Vitamin D deficiency including osteomalacia and rickets

What is vitamin D?¹

Vitamin D is a fat-soluble vitamin that regulates calcium and phosphate homeostasis. It promotes the absorption of calcium and phosphorus from the bowel and enables mineralisation of newly formed osteoid tissue in bones, as well as having a role in neuromuscular function.

Vitamin D circulates in the blood as both vitamin D₃ (colecalciferol) and vitamin D₂ (ergocalciferol). Vitamin D₃ is synthesised in the skin from 7-dehydrocholesterol (a form of cholesterol naturally found in the skin) by the action of sunlight containing ultraviolet B (UVB) radiation (or by artificial UVB light). Both vitamin D₃ and D₂ can also be obtained from natural foods (limited source), fortified foods, and food supplements.

Dietary and skin-derived vitamin D are biologically inactive and require enzymatic conversion to the active metabolite 1,25-hydroxyvitamin D (1,25[OH]2D). Vitamin D is converted in the liver to 25-hydroxyvitamin D (25[OH]D), the main circulating metabolite. This is then converted to 1,25(OH)2D in the kidneys and other tissues. The production of 1,25(OH)2D is regulated by the action of parathyroid hormone (PTH) on the kidneys.

Recommended vitamin D thresholds in the UK in respect to bone health are:

• An increased risk of vitamin D deficiency occurs at serum 25[OH]D levels less than 25 nmol/L.

• Vitamin D levels may be inadequate (or insufficient) in some people when serum 25(OH)D is between 25-50 nmol/L.

• Vitamin D levels are sufficient for most people when serum 25(OH)D is greater than 50 nmol/L.

What does vitamin D do?^{1 2 3}

Normal bone mineralisation depends on adequate calcium and phosphate and this is maintained by vitamin D.⁴

Osteomalacia (adults) and rickets (children) are caused by 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.

• Rickets results from the same underlying process, occurring in children and adolescents before the growth plates have closed.

There is debate regarding the role of vitamin D in non-musculoskeletal disorders such as autoimmune disease, cancer, mental health problems, and cardiovascular disease.

Available evidence from systematic reviews on the effects of vitamin D on mortality has been inconclusive. One review found that vitamin D supplementation significantly reduced the risk of cancer death, but neither vitamin D₃ nor vitamin D₂ was associated with a significant reduction in all cause mortality.⁵ Other studies have shown reduction in cancer rates, particularly colorectal and breast cancer, in post-menopausal women.⁶

The recommended daily intake of vitamin D for adults in the UK is 400 IU (10 micrograms) per day for an adult. For children:

• Children from birth to 4 years of age should be given daily vitamin D supplement drops:

  • Children aged 0-1 year (including exclusively and partially breastfed infants), a vitamin D supplement containing 8.5-10 micrograms (340-400 IU) daily.

  • Children aged 1-4 years, a vitamin D supplement containing 10 micrograms (400 IU) daily.

• Children who have more than 500 mL of infant formula a day do not need any additional vitamin D, as formula milk is already fortified.

• Children and young people eligible for the NHS Healthy Start scheme can obtain free vitamin drops (containing 7.5 micrograms/300 IU of vitamin D3, 233 micrograms of vitamin A, and 20 mg of vitamin C). For other children, vitamin supplement preparations can be bought over the counter.

• Consider daily vitamin D supplementation for all other children including those at high risk of vitamin D deficiency, particularly if they are unable to maintain adequate vitamin D levels through safe sunlight exposure and diet. For children aged 1 month to 18 years at high risk, a vitamin D supplement containing 400-600 international units (IU) daily.
  

Sunlight

Over 90% of vitamin D is derived from UVB light and the rest is obtained from the diet. In a fair-skinned person, 20-30 minutes of sunlight exposure on the face and forearms at midday is estimated to generate the equivalent of around 2,000 IU of vitamin D. Two or three such exposures to sunlight each week are sufficient to achieve healthy vitamin D levels during the summer. For people with pigmented skin and the elderly, the amount of sunlight exposure should be increased by a factor of between 2 and 10 in order to achieve the same level of vitamin D synthesis. Between October and April each year, 90% of the UK does not get sufficient exposure to the UVB light necessary for vitamin D synthesis and so people are then reliant on dietary sources of vitamin D.

Dietary intake

Food sources of vitamin D include oily fish, liver, egg yolks, fortified margarine and fortified breakfast cereals. Only a few foods contain substantial amounts of vitamin D and the most significant dietary source is oily fish and cod liver oil. There is little or no vitamin D content in UK milk and dairy products. Only infant formula milk and margarine have statutory vitamin D supplementation in the UK. Farmed fish may have less vitamin D content than wild fish. Therefore, a low dietary vitamin D intake, combined with a lack of skin synthesis throughout the year, leads to a high prevalence of vitamin D insufficiency in the UK.

