Osteomalacia (adults) and rickets (children) are caused by an inadequate supply of vitamin D leading to inadequate mineralisation of bone matrix. Vitamin D deficiency causes low calcium and phosphate, which lead to secondary hyperparathyroidism.

• Osteomalacia results from a loss of skeletal mass caused by inadequate mineralisation of the normal osteoid tissue after the closure of the growth plates.¹
• Rickets results from the same underlying process, occurring in children and adolescents before the growth plates have closed.

Normal bone mineralisation depends on adequate calcium and phosphate and this is maintained by vitamin D. Vitamin D is supplied either in the diet or produced from a precursor in the skin following exposure to ultraviolet light. 90% of our daily vitamin D requirement is usually obtained by the action of sunlight on the skin and 10% is obtained from the diet.

• Good food sources of vitamin D include oily fish, liver, egg yolks, fortified margarine and fortified breakfast cereals.
• Production of metabolically active vitamin D requires hydroxylation, which occurs first in the liver and then in the kidneys to produce 1,25-dihydroxyvitamin D3.

A 25-hydroxyvitamin D concentration below around 25 nmol/L (10 μg/L) is probably consistent with vitamin D deficiency, which may be associated with osteomalacia. Concentrations of 30-50 nmol/L (12-20 μg/L) are generally considered a sign of vitamin D insufficiency, in which there may be biochemical disturbances with or without nonspecific musculoskeletal symptoms.²

Epidemiology

• Vitamin D deficiency continues to be common in children and adults. It has been estimated that 1 billion people worldwide have vitamin D deficiency.³
• One study found the prevalence of rickets in non-Caucasian children to be 1.6%.⁴
• In the UK, the prevalence of vitamin D insufficiency in all adults is about 14.5% and possibly more than 30% in those over 65 years old.²

Risk factors

• Dark skin, especially South Asian, African Caribbean and Middle Eastern; prevalence of vitamin D insufficiency is as high as 94% in otherwise healthy South Asian adults.^2,5
• Children and those aged over 65 years.
• Pregnancy.
• Routine covering of face and body, e.g. wearing a veil.
• An infant who has prolonged breast-feeding without vitamin D supplementation, especially if the mother is vitamin D-deficient (increased risk of severe vitamin D deficiency presenting with neonatal fitting).
• Housebound or institutionalised.
• Poverty.
• Vegetarianism.
• Alcoholism.
• Living in countries at high latitude.
• Family history of vitamin D deficiency
• Chronic disease, e.g. malabsorption, renal or liver disease.

Causes

Vitamin D deficiency is most often caused by nutritional deficiency but can be secondary to a wide range of other underlying causes, such as disorders of the gut, pancreas, liver and kidney.⁶

• Gastrointestinal causes of reduced absorption of vitamin D, e.g. surgery (stomach and bowel resections), chronic pancreatic disease, biliary disease (e.g. primary biliary cirrhosis, biliary fistulae, biliary atresia), Crohn's disease, coeliac disease, gastrointestinal loops and fistulae.
• Liver disease, e.g. cirrhosis.
• Renal disease causing defective 1,25-dihydroxyvitamin D synthesis.
• Drugs: anticonvulsants (induction of hepatic enzymes results in increased vitamin D metabolism), colestyramine (inhibits vitamin D absorption); rifampicin (interferes with vitamin D metabolism); cadmium (inhibits 1,25-hydroxyvitamin D production).
• Severe dietary calcium deficiency can cause rickets despite adequate vitamin D.⁷
• Rare causes:
  • Hypophosphataemia: tumour-induced, Fanconi's syndrome, phosphate depletion, metals such as cadmium and lead that may lead to renal phosphate wasting.
  • Systemic acidosis, renal tubular acidosis.
  • Intoxication with diphosphonate, fluoride, aluminum (caused by excessive antacid ingestion, or in fluids used in dialysis).
  • Autonomous hyperparathyroidism presenting as vitamin D-deficient osteomalacia.
  • Mesenchymal tumour - oncogenic osteomalacia.
• Genetic causes:
  • Hypophosphataemic rickets: X-linked dominant disorder characterised by growth retardation, inadequate mineralisation of bone, hypophosphataemia, and renal defects in phosphate reabsorption and vitamin D metabolism.
  • Vitamin D-dependent rickets type I (failure of conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D) and II (end organ insensitivity to 1,25-dihydroxyvitamin D).
  • Adult-onset vitamin D-resistant hypophosphataemic osteomalacia (autosomal dominant).
  • Proximal renal tubule dysfunction: hereditary Fanconi's syndrome.

