Vitamin D Deficiency

Vitamin D deficiency is defined by an inadequate serum 25-hydroxyvitamin D (25-OH vitamin D), the major circulating form and the best marker of vitamin D status. The consequences follow in order: intestinal calcium absorption is impaired, secondary hyperparathyroidism compensates, and skeletal disease follows. That disease is rickets in children, whose growth plates are affected, and osteomalacia in adults, with defective bone mineralisation.

Who is deficient. Deficiency or insufficiency affects an estimated 1 billion people worldwide. The figures for particular groups:

• 30-50% of community-dwelling elderly have levels below 50 nmol/L
• 40-60% of institutionalised elderly are deficient across high-income countries
• 50-70% of hip fracture patients are deficient
• 25-40% of patients develop deficiency after bariatric surgery without supplementation
• Dark-skinned populations at high latitudes carry a 5-10 times higher risk

Where they live. Prevalence rises with latitude. Above 35 degrees north or south, winter UVB is too weak for cutaneous synthesis. Immigrants from equatorial regions to high latitudes are a high-risk population, and South Asian, Middle Eastern and East African migrants to high-latitude countries are a recognised high-risk group, combining skin pigmentation with concealing dress.

Made in the skin. UVB radiation at 290-315 nm converts 7-dehydrocholesterol in the skin to pre-vitamin D3, which isomerises to vitamin D3 (cholecalciferol). This requires adequate sun exposure, and melanin blocks UVB absorption, so dark skin needs 3-5 times longer exposure.

Taken in the diet. The natural sources are fatty fish (salmon, mackerel), fish liver oils and egg yolks; milk, cereals and orange juice are fortified. Diet typically provides 200-400 IU daily, which is insufficient without supplementation in high-risk groups.

Activated in two steps. One hydroxylation in the liver, one in the kidney:

1. Liver. 25-hydroxylase converts vitamin D3 to 25-OH vitamin D, the primary storage form.
2. Kidney. 1-alpha hydroxylase converts 25-OH vitamin D to 1,25-dihydroxy vitamin D (calcitriol), the active hormone, tightly regulated by PTH, calcium and phosphate.

What it does. Its primary role is calcium homeostasis, through four actions:

• Increases intestinal calcium absorption by upregulating calcium-binding proteins in the small intestine
• Provides adequate calcium and phosphate for hydroxyapatite formation, and so for bone mineralisation
• Enhances distal tubular calcium reabsorption
• Suppresses PTH secretion when calcium is adequate

Beyond the skeleton. Vitamin D receptors in skeletal muscle regulate calcium-dependent contraction, which is the basis of the myopathy described below. Vitamin D also modulates innate and adaptive immunity, so deficiency increases infection risk, and it has anti-proliferative effects in many tissues.

The metabolic cascade. Once 25-OH vitamin D falls below 50 nmol/L, the derangements run in sequence:

1. Intestinal calcium absorption falls, its efficiency dropping from 30-40% to 10-15%
2. Mild hypocalcaemia triggers the parathyroid glands
3. Secondary hyperparathyroidism: PTH rises to maintain the serum calcium
4. PTH-mediated bone resorption releases calcium from the skeleton
5. PTH inhibits proximal tubular phosphate reabsorption, and the kidney wastes phosphate
6. Hypophosphataemia impairs mineralisation
7. Osteoid accumulates but cannot mineralise: osteomalacia
8. Skeletal deformities and fractures follow in severe, prolonged deficiency

Same disease, different age. Rickets is the deficiency acting on open, actively growing plates: the growth plate fails to mineralise, growth is stunted and milestones are delayed. Osteomalacia is the same deficiency once the plates have closed; growth is complete and normal, and the failure lies in mineralisation of osteoid.

The myopathy. Vitamin D receptors in skeletal muscle regulate calcium homeostasis within the myocytes, and deficiency impairs calcium-dependent contraction. The weakness is proximal, hip flexors and shoulder abductors more than distal muscles, and biopsy shows type II (fast-twitch) fibre atrophy. It is independent of bone disease, can occur without osteomalacia, and resolves with replacement.

By level. Vitamin D status is classified on the serum 25-OH vitamin D, and treatment intensity escalates with severity.

