Aetiology

Vitamin D metabolism is dependent on sunlight and enzymatic conversion in the liver and kidneys. Ultraviolet light converts 7-dehydrocholesterol to colecalciferol (vitamin D3). Colecalciferol may also be obtained from the diet. Colecalciferol is converted to calcidiol (25-hydroxyvitamin D) by vitamin D 25-hydroxylase in the liver. Calcidiol is converted to calcitriol (1,25-dihydroxyvitamin D) by 1-alpha-hydroxylase in the kidney. Ergocalciferol (vitamin D2) is obtained from the diet and is metabolised in a similar manner as colecalciferol.[4]

Causes of calcium-deficient rickets include nutritional or malabsorptive vitamin D deficiency, a defect of 1-alpha-hydroxylase, dysfunction of the vitamin D receptor, dietary calcium deficiency, or chronic renal failure resulting in decreased renal vitamin D synthesis.[5]

The main reasons for inadequate vitamin D supply in infants from Western countries are prolonged breastfeeding without vitamin D supplementation and concomitant avoidance of sun exposure. Genetic factors and air pollution have been implicated in vitamin D deficiency in Indian children.[13] At latitudes above 40º north or south, no effective synthesis of colecalciferol occurs in winter months, so deficiency is more common.​[9][16]

Phosphate-deficient rickets is almost always caused by renal phosphate wasting. Genetic hypophosphataemic rickets, oncogenic hypophosphataemic rickets, and rickets associated with McCune-Albright syndrome result from excessive blood levels of fibroblast growth factor-23 (FGF-23), a hormone (secreted by osteoblasts, osteoclasts, and osteocytes) that decreases phosphate reuptake in the kidney. Hereditary hypophosphataemic rickets with hypercalcuria, Fanconi syndrome, and renal tubular acidosis type II are caused by mutations in ion transporter genes.[6][17] Nutritional deficiency of phosphate is a rare cause of rickets. Phosphate is abundant in most diets but may not be sufficient in growing infants, or it may be precipitated in the stomach by antacids.​[5]

Medications that can cause calcium and phosphorus deficiency include loop diuretics and corticosteroids, and phenytoin can cause target organ resistance to calcitriol.[4]

Pathophysiology

Growth plate thickness is determined by chondrocyte proliferation and hypertrophy, vascular invasion, and conversion into primary bone spongiosa. Mineral deficiency prevents the normal process of bone mineral deposition. If mineral deficiency (whether calcium or phosphate) occurs at the growth plate, growth slows and there is delayed bone age. This condition is called rickets. Poor mineralisation of trabecular bone, resulting in a greater proportion of unmineralised osteoid, is the condition of osteomalacia. Rickets is found only in growing children before fusion of the epiphyses, whereas osteomalacia is present at all ages. All rickets patients have osteomalacia, but not all patients with osteomalacia have rickets. If the underlying condition does not improve, bone deformity occurs.[3]​​[5]

In calcium-deficient rickets, the primary defect results from lack of vitamin D, or lack of vitamin D effect. This results in decreased calcium absorption in the gut.[18] This reduction in calcium absorption increases parathyroid hormone secretion, which acts to preserve blood calcium levels by 1) activating bone resorption, 2) decreasing renal calcium loss, 3) increasing renal phosphate loss, and 4) increasing vitamin D activation by upregulating the vitamin D 1-alpha-hydroxylase enzyme in the kidney. The combination of decreased calcium and phosphate availability results in rickets.

In phosphate-deficient rickets, the primary defect causes severe renal phosphate wasting. Decreased phosphate availability results in rickets.

Classification

Causes of rickets[3]​[5][6]

1. Calcium-deficient rickets with secondarily elevated parathyroid hormone levels (sometimes referred to as hypocalcaemic rickets):

  • Lack of vitamin D due to

    • Decreased sun exposure

    • Dietary-deficient intake

    • Malabsorption

    • Liver disease (affects conversion of colecalciferol to calcidiol)

    • Anticonvulsant drugs (phenytoin may cause target organ resistance to calcitriol)

    • Renal osteodystrophy

    • Type I or pseudovitamin D-deficient rickets occurs because of a defect in 1-alpha-hydroxylase, the enzyme responsible for the conversion of 25-hydroxyvitamin D into the active metabolite.

  • End-organ resistance

    • Very rare autosomal recessive disorder associated with end-organ resistance to calcitriol, usually caused by mutations in the gene encoding the vitamin D receptor. This is called type II vitamin D-dependent rickets.

  • Dietary calcium deficiency.

2. Phosphate-deficient rickets (without secondarily elevated parathyroid hormone levels) may be caused by:

  • Renal phosphate wasting

    • Genetic hypophosphataemic rickets

      • X-linked hypophosphataemic rickets

      • Autosomal dominant hypophosphataemic rickets

      • Autosomal recessive hypophosphataemic rickets

      • McCune-Albright syndrome

      • Hereditary hypophosphataemic rickets with hypercalcuria

      • Fanconi syndrome

      • Renal tubular acidosis (type 2/proximal)

    • Oncogenic hypophosphataemia

  • Phosphate deficiency from poor intake or malabsorption.

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