Presentation

Maintain a high index of clinical suspicion, especially in elderly patients who present with fractures of the proximal femur, those with osteoporosis and people of South Asian descent. People with suboptimal levels often have no symptoms and so awareness and prevention are very important, especially in young children and pregnant women.

Rickets

Classic presentation is a child with bony abnormalities such as leg-bowing and knock-knees. There may be bony deformities of the chest, pelvis and skull, delayed dentition, poor growth, and bone pain.

• Softening of the skull (craniotabes) and frontal bossing in the first few months of life; delayed closure of fontanelles.
• Tender swollen joints.
• Enlargement of the ends of the ribs ('rachitic rosary') due to expansion of the costochondral junction in a 3-6 month-old child.
• Deformed bones, bowing of the legs, knock-knees.
• Delayed walking or a waddling gait.
• Impaired growth; short stature and poor weight gain.
• The child is often miserable because of bone and joint pain.
• May present with fractures in severe cases.
• Dental deformities include delayed formation of teeth, enamel hypoplasia, and increased incidence of cavities in the teeth (dental caries).
• May present with symptoms of hypocalcaemia requiring urgent paediatric referral (e.g. convulsions, irritability, tetany, breathing difficulties with apnoea or stridor), cardiomyopathy or cardiac arrest, especially in very young infants.

Osteomalacia

• Mildly affected patients may present with widespread bone pain and tenderness (especially low back pain and in the hips), proximal muscle weakness and lethargy.
• Signs of the underlying disease (e.g. renal failure, malabsorption) may predominate.
• Early symptoms include gradual onset and persistent fatigue, and bone and joint pain and tenderness.
• Later symptoms include muscular weakness (especially proximal) and paraesthesia.
• Severely affected patients may have difficulty walking and may have a waddling gait or a change in gait, with proximal muscle weakness and marked adductor spasm.
• Other signs include costochondral swelling (rachitic rosary), spinal curvature and signs of hypocalcaemia (e.g. tetany, carpopedal spasm).
• Tenderness over pseudofractures (which represent a lucent band of decreased cortical density, perpendicular to bone surface, often multiple, and with or without callus formation).
• The patient may experience multiple fractures which are often bilateral and symmetrical. Typical sites include the femoral neck, scapula, pubic rami, ribs and vertebrae.
• Skeletal deformity can occur in the vertebral bodies and skull. There may be forward projection of the breastbone (pigeon chest) and deformities of the spine, including scoliosis or kyphosis.
• Other signs include dental deformities and hyporeflexia.

Possible long-term effects

• Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers.⁸
• Vitamin D deficiency may contribute to atherosclerosis and increased cardiovascular morbidity and mortality.⁹

Differential diagnosis

• The radiographic appearance of osteomalacia may be normal or similar to findings noted with osteoporosis.
• The differential diagnosis of generalised osteopenia includes osteomalacia, hyperparathyroidism, osteitis fibrosa, Paget's disease of bone and myeloma.
• Chronic excessive fluoride ingestion, etidronate overdose, aluminium toxicity.
• Other possibilities to exclude are rheumatoid arthritis, dermatomyositis, polymyositis, muscular dystrophy, malignant disease, polymyalgia rheumatica, hypothyroidism, hyperthyroidism.

Investigations

Initial investigations

• Blood biochemistry: renal function, electrolytes (including serum calcium and phosphate), liver function tests.
• Serum vitamin D and parathyroid hormone levels are not routinely recommended for high-risk symptomatic with clear clinical evidence of vitamin D deficiency but vitamin D levels are otherwise required for assessment. Vitamin D levels are generally categorised as:²
  • Normal vitamin D level: above 50 nmol/L
  • Vitamin D insufficient: 25-50 nmol/L
  • Vitamin D deficient: below 25 nmol/L
• Results may include mild hypocalcaemia, hypophosphataemia, raised alkaline phosphatase, low vitamin D (except vitamin D-resistant rickets).
• Full blood count: anaemia suggests possible malabsorption.

