Osteoclasts are thought to be solely responsible for the removal of bone matrix. However, we show here that osteocytes can also remove bone matrix by reversibly remodeling their perilacunar/canalicular matrix during the reproductive cycle. In contrast, no osteocytic remodeling was observed with experimental unloading despite similar degrees of bone loss. Gene array analysis of osteocytes from lactating animals revealed an elevation of genes known to be utilized by osteoclasts to remove bone including Tartrate Resistant Acid Phosphatase, TRAP, and cathepsin K that returned to virgin levels upon weaning. Infusion of Parathyroid Hormone Related Peptide, PTHrP, known to be elevated during lactation, induced TRAP activity and cathepsin K expression in osteocytes concurrent with osteocytic remodeling. Conversely, animals lacking the Parathyroid Hormone Type 1 receptor, PTHR1, in osteocytes failed to express TRAP or cathepsin K or to remodel their osteocyte perilacunar matrix during lactation. These studies show that osteocytes remove mineralized matrix through molecular mechanisms similar to those utilized by osteoclasts.

A significant portion of milk calcium comes from the mother's skeleton, and lactation is characterized by rapid bone loss. The most remarkable aspect of this bone loss is its complete reversibility, and the time after weaning is the most rapid period of skeletal anabolism in adults. Despite this, little is known of the mechanisms by which the skeleton repairs itself after lactation. We examined changes in bone and calcium metabolism defining the transition from bone loss to bone recovery at weaning in mice. Bone mass decreases during lactation and recovers rapidly after weaning. Lactation causes changes in bone microarchitecture, including thinning and perforation of trabecular plates that are quickly repaired after weaning. Weaning causes a rapid decline in urinary C-telopeptide levels and stimulates an increase in circulating levels of osteocalcin. Bone histomorphometry documented a significant reduction in the numbers of osteoclasts on d 3 after weaning caused by a coordinated wave of osteoclast apoptosis beginning 48 h after pup removal. In contrast, osteoblast numbers and bone formation rates, which are elevated during lactation, remain so 3 d after weaning. The cessation of lactation stimulates an increase in circulating calcium levels and a reciprocal decrease in PTH levels. Finally, weaning is associated with a decrease in levels of receptor activator of nuclear factor-kappaB ligand mRNA in bone. In conclusion, during lactation, bone turnover is elevated, and bone loss is rapid. Weaning causes selective apoptosis of osteoclasts halting bone resorption. The sudden shift in bone turnover favoring bone formation subsequently contributes to the rapid recovery of bone mass.

Despite the dramatic bone loss that occurs during lactation, bone mineral density rapidly recovers after offspring are weaned and milk production stops. The goal of this study is to quantify site-specific changes in bone quantity and quality during and after lactation in a mouse model. We used micro computed tomography (mCT), individual trabecula segmentation (ITS), digital topological analysis (DTA)-based tissue mineral density (TMD) analysis, and micro finite element analysis (mFEA) to quantify the effects of lactation and weaning on bone microarchitecture, mineralization, and stiffness at the spine, tibia, and femur. We found a significant decrease in trabecular plate microarchitecture, tissue mineralization of the trabecular surface, trabecular central skeleton, and intervening envelopes, and whole bone stiffness in lactating versus nulliparous mice at all three sites. In recovered mice, all these different aspects of bone quality were comparable to nulliparous mice at the spine. In contrast, trabecular plate microarchitecture and whole bone stiffness at the tibia and femur in recovered mice were lower than nulliparous mice, as were central trabecular tissue mineralization and cortical structure at the femur. These findings are consistent with clinical observations of partial recovery of femoral bone mineral density BMD after lactation in humans. The observed differences in trabecular surface tissue mineralization in nulliparous, lactating, and recovered mice are consistent with prior observations that maternal bone turnover shifts from resorption to formation at the time of pup weaning. The significant differences in trabecular central tissue mineralization during these three states suggest that osteocytes may contribute to the reversible loss of mineral during and after lactation. Future studies are necessary to determine whether differing functions of various bone cells at individual skeletal sites cause site-specific skeletal changes during and after lactation. ß

Mice lose 20% to 25% of trabecular bone mineral content (BMC) during lactation and restore it after weaning through unknown mechanisms. We found that tibial Pthrp mRNA expression was upregulated fivefold by 7 days after weaning versus end of lactation in wild-type (WT) mice. To determine whether parathyroid hormone–related protein (PTHrP) stimulates bone formation after weaning, we studied a conditional knockout in which PTHrP is deleted from preosteoblasts and osteoblasts by collagen I promoter–driven Cre (CreColI). These mice are osteopenic as adults but have normal serum calcium, calcitriol, and parathyroid hormone (PTH). Pairs of Pthrpflox/flox;CreColI (null) and WT;CreColI (WT) females were mated and studied through pregnancy, lactation, and 3 weeks of postweaning recovery. By end of lactation, both genotypes lost lumbar spine BMC: WT declined by 20.6% ± 3.3%, and null decreased by 22.5% ± 3.5% (p < .0001 versus baseline; p = NS between genotypes). During postweaning recovery, both restored BMC to baseline: WT to –3.6% ± 3.7% and null to 0.3% ± 3.7% (p = NS versus baseline or between genotypes). Similar loss and full recovery of BMC were seen at the whole body and hind limb. Histomorphometry confirmed that nulls had lower bone mass at baseline and that this was equal to the value achieved after weaning. Osteocalcin, propeptide of type 1 collagen (P1NP), and deoxypyridinoline increased equally during recovery in WT and null mice; PTH decreased and calcitriol increased equally; serum calcium was unchanged. Urine calcium increased during recovery but remained no different between genotypes. Although osteoblast-derived PTHrP is required to maintain adult bone mass and Pthrp mRNA upregulates in bone after weaning, it is not required for recovery of bone mass after lactation. The factors that stimulate postweaning bone formation remain unknown. © 2011 American Society for Bone and Mineral Research.

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