Absence of Calcitriol Causes Increased Lactational Bone Loss and Lower Milk Calcium but Does Not Impair Post‐lactation Bone Recovery in Cyp27b1 Null Mice

We hypothesized that adaptation to calcium supply demands of pregnancy and lactation do not require calcitriol. Adult Cyp27b1 null mice lack calcitriol and have hypocalcemia, hypophosphatemia, and rickets. We studied wild‐type (WT) and null sister pairs raised on a calcium‐, phosphorus‐, and lactose‐enriched “rescue” diet that prevents hypocalcemia and rickets. Bone mineral content (BMC) increased >30% in pregnant nulls, declined 30% during lactation, and increased 30% by 4 weeks post‐weaning. WT showed less marked changes. Micro‐CT revealed loss of trabecular bone and recovery in both genotypes. In lactating nulls, femoral cortical thickness declined >30%, whereas endocortical perimeter increased; both recovered to baseline after weaning; there were no such changes in WT. Histomorphometry revealed a profound increase in osteoid surface and thickness in lactating nulls, which recovered after weaning. By three‐point bend test, nulls had a >50% decline in ultimate load to failure that recovered after weaning. Although nulls showed bone loss during lactation, their milk calcium content was 30% lower compared with WT. Serum parathyroid hormone (PTH) was markedly elevated in nulls at baseline, reduced substantially in pregnancy, but increased again during lactation and remained high post‐weaning. In summary, pregnant Cyp27b1 nulls gained BMC with reduced secondary hyperparathyroidism, implying increased intestinal calcium delivery. Lactating nulls lost more bone mass and strength than WT, accompanied by increased osteoid, reduced milk calcium, and worsened secondary hyperparathyroidism. This implies suboptimal intestinal calcium absorption. Post‐weaning, bone mass and strength recovered to baseline, whereas BMC exceeded baseline by 40%. In conclusion, calcitriol‐independent mechanisms regulate intestinal calcium absorption and trabecular bone metabolism during pregnancy and post‐weaning but not during lactation; calcitriol may protect cortical bone during lactation. © 2017 American Society for Bone and Mineral Research.