Pregnancy and lactation impose extraordinary demands on maternal calcium homeostasis. During pregnancy, maternal calcium metabolism adapts to support fetal skeletal mineralization, whereas during lactation, calcium is rapidly mobilized from the maternal skeleton for milk production. These adaptations require coordinated communication between calcium-sensing tissues, the brain, and skeleton.

During lactation in mice, the calcium-sensing receptor (CaSR) is expressed on mammary epithelial cells, converting the gland into a calcium-sensing organ (1). By detecting extracellular calcium, CaSR reciprocally regulates two outputs, suppressing parathyroid hormone-related protein (PTHrP) secretion while enhancing calcium transport into milk, thereby linking calcium availability to skeletal mobilization (1,2). The result is rapid and profound maternal bone loss (3).

Alongside this CaSR-regulated skeletal mobilization, previous work identified a complementary brain-to-bone pathway that becomes active during lactation as a simultaneous compensatory mechanism for the maternal skeleton. In mice, CCN3 is produced by neurons in the arcuate nucleus of the hypothalamus during lactation and acts as a potent osteoanabolic factor, stimulating skeletal stem cell activity and bone formation (4). Thus, bone formation is stimulated during lactation, concurrent with the marked increase in skeletal resorption, rather than beginning only after weaning.

In a post hoc analysis of a longitudinal postpartum cohort, CCN3 remained stable in breastfeeding women but declined by approximately 50% in non-breastfeeding women by 18 months. Among breastfeeding women, CCN3 was associated with bone formation markers, and greater early

postpartum CCN3 exposure predicted higher lumbar spine and total hip BMD during subsequent skeletal recovery (5).

Together, these findings reveal an integrated reproductive program linking calcium sensing and skeletal mobilization with simultaneous osteoanabolic signaling to meet offspring mineral requirements while preserving the maternal skeleton’s capacity for recovery.