Vitamin D deficiency in guinea pigs:: Exacerbation of bone phenotype during pregnancy and disturbed fetal mineralization, with recovery by 1,25(OH)2D3 infusion or dietary calcium-phosphate supplementation

Vitamin D (D) deficiency during human pregnancy appears to disturb fetal growth and mineralization, but fetal development is normal in D-deficient rats and vitamin D receptor gene-ablated mice. We used the guinea pig model to investigate maternal and fetal effects of D deficiency. Pregnant (Pr) and nonpregnant (NPr) animals were led a D-replete (+ D) or D-deficient diet (-D) for 8 weeks. We further studied whether the effects of a -D diet are reversed by continuous 1,25(OH)(2)D-3 infusion (-D + 1,25) and/or by a lactose-, Ca- and P-enriched D-deficient diet (-D + Ca/P). Bone analyses included histomorphometry of the proximal tibiae, dual-energy X-ray absorptiometry (DXA), and quantitative computed tomography (QCT) of the femora. Depletion of 25(OH)D-3 and 1,25(OH)(2)D-3 levels and the D-deficiency syndrome were more severe in pregnant animals. Indeed, Pr/-D but not NPr/-D guinea pigs were hypophosphatemic, and showed robust increases in growth plate width and osteoid surface and thickness; in addition, bone mineral density on DXA was lower in Pr/-D animals only, which was exclusively in cortical bone on QCT. Bone phenotype was partly normalized in Pr/-D + 1,25 and Pr/-D + Ca/P animals. Compared with + D fetuses, -D fetuses had very low or undetectable 25(OH)D-3 and 1,25(OH)(2)D-3, were hypercalcemic and hypophosphatemic, and had lower osteocalcin levels. In addition, body weight and total body bone mineral content were 10-15% lower; histomorphometry showed hypertrophic chondrocyte zone expansion and hyperosteoidosis. 1,25(OH)(2)D-3 levels were restored in -D + 1,25 fetuses, and the phenotype was partially corrected. Similarly.. the fetal + D phenotype was rescued in large part in -D + Ca/P fetuses, despite undetectable circulating 25(OH)D-3 and 1,25(OH)(2)D-3. We conclude that pregnancy markedly exacerbates D deficiency, and that augmenting Ca and P intake overrides the deleterious effects of D deficiency on fetal development.