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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.

Osteoclasts are thought to be solely responsible for the removal of bone matrix. However, we show here that osteocytes can also remove bone matrix by reversibly remodeling their perilacunar/canalicular matrix during the reproductive cycle. In contrast, no osteocytic remodeling was observed with experimental unloading despite similar degrees of bone loss. Gene array analysis of osteocytes from lactating animals revealed an elevation of genes known to be utilized by osteoclasts to remove bone, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K, that returned to virgin levels upon weaning. Infusion of parathyroid hormone-related peptide (PTHrP), known to be elevated during lactation, induced TRAP activity and cathepsin K expression in osteocytes concurrent with osteocytic remodeling. Conversely, animals lacking the parathyroid hormone type 1 receptor (PTHR1) in osteocytes failed to express TRAP or cathepsin K or to remodel their osteocyte perilacunar matrix during lactation. These studies show that osteocytes remove mineralized matrix through molecular mechanisms similar to those utilized by osteoclasts., (Copyright © 2012 American Society for Bone and Mineral Research.)

Despite the dramatic bone loss that occurs during lactation, bone mineral density rapidly recovers after offspring are weaned and milk production stops. The goal of this study is to quantify site-specific changes in bone quantity and quality during and after lactation in a mouse model. We used micro computed tomography (µCT), individual trabecula segmentation (ITS), digital topological analysis (DTA)-based tissue mineral density (TMD) analysis, and micro finite element analysis (µFEA) to quantify the effects of lactation and weaning on bone microarchitecture, mineralization, and stiffness at the spine, tibia, and femur. We found a significant decrease in trabecular plate microarchitecture, tissue mineralization of the trabecular surface, trabecular central skeleton, and intervening envelopes, and whole bone stiffness in lactating versus nulliparous mice at all three sites. In recovered mice, all these different aspects of bone quality were comparable to nulliparous mice at the spine. In contrast, trabecular plate microarchitecture and whole bone stiffness at the tibia and femur in recovered mice were lower than nulliparous mice, as were central trabecular tissue mineralization and cortical structure at the femur. These findings are consistent with clinical observations of partial recovery of femoral bone mineral density BMD after lactation in humans. The observed differences in trabecular surface tissue mineralization in nulliparous, lactating, and recovered mice are consistent with prior observations that maternal bone turnover shifts from resorption to formation at the time of pup weaning. The significant differences in trabecular central tissue mineralization during these three states suggest that osteocytes may contribute to the reversible loss of mineral during and after lactation. Future studies are necessary to determine whether differing functions of various bone cells at individual skeletal sites cause site-specific skeletal changes during and after lactation., (Copyright © 2012 American Society for Bone and Mineral Research.)

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.

Mice lose 20% to 25% of trabecular bone mineral content (BMC) during lactation and restore it after weaning through unknown mechanisms. We found that tibial Pthrp mRNA expression was upregulated fivefold by 7 days after weaning versus end of lactation in wild-type (WT) mice. To determine whether parathyroid hormone-related protein (PTHrP) stimulates bone formation after weaning, we studied a conditional knockout in which PTHrP is deleted from preosteoblasts and osteoblasts by collagen I promoter-driven Cre (Cre(ColI) ). These mice are osteopenic as adults but have normal serum calcium, calcitriol, and parathyroid hormone (PTH). Pairs of Pthrp(flox/flox) ;Cre(ColI) (null) and WT;Cre(ColI) (WT) females were mated and studied through pregnancy, lactation, and 3 weeks of postweaning recovery. By end of lactation, both genotypes lost lumbar spine BMC: WT declined by 20.6% ± 3.3%, and null decreased by 22.5% ± 3.5% (p < .0001 versus baseline; p = NS between genotypes). During postweaning recovery, both restored BMC to baseline: WT to -3.6% ± 3.7% and null to 0.3% ± 3.7% (p = NS versus baseline or between genotypes). Similar loss and full recovery of BMC were seen at the whole body and hind limb. Histomorphometry confirmed that nulls had lower bone mass at baseline and that this was equal to the value achieved after weaning. Osteocalcin, propeptide of type 1 collagen (P1NP), and deoxypyridinoline increased equally during recovery in WT and null mice; PTH decreased and calcitriol increased equally; serum calcium was unchanged. Urine calcium increased during recovery but remained no different between genotypes. Although osteoblast-derived PTHrP is required to maintain adult bone mass and Pthrp mRNA upregulates in bone after weaning, it is not required for recovery of bone mass after lactation. The factors that stimulate postweaning bone formation remain unknown., (Copyright © 2011 American Society for Bone and Mineral Research.)

