Metabolic activities affect femur and lumbar vertebrae remodeling, and anti-resorptive risedronate disturbs femoral cortical bone remodeling

Metabolic activities are closely correlated with bone remodeling and long-term anti-resorptive bisphosphonate treatment frequently causes atypical femoral fractures through unclear mechanisms. To explore whether metabolic alterations affect bone remodeling in femurs and lumbar vertebrae and whether anti-osteoporotic bisphosphonates perturb their reconstruction, we studied three mouse strains with different fat and lean body masses (BALB/c, C57BL6, and C3H mice). These mice displayed variable physical activity, food and drink intake, energy expenditure, and respiratory quotients. Following intraperitoneal calcein injection, double calcein labeling of the femoral diaphysis, as well as serum levels of the bone-formation marker procollagen type-I N-terminal propeptide and the bone-resorption marker C-terminal telopeptide of type-I collagen, revealed increased bone turnover in mice in the following order: C3H > BALB/c ≥ C57BL6 mice. In addition, bone reconstitution in femurs was distinct from that in lumbar vertebrae in both healthy control and estrogen-deficient osteoporotic mice with metabolic perturbation, particularly in terms of femoral trabecular and cortical bone remodeling in CH3 mice. Interestingly, subcutaneous administration of bisphosphonate risedronate to C3H mice with normal femoral bone density led to enlarged femoral cortical bones with a low bone mineral density, resulting in bone fragility; however, this phenomenon was not observed in mice with ovariectomy-induced femoral cortical bone loss. Together, these results suggest that diverse metabolic activities support various forms of bone remodeling and that femur remodeling differs from lumbar vertebra remodeling. Moreover, our findings imply that the adverse effect of bisphosphonate agents on femoral cortical bone remodeling should be considered when prescribing them to osteoporotic patients. The metabolic status of post-menopausal women may influence their susceptibility to osteoporosis and their risk of femur fractures when taking anti-osteoporosis drugs. Metabolic activity influences bone density and turnover, particularly following estrogen loss after menopause. Long-term osteoporosis treatment with bisphosphate drugs causes femur fractures in some patients, but the reasons for this are unclear. Kyung-Jae Lee at Keimyung University, Daewon Jeong at Yeungnam University, both in Daegu, South Korea, and co-workers studied three mice strains with phenotypes showing different fat and lean-body masses and found distinct variations between femur and lumbar vertebrae remodeling, with femur remodeling more readily affected by metabolic activity. Both control and estrogen-deficient mice with high levels of body fat exhibited abnormal femur remodeling. Treatment with bisphosphates caused femur fragility in control mice in this group, but not in the estrogen-deficient mice.