Combined physical and pharmaceutical anabolic osteoporosis therapies synergistically increase bone response and local mechanoregulation

Bone loss in postmenopausal osteoporosis is caused by an imbalance between bone formation and resorption in the remodeling process. Existing pharmaceutical therapies act on the cellular mechanisms that allow bone to adapt to mechanical demands by a process called mechanoregulation. This process ensures at the tissue level that bone is formed where needed and resorbed where redundant. Here, we report the effects of combining pharmaceutical therapies, both anti-catabolic and anabolic, with mechanical loading in a mouse model of osteoporosis. Ovariectomized mice were treated with bisphosphonates, parathyroid hormone, sclerostin antibodies, or no treatment (vehicle) for a period of four weeks. At the same time, their sixth caudal vertebrae were subjected to cyclic mechanical or sham loading. Bi-weekly time-lapsed in vivo micro-computed tomography revealed that mechanical loading synergistically enhanced the increase in trabecular bone response to anabolic, but not to anti-catabolic, osteoporosis treatments. Comparing bone formation and resorption volumes to the underlying mechanical environment demonstrated that all treatments showed higher strain values in regions preceding bone formation and lower strain values in regions preceding bone resorption. Compared to vehicle, higher mechanoregulation was found in anabolic, and lower mechanoregulation in anti-catabolic treatments. However, combining anabolic and physical treatments synergistically increased mechanoregulation, indicating that mechanical loading amplifies the effectiveness of anabolic therapies by driving bone (re)modeling to better align with the bone’s mechanical demands. These findings suggest that incorporating load-bearing physical therapy into anabolic pharmaceutical treatment regimens holds promise for enhancing therapeutic outcomes in osteoporosis management.