Overrepresentation of multiple birth pregnancies in young infants with four metabolic bone disorders: further evidence that fetal bone loading is a critical determinant of fetal and young infant bone strength.

UNLABELLED: The frequency of multiple birth pregnancies, mostly twin pregnancies, was overrepresented in four different groups of young infants with fractures and bone abnormalities. This finding suggests that fetal bone loading through fetal movement is an important determinant of fetal bone formation and its resultant bone strength. INTRODUCTION: It has been suggested that intrauterine confinement related to the multiple birth pregnancy (MBP) may lead to an increased risk for fragility fractures in young infants as a result of decreased fetal bone loading. METHODS: To objectively test this idea, the frequency of MBPs was evaluated in five groups of young infants with bone disorders: (1) infants exposed to prolonged in utero exposure to magnesium, (2) infants with dietary copper deficiency, (3) infants with rickets from vitamin D deficiency, (4) infants with temporary brittle bone disease, and (5) infants with multiple unexplained fractures in which child abuse was the most likely diagnosis. RESULTS: Compared to a control group and controlled for preterm birth, there was a statistically greater frequency of MBPs in each group. CONCLUSIONS: The results of this study suggest the following: (a) The overrepresentation of MBPs (95 % twins) in these five groups indicates that fetal bone loading is a critical determinant of fetal bone strength; (b) fetal and young infant bone strength is a multifactorial characteristic; and (c) infants from MBPs are at increased risk for fragility fractures during the first 12 months of life, and thus may be mistakenly diagnosed as victims of child abuse.

Developmental exposure to As, Cd, and Pb mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.

We studied the effect of metal mixture (MM), comprising As, Cd, and Pb, in developing female rat skeleton from gestation day 5 until postnatal day 60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the groundwater of India, i.e., As: 0.38 ppm, Pb: 0.22 ppm, and Cd: 0.098 ppm or 10× of the ratio to developing rats, exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary and secondary spongiosa, and hypomineralized osteoids-a major characteristic of osteomalacia. In addition, compared with the control, MM-treated rats were clearly osteopenic based on bone mineral density, microarchitecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture-healing ability of MM group was delayed and accompanied by inferior quality of the healed bone. Together, these data demonstrated that the mixture of As, Cd, and Pb induced synergistic toxicity to developing skeleton, thereby diminishing modeling-directed bone accrual, inducing osteopenia and dampening fracture healing.

Skeletal dysplasias with osteopenia in the newborn: the value of alkaline phosphatase.

Alkaline phosphatase is a commonly measured enzyme in clinical practice. Normal, excessively elevated and depressed serum or plasma levels have clinical value in the approach to the differential diagnosis of skeletal dysplasias associated with osteopenia in the newborn period. Two cases are described to illustrate this contention. In the first case we describe a neonate with congenital hypophosphatasia and markedly depressed levels of plasma alkaline phosphate, and in the second case we report a patient with a fracture of the femur, congenital rickets and an elevated alkaline phosphate level. In skeletal dysplasias with osteopenia, the nature of the abnormality in alkaline phosphate values, in association with that of calcium and phosphate, is an invaluable diagnostic aid in differential diagnosis.

Late gestation modulation of fetal glucocorticoid effects requires the receptor for leukemia inhibitory factor: an observational study.

BACKGROUND: Ablation of the low-affinity receptor subunit for leukemia inhibitory factor (LIFR) causes multi-systemic defects in the late gestation fetus. Because corticosterone is known to have a broad range of effects and LIF function has been associated with the hypothalamo-pituitary-adrenal axis, this study was designed to determine the role for LIFR in the fetus when exposed to the elevated maternal glucocorticoid levels of late gestation. Uncovering a requirement for LIFR in appropriate glucocorticoid response will further understanding of control of glucocorticoid function. METHODS: Maternal adrenalectomy or RU486 administration were used to determine the impact of the maternal glucocorticoid surge on fetal development in the absence of LIFR. The mice were analyzed by a variety of histological techniques including immunolabeling and staining techniques (hematoxylin and eosin, Alizarin red S and alcian blue). Plasma corticosterone was assayed using radioimmunoassay. RESULTS: Maternal adrenalectomy does not improve the prognosis for LIFR null pups and exacerbates the effects of LIFR loss. RU486 noticeably improves many of the tissues affected by LIFR loss: bone density, skeletal muscle integrity and glial cell formation. LIFR null pups exposed during late gestation to RU486 in utero survive natural delivery, unlike LIFR null pups from untreated litters. But RU486 treated LIFR null pups succumb within the first day after birth, presumably due to neural deficit resulting in an inability to suckle. CONCLUSION: LIFR plays an integral role in modulating the fetal response to elevated maternal glucocorticoids during late gestation. This role is likely to be mediated through the glucocorticoid receptor and has implications for adult homeostasis as a direct tie between immune, neural and hormone function.