Suckling and prolactin (PRL) both inhibit the hypothalamic gonadotropin-releasing hormone (GnRH) pulse center, which in turn suppresses the gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), leading to low levels of the ovarian sex steroids (estradiol [E₂] and progesterone [PROG]). PRL may also have direct effects on its receptor in bone cells. PTHrP production and release from the breasts is stimulated by suckling, PRL, low estradiol, and the calcium receptor. PTHrP enters the bloodstream and combines with systemically low estradiol levels to markedly upregulate bone resorption and (at least in rodents) osteocytic osteolysis. These activities release calcium and phosphate, which reach the breast ducts and are actively pumped into the breast milk. PTHrP also passes into milk at high concentrations, but whether swallowed PTHrP plays a role in regulating calcium physiology of the neonate is uncertain. In addition to stimulating milk ejection, oxytocin (OT) may directly affect osteoblast and osteoclast function. Calcitonin may inhibit skeletal responsiveness to PTHrP and low estradiol. The inset at the top right depicts a cross-section of cortical and trabecular bone from a vertebral body at a micron level of magnification. At the onset of lactation, multinucleated osteoclasts and osteocytes are poised to resorb mineral from bone. The inset at the bottom right depicts progressive trabecular thinning by osteoclasts, whereas osteocytic osteolysis leads to a progressive increase in the lacunar area. The two processes contribute to increased cortical porosity.