Osteomalacia

Osteomalacia is a metabolic bone disease of defective mineralisation of newly formed osteoid in mature bone. It is the adult equivalent of rickets, which affects growing bones in children. The hallmark is an accumulation of unmineralised or undermineralised osteoid, and the result is soft, deformable bone with an increased risk of fracture.

Not osteoporosis. Osteoporosis is a loss of bone mass. Osteomalacia has normal or increased osteoid, with inadequate calcium and phosphate deposited in it.

Who is deficient. Between 30 and 50% of institutionalised elderly people have vitamin D deficiency (less than 50 nmol/L), against 10-15% of the community-dwelling elderly. Without supplementation, 25-40% of patients develop deficiency after bariatric surgery, and dark-skinned populations living at high latitudes carry a 5-10 times higher risk.

Who gets it. Women outnumber men 3:1, and postmenopausal women are at highest risk. Risk rises with age, through reduced sunlight exposure and decreased skin synthesis, and prevalence is higher at latitudes greater than 35 degrees, where UVB exposure is reduced.

What mineralisation needs. Normal bone mineralisation requires adequate calcium, phosphate and alkaline phosphatase. Vitamin D is essential for intestinal calcium absorption and renal phosphate reabsorption, so a deficiency of vitamin D or of phosphate sets off a sequence:

1. Reduced calcium and phosphate availability
2. Inadequate hydroxyapatite crystal formation in osteoid
3. Accumulation of unmineralised osteoid (increased osteoid volume)
4. Secondary hyperparathyroidism, a compensatory response to hypocalcaemia
5. Further phosphate wasting, as PTH drives renal phosphate loss
6. Progressive bone softening and deformity

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The bone that results. Osteoid seams widen and the mineralisation lag time lengthens; the histomorphometric numbers are set out in their own section below. Bone stiffness and mechanical strength fall, and the trabeculae thin while their connectivity is preserved.

What the patient feels. Pathological fractures follow minimal trauma, bone pain comes from periosteal stress and microfractures, vitamin D deficiency produces a proximal myopathy, and the soft bone bows and compresses into skeletal deformity.

FGF23. FGF23 (fibroblast growth factor 23) causes renal phosphate wasting and inhibits 1-alpha hydroxylation of vitamin D. Small mesenchymal tumours, often benign, can secrete it, and the result is tumour-induced (oncogenic) osteomalacia.

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Causes. They group by what fails:

• Vitamin D deficiency - dietary lack; inadequate sunlight (elderly, institutionalised, cultural clothing, high latitude); vegan diet without supplementation
• Malabsorption - coeliac disease, Crohn's disease, post-gastrectomy, small bowel disease, cholestatic liver disease
• Impaired vitamin D hydroxylation - severe renal or liver disease (1-alpha or 25-hydroxylation)
• Anticonvulsants - phenytoin and phenobarbital induce hepatic vitamin D metabolism
• Phosphate loss - renal phosphate wasting (Fanconi syndrome), tumour-induced (FGF23)
• Tubular defects - renal tubular acidosis, chronic kidney disease
• Mineralisation defects - hypophosphatasia, medications

The clinical triad is bone pain, proximal myopathy and fractures.

Bone pain. The pain is diffuse and worse with weight-bearing and pressure. The bones are tender to palpation over the sternum, ribs, pelvis and long bones, and pain can be provoked by sternal pressure, rib compression and pelvic compression.

Fractures and deformity. Pathological fractures follow minimal trauma, in weight-bearing bones. The deformities are leg bowing (varus or valgus), spinal kyphosis and vertebral compression.

Weakness. The gait is antalgic or waddling, from bone pain and proximal myopathy together, and the patient has difficulty rising. Hip flexion (iliopsoas) and knee extension (quadriceps) are weak, with power of grade 3-4 out of 5 in the hip flexors and shoulder abductors. Myalgias (muscle pain and cramping), fatigue and general malaise sit alongside it.

Tetany. Severe hypocalcaemia brings tetany, with Chvostek's sign (facial twitch) and Trousseau's sign (carpopedal spasm).

Vitamin D. Skeletal muscle expresses the vitamin D receptor, and calcitriol influences myocyte calcium handling and the maintenance of fast-twitch type II fibres. Deficiency produces selective type II fibre atrophy on muscle histology.

Phosphate. Phosphate is required for ATP generation and for the phosphocreatine energy shuttle. Low serum phosphate impairs muscle contractility and energy supply, contributing directly to weakness and fatigue, and the two deficiencies act on muscle together.

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What you find. The weakness is symmetrical and proximal, the pelvic girdle affected more than the shoulder girdle, with a myopathic (waddling) gait, difficulty rising from a chair or climbing stairs, and a positive Gowers manoeuvre. It is often painful and accompanied by bone tenderness, a clue that it is metabolic rather than a pure myopathy. Deep tendon reflexes are preserved, which helps exclude a primary neuropathy.