Epidemiology^{1 2}

• Vitamin D deficiency continues to be common in children and adults.

• The UK National Diet and Nutrition Survey reported low vitamin D status (serum 25-hydroxyvitamin D (25[OH]D) concentrations below 25 nmol/L) from combined results from a four-year rolling programme (2008/2009 to 2011/2012) in 23% of adults aged 19-64 years and 21% of adults aged 65 years and over. When subdivided by season, in the winter months of January to March, this increased to 29.3% of people aged 65 years and over, and 40% of people aged 19-64 years.

• The same survey reported that 7.5% of children aged 1.5-3 years, 14% of children aged 4-10 years and 22% of children aged 11-18 years had a serum 25(OH)D concentration below 25 nmol/L. When subdivided by season, in the winter months of January to March this increased to 40% of children aged 11-18 years, compared with 13.4% in the summer months of July to September for the same age group.

• The highest prevalence of deficiency is found among older adults, individuals with obesity, nursing home residents, and hospitalised patients.⁶

• Women are more likely to be vitamin D deficient than men.⁷

Risk factors for vitamin D deficiency

• 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. This is the case both in those who are living in South Asia and in Europe or North America.⁶

• Children and those aged over 65 years.

• Pregnancy.

• Obesity.

• Routine covering of the face and body.

• An infant who is exclusively breastfed, particularly beyond 6 months of age.

• Housebound or institutionalised.

• Poverty.

• Vegetarianism.

• Alcoholism.

• Living in countries at high latitude.

• Family history of vitamin D deficiency.

• Chronic kidney disease. This is increased further with haemodialysis, concomitant liver disease or a previous liver transplant.⁶

Vitamin D deficiency causes⁸

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

• Gastrointestinal malabsorption: for example, surgery (stomach and bowel resections), other causes of short bowel syndrome, chronic pancreatic disease, cystic fibrosis, biliary disease (for example, primary biliary cirrhosis, biliary fistulae, biliary atresia), Crohn's disease and coeliac disease.

• Liver disease - for example, cirrhosis.

• Renal disease causing defective 1,25-dihydroxyvitamin D synthesis.

• Drug causes include anticonvulsants (particularly phenytoin, carbamazepine, phenobarbital), rifampicin, highly active antiretroviral therapy (HAART), colestyramine and cadmium.

• Severe dietary calcium deficiency can cause rickets despite adequate vitamin D.

• 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, aluminium (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 restriction, 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 (25-OHD) 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.

Vitamin D deficiency symptoms³

Maintain a high index of clinical suspicion. People with suboptimal levels often have no symptoms and so awareness and prevention are very important, especially in young children, the elderly and pregnant women. Vitamin D deficiency should be suspected in children with known risk factors who are unwell with pain, irritability and poor growth or skeletal deformities, and in all children with a seizure disorder.

• Children:

  • Severe vitamin D deficiency may cause hypocalcaemic seizures or tetany, particularly in the neonatal period and during periods of rapid growth in adolescence.

  • From the age of 6 months, children with vitamin D deficiency often present with bony deformity (rickets). Bowing of the legs (genu varum) is typical, but knock knees (genu valgum) can also occur. Anterior bowing of the femur and internal rotation at the ankle are frequently found, along with swelling at the wrist, prominent costochondral joints, and a soft, deformable skull (craniotabes).

  • Children with vitamin D deficiency may be irritable and reluctant to weight-bear, and manifest impaired growth.

  • An increased susceptibility to infections and respiratory symptoms may be a caused by a 'rachitic lung', with reduced lung expansion and muscle weakness.

  • Severe vitamin D deficiency can result in cardiomyopathy and potentially fatal heart failure.

• Adults:

  • Pain and proximal muscle weakness are the main features of vitamin D deficiency in adults. Symptoms may be mild and nonspecific with a general lack of well-being.

  • Rib, hip, pelvis, thigh and foot pain are typical.

  • More diffuse muscular aches and muscle weakness, including in the limbs and back, are also common.

  • Low bone density on dual-energy X ray absorptiometry (DXA) scanning, pathological fractures or osteopenia on plain X-rays may reflect osteomalacia, and these findings warrant assessment of vitamin D status.

Rickets^{2 9}

Classic presentation is a child with bony abnormalities such as leg-bowing and knock knees (but remember that both bow legs and knock knees are normal at different stages of child development). 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- to 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 (for example, convulsions, irritability, tetany, breathing difficulties with apnoea or stridor), cardiomyopathy or cardiac arrest, especially in very young infants.

