Interactions between breast, bone, and brain regulate mineral and skeletal metabolism during lactation

Abstract

Mammalian reproduction requires that nursing mothers transfer large amounts of calcium to their offspring through milk. As a result, lactation is associated with dramatic alterations in bone and mineral metabolism, including reversible bone loss. One theme that has emerged from recent studies examining these adaptations is that the lactating breast actively participates in regulating bone and mineral metabolism. This review will detail our current knowledge of interactions between the breast, skeleton, and hypothalamus during lactation and will consider implications that this reproductive physiology has for the pathophysiology of osteoporosis and breast cancer.

Figure 1. Reversible bone loss during lactation

Three-dimensional reconstructions of representative lumbar vertebrae from aged-matched, nulliparous (A), lactating (B) and weaned (C, 28 days post weaning) mice. Lactation is associated with significant bone loss as well as structural changes such as trabecular thinning, trabecular perforation and a shift from a plate-like to rod-like appearance of trabeculae (compare A&B). After weaning (C), bone mass and trabecular architecture rapidly revert back to that seen in nulliparous animals.

Figure 2. Weaning triggers osteoclast apoptosis

A and B show toluidine blue-stained sections through the proximal tibia from mice at 12 days of lactation (A) and 3 days after weaning of pups (B). During lactation, both osteoclasts (red arrowheads) and osteoblasts (green arrowheads) are plentiful on trabecular surfaces. However, 3 days after weaning (B), osteoclasts are much reduced in number and osteoblasts surround many individual trabeculae. C and D demonstrate sections of bone that have been stained for both acid phosphatase activity and subjected to TUNEL assay. Osteoclasts stain red and apoptotic nucleii stain black. On day 12 of lactation (C), acid phosphatase-positive osteoclasts are abundant and are TUNEL negative (black arrowheads). One can appreciate TUNEL positive cells in the bone marrow, which serve as an internal, positive control. 48-hours after weaning (D), the overall numbers of acid phosphatase-positive cells are reduced. In addition, acid phosphatase-positive cells are frequently separated from the bone surface, appear fragmented and are TUNEL positive (black arrowheads) consistent with the occurrence of widespread osteoclast apoptosis.

Figure 3. Crosstalk between breast, bone and brain during lactation

Suckling stimulates hypothalamic centers that then suppress GnRH secretion. This leads to hypothalamic hypogonadism and low estrogen levels, which stimulates bone resorption. The breast secretes PTHrP into the circulation, which also stimulates bone resorption. The bone resorption caused by increased PTHrP and low estrogen levels liberates calcium from the skeleton into the circulation. When calcium is delivered to the lactating breast, it stimulates the calcium-sensing receptor, which promotes calcium transport into milk and inhibits PTHrP secretion from the breast, defining a classic negative feedback loop between breast and bone. If calcium delivery to the breast falls, calcium usage (transport) is decreased and more PTHrP is produced to increase bone resorption, liberating additional skeletal calcium and preventing hypocalcemia. The calcium sensing receptor allows mammary epithelial cells to monitor their calcium supply and to coordinate their demand for calcium and maternal bone metabolism accordingly.