Tests. EMG is often normal or shows non-specific myopathic units, without the fibrillations of active myositis. The biochemical panel, low vitamin D or phosphate with a high alkaline phosphatase, points to the true cause.

Recovery. The myopathy is reversible with correction of the underlying deficiency. Muscle power typically begins to improve within a few weeks and largely recovers over 3-6 months of vitamin D (and, where relevant, phosphate) replacement, often before Looser zones heal radiographically. Persistent weakness after adequate replacement should prompt a search for a second, unrelated neuromuscular cause.

Vitamin D thresholds. The 25-OH vitamin D bands used on this page are below; guideline bodies draw the lines differently, as the Controversies and Guidelines sections set out.

• Severe deficiency - less than 25 nmol/L (less than 10 ng/mL)
• Deficiency - 25-50 nmol/L (10-20 ng/mL)
• Insufficiency - 50-75 nmol/L (20-30 ng/mL)
• Optimal for bone health - 75-125 nmol/L (30-50 ng/mL)

Further tests. Beyond the core panel:

• Urinary calcium - low (less than 2.5 mmol per 24 hours)
• Urinary phosphate - elevated in renal phosphate wasting
• FGF23 - elevated in tumour-induced osteomalacia, where the pattern is hypophosphataemia, an elevated FGF23 and a low 1,25-OH vitamin D
• Renal function - for chronic kidney disease (impaired 1-alpha hydroxylation)
• Liver function - for cholestatic disease (impaired vitamin D absorption)

When to biopsy. Bone biopsy is the gold standard. Its indications:

• Diagnostic uncertainty after clinical, biochemical and radiographic evaluation
• Suspected hypophosphatasia or a rare mineralisation disorder
• Pre-treatment assessment in oncogenic osteomalacia

How double-labelling works. Tetracyclines chelate calcium and fluoresce, so they deposit as a bright band wherever mineralisation is active at the time of dosing. Two short courses are given before the undecalcified transiliac biopsy, separated by a label-free interval. A common schedule is a short course, roughly a fortnight off, then a second short course, with the biopsy a few days later.

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What the labels measure. Two quantities come from them:

• Mineral apposition rate (MAR) - the distance between the two labels divided by the number of days between them, in micrometres per day (normal roughly 0.6 to 1.0)
• Mineralisation lag time (MLT) - the time osteoid waits before it mineralises, derived from osteoid seam thickness relative to the apposition rate (normal under roughly 20 to 25 days; osteomalacia greater than 100 days)

The osteomalacic biopsy. Osteoid volume is increased (greater than 15% against a normal of less than 5%), osteoid seams are widened (greater than 12 micrometres), and tetracycline labelling shows a delayed mineralisation front. In severe osteomalacia mineralisation is so impaired that there may be only a single, diffuse ("smudgy") label or no uptake at all, itself a strong pointer to the diagnosis.

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Osteoid alone is not enough. The diagnosis needs both:

• Increased osteoid - raised osteoid volume, thickness and surface
• Defective mineralisation - a prolonged MLT or reduced apposition on tetracycline labelling

Increased osteoid without a prolonged lag time is seen in high-turnover states (hyperparathyroidism, hyperthyroidism, Paget disease), where the osteoid simply reflects fast formation, not a mineralisation block. It is the prolonged lag time that separates true osteomalacia from these mimics.

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Why the distinction matters. Osteomalacia does not respond to bisphosphonates. Unlike osteoporosis, it needs vitamin D replacement.

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Where they break. The high-risk sites for pathological fracture:

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

Principles. The medical treatment comes first:

1. Optimise medical management first - vitamin D and calcium replacement
2. Prophylactic fixation for impending fractures (Looser zones greater than 50% cortical width, symptomatic); the Controversies section below explains how soft that threshold is
3. Fracture fixation with caution, using the techniques in the alert below
4. Longer immobilisation than for normal fractures, because healing is delayed

Before arthroplasty. Screen all arthroplasty candidates for vitamin D deficiency, optimise vitamin D to greater than 75 nmol/L before elective surgery, and correct calcium and phosphate abnormalities (see Controversies for the strength of the evidence behind universal screening).

At operation. There is a risk of periprosthetic fracture during insertion, especially with press-fit stems, so reaming and broaching must be careful. Poor bone quality may favour cemented fixation.

After arthroplasty. Osseointegration of uncemented implants is delayed, aseptic loosening is a risk if vitamin D is not repleted, and periprosthetic fracture can follow minimal trauma. Vitamin D and calcium continue indefinitely.