Osteomalacia^{1 10}

• 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 (for example, chronic kidney disease, 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 (for example, 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.

Differential diagnosis

• The radiographic appearance of osteomalacia may be normal or similar to findings noted with osteoporosis.

• The differential diagnosis of generalised osteopenia includes 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 and polymyositis, muscular dystrophy, malignant disease, polymyalgia rheumatica, hypothyroidism, hyperthyroidism and fibromyalgia.

Investigations

Initial investigations for vitamin D deficiency

• Blood biochemistry: renal function, electrolytes (including serum calcium and phosphate), LFTs, parathyroid hormone (PTH) level:³

  • More than 80% of adults with osteomalacia have a high concentration of serum alkaline phosphatase.

  • Hypocalcaemia, hypomagnesaemia and hypophosphataemia may be present, depending on the severity and chronicity of the disease and the patient's dietary calcium intake.

  • Elevation of plasma PTH (secondary hyperparathyroidism) is typical but not always found in patients with osteomalacia.

• FBC: anaemia suggests possible malabsorption.

• Urine ACR and U and Es to help determine whether the patient has underlying chronic kidney disease.

Vitamin D levels¹

• Vitamin D status is most reliably determined by assay of serum 25-hydroxyvitamin D (25-OHD):³

  • Vitamin D deficiency: individuals with symptomatic osteomalacia or rickets have serum 25-OHD concentrations of less than 25 nmol/L (10 micrograms/L).

  • A much larger proportion of the UK population have vitamin D insufficiency, with serum 25-OHD concentrations between 25 nmol/L and 50 nmol/lL(10-20 micrograms/L).

  • Serum 25-OHD concentrations between 50-75 nmol/I are considered healthy but optimal vitamin D status is when serum concentrations of 25-OHD are 75 nmol/L (30 micrograms/L) or more.

Check the vitamin D level by measuring serum 25-hydroxyvitamin D (25[OH]D) if a person has musculoskeletal symptoms that may be attributable to vitamin D deficiency, such as:

• Suspected bone disease that may be improved with vitamin D treatment, such as osteomalacia or osteoporosis, eg chronic widespread pain with other features of osteomalacia, such as proximal muscle weakness.

• Known bone disease, where correction of vitamin D deficiency is needed prior to specific treatment, such as:

  • Prior to osteoporosis treatment with a potent antiresorptive agent (zoledronate, denosumab, or teriparatide).

  • Prior to Paget's disease treatment with a bisphosphonate.

Do not routinely test for vitamin D deficiency in people who are asymptomatic.

Asymptomatic people at higher risk of vitamin D deficiency do not need routine testing for vitamin D deficiency, but should be advised on the need for maintenance dose vitamin D supplementation.

People with osteoporosis and fragility fracture who are treated with vitamin D supplements and an oral antiresorptive agent do not need routine testing for vitamin D deficiency.

If vitamin D deficiency or insufficiency is diagnosed following blood testing, consider additional investigations:

• Bone profile (calcium, phosphate, and alkaline phosphatase) and parathyroid hormone (PTH) level: to assess for a disorder of bone mineralisation, such as osteomalacia:

• Investigations to assess for an underlying cause or alternative diagnosis may include:

  • Full blood count, B12 and folate to identify other deficiencies.

  • Renal and liver function tests.

  • Thyroid function tests.

  • Coeliac serology if coeliac disease is suspected as a cause of malabsorption.

Further investigations for rickets/osteomalacia

• 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).

• 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.

  • Low bone density on DXA scanning.

  • 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.

Vitamin D deficiency treatment^{1 2}

The treatment of vitamin D deficiency includes:

• Education: dietary advice.

• Encourage exposure to sunlight.

• Vitamin D supplementation.

• Treatment of any underlying condition.

• Treatment of pain.

• Orthopaedic intervention - may be required.

Oral vitamin D3 is the vitamin D preparation of choice for the treatment of vitamin D deficiency, and vitamin D2 is an alternative option in some clinical situations.

Referral

Seek specialist advice or arrange referral before starting vitamin D treatment if:

• A child has clinical features of rickets, or a child has hypocalcaemia.

• There is a medical condition that predisposes to hypercalcaemia, such as granulomatous disease (sarcoidosis, tuberculosis), metastatic bone disease, some lymphomas, or primary hyperparathyroidism, as there is an increased risk of vitamin D toxicity.

• There is a gastrointestinal or malabsorption disorder resulting in an inability to maintain adequate vitamin D status, as intensive high-dose replacement or maintenance treatment may be needed under specialist supervision.

• There are active renal stones or there is a history of renal stones, due to the risk of vitamin D toxicity causing hypercalciuria and renal stone disease.

