Modelling-based bone formation upon bone’s periosteal (outer), and the endocortical and trabecular components of the endosteal (inner) surfaces, slows after completion of longitudinal growth. Concurrently, balanced remodeling upon all three (intracortical, endocortical, trabecular) components of the endosteal surface renews matrix volume, morphology and composition. At some time during early adulthood, the volumes of bone resorbed and deposited by each bone multicellular unit (BMU) both decrease but less bone is deposited than was resorbed by each BMU. The resulting negative remodeling imbalance is the necessary and sufficient morphological basis of bone loss and structural deterioration. However, before menopause, any reduction in total bone volume, microarchitectural deterioration, or loss of bone strength is minimal because the birth rate of BMUs is slow, modest modeling-based bone formation upon the periosteal and perhaps endosteal surfaces offsets bone loss, and periosteal bone formation shifts cortical bone volume radially maintaining resistance to bending.
Around mid-life, oestrogen deficiency of menopause worsens remodeling imbalance and increases the birth rate of BMUs. Remodeling now becomes widespread and produces two types of deficit in mineralized matrix volume. The reversible (transient) deficit is due to the normal delay in onset and slowness of the matrix synthesis, deposition and mineralization. This deficit is focally transient because refilling of the excavated cavity eventually occurs, but it is globally ever-present because the refilling of cavities excavated weeks to months early is accompanied by concurrent excavation of new cavities at other locations. The magnitude of this ‘remodeling space’ deficit (excavated cavities, cavities with osteoid, cavities with incompletely mineralized bone) depends on the birth rate of BMUs, and so it is responsive to remodeling suppressants. The incomplete refilling of cavities caused by remodeling imbalance produces the second type of deficit – the irreversible (permanent) deficit in mineralized matrix volume which compromises total bone volume and its microarchitecture; cortices thin and become porous, trabeculae are completely resorbed, perforated and disconnected. Trabecular surface area available for remodeling decreases while intracortical and endocortical surface areas increase facilitating more remodeling of an ever-diminishing bone volume; 80% of bone loss is cortical. Remodeling suppression cannot reverse the reduced total cortical and trabecular bone volume and microstructural destruction; anabolic therapy is needed. Unbalanced remodeling upon the endocortical and trabecular surfaces may also remove modest concurrent modeling-based bone formation upon these two surfaces.
This cellular activity upon the periosteal and endosteal surfaces produce the macro-, micro-, nano- and pico-level structural changes causing bone fragility. Reduced periosteal apposition slows the radial drift of the cortex. Resistance to bending decreases to the 7th power of cortical porosity and the 3rd power of trabecular density so fragility increases disproportionate to the bone loss causing it. This partly explains why ~70% of fractures arise among women seemingly at low risk with ‘osteopenia’. Changes at higher resolution also contribute to fragility. For example, incompletely refilled cavities, osteocyte death and lacunar mineralization produce stress concentrators predisposing to microcrack generation, increased inter-osteonal (interstitial) matrix mineral density, accumulating advanced glycation end products (AGEs) facilitate microcrack propagation while replacement of mineralized bone with young under-mineralized bone reduces osteonal matrix mineral density limiting crack propagation. AGEs reduce uncoiling of non-collagenous proteins which dissipate stress. Strains damage mineral platelets causing intra-osteonal diffuse damage. The heterogeneous cellular and morphological origins of bone fragility are rational targets for single, combined and sequential antiresorptive and anabolic therapy.