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Lactation is associated with increased bone turnover and rapid bone loss, which liberates skeletal calcium used for milk production. Previous studies suggested that an increase in the skeletal expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand (RANKL) coupled with a decrease in osteoprotegerin (OPG) levels likely triggered bone loss during lactation. In this study, we treated lactating mice with recombinant OPG to determine whether bone loss during lactation was dependent on RANKL signaling and whether resorption of the maternal skeleton was required to support milk production. OPG treatment lowered bone resorption rates and completely prevented bone loss during lactation but, surprisingly, did not decrease osteoclast numbers. In contrast, OPG was quite effective at lowering osteoblast numbers and inhibiting bone formation in lactating mice. Furthermore, treatment with OPG during lactation prevented the usual anabolic response associated with reversal of lactational bone loss after weaning. Preventing bone loss had no appreciable effect on milk production, milk calcium levels, or maternal calcium homeostasis when mice were on a standard diet. However, when dietary calcium was restricted, treatment with OPG caused maternal hypocalcemia, maternal death, and decreased milk production. These studies demonstrate that RANKL signaling is a requirement for bone loss during lactation, and suggest that osteoclast activity may be required to increase osteoblast numbers during lactation in preparation for the recovery of bone mass after weaning. These data also demonstrate that maternal bone loss is not absolutely required to supply calcium for milk production unless dietary calcium intake is inadequate.

Vitamin D deficiency causes rickets, requiring vitamin D at doses greater than daily dietary intake. Several treatment regimens are found in the literature, with wide dosing ranges, inconsistent monitoring schedules, and lack of age-specific guidelines. We describe 3 children, ages 2 weeks to 2 and 9/12 years, who recently presented to our institution with hypercalcemia and hypervitaminosis D (25-hydroxyvitamin D levels >75 ng/mL), associated with treatment of documented or suspected vitamin D-deficient rickets. The doses of vitamin D used were within accepted guidelines and believed to be safe. The patients required between 6 weeks and 6 months to correct the elevated serum calcium, with time to resolution of hypercalcemia related to age and peak serum calcium, but not to peak 25-hydroxyvitamin D level. With recent widespread use of vitamin D in larger dosages in the general population, we provide evidence that care must be taken when using pharmacologic dosing in small children. With limited dosing guidelines available on a per weight basis, the administration of dosages to infants that are often used in older children and adults has toxic potential, requiring a cautious approach in dose selection and careful follow-up. Dosage recommendations may need to be reassessed, in particular, where follow-up and monitoring may be compromised.

Lactating mammals must supply large amounts of calcium to the mammary gland where it is transported across mammary epithelial cells and into milk. This demand for calcium is associated with transient loss of bone mass, triggered, in part, by the secretion of parathyroid hormone-related protein (PTHrP) from the mammary gland into the circulation. The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium ions. It is responsible for coordinating calcium homeostasis by regulating parathyroid hormone secretion in the parathyroid glands and by regulating calcium handling in the renal tubules. Previous studies had shown that the CaR is expressed on mammary epithelial cells during lactation, and it had been suggested that CaR signaling in the mammary gland helps to coordinate its production of PTHrP and calcium transport into milk. In this study, we examined mammary gland PTHrP production and calcium transport in CaR(+/-) mice, a genetic model of CaR insufficiency. We found that haploinsufficiency for the CaR resulted in increased PTHrP production both in vivo and in vitro. In contrast, CaR haploinsufficiency impaired calcium transport into milk in vivo and transepithelial calcium transport by mammary epithelial cells in vitro. These data provide genetic confirmation that the CaR regulates PTHrP production and calcium transport in the lactating mammary gland. This allows the mammary gland to become a calcium-sensing organ and to participate in systemic calcium homeostasis during lactation.