27th February 2025

Congenital causes of rickets/osteomalacia and similar conditions

If low sun exposure, poor diet or malabsorption are excluded, congenital causes of rickets and osteomalacia should be sought.

Vitamin D-resistant rickets

In addition to chronic renal failure, impaired 1α-hydroxylation of calcifediol occurs in vitamin D-resistant rickets type I, caused by an autosomal recessive loss-of-function mutation in the renal 25(OH)D 1α-hydroxylase. Calcifediol levels may be normal, while calcitriol (1,25(OH)2D) is low, so supplementation is with calcitriol instead of ergocalciferol/cholecalciferol. Inactivating mutations in the vitamin D receptor results in vitamin D-resistant rickets type II, another autosomal recessive disorder, though calcitriol levels may instead be raised alongside PTH. Very high doses of calcitriol are given alongside calcium and phosphate supplements (though not together to avoid GI calcium phosphate mineral precipitation).

Hypophosphataemic rickets and osteomalaica

The protein FGF23 acts similarly to PTH in down-regulating sodium/phosphate co-transporters in the proximal tubule to increase phosphate excretion in urine and can additionally reduce synthesis of calcitriol. Hypophosphataemic rickets increases FGF23 levels (through increased production or resistance to degradation) via autosomal dominant, autosomal recessive, and X-linked dominant mutations. Tumour-induced hypophosphataemic osteomalacia is seen in mesenchymal tumours with ectopic production of FGF23. In addition to vitamin D ± calcium, phosphate supplementation is required in these conditions.

Hypophosphatasia

Hypophosphatasia sees autosomal dominant or autosomal recessive mutations in the gene for ALP, resulting in reduced bone mineralisation and phosphate accumulation in bone. ALP levels are low or undetectable, while other biochemistry is normal. Though once fatal, asfotase alfa (a recombinant form of ALP) has transformed outcomes.

Other causes of osteomalacia

Other potential causes of osteomalacia include chronic acidosis (prevents calcium phosphate mineral formation), aluminium ingestion (e.g., through certain antacids, phosphate binders and dialysate fluids), and Fanconi syndrome.