Towards understanding how bisphosphonate‐dependent alterations to nutrient canal integrity can contribute to risk for atypical femoral fractures: Biomechanical considerations and potential relationship to a real‐world analogy

Abstract

Bisphosphonates are a class of drugs which have shown good efficacy in the treatment of post‐menopausal osteoporosis, as well as a good safety profile. However, side‐effects such as risk for atypical femoral fractures (AFF) have appeared, leading to a decline in use of the drugs by many patients who would benefit from the treatment. While patient characteristics have contributed to improved understanding of risk factors, the mechanisms involved that explain AFF risk have not appeared. Recently, the possibility that the mechanism(s) involved drug‐induced modification of cells of the nutrient canals of the femur and subsequent compromise in the bone matrix has been published. The present Hypothesis article builds on the concept presented earlier and expands into biomechanical considerations. An analogy of the mechanisms involved to a real‐life scenario is also presented. While this analogy has limitations, consideration of the biomechanical implications of progressive alterations to defects presented by compromised nutrient canal‐bone matrix also presents potential relationships with AFF risk.

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

“…JJ. Endothelial cells of the vasculature can differentiate to form paracrine systems with other cells in a local environment and thus form unique paracrine systems with distinctive characteristics (reviewed in [112]; discussed in [113,114]).…”

“…All of the tissues involved in the post-menopausal conditions/diseases are vascularized except articular cartilage in OA and that condition is likely due to alterations in the other tissues that are involved in joint functioning and the cartilage is only the "weak link" in the disease process (discussed in [10]). While all of the relevant tissues are vascularized, it is likely that the endothelial cells in the different tissues have differentiated to effectively function in those tissues in a paracrine manner (reviewed in [112,[174][175][176]; discussed in [113,114]). Such tissue-specific characteristics appear to be lost when endothelial cells are cultured in vitro [177] but also appear to utilize epigenetic modifications in the regulation of their function in specific environments [178].…”