Pulsed electromagnetic fields modify the adverse effects of glucocorticoids on bone architecture, bone strength and porous implant osseointegration by rescuing bone-anabolic actions

Long-term glucocorticoid therapy is known to induce increased bone fragility and impaired skeletal regeneration potential. Growing evidence suggests that pulsed electromagnetic fields (PEMF) can accelerate fracture healing and increase bone mass both experimentally and clinically. However, how glucocorticoid-treated bone and bone cells respond to PEMF stimulation remains poorly understood. Here we tested the effects of PEMF on bone quantity/quality, bone metabolism, and porous implant osseointegration in rabbits treated with dexamethasone (0.5 mg/kg/day, 6 weeks). The micro-CT, histologic and nanoindentation results showed that PEMF ameliorated the glucocorticoid-mediated deterioration of cancellous and cortical bone architecture and intrinsic material properties. Utilizing the new porous titanium implant (Ti2448) with low toxicity and low elastic modulus, we found that PEMF stimulated bone ingrowth into the pores of implants and enhanced pen-implant bone material quality during osseous defect repair in glucocorticoid-treated rabbits. Dynamic histomorphometric results revealed that PEMF reversed the adverse effects of glucocorticoids on bone formation, which was confirmed by increased circulating osteocalcin and P1NP. PEMF also significantly attenuated osteocyte apoptosis, promoted osteoblast-related osteocalcin, Runx2 and Osx expression, and inhibited osteocyte-specific DKK1 and Sost expression (negative regulators of osteoblasts) in glucocorticoid-treated skeletons, revealing improved functional activities of osteoblasts and osteocytes. Nevertheless, PEMF exerted no effect on circulating bone-resorbing cytokines (serum TRAcP5b and CTX-1) or skeletal gene expression of osteoclast-specific markers (TRAP and cathepsin K). PEMF also significantly upregulated skeletal gene expression of canonical Wnt ligands (Wnt1, Wnt3a and Wnt10b), whereas PENT did not alter non-canonical Wnt5a expression. This study demonstrates that PEMF treatment improves bone mass, strength and porous implant osseointegration in glucocorticoid-treated rabbits by promoting potent bone-anabolic action, which is associated with canonical Wnt-mediated improvement in osteoblast and osteocyte functions. This study provides a new treatment alternative for glucocorticoid-related bone disorders in a convenient and non-invasive manner.