Osteoporosis is now a leading health concern and is characterized by the deterioration of bone quality and quantity, which results in increasing risk of fragility fractures. Antiresorptive therapies, which inhibit bone resorption, are currently the first-line option for patients with osteoporosis. These therapies, however, mainly prevent bone deterioration, which is insufficient for the significant number of patients with severe low bone mass or high risk of fractures. Accumulating evidence demonstrates that osteoanabolic therapies, which stimulate new bone formation, are associated with greater and more rapid reductions in fracture risk compared with antiresorptive treatments. Since current osteoanabolic therapies have limitations, including the restriction of the treatment period and concerns about adverse effects, healthcare providers need navigation of appropriate treatment strategies.

Currently, available osteoanabolic agents are teriparatide, abaloparatide, and romosozumab. Teriparatide is a N-terminal fragment (1–34 amino acids) of parathyroid hormone (PTH) that can bind parathyroid hormone receptor type 1, PTH1R, to activate it similarly to the full-length (1–84 amino acids) hormone. Abaloparatide, an analog of PTH-related protein, also activates PTH1R. Daily subcutaneous injections of teriparatide and abaloparatide have been globally approved as an anabolic therapy for severe osteoporosis. Once or twice-weekly subcutaneous injection of teriparatide, as an alternative therapeutic regimen, is also available in some areas, such as Japan. Activation of PTH1R promptly increases the number of osteoblasts to stimulate bone formation, and later on, activate osteoclastic bone resorption. Therefore, teriparatide and abaloparatide demonstrate anabolic effects on bone through enhancing bone remodeling. Treatment periods of those drugs are limited up to 24 months for teriparatide and 18 months for abaloparatide because of their safety concerns about developing osteosarcoma. However, such a restriction for teriparatide has been waved in some countries.

Sclerostin is a pivotal inhibitor of bone formation and has been discovered through investigating patients with rare autosomal recessive syndromes associated with high bone mass, sclerosteosis and van Buchem disease. Sclerostin suppresses bone formation by inhibiting WNT-βcatenin signals through the LRP5/6-Frizzled receptor complex in osteoblasts. In addition, it activates osteoclastic bone resorption. Anti-sclerostin monoclonal antibody, romosozumab, inhibits the actions of sclerostin, leads to activation of the WNT-βcatenin signaling pathway, and enhances bone formation in bone-generating cells while reducing bone resorption. Therefore, romosozumab demonstrates anabolic effects on bone through enhancing bone modeling but not remodeling. However, inhibiting sclerostin actions drives a compensatory increase in DKK1 expression (another inhibitor of WNT signaling), which limits anabolic actions and reduces the ability of romosozumab to promote bone formation. Romosozumab is currently approved for a 12-month treatment period, since its anabolic actions wean with time.

Since either osteoanabolic agent generally has a limitation of the treatment period, a sequential therapy strategy is mandatory. Recent clinical studies may address the issue of which sequences are reasonable to enhance therapeutic merits.

The efficacy of romosozumab and PTH1R activators, teriparatide and abaloparatide, on preventing osteoporotic fractures is robust. However, there remains a concern about increased cardiovascular adverse events related to romosozumab. We need solid evidence to establish an appropriate and reasonable guide to prescribe romosozumab in our clinical practice. Patients with diabetes mellitus and chronic kidney disease, especially on maintenance hemodialysis have a high risk of cardiovascular events as well as osteoporotic fractures. Osteoanabolic agents are often indicated in those patients with osteoporosis. Therefore, their risks on cardiovascular events should be estimated with careful consideration of the risk–benefit balance. Accumulating evidence through observational studies in daily clinical practice can be essential to address this issue.

In this special issue of the Journal of Bone and Mineral Metabolism, the authors review and discuss the theme of osteoanabolic agents for fracture prevention. The scope covers diverse topics, mechanisms of bone formation from viewing molecular, cellular, and histological aspects, and a review of available data from clinical trials to answer the questions of efficacy, effectiveness, and safety of osteoanabolic agents. Real-world data are important to uncover effectiveness and safety for patients out of target in pivotal phase 3 clinical studies to establish the efficacy of osteoanabolic agents to prevent fractures. We believe articles in this special issue help readers from diverse fields understand broad aspects of osteoanabolic agents beyond evidence from principal randomized controlled trials for their development and what questions are yet to be answered.

Yasuhiro Takeuchi, M.D., Ph.D

Hiroshi Hagino, M.D., Ph.D