• There is severe liver disease or end-stage chronic kidney disease, as specialist treatment with activated vitamin D metabolites may be needed.

Lifestyle advice

Safe sun exposure to help skin synthesis of vitamin D. Most people can make sufficient vitamin D by going out for short periods in strong sunlight, and leaving only areas of skin that are often exposed uncovered (such as the forearms, hands, or lower legs). Longer periods of sun exposure may be needed for people with dark pigmented skin. Prolonged exposure to strong sunlight (for example, leading to burning or tanning) is unlikely to provide additional benefit, and should be avoided. The use of sunbeds is ineffective for vitamin D synthesis, is potentially harmful and should be avoided.

NB: infants aged under 6 months should be kept out of direct strong sunlight.

Provide advice on dietary sources of vitamin D (for example, oily fish, red meat, liver, egg yolks and fortified foods). Advise that it is difficult to obtain sufficient vitamin D from food sources alone. Advise continued long-term maintenance vitamin D supplementation to prevent recurrent vitamin D deficiency and to maintain bone health. If dietary calcium intake is inadequate, advise the person to take calcium supplementation. Food sources of calcium include dairy, green leafy vegetables, bread and anything made with fortified flour, sardines and pilchards.

The recommended daily calcium intake for children to prevent rickets is:

• Birth to 6 months: 200 mg a day.

• 12 months: 260 mg a day.

• Over 12 months: more than 500 mg a day.

Adults

If rapid correction of vitamin D deficiency is needed - for example, symptoms or about to start treatment with a potent antiresorptive agent (zoledronate, denosumab, or teriparatide) - prescribe a fixed loading dose followed by regular maintenance vitamin D therapy one month after loading. The loading regimen should provide a total of approximately 300,000 international units (IU) of vitamin D, given either as separate weekly or daily doses over 6-10 weeks.

Ensure maintenance therapy of vitamin D equivalent to 800-2000 IU daily (up to a maximum of 4000 IU daily for certain conditions such as malabsorption following specialist advice), given either daily or intermittently at a higher equivalent dose. Vitamin D may be prescribed for people with osteoporosis or a chronic condition or surgery that results in deficiency or malabsorption. For other people, maintenance therapy should be bought over the counter.

If correction of vitamin D deficiency is less urgent and when co-prescribing vitamin D supplements with an oral antiresorptive agent, maintenance therapy may be started without the use of loading doses.

Assess the person's need for calcium supplementation. Consider using an online calcium calculator, such as the UK Centre for Genomic and Experimental Medicine (CGEM) calcium calculator.

• If inadequate calcium intake of less than 700 mg a day (or less than 1000 mg a day if the person has osteoporosis), advise to increase dietary calcium intake. If the person is unable or unwilling to increase dietary calcium intake, consider the need for calcium supplements.

• Combination calcium and vitamin D preparations (such as Calcichew D3®) are not recommended for people needing high-dose vitamin D treatment, as they contain very low levels of vitamin D (200-400 IU per tablet) and may increase the risk of hypercalcaemia.

Advise maintaining adequate vitamin D levels through safe sunlight exposure and diet.

Arrange follow-up for people with vitamin D deficiency to reassess serum calcium and vitamin D levels (if clinically indicated), and to check for ongoing symptoms.

Children

If rapid correction of vitamin D deficiency is needed, a fixed loading dose is given for 8-12 weeks, followed by regular maintenance vitamin D therapy one month after loading.

There is need for long-term maintenance vitamin D supplements, unless there is a significant lifestyle change to improve vitamin D status. For children aged 1 month to 18 years, a vitamin D supplement containing 400-600 IU daily is needed.

This dose is also advised as long-term maintenance for correction of vitamin D insufficiency (unless there is a significant lifestyle change to improve vitamin D status), without the use of loading doses.

Monitoring

• Serum calcium concentrations should be checked regularly for a few weeks after starting treatment for vitamin D deficiency and then vitamin D, 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.

• 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 aged 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 - for example, those who get no sunshine, elderly, taking anticonvulsant medications, liver or kidney disease).

Prognosis^{1 2}

• This 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 (for example, 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.

• Following treatment for vitamin D deficiency or insufficiency, lifestyle changes and vitamin D supplementation are likely to be needed long-term to maintain optimum vitamin D levels.

Vitamin D deficiency prevention

Information about appropriate sunlight exposure, the use of vitamin D supplements, and eating oily fish should be made available to the whole population.³

• 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 - for example, 800 IU daily).

• For breastfed infants, vitamin D supplementation 400 IU/day for up to six months increases 25‐OH vitamin D levels and reduces vitamin D insufficiency.¹¹

• Early diagnosis and treatment of potential causes such as intestinal malabsorption or chronic kidney disease.