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

Despite bone’s natural adaptation to mechanical demands, the role of physical therapy alongside osteoporosis drug treatments remains unclear, leaving patients questioning its interaction with medications. Emerging research aims to clarify whether combining physical with drug therapies offers better outcomes for bone strength than either approach alone. Here, we use in vivo micro-computed tomography and computational mechanics to investigate the effect of combined physical and drug treatment in a mouse model of osteoporosis. We show that combining mechanical loading with drugs led to synergistically enhanced bone volume, strength, and mechanoregulation in anabolic (parathyroid hormones and sclerostin antibodies) but not in anti-catabolic (bisphosphonate) treatments. At the cellular level, combining drug treatment with mechanical loading shifted (re)modeling thresholds towards higher mechanosensitivity of the cells as described in Frost’s mechanostat theory more than 30 years ago. Mechanical loading combined with anabolic treatments shifts formation and resorption saturation levels towards higher, with bisphosphonates towards lower response to mechanical signals. These results underline the potential of combining anabolic drug therapies with physical activity to optimize osteoporosis treatment.