During lactation, calcium is mobilized from the maternal skeleton to supply the breast for milk production. This results in rapid but fully reversible bone loss. Prior studies have suggested that PTHrP, secreted from the breast, and estrogen deficiency, due to suckling-induced central hypogonadism, combine to trigger bone resorption. To determine whether this combination was sufficient to explain bone loss during lactation, we raised PTHrP levels and decreased levels of estrogens in nulliparous mice. PTHrP was infused via osmotic minipumps and estrogens were decreased either by using leuprolide, a long-acting GnRH agonist, or by surgical ovariectomy (OVX). Bone mineral density declined by 23.2 ± 1.3% in the spine and 16.8 ± 1.9% in the femur over 10 d of lactation. This was accompanied by changes in trabecular architecture and an increase in both osteoblast and osteoclast numbers. OVX and PTHrP infusion both induced a modest decline in bone mineral density over 10 d, but leuprolide treatment did not. The combination of OVX and PTHrP was more effective than either treatment alone, but there was no interaction between PTHrP and leuprolide. None of the treatments reproduced the same degree of bone loss caused by lactation. However, both forms of estrogen deficiency led to an increase in osteoclasts, whereas infusion of PTHrP increased both osteoblasts and osteoclasts. Therefore, although the combination of PTHrP and estrogen deficiency contributes to bone loss, it is insufficient to reproduce the full response of the skeleton to lactation, suggesting that other factors also regulate bone metabolism during this period.

Background/aims: Constitutional delay of growth and puberty (CDGP) with short stature is one of the most common problems in pediatrics. We compared the effects of letrozole with that of oxandrolone on predicted adult height (PAH), puberty, bone mineral density, serum insulin-like growth factor 1 (IGF-1) and blood lipoproteins., Methods: In a prospective, double-blind, randomized, placebo-controlled clinical trial, 91 CDGP boys (12.6-14.6 years old) with predicted short stature were treated with letrozole (2.5 mg/day), oxandrolone (2.5 mg/day), or placebo, at the outpatient pediatric endocrine clinic of Mofid Children's Hospital in Tehran for 2 years., Results: Letrozole differed from oxandrolone and placebo in significantly increasing PAH (p < 0.05), and slightly but significantly decreasing HDL-cholesterol. Oxandrolone, and to a lesser degree letrozole, significantly increased the height standard deviation score and bone age compared to placebo., Conclusion: This first randomized controlled clinical trial in CDGD teenage boys with predicted short stature shows that letrozole increases PAH more than oxandrolone and advances pubertal stage and bone mineralization less., (Copyright © 2010 S. Karger AG, Basel.)

Children and adolescents may be affected by a host of metabolic diseases that primarily impact the integrity of the skeletal system. Often, the underlying problem involves impairment in calcium, phosphate or vitamin D homeostasis. Alternatively, hormonal imbalances, such as in parathyroid hormone, may be at the heart of the problem. Recent advances in our diagnostic capabilities, such as the wide availability of assays for parathyroid hormone, ionized calcium, and vitamin D metabolites; genetic testing for hereditary disorders of bone; and widespread use of bone densitometry technologies, have improved our diagnostic acumen. However, at the same time, familiarity with these new developments is limited and may lead to misinterpretation without a careful understanding of certain features of these tests. Thus, our mission is to discuss the strengths and shortcomings of these diagnostic modalities and to provide a concise review of nuances involved in interpretation of data when using these techniques.

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-kappaB 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.

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.