<scp>3D</scp> morphological analysis of age and sex‐related changes in human cortical bone remodeling spaces using micro‐ <scp>CT</scp>

Bone remodeling is the fundamental process of internal turnover through which bone tissue is renewed, repaired, and maintained. Achieved by the spatially and temporally coordinated actions of the basic cellular unit (BMU), this process is intimately linked to age-related increases in cortical porosity, which could be attributed to the imbalance or uncoupling between resorption and formation. Classically, the space carved out by the BMU is depicted to have a cutting cone tunneling through the bone matrix, and a tapering closing cone being filled in with new bone. The morphology of these spaces can reflect the dynamics of the BMU, where excess resorption leads to an enlarged cutting cone, decreased formation results in a shortened closing cone and larger Haversian canal diameter, and the uncoupling or delayed coupling creates a prolonged transition zone between resorption and formation. Using a micro-CT imaging modality that allows for three-dimensional visualization of remodeling events, we hypothesized that with aging, remodeling spaces would exhibit evidence of imbalance and/or uncoupling and this pattern would be more pronounced in women due to the effect of menopause. Micro-CT scans of anterior femoral midshaft specimens from 58 human donors (22 females, 36 males; age range: 20-82 years) were analyzed, yielding a total of 184 remodeling spaces with classically described morphology (a cutting cone followed by a closing cone and then a canal with stable diameter). Lengths and radii representative of the 3D size and shape of the remodeling spaces were measured and analyzed. Results showed that remodeling space morphology exhibits great inter and intraindividual variation, while no differences in the distribution of any measurements were found between sexes. Counter to our hypothesis, remodeling space dimensions decrease with increasing age, and no linear relationship between transition zone length and age was found. Rather, transition zone length was longer in older females but also in younger males, potentially indicating different underlying mechanisms causing prolonged transition zones, with the caveat that this pattern is only significant after removal of outliers. This study was the first to demonstrate the value of 3D analysis at the level of individual remodeling spaces in human cortical bone. Sex and age differences in morphology (or the lack thereof) indicate the intricate interplay of local and systemic controls from different mechanical, hormonal and cell senescence factors on remodeling dynamics, and the potential existence of seemingly normal remodeling events superimposed against the backdrop of overall progressive age-related bone loss. Importantly, our focus on classical remodeling space morphology excludes irregular patterns arising from interconnecting or coalescing pores and trabecularization of the cortex, which is a main limitation to be considered.