Reading the thresholds. Below 25 nmol/L deficiency is severe and goes with symptomatic disease; most osteomalacia occurs at these levels. 50 nmol/L is the minimum target for bone health and 75-125 nmol/L is optimal. Where sufficiency begins is disputed between the major bodies, as the Controversies section sets out.

By cause. The causes group by where the pathway fails:

• Inadequate synthesis: the elderly have less 7-dehydrocholesterol in the skin; dark skin at high latitude; an indoor, homebound or institutionalised life; cultural clothing covering the skin; sunscreen overuse.
• Inadequate intake: a vegan diet, or too little fortified food.
• Malabsorption: coeliac disease, Crohn's disease, post-bariatric surgery and pancreatic insufficiency.
• Impaired activation: cholestatic liver disease impairs 25-hydroxylation, the primary activation step; chronic kidney disease impairs 1-alpha hydroxylation, the final one.
• Increased catabolism: anticonvulsants (phenytoin, phenobarbital, carbamazepine) and rifampicin induce hepatic vitamin D metabolism.

Many patients are asymptomatic until a pathological fracture or an incidental biochemical finding brings them to attention.

Examination. The gait is antalgic from pain or waddling from Trendelenburg weakness. Sternal pressure, rib compression and pelvic compression are painful, and chronic cases show leg bowing or kyphosis.

Power and reflexes. Hip flexion (iliopsoas) and knee extension (quadriceps) are reduced to grade 3-4 out of 5, the patient cannot rise from a squat without using the hands, and the deep tendon reflexes are reduced.

Signs of tetany. Look for them when hypocalcaemia is severe:

• Chvostek's sign: facial twitch on tapping the facial nerve
• Trousseau's sign: carpopedal spasm on inflating a blood pressure cuff

General. Pallor reflects anaemia of chronic disease in severe deficiency. In rickets the dentition is poor, with delayed eruption and enamel defects.

25-OH vitamin D. This is the primary screening test, for the reasons in the pearl above; 1,25-dihydroxy vitamin D is not useful for screening. Measure it in any patient with suspected deficiency or bone disease. Preoperative screening before arthroplasty is discussed under Orthopaedic Implications.

Supporting biochemistry. The PTH-driven pattern is what to recognise:

• Calcium low-normal or low, because secondary hyperparathyroidism compensates at first
• Phosphate typically low, from PTH-mediated renal phosphate wasting
• PTH elevated, the secondary hyperparathyroidism itself
• ALP elevated, from osteoblast activity (explained in the pearl below)
• 24-hour urine calcium low, under 2.5 mmol per 24 hours; the calcium-creatinine clearance ratio helps exclude familial hypocalciuric hypercalcaemia

Looking for the cause. Creatinine and eGFR assess for chronic kidney disease, and liver function tests screen for cholestatic disease. Coeliac serology (anti-TTG, anti-endomysial antibodies) is sent if malabsorption is suspected, and inflammatory markers if inflammatory bowel disease is.

Osteomalacia (Adults)Rickets (Children)

Looser zones. Pseudofractures are pathognomonic of osteomalacia: radiolucent bands perpendicular to the cortex, with no periosteal reaction. They are characteristically bilateral and symmetric, which distinguishes them from stress fractures. Common sites are the femoral neck, pubic rami, ribs, scapula and proximal ulna, and the most exam-relevant are the medial femoral neck, pubic rami and lateral scapular border.

View larger

The rest of the film. Generalised osteopenia, cortical thinning and a coarsened trabecular pattern, with pathological fractures at the sites of Looser zones.

Further imaging if needed. A bone scan shows multiple symmetric hot spots at the Looser zones, MRI shows bone marrow oedema at pseudofracture sites, and CT assesses fracture risk and helps plan surgery.

The physis. Changes are most marked at the fastest-growing physes, the distal radius and ulna at the wrist, and the knee. The classic findings:

• Widened growth plates, with metaphyseal widening
• Cupping and fraying of the metaphyses, especially at the wrists, knees and ankles
• Loss of the sharp metaphyseal margin
• Coarse trabecular pattern
• Delayed epiphyseal ossification, and a bone age less than the chronological age
• Bowing: genu varum or genu valgum
• Rachitic rosary: costochondral junction swelling on the chest radiograph

Healing. After replacement, a dense provisional zone of calcification returns across the metaphysis.

