Novel anatomic adaptation of cortical bone to meet increased mineral demands of reproduction

• We investigated the skeletal effects during reproduction in a mouse model of compromised mineral homeostasis.
• HYP mice had dramatic increases in intracortical porosity characterized by elevated serum PTH and MMP-13.
• Chronic abnormal serum biochemistries that characterize XLH return to within the normal range during pregnancy.
• HYP and wild-type mice had increased carbonate ion substitution in the bone mineral matrix during pregnancy and lactation.
• This form of mineral turnover provides mineral without osteoclast resorption in cortical bone during periods of high demand.

The goal of this study was to investigate the effects of reproductive adaptations to mineral homeostasis on the skeleton in a mouse model of compromised mineral homeostasis compared to adaptations in control, unaffected mice. During pregnancy, maternal adaptations to high mineral demand include more than doubling intestinal calcium absorption by increasing calcitriol production. However, calcitriol biosynthesis is impaired in HYP mice, a murine model of X-linked hypophosphatemia (XLH). In addition, there is a paucity of mineralized trabecular bone, a primary target of bone resorption during pregnancy and lactation. Because the highest density of mineral is in mature cortical bone, we hypothesized that mineral demand is met by utilizing intracortical mineral reserves. Indeed, analysis of HYP mice revealed dramatic increases in intracortical porosity characterized by elevated serum PTH and type-I collagen matrix-degrading enzyme MMP-13. We discovered an increase in carbonate ion substitution in the bone mineral matrix during pregnancy and lactation of HYP mice, suggesting an alternative mechanism of bone remodeling that maintains maternal bone mass during periods of high mineral demand. This phenomenon is not restricted to XLH, as increased carbonate in the mineral matrix also occurred in wild-type mice during lactation. Taken together, these data suggest that increased intracortical perilacunar mineral turnover also contributes to maintaining phosphate levels during periods of high mineral demand. Understanding the mechanisms of skeletal contribution to mineral homeostasis is important to improving the treatment and prevention of fracture risk and bone fragility for female patients with XLH, but also provides important insight into the role and unique adaptations of the maternal skeleton to the demands of fetal development and the needs of postnatal nutrition.