Chapter 8. Skeletal Physiology: Fetus and Neonate Christopher S. Kovacs Faculty of Medicine-Endocrinology, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada INTRODUCTION Because of obvious limitations in studying human fetuses and (to a lesser degree) neonates, human regulation of fetal and neonatal mineral homeostasis must be largely inferred from studies in animals. Some observations in animals may not apply to humans. This chapter briefly reviews existing human and animal data, including older studies of surgically manipu- lated animals and recent studies of mice engineered to lack calciotropic hormones or receptors. Detailed references are available in two comprehensive reviews. (1,2) FETUS Much of normal mineral and bone homeostasis in the adult can be explained by the interactions of PTH, 1,25- dihydroxyvitamin D or calcitriol (1,25-D), calcitonin, and the sex steroids. In contrast to the adult, comparatively little has been known about how mineral and bone homeostasis is reg- ulated in the fetus. Fetal mineral metabolism has been uniquely adapted to meet the specific needs of this developmental pe- riod, including the requirement to maintain an extracellular level of calcium (and other minerals) that is physiologically appropriate for fetal tissues and to provide sufficient calcium (and other minerals) to fully mineralize the skeleton before birth. Mineralization occurs rapidly in late gestation, such that a human accretes 80% of the required 30 g of calcium in the third trimester, whereas a rat accretes 95% of the required 12.5 mg of calcium in the last 5 days of its 3-week gestation. Minerals Ions and Calciotropic Hormones A consistent finding among human and other mammalian fetuses is a total and ionized calcium concentration that is significantly higher than the maternal level during late gesta- tion. Similarly, serum phosphate is significantly elevated, and serum magnesium is minimally elevated above the maternal concentration. The physiological importance of these elevated levels is not known. A calcium level equal to the maternal calcium concentration (and not above it) seems to be sufficient to ensure adequate mineralization of the fetal skeleton, and fetal survival to term is unaffected by extremes of hypocalce- mia in several animal models. The increased calcium level is robustly maintained despite chronic, severe maternal hypocal- cemia of a variety of causes. For example, adult humans and mice with nonfunctional vitamin D receptors have severe hy- pocalcemia, but murine fetuses with the same abnormality have normal serum calcium concentrations. (3) Calciotropic hormone levels are also maintained at levels that differ from the adult. These differences seem to reflect the relatively different roles that these hormones play in the fetus and are not an artifact of altered metabolism or clearance of these hormones. Intact PTH levels are much lower than ma- ternal PTH levels near the end of gestation, but it is unknown whether fetal PTH levels are low throughout gestation after the formation of the parathyroids or only in late gestation. The low level of PTH is critically important, because fetal mice lacking parathyroids and PTH have marked hypocalcemia and under- mineralized skeletons. (4) Circulating 1,25-D levels are also lower than the maternal level in late gestation and seem to be largely if not completely derived from fetal sources. The low circulating levels of 1,25-D in the fetus may be a response to high serum phosphate and suppressed PTH levels in late ges- tation. With respect to 1,25-D, the low levels of this hormone may reflect its relative unimportance for fetal mineral ho- meostasis, because both vitamin D deficiency and absence of vitamin D receptors do not impair serum mineral concentra- tions or the mineralization of the fetal skeleton. (3) Fetal calci- tonin levels are higher than maternal levels and are thought to reflect increased synthesis of the hormone. Apart from re- sponding appropriately to changes in the serum calcium con- centration, there is little evidence of an essential role for calcitonin in fetal mineral homeostasis. (5) PTH-related protein (PTHrP) is normally not present in the human adult circulation (outside of pregnancy and lactation), but in cord blood, PTHrP levels are up to 15-fold higher than that of PTH. PTHrP is produced in many tissues and plays multiple roles during embryonic and fetal development. The absence of PTHrP (in the Pthrp-null fetal mouse) leads to abnormalities of chondrocyte differentiation and skeletal de- velopment, (6) modest hypocalcemia, (7) and reduced placental calcium transfer. Such Pthrp-null fetuses have increased PTH levels (8) but still remain modestly hypocalcemic, indicating that PTH does not make up for lack of PTHrP in maintaining a normal calcium concentration in the fetal circulation. The role (if any) of the sex steroids in fetal skeletal devel- opment and mineral accretion is unknown, largely because the relevant analyses have not been performed in the relevant mouse models, and corresponding human data are absent. Estrogen receptor  and  knockout mice have been shown to have altered skeletal metabolism that develops postnatally, but the fetal skeleton has not been examined in detail. Similarly, postnatal skeletal roles of RANK, RANKL, and osteoprote- gerin have been shown in relevant knockout mice, but the role that this system plays in fetal mineral metabolism is not yet known. Fetal Parathyroids Intact parathyroid glands are required for maintenance of normal fetal calcium, magnesium, and phosphate levels; lack of parathyroids and PTH causes a greater fall in the fetal blood calcium than lack of PTHrP. Fetal parathyroids are also re- quired for normal accretion of mineral by the skeleton and may be required for regulation of placental mineral transfer. Studies in fetal lambs have indicated that the fetal parathyroids may contribute to mineral homeostasis by producing both PTH and PTHrP, whereas a detailed study of rats indicates that the fetal parathyroids produce only PTH. Whether human fetal parathy- roids produce PTH alone or PTH and PTHrP together is un- clear. Calcium Sensing Receptor The calcium sensing receptor (CaSR) sets the serum calcium level in adults by regulating PTH, but it does not seem to set the serum calcium level in fetuses. Instead, the fetal serum calcium is driven above the maternal level by the action of PTHrP, while in turn, the CaSR appropriately suppresses PTH in response to this elevated calcium level (Fig. 1A). In the absence of PTHrP (Pthrp-null mice), the fetal serum calcium falls to the normal adult level, and the serum PTH is increased, The author has reported no conflicts of interest. © 2006 American Society for Bone and Mineral Research 50