DEXA. Bone mineral density is low (T-score less than -2.5 at spine or hip), but DEXA alone cannot distinguish osteomalacia from osteoporosis, so the biochemistry is essential to the diagnosis.

Bone biopsy. Biopsy is the gold standard but is rarely needed in practice, because the diagnosis is typically made on clinical, biochemical and radiographic grounds. It is an iliac crest biopsy with tetracycline double-labelling, processed as undecalcified sections for histomorphometry. The indications:

• Diagnostic uncertainty after clinical, biochemical and radiographic evaluation
• Suspected hypophosphatasia or a rare mineralisation disorder
• Excluding other bone diseases, such as renal osteodystrophy or osteopetrosis

What biopsy shows. In vitamin D deficiency osteomalacia:

• Increased osteoid volume, greater than 15% (normal less than 5%)
• Widened osteoid seams, greater than 12 micrometres thick
• Prolonged mineralisation lag time, greater than 100 days (normal less than 25 days)
• Reduced mineralisation surface, with tetracycline double-labelling showing a delayed mineralisation front

Making the diagnosis. A low 25-OH vitamin D with the supporting biochemical pattern above makes the diagnosis, with a normal or elevated 1,25-dihydroxy vitamin D. Looser zones on radiographs confirm osteomalacia.

Differential diagnosis. Several conditions mimic vitamin D deficiency osteomalacia, especially when the biochemistry is only partly typical. The pattern of calcium, phosphate, ALP, PTH and 25-OH vitamin D usually separates them.

Principles. Check the baseline 25-OH vitamin D first, because the level guides the dosing intensity. Replace with oral cholecalciferol (vitamin D3), preferred as more potent than D2, and add calcium. Oral absorption is adequate unless malabsorption is severe, so IV replacement is not used unless the situation is critical.

Malabsorption. Coeliac disease, Crohn's disease and bariatric surgery need higher doses, 50,000 IU weekly long-term or 3000-6000 IU daily. Check 25-OH vitamin D at 3 months to confirm an adequate rise, and consider IM or IV replacement in the rare patient with severe malabsorption.

Chronic kidney disease. Below an eGFR of 30 mL/min, activated vitamin D (calcitriol) is required, because standard cholecalciferol is ineffective without 1-alpha hydroxylation. The dose is calcitriol 0.25-1 microgram daily, titrated to PTH and calcium, with monitoring for hypercalcaemia and hyperphosphataemia.

Institutionalised elderly. Universal supplementation is recommended, 800-1000 IU daily with calcium 1200 mg daily, and in this group the combination with calcium reduces fracture risk. The Evidence Base below shows how far that finding travels: in unselected, vitamin D-replete adults, supplementation has not prevented fractures.

Treating the cause. Treat the underlying condition alongside replacement:

• Coeliac disease: a strict gluten-free diet restores absorption
• Inflammatory bowel disease: control the inflammation, and use the higher doses above
• Post-bariatric surgery: lifelong high-dose supplementation is mandatory
• Cholestatic liver disease: supplement the fat-soluble vitamins (A, D, E, K)
• Enzyme-inducing anticonvulsants and rifampicin: increase the vitamin D dose, or change to a non-inducing anticonvulsant
• Cholestyramine binds vitamin D: separate the doses by 4 hours
• Orlistat blocks fat absorption: avoid it or increase the dose

Sunlight. Encourage safe sun exposure, 10-15 minutes of midday sun on the arms and legs 2-3 times weekly, and avoid excessive sunscreen so that some UVB penetrates, balanced against the risk of skin cancer. Add the dietary sources above, and supplement universally in high-risk groups: the elderly, dark skin and high latitude.

Fracture healing. Deficiency delays union or causes nonunion, because callus mineralisation is inadequate. There is too little calcium and phosphate to mineralise it, osteoblast function and differentiation are impaired, and angiogenesis is reduced (vitamin D regulates VEGF). Healing bone is mechanically weaker, and union takes 50-100% longer than in vitamin D-replete patients.

The fracture patient. Optimise vitamin D before elective fracture fixation, and replace aggressively after an acute fracture, at 50,000 IU weekly. Monitor union, which may need longer protected weight-bearing, and bone stimulation is worth considering if delayed union persists.

