Vitamin D action: lessons learned from hereditary 1,25-dihydroxyvitamin-D-resistant rickets patients.

PURPOSE OF REVIEW: Hereditary 1,25-dihydroxyvitamin-D [1,25(OH)(2)D(3)]-resistant rickets (HVDRR) is a rare genetic disease caused by generalized resistance to 1,25(OH)(2)D(3). Less than 100 cases are reported in the literature. These patients provide an experiment by nature enabling us to understand the role of vitamin D, especially in light of the ongoing debate concerning normal vitamin D levels and the supplement dosage that should be recommended. This article summarizes the role of vitamin D in calcium absorption, rennin-angiotensin system (RAS), and cardiac state in HVDRR patients. RECENT FINDINGS: The precise spectrum of vitamin D activities can now be better evaluated by critical analysis of mouse models with targeted deletion of the gene encoding the vitamin D receptor (VDR). Of special interest is the unraveling of the role of VDR in calcium absorption and cardiac status in VDR-knockout mice. The facts that VDR-knockout mice up-regulate intestinal calcium absorption and skeletal mineralization independently of the VDR during pregnancy and lactation point to the existence of VDR-independent mechanisms that are involved in calcium absorption. The observation that mice with genetic disruption of the 1α-hydroxylase gene or of the VDR gene have an overstimulated RAS and consequently develop high blood pressure and cardiac hypertrophy raised concern about potential risks to the cardiovascular system in HVDRR patients. SUMMARY: The current review summarizes the new understanding of the effects of vitamin D on calcium absorption, the RAS, and heart hypertrophy derived from studying HVDRR patients from infancy to their mid-30s.

Calcium absorption, kinetics, bone density, and bone structure in patients with hereditary vitamin D-resistant rickets.

BACKGROUND: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor gene. Children with HVDRR suffer from severe hypocalcemia and rickets that are treatable with extremely high-dose calcium supplements. Surprisingly, spontaneous recovery of calcium metabolism occurs after the end of puberty without the need for further calcium supplementation. OBJECTIVES: To evaluate the role of vitamin D receptor in intestinal calcium absorption and bone, we investigated intestinal fractional calcium absorption (FCA), bone calcium accretion (Vo+), bone mineral density (BMD), and bone structure parameters in HVDRR patients from infancy into adulthood. PATIENTS AND METHODS: Seventeen HVDRR patients aged 1.5-37 yr were investigated. FCA and Vo+ were determined by stable-calcium isotopes. BMD was determined by dual-energy x-ray absorptiometry and bone structure by high-resolution magnetic resonance imaging. RESULTS: FCA in patients aged 1.5-17 yr was 34.9 ± 11.2% compared with 57.3 ± 2.0% in age-matched controls (P < 0.00004), whereas in patients aged 18-26 yr, it was 82.0 ± 7.8 and 53.6 ± 1.2% in controls (P < 0.001). FCA of patients older than 29 yr was comparable to controls. Patients aged 18-26 yr had higher Vo+ than controls (P < 0.02). Patients under 18 and over 29 yr of age had Vo+ comparable to controls. Femoral-neck BMD Z-score was -2.38 ± 0.3 in patients under 18 yr and 0.28 ± 0.87 in postpubertal patients (P < 0.0001). Bone structure by high-resolution magnetic resonance imaging and bone parameters of HVDRR patients and controls were similar. CONCLUSIONS: Evidence from HVDRR patients reveals that calcium absorption is highly vitamin D dependent during infancy until the end of puberty, after which there is a period of about 10 yr in which mechanisms other than vitamin D-dependent ones are substantially involved in calcium absorption.