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

Section of Pediatric Endocrinology (L.A.), Department of Pediatrics, Section of Endocrinology and Metabolism (P.D., J.V., J.J.W.), Department of Internal Medicine, and Department of Orthopaedics and Rehabilitation (T.N., M.C.H.), Yale University School of Medicine, New Haven, Connecticut 06520-8020; and Department of Orthopaedic Surgery (D.J.A.), University of Connecticut Health Center, Farmington, Connecticut 06034-4037

Address all correspondence and requests for reprints to: John J. Wysolmerski, M.D., Section of Endocrinology and Metabolism, Yale University School of Medicine, TAC S131, 333 Cedar Street, New Haven, Connecticut 06520-8020. E-mail: john.wysolmerski{at}yale.edu.

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-B 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.

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