Before arthroplasty. Roughly one-third of arthroplasty patients are deficient preoperatively, and deficiency is markedly more frequent in periprosthetic joint infection. Consider measuring 25-OH vitamin D before elective arthroplasty, especially in high-risk patients, and delay surgery until repleted if deficiency is severe (less than 25 nmol/L). Where deficiency is found, optimise to greater than 50-75 nmol/L before surgery, as many units screen and do; aim for greater than 75 nmol/L, the level optimal before elective arthroplasty.

What deficiency costs the arthroplasty. The problems run from the operating table to the late follow-up:

• Intraoperatively, poor bone quality: soft bone, reduced screw purchase, and a risk of periprosthetic fracture during insertion, especially with press-fit stems
• Infection, with an odds ratio of 2.4, attributed to vitamin D's role in immune function
• Delayed mobilisation, because the proximal myopathy impairs rehabilitation, and a prolonged hospital stay
• Aseptic loosening from impaired osseointegration of uncemented implants
• Periprosthetic fracture with minimal trauma

Reading the infection link. The association is not proof of cause. Separately, the Maier study measured 25-OH vitamin D when the infection presented (see the Evidence Base), and high-quality outcome trials showing that correcting deficiency improves implant outcomes are still lacking.

After arthroplasty. Continue vitamin D and calcium indefinitely. Aggressive physiotherapy overcomes the muscle weakness, and thromboprophylaxis covers the risk of prolonged immobilisation.

Pathological fractures. In osteomalacia the high-risk sites are:

• Femoral neck, often bilateral, at sites of Looser zones
• Proximal femur: subtrochanteric and intertrochanteric
• Pelvis: pubic rami and sacrum
• Ribs, multiple and painful
• Vertebrae: compression fractures

Deficiency also brings progressive skeletal deformity (bowing) and accelerated osteoporosis.

Medical management first. In pathological fractures, optimise medical management first with vitamin D and calcium replacement, and replace aggressively around the operation to accelerate healing.

The bone. Osteomalacic bone is soft and poorly mineralised, so screws have reduced purchase and holding power, and intraoperative fracture is more likely. Fix fractures with caution, spreading the load: longer plates with more screws, locking plates to minimise screw toggle, and cement augmentation for screw purchase, including in proximal femur fractures.

Prophylactic fixation. Looser zones involving greater than 50% of the cortex carry a high fracture risk. Impending fractures (Looser zones greater than 50% of the cortical width, symptomatic) are fixed prophylactically with an intramedullary nail or plate, optimising vitamin D before and after.

Arthroplasty fixation. Press-fit components may fail in poor-quality bone. Cemented fixation is preferred, and should be considered whenever the bone is very osteopenic.

Postoperative care. Continue replacement at 50,000 IU weekly with calcium 1200 mg daily, and extend the protected weight-bearing. Check calcium at 1 week and 1 month and vitamin D at 3 months postoperatively, expect PTH and ALP to normalise, and confirm union on serial radiographs. Long-term care is the lifelong maintenance and monitoring above, addressing the underlying cause if deficiency persists.

Biochemical response. The expected timeline:

• Calcium and phosphate normalise by 4-12 weeks
• PTH decreases by 3-6 months, and may take longer with severe secondary hyperparathyroidism
• Alkaline phosphatase declines by 6-12 months, and may rise at first as bone heals

Clinical response. The expected timeline:

• Bone pain improves by 6-12 weeks
• Muscle weakness reverses by 3-6 months as the proximal myopathy resolves
• Looser zones heal by 6-12 months, with radiographic evidence of mineralisation
• Fracture risk decreases once vitamin D is greater than 50 nmol/L

Poor prognostic factors. The outlook is worse with:

• Severe, prolonged deficiency, which may leave permanent skeletal deformities
• An uncontrolled underlying cause, such as malabsorption or chronic kidney disease
• Non-compliance with supplementation
• Concurrent osteoporosis, which may require additional antiresorptive therapy

Global Epidemiology

• Vitamin D deficiency or insufficiency affects an estimated 1 billion people worldwide
• Highest burden at high latitudes in winter, in darker-skinned populations, and in concealed-dress and institutionalized groups
• Nutritional rickets remains common in parts of South Asia, the Middle East and sub-Saharan Africa, and persists in migrant communities at high latitude

Side-by-Side Guidance

High- vs Limited-Resource Practice

• High-resource settings: ready 25-OH vitamin D assays, fortified foods, and cholecalciferol availability; debate is about screening intensity and targets.
• Limited-resource settings: assays may be unavailable and diagnosis is clinical plus radiographic; emphasis shifts to public-health prevention (food fortification, antenatal and infant supplementation) over individual testing.
• Calcium deficiency (low dietary intake) is a co-driver of rickets in some low-income regions, so calcium as well as vitamin D may be needed.

