Weaning Triggers a Decrease in Receptor Activator of Nuclear Factor-κB Ligand Expression, Widespread Osteoclast Apoptosis, and Rapid Recovery of Bone Mass after Lactation in Mice

Abstract

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.

Irreversible Deterioration of Cortical and Trabecular Microstructure Associated With Breastfeeding

“…(10) Studies in rodent species variously report reversibility, partial or no reversibility after weaning. (13)(14)(15)(16)(17)(18) While trabecular bone is remodeled in rodents, rodents continue to grow throughout life and do not remodel cortical bone, or do so to a limited degree late in life. The synthesis of new trabeculae during continued growth may explain why the loss of trabecular bone is reversible.…”

“…Studies in rodent and other animal models demonstrate that trabeculae perforate, their numbers decrease, and cortical porosity increases. (10)(11)(12)(13)(14)(15)(16)(17)(18) This structural deterioration has been reported to be reversible in some animal models. (7,17,18) Bone loss during breastfeeding in humans is reported, but whether the microstructural deterioration is reversible after cessation of breastfeeding in human subjects is uncertain.…”

Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals

“…During lactation women and other mammals lose a significant portion of bone mass, which is restored after lactation ceases (2,8,26,54). Failure to mobilize bone calcium extraction at the onset of lactation causes hypocalcemia in dairy cows, leading to a severe convulsive syndrome referred to as periparturient paresis or "milk fever" (17, 35).…”

Femoral bone mineral density and bone mineral content in bromocriptine-treated pregnant and lactating rats

“…Predominant bone loss in metaphyses may be due to the fact that the trabecular sites have more surface areas for bone resorption than the cortical sites. Several weeks after weaning, bone mass appeared to be completely restored to the normal level [16], presumably due to an increase in osteoclast apoptosis and decreased expression of osteoblast-derived bone resorption mediator, receptor activator of nuclear factor jB ligand (RANKL) [29].…”