Expected response to treatment. Muscle recovery is covered with the myopathy above; the rest of the timetable:

• Calcium and phosphate normalise by 4-12 weeks
• PTH decreases by 3-6 months, and may take longer if severe
• Alkaline phosphatase declines by 6-12 months, and may initially rise as bone heals
• Bone pain improves by 6-12 weeks
• Looser zones heal by 6-12 months (radiographic evidence of mineralisation)
• Fracture risk decreases once vitamin D is greater than 50 nmol/L

Poor prognostic factors. Watch for:

• Severe, prolonged deficiency - may leave permanent skeletal deformities
• Uncontrolled underlying cause (malabsorption, chronic kidney disease)
• Non-compliance with supplementation
• Oncogenic osteomalacia with an unresectable tumour

Global Epidemiology

• Vitamin D deficiency is one of the most prevalent micronutrient deficiencies worldwide, but its consequences vary by latitude, skin pigmentation, diet, sun exposure and food-fortification policy.
• Nutritional osteomalacia remains common in South Asia, the Middle East and North Africa, driven by limited effective UVB exposure (concealing dress, high latitude in winter, air pollution) and low dietary calcium/vitamin D.
• In high-income countries, frank osteomalacia is now mostly seen in the institutionalized elderly, malabsorption (coeliac disease, IBD, post-bariatric surgery), chronic kidney/liver disease, and dark-skinned migrants at higher latitudes.

Side-by-Side Guideline Comparison

• Key controversy: the Endocrine Society favours a higher individual target (above 75 nmol/L) for at-risk patients, whereas the IOM and several national bodies regard about 50 nmol/L as adequate for the general population. For symptomatic/biopsy-proven osteomalacia all bodies agree on therapeutic replacement plus calcium.

Registry & Outcome Notes

• There is no dedicated osteomalacia registry; relevant arthroplasty registries (NJR, AJRR, AOANJRR, Swedish/Norwegian) track revision and periprosthetic fracture, where poor bone quality and metabolic bone disease are recognised contributors to early failure and periprosthetic fracture.

High- vs Limited-Resource Practice

• High-resource: routine 25-OH vitamin D, PTH, FGF23 assays; functional imaging (68Ga-DOTATATE PET/CT, whole-body MRI) for TIO; access to burosumab and calcitriol.
• Limited-resource: diagnosis often clinical/radiographic and biochemical (calcium, phosphate, ALP); calcium plus vitamin D remains the cost-effective cornerstone and the global consensus stresses combined calcium-vitamin D because dietary calcium deficiency alone can cause osteomalacia/rickets even with adequate vitamin D.

Oncogenic Osteomalacia

• Rare FGF23-secreting mesenchymal tumours require functional then anatomical imaging (68Ga-DOTATATE PET/CT, whole-body MRI, selective venous FGF23 sampling) for localisation. Surgical excision is curative; burosumab is the option for unresectable/unlocalised disease.

Related pages: Vitamin D Deficiency for the upstream biochemical state, most of which never reaches a mineralization defect; Rickets for the same disease before physeal closure, where the growth plate rather than the cortex takes the deformity; XLH and Oncogenic Osteomalacia for the FGF23-driven hypophosphataemic forms summarised here; Renal Osteodystrophy for the mixed lesion in which Looser zones also appear and vitamin D replacement alone is wrong; Hypophosphatasia for the mineralization defect with a LOW alkaline phosphatase, which inverts this page's key biochemical signature; Osteoporosis for the low-bone-mass disease this is most often mistaken for, and where bisphosphonates given to an undiagnosed osteomalacic patient will worsen the mineralization defect; Hyperparathyroidism and Paget's Disease of Bone for the other causes of a raised alkaline phosphatase; Medial Tibial Stress Syndrome for the athletic mimic in which bilateral tibial pseudofractures occur with high, not low, bone density; and Periprosthetic Joint Infection for the outcome the arthroplasty evidence on this page is reaching for.

The target 25-OH vitamin D. Disagreement persists between bodies that target above 75 nmol/L for at-risk individuals (Endocrine Society) and those satisfied with about 50 nmol/L for the population (IOM, several national bodies). No high-quality trial defines the ideal target specifically for osteomalacia healing.

Calcium or vitamin D. The 2016 global consensus highlighted that dietary calcium deficiency alone can cause rickets or osteomalacia even with adequate vitamin D, and that calcium-only or vitamin D-only therapy may be inadequate. The relative contribution varies by region and diet.

The threshold for prophylactic fixation. The often-quoted "fix Looser zones over 50% of cortical width" rule is expert convention extrapolated from impending-fracture (Mirels-type) reasoning, not a validated osteomalacia-specific threshold. Decisions remain individualised, by site, symptoms and response to medical therapy.

Cemented or uncemented in soft bone. Cemented fixation is widely preferred for poor bone quality, but high-quality comparative data specifically in osteomalacic bone are lacking. Recommendations are extrapolated from osteoporotic and elderly cohorts.

Where burosumab sits. Burosumab improves phosphate, histology and fractures in TIO, but the data come from small open-label cohorts without comparators, and access and cost vary widely. Surgical cure remains first-line when the tumour is localisable.

Routine pre-arthroplasty screening. Associations between low vitamin D and PJI or poorer outcomes are observational. No RCT confirms that universal preoperative screening-and-treat improves hard arthroplasty outcomes, though correction is low-risk and biologically plausible.