The exam-relevant debates in vitamin D centre on who to test, what level to aim for, and when supplementation actually helps.

Related pages: Osteomalacia and Rickets are the same disease of defective mineralisation in the mature and growing skeleton respectively, and are what severe deficiency actually produces; Calcium Homeostasis and Metabolic Bone Disease holds the PTH-calcium-phosphate axis that makes sense of every biochemical pattern on this page, with Hyperparathyroidism covering the secondary form that deficiency drives and the primary form that must be distinguished from it; Osteoporosis is the commonest reason a surgeon checks a vitamin D level, and Bisphosphonates is the reason it must be corrected first - an antiresorptive given to a deficient patient risks symptomatic hypocalcaemia and will not work properly; DEXA and Bone Densitometry and Metabolic Bone Imaging cover the imaging that distinguishes low bone mass from unmineralised osteoid, including the Looser zone; Bone Healing and Nonunion Management are where the Brinker card belongs clinically - screen the unexplained nonunion metabolically before operating again; Glucocorticoid-Induced Secondary Osteoporosis is a common coexisting cause of fragility; XLH and Oncogenic Osteomalacia covers the phosphate-wasting mimics that do not respond to plain vitamin D; and Periprosthetic Joint Infection is the association the Maier card reports, where reverse causation has never been excluded.

Cholecalciferol (D3) is generally preferred as the more potent form, yet the Endocrine Society guidance (Holick 2011) records that either vitamin D2 or D3 is acceptable for treating deficiency - an apparent tension worth resolving.

• The two forms. Cholecalciferol (D3) is the form made in skin and found in animal foods; ergocalciferol (D2) is plant/fungal-derived and the traditional high-dose prescription form. Both are 25-hydroxylated in the liver and then activated in the kidney by the same pathway.
• Why D3 is generally preferred. Dose-for-dose, D3 raises and sustains serum 25-OH-D more effectively than D2: D3's 25-hydroxy metabolite binds vitamin D binding protein with higher affinity and is cleared more slowly (longer half-life), so it holds a higher steady-state level. D2 is metabolised and cleared faster, and large intermittent D2 doses can even transiently lower measured 25-OH-D3. This difference matters most for maintenance and for intermittent (weekly / monthly) or bolus regimens.
• When it does not matter. For correcting simple deficiency with frequent (daily or weekly) dosing, either form works, which is why the Endocrine Society accepts D2 or D3. D2 remains useful as a vegetarian/vegan-acceptable prescription high-dose option and where D3 is unavailable.
• The exam answer. Prefer D3 (especially for maintenance and intermittent dosing); accept D2 as an equivalent option for correcting deficiency and for patients who need a non-animal source.

• Why replete first. A vitamin-D-deficient skeleton is in a PTH-driven, calcium-hungry state, leaning on bone resorption to defend the serum calcium. Giving a potent antiresorptive (bisphosphonate or denosumab) switches off that resorption while the gut is still absorbing calcium poorly, and can precipitate severe symptomatic hypocalcaemia - the classic denosumab / zoledronate hypocalcaemia trap. So check and correct 25-OH-D and calcium, and confirm normocalcaemia, before the first antiresorptive dose.
• Do not treat osteomalacia with a bisphosphonate. Antiresorptives treat osteoporosis (too little otherwise-normal bone); osteomalacia is unmineralised osteoid, which a bisphosphonate does not fix and may worsen by further suppressing turnover. Because DEXA cannot separate the two (it reads both as low BMD), a low-BMD patient with the osteomalacic biochemical pattern (low phosphate, high ALP, high PTH, low 25-OH-D, Looser zones) must be repleted and re-assessed, not simply started on an antiresorptive.
• The sequence. Replete vitamin D and calcium, confirm calcium/phosphate/ALP/PTH have normalised and any osteomalacia has healed, then re-measure BMD and start an antiresorptive only if genuine osteoporosis persists.