Selective PDE4 inhibition enhances bone mass by stimulating bone formation and suppressing bone resorption

Osteoporosis is a common skeletal disease that increases fracture risk and is a major cause of morbidity, mortality, and diminished quality of life in the elderly. Although bone anabolic therapies are available, inconvenient routes of administration and concerns regarding potential adverse effects substantially limit their use. Consequently, anti-resorptive drugs that slow further bone loss without rebuilding lost bone mass or restoring load-bearing strength remain the dominant therapies. Many patients nevertheless sustain fractures despite treatment, underscoring the weaknesses of this approach and the need for new anabolic strategies. The immune system plays an important role in regulating both bone formation and resorption, raising the possibility that immune pathways can be therapeutically harnessed to promote bone anabolism. Recent studies have further linked the gut microbiota to this osteoimmune network, demonstrating that microbiota-derived metabolites can promote T cell-dependent anabolic signaling in bone. It has previously been shown that broad-spectrum phosphodiesterase (PDE) inhibitors such as pentoxifylline (PTX) stimulate bone formation and promote bone accrual in animal models. We recently demonstrated that a major mechanism of PTX-induced bone anabolism is through an osteoimmunological pathway in which activated CD8 T cells trigger production of Wnt10b, a bone-anabolic Wnt ligand. However, PTX also directly promotes osteoclast bone resorption, limiting bone gain, while its adverse-effect profile further restricts its therapeutic utility. Here, we investigated the bone anabolic properties of apremilast, an FDA-approved PDE4-selective inhibitor targeting a major PDE regulating cAMP signaling in CD8 T cells. Micro-computed tomography demonstrated significant trabecular bone accrual and improved microarchitecture in femurs and vertebrae of apremilast-treated female C57BL/6J mice. Quantitative histomorphometry confirmed increased bone formation and reduced osteoclast indices. In vitro , apremilast did not directly stimulate osteoblast differentiation or mineralization but increased Wnt10b expression by CD8 T cells, supporting an indirect immune-mediated anabolic mechanism. Critically, unlike PTX, apremilast dose-dependently inhibited osteoclast differentiation from primary monocytes. These findings are consistent with an anabolic pathway, together with suppression of osteoclastogenesis, creating a remodeling environment favorable for net bone gain. These findings identify apremilast as an immunomodulatory regulator of bone remodeling and provide a rationale for further evaluation of PDE4 inhibition in preclinical models of osteoporosis.