient’s sex and gonadal function. Ovariectomized (OVX) rats will be used to simulate post-menopausal osteoporosis and orchiectomized (ORX) rats will be used to simulate hypogonadism in aged men. Age-matched, intact male and female rats will be used as young adults with intact gonadal function. We hypothesize that skeletal responses to anabolic treatment discontinuation and cyclic administration regimen are influenced by both sex and sex hormones. In the Aim 1, we will elucidate the influence of sex and sex hormones on the cellular mechanisms behind the dynamic responses of MBF and RBF to anabolic treatment discontinuation. In the Aim 2, we will optimize cyclic administration regimens of anabolic agents with and without an intervening anti-resorptive agent to achieve the best treatment efficacy based on sex and gonadal function. The proposed studies will supplement essential data regarding the influence of sex and gonadal function on development and retention of MBF and RBF to improve personalized, long-term clinical care for osteoporosis by considering patient sex and gonadal functions.