Osteonecrosis of the jaw and bisphosphonates in children and adolescents

Abstract

Nutritional rickets most commonly results from vitamin D deficiency and is typically associated with inadequate sunlight. Thus, the existence of rickets in many tropical countries, where sunlight is abundant, is unexpected, and has suggested that genetic, hormonal, and other nutritional factors may cause rickets in susceptible children. We recently identified a missense mutation (Leu99Pro) in exon 2 of CYP2R1, the gene encoding the key hepatic vitamin D 25hydroxylase, in members of 2 of 10 Nigerian families in which more than 1 subject had rickets. One proband (T133), his affected brother (T133-1) and their father (T133-5) were homozygous (CYP−/−) for the L99P allele; his mother and two sisters were heterozygous (CYP−/+) for the L99P allele, and one of the sisters had a history of genu varum that resolved spontaneously as a toddler. The second proband (K170) and her affected sister were both heterozygous for the L99P mutation. Their mother was homozygous for the wild type allele while their clinically unaffected father was heterozygous. Biochemical analyses showed that homozygous brothers T133 and T133-1 were hypocalcemic with elevated alkaline phosphatase; their homozygous father T133-5 and all heterozygous subjects had normal serum calcium and alkaline phosphatase concentrations. Because in vitro analyses of CYP2R1 function had shown that the L99P enzyme retained modest residual activity, we administered 50,000 IU of ergocalciferol (D2) or cholecalciferol (D3) on separate occasions to subjects and determined serum levels of 25 (OH)D2 and 25(OH)D3 by isotope-dilution liquid chromatography-tandem mass spectrometry on days 0, 1, 3, and 7. Peak values were achieved on day 3 (see Table). We conclude that homozygous or heterozygous mutation of the CYP2R1 gene is a cause of rickets, and represents a new form of vitamin D dependent rickets. Remarkably, the phenotype appears to improve with age and treatment with calcium, suggesting the involvement of other genetic, hormonal or environmental factors that can compensate for loss of CYP2R1 vitamin D 25 hydroxylase activity. The role of variant alleles of CYP2R1 in the pathogenesis of vitamin D deficiency and/or metabolic bone disease worldwide remains to be determined.