Further investigations

• Urine microscopy to help determine whether the patient has underlying renal failure.
• In children with low vitamin D levels identified, a wrist X-ray is required to diagnose rickets (definitive diagnosis of rickets requires radiography of a long bone which shows cupping, splaying and fraying of the metaphysis - for example, champagne glass wrist).¹⁰
• Radiology is unnecessary for adults if the diagnosis is clear but may include:
  • Plain X-ray of weight-bearing bones (neck of femur, pelvis, pubic rami, ribs, outer border of the scapulae and metatarsals) may show characteristic features such as coarsened trabeculae, osteopenia, pseudofractures ('Looser's zones' - linear areas of low density surrounded by sclerotic borders) and fractures; pseudofractures are particularly seen at the lateral border of the scapula, inferior femoral neck and medial femoral shaft.
  • MRI scanning helps to evaluate the soft tissues for ligament rupture.
  • CT scanning can help to evaluate pathological fractures.
  • Bone scan will show increased skeletal uptake of radioactive isotope ('hot spots') in the ribs and near joints.
• Iliac bone biopsy will show a failure of mineralisation and wide osteoid seams but bone biopsy is now rarely required.²

Management

Referral

All children with rickets should be referred to a paediatrician.¹⁰ It is advisable to refer an adult with vitamin D deficiency to a relevant specialist if:²

• There is no obvious cause.
• There is unexplained weight loss or anaemia or any other suggestion of coeliac disease or fat malabsorption.
• If medication (e.g. antiepileptic drugs, rifampicin) might be the cause.
• If the patient has hepatic or renal disease.
• If there is any illness associated with undue sensitivity to vitamin D and so an increased risk of toxicity with treatment (e.g. sarcoidosis, tuberculosis, lymphoma, primary hyperparathyroidism).
• Symptomatic patients who have taken supplements as directed for about 2 months with no improvement clinically or in vitamin D status.

General management

• Education: dietary advice (refer to a dietician).
• Encourage exposure to sunlight.
• Treatment of any underlying condition.
• Treatment of pain.
• Orthopaedic intervention may be required.

Specific treatment

• Simple dietary osteomalacia: exposure to sunlight combined with oral vitamin D. Combination with phosphate may accelerate bone healing.
• The effective dose and choice of preparation depends on the cause of the osteomalacia:
  • Adults with confirmed primary vitamin D deficiency require a minimum daily dose of oral vitamin D of 20 micrograms (800 IU), which takes at least a year for bone to normalise. Higher doses of vitamin D (maximum 2,200 IU daily) may be required, especially in at-risk groups.²
  • Lack of response to standard recommended doses of vitamin D suggests that the osteomalacia may not be due to simple vitamin D deficiency but an underlying cause, e.g. malabsorption or renal failure.
  • Chronic fat malabsorption and liver disease: oral ergocalciferol at high dose with serum calcium levels being monitored to avoid toxicity. Up to 1 mg (40,000 units) daily of ergocalciferol is often required. Alternatively treat with 1,25-dihydroxycholecalciferol (calcitriol).
  • High doses (above 1,000 IU daily) should not be used for pregnant women because of uncertainty regarding adverse effects on the fetus.
  • The daily doses of ergocalciferol (vitamin D2) for children recommended by the British National Formulary for Children (BNFC) are (all doses adjusted as necessary): for those aged 1-6 months: 75 micrograms (3,000 IU), 6 months-12 years: 150 micrograms (6,000 IU), 12-18 years: 250 micrograms (10,000 IU).¹¹ These doses are at the higher end of the treatment doses used in the above trials and patients may need to be monitored for hypercalcaemia. Some clinicians use half these doses with good effect.¹⁰
• Adverse effects of vitamin D treatment are very unusual but very high doses can cause raised blood calcium levels leading to polyuria, nausea, vomiting, constipation, dizziness and headaches.
• Vitamin D is contra-indicated in patients with hypercalcaemia or metastatic calcification. Relative contra-indications include primary hyperparathyroidism, renal stones, and severe hypercalciuria.²
• Caution is required when prescribing vitamin D for patients also taking certain drugs, including thiazide diuretics (which impair calcium excretion) and digoxin (enhance the effect of digoxin).

Monitoring

• Serum calcium concentrations should be checked regularly for a few weeks after starting treatment for vitamin D deficiency and then vitamin D, parathyroid hormone (PTH) and calcium concentrations should be checked after 3-4 months of treatment to assess efficacy and adherence to therapy. Vitamin D and calcium concentrations should be checked every 6-12 months.²
• Renal disease: 1,25-dihydroxycholecalciferol with response monitored until alkaline phosphatase level returns to normal, when therapy should be reduced to maintenance. Alfacalcidol (1-hydroxy derivative of calciferol) can be used in vitamin D deficiency due to renal disease.
• Renal tubular disorders and hypophosphataemia: the acidosis needs to be corrected by giving bicarbonate and an adequate phosphate intake of 3-5 g/day. Small doses of 1,25-dihydroxycholecalciferol may also be required.
• Hypocalcaemic tetany requires urgent treatment with intravenous calcium gluconate (10 mmol of a 10% solution initially).

