Although increased circulating levels of parathyroid hormone (PTH) with mild hypocalcemia has been reported in Hyp mice, hyperparathyroidism in XLH is postulated to arise from the standard use of phosphate salts, which induce chronic stimulation of PTH secretion. In this study, we sought to examine the role of PTH in the metabolic derangements associated with Hyp by generating hemizygous hypophosphatemic (Hyp/Y) mice homozygous for the Pth-null allele (Pth^-/-;Hyp/Y).

Early postnatal lethality was observed in the Pth^-/-;Hyp/Y mice. Within the first six hours postpartum serum phosphorus levels increased to levels comparable to those in the Pth^-/- mice, while in Hyp mice, it decreased during the first 48 hr after birth. Serum calcium concentration started low after birth and remained reduced in both Pth^-/-;Hyp/Y and Pth^-/- mice, although more profoundly so in the former group, while in Hyp/Y mice, the levels were initially lower than but reached wild-type levels by 24 hr. Circulating PTH levels in Hyp/Y mice were higher than wild-type levels throughout the first 48 hr after birth and continued to be so well into adulthood. Twice daily administration of PTH 1-34 to Pth^-/-;Hyp/Y newborn mice increased serum calcium levels and prevented their early demise.

The findings here indicate that the cause of death in the Pth^-/-;Hyp/Y mice is severe hypocalcemia. A potential role for FGF-23 in promoting secondary hyperparathyroidism by suppressing renal 25-hydroxyvitamin D₃-1alpha-hydroxylase (Cyp27b1) activity while increasing that of renal 25-hydroxyvitamin D₃ 24-hydroxylase (Cyp24) is proposed. Hyperparathyroidism, therefore, is an integral component in the pathophysiology of Hyp and likely XLH and serves to prevent severe hypocalcemia in mice and perhaps in patients afflicted with the disorder.