26th February 2025

Vitamin D deficiency, rickets and osteomalacia

Vitamin D deficiency

In UK populations, >80% of vitamin D is derived from exposure to sunlight, with the remainder acquired through dietary sources. Except in uncomplicated deficiency of doubtful clinical significance, measurement of renal function, calcium, phosphate, PTH, and ALP should be considered, particularly if complications of deficiency are suspected.

Risk factors for deficiency include poor sun exposure, darker complexion, pregnancy/breastfeeding, obesity, age over 65, malabsorption disorders, and severe hepatic or renal disease. Vitamin D deficiency is also associated with a range of other conditions, including diabetes, most cancers, and auto-inflammatory diseases, though this is unlikely causative in any significant way.

Those with risk factors are advised to take a 400 IU supplement of vitamin D2 or D3 daily, with all other adults advised to take supplements only in the autumn and winter. If found to be deficient, non-urgent cases (i.e. asymptomatic, no relevant comorbidities, no drug indications) can be treated with a maintenance regimen of 800-2,000 IU daily, whereas those requiring faster correction require a loading dose of 280,000-300,000 IU over 6-10 weeks before reducing to maintenance levels.

Caution is advised when prescribing in pregnant or breastfeeding patients, while patients with a high risk of hypercalcaemia or renal stones, gastrointestinal disorders resulting in vitamin D malabsorption, or end-stage liver or kidney disease (i.e. have impaired hydroxylation of vitamin D to its active metabolite) should not receive standard supplementation.

Rickets and osteomalacia

Severe vitamin D deficiency (through decreased sun exposure, poor diet or malabsorption) is the most common cause of rickets, seen in children before growth plate closure, and osteomalacia.

Rickets

Rickets is characterised by inappropriate expansion of the growth plate, preventing its replacement by osteoblasts.

Clinical features include developmental delay, hypotonia, bowing of the legs, end thickening of long bones, ‘rickety rosary’ (costochondral nodularity), craniotabes, and frontal/parietal bossing.

Osteomalacia

Osteomalacia is characterised by impaired mineralisation of bone matrix proteins, with hypocalcaemia and hypophosphataemia directly involved in the pathophysiology. Prolonged deficiencies in these minerals for any reason may, therefore, result in osteomalacia.

Clinical manifestations include fatigue, generalised aches and pains, bone pain and tenderness, proximal myopathy with waddling gait, and an increased risk of fractures. If not already present, significant hypocalcaemia can eventually develop, as osteoclasts are unable to further mobilise calcium from unmineralised bone. High bone turnover often results in a raised ALP.

Though definitive, bone biopsy is rarely performed, and instead, diagnosis most often relies on history, examination and biochemistry. Imaging may also be of use as plain film radiographs might show transverse lines of increased lucency (pseudofractures or Looser’s zones), and DXA may demonstrate low BMD. Alongside the increased risk of fracture, low BMD often means osteomalacia is mistaken for osteoporosis. However, in contrast to osteomalacia, the ratio of mineralised to unmineralised bone remains constant in osteoporosis.

Treatment consists of loading doses of vitamin D followed by daily maintenance therapy, with calcium supplementation as required.

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.

References

• National Institute for Health and Care Excellence. CKS: Vitamin D deficiency in adults [Internet]. NICE. 2022 [cited 2023 Feb 20]. Available from: https://cks.nice.org.uk/topics/vitamin-d-deficiency-in-adults/
• Palacio C, Warda F. Rickets [Internet]. BMJ Best Practice. 2021 [cited 2023 Feb 20]. Available from: https://bestpractice.bmj.com/topics/en-gb/635
• Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci USA. 2005;102(27):9637–42
• Sinnott B. Osteomalacia [Internet]. BMJ Best Practice. 2021 [cited 2023 Feb 20]. Available from: https://bestpractice.bmj.com/topics/en-gb/517
• Merck, Sharp & Dohme. Differentiating osteoporosis and osteomalacia [Internet]. MSD Manual Professional Version. 2023 [cited 2023 Feb 20]. Available from: https://www.msdmanuals.com/en-gb/professional/multimedia/table/differentiating-osteoporosis-and-osteomalacia