Once vitamin D deficiency has been treated, prevention is required to prevent recurrence. This includes correction of any underlying cause, lifestyle advice (diet, sunshine) and often long-term vitamin D supplements:

• Babies under 1 year: 200 units (5 micrograms) daily.
• Children aged over 1 year: 280-400 units (7-10 micrograms) daily.
• Adults: 400 units (10 micrograms) daily (more for certain groups, e.g. those who get no sunshine, elderly, taking anticonvulsant medications, liver or kidney disease).

Prognosis

• Depends on the underlying cause but the outcome of treatment of vitamin D deficiency is generally very good.
• Treatment of simple deficiency with vitamin D replacement and/or sunlight and correction of predisposing factors should lead to dramatic improvements.
• Rickets and osteomalacia should respond rapidly to vitamin D. Increased mobility with increase in muscle strength may be the first clinical response but there may be a temporary increase in bone pain.
• Some groups (e.g. those in long-term institutional care) may require long-term maintenance therapy.
• As long as there is no specific resistance to treatment then bone healing often begins within a few weeks of starting treatment and complete healing within six months.

Prevention

• Education: dietary advice, advice about the importance of sun exposure.
• Either colecalciferol or ergocalciferol can be used to prevent primary vitamin D deficiency. A daily dose of 400 IU (10 micrograms) prevents simple vitamin D deficiency in otherwise healthy adults at risk of deficiency (those adults at high risk of vitamin D deficiency may require higher doses, e.g. 800 IU daily).²
• Vitamin D supplements are recommended for all pregnant women, breast-feeding women and breast-fed babies:
  • Pregnancy and breast-feeding: an oral supplement of 10 micrograms (400 units) of ergocalciferol daily (20 micrograms daily for people whose exposure to sunlight is limited and in those whose diet is deficient in vitamin D).
  • Babies: all breast-fed babies should receive vitamin drops (Abidec® or Dalivit®).
  • Infants who are breast-fed and children and adolescents who consume less than 1 L of vitamin D-fortified milk per day will likely need supplementation to reach 400 IU of vitamin D per day.¹²
• Early diagnosis and treatment of potential causes such as intestinal malabsorption or renal failure.

Document references

1. Kline MJ; Osteomalacia and Renal Osteodystrophy, eMedicine, Mar 2010
2. Drug and Therapeutics Bulletin, April 2006 44: 25-29. Primary vitamin D deficiency in adults. (Requires a subscription)
3. Holick MF; Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.
4. Ashraf S, Mughal MZ; The prevalence of rickets among non-Caucasian children. Arch Dis Child. 2002 Sep;87(3):263-4.
5. Roy DK, Berry JL, Pye SR, et al; Vitamin D status and bone mass in UK South Asian women. Bone. 2007 Jan;40(1):200-4. Epub 2006 Sep 6. [abstract]
6. Wharton B, Bishop N; Rickets. Lancet. 2003 Oct 25;362(9393):1389-400. [abstract]
7. Pettifor JM; Nutritional rickets: deficiency of vitamin D, calcium, or both? Am J Clin Nutr. 2004 Dec;80(6 Suppl):1725S-9S. [abstract]
8. Giovannucci E, Liu Y, Rimm EB, et al; Prospective study of predictors of vitamin D status and cancer incidence and J Natl Cancer Inst. 2006 Apr 5;98(7):451-9. [abstract]
9. Gaddipati VC, Kuriacose R, Copeland R, et al; Vitamin D deficiency: an increasing concern in peripheral arterial disease. J Am Med Dir Assoc. 2010 Jun;11(5):308-11. [abstract]
10. Drug and Therapeutics Bulletin; Primary vitamin D deficiency in children. February 2006 44: 12-16; (Requires a subscription)
11. British National Formulary for Children; British Medical Association and Royal Pharmaceutical Society of Great Britain. London
12. Casey CF, Slawson DC, Neal LR; VItamin D supplementation in infants, children, and adolescents. Am Fam Physician. 2010 Mar 15;81(6):745-8. [abstract]

Internet and further reading

• Osteomalacia, Wheeless' Textbook of Orthopaedics
• Tangpricha V; Vitamin D Deficiency and Related Disorders, eMedicine, Oct 2009
• Greer FR; Rickets, eMedicine, Apr 2010
• Update on Vitamin D, Scientific Advisory Committee on Nutrition, February 2007

Acknowledgements