Osteomalacia

• Osteomalacia is a metabolic bone disease defined by defective mineralisation of mature osteoid after epiphyseal plate closure.
• This defective mineralisation leads to soft, weak bones due to the accumulation of unmineralised bone matrix (osteoid).
• It is a distinct pathological entity from osteoporosis, which involves normal mineralisation of reduced bone mass.

Vitamin D Deficiency and Metabolic Disruption

• The most common cause of osteomalacia globally is vitamin D deficiency, typically due to a combination of inadequate dietary intake and insufficient ultraviolet B (UV-B) light exposure.
• Factors reducing cutaneous synthesis of vitamin D include dark skin pigmentation, the use of sunscreen, wearing skin-covering clothing, obesity (due to adipose sequestration), and advanced age.
• Nutritional causes include diets low in vitamin D-rich foods or fortified products. Even with adequate sun exposure, deficiencies may occur due to insufficient dietary intake.
• Malabsorptive disorders such as coeliac disease, Crohn disease, cholestasis, cystic fibrosis, and post-surgical states (e.g. gastrectomy, gastric bypass) can impair absorption of fat-soluble vitamins, including vitamin D.
• Vitamin D metabolism can also be disrupted by chronic kidney disease (loss of renal 1-alpha-hydroxylase), liver disease (impaired 25-hydroxylation), nephrotic syndrome (urinary loss of vitamin D-binding protein), and pregnancy (increased metabolic demand and reduced calcidiol).
  
  

Calcium Deficiency

• Inadequate calcium intake may contribute independently or in combination with vitamin D deficiency.
• Populations with limited dairy consumption or food insecurity, and individuals with lactose intolerance or strict vegan diets are at increased risk.
• Childhood calcium deficiency has been shown to impair skeletal development and mineralisation, a risk that may carry over into adulthood.
  
  

Phosphate Depletion

• Hypophosphataemia is a key contributor to defective bone mineralisation and may arise from dietary deficiency, renal phosphate wasting, or hormonal disturbances.
• Causes include primary renal phosphate-wasting syndromes such as:
  • X-linked hypophosphataemic rickets (PHEX gene variants),
  • Autosomal dominant hypophosphataemia (FGF23 variants),
  • Autosomal recessive forms,
  • Tumour-induced osteomalacia (mesenchymal tumours secreting FGF23),
  • Fanconi syndrome (e.g. due to myeloma, Sjögren’s syndrome, heavy metal exposure, or medications).
• Secondary hyperparathyroidism from vitamin D deficiency can also promote phosphate loss through increased urinary excretion.
  
  

Renal Tubular Acidosis (RTA)

• Proximal (type 2) RTA and Fanconi syndrome reduce renal reabsorption of phosphate and bicarbonate, leading to chronic acidosis and impaired bone mineralisation.
• Metabolic acidosis promotes urinary calcium loss and inhibits bone matrix calcification directly.
• Distal (type 1) RTA may also be associated with osteomalacia, though this link is less established.
  
  

Chronic Kidney Disease (CKD)

• In CKD, impaired activation of vitamin D, phosphate retention, and chronic acidosis contribute to mineral and bone disorder (CKD-MBD), a recognised cause of osteomalacia.
• Though historically aluminium exposure via phosphate binders was a major contributor, safer alternatives have reduced this risk.
  
  

Drug-Induced Osteomalacia

• Certain medications disrupt vitamin D metabolism:
  • Antiepileptics (phenobarbital, phenytoin, carbamazepine) increase hepatic catabolism of vitamin D.
  • Antifungals (ketoconazole) and some antibiotics (isoniazid, rifampicin) impair vitamin D hydroxylation.
  • Corticosteroids may enhance vitamin D inactivation through induction of 24-hydroxylase.
    
    

Mineralisation Inhibitors

• Substances that directly inhibit bone mineralisation include:
  • Etidronate, a first-generation bisphosphonate, due to its structural similarity to pyrophosphate.
  • Aluminium, which interferes with phosphate absorption and bone matrix mineralisation.
  • Fluoride, in excessive amounts (e.g. from tea, toothpaste, or endemic sources), can impair mineralisation, particularly in combination with poor nutrition.
    
    

Hypophosphatasia

• A rare genetic disorder caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene.
• Leads to accumulation of pyrophosphate, a natural inhibitor of mineralisation.
• Clinical severity varies from perinatal lethality to adult-onset osteomalacia or isolated dental manifestations.
• Laboratory findings include low serum alkaline phosphatase and elevated serum or urinary phosphoethanolamine.
  
  

Disorders of Bone Matrix Formation

• Axial osteomalacia is a rare condition typically presenting with axial skeletal pain, radiographic trabecular coarsening, and histological evidence of osteoid accumulation without adequate mineralisation.
• Fibrogenesis imperfecta ossium is a progressive disorder affecting the entire skeleton, marked by histological absence of collagen fibrils and sometimes associated with monoclonal gammopathy.
  
  
  
  

Impaired Mineralisation of Osteoid Matrix

• Osteomalacia results from defective mineralisation of newly formed osteoid at bone formation sites.
• Mineralisation requires the coordinated presence of three key conditions:
  • Normal extracellular concentrations of calcium and phosphate
  • A physiologically neutral pH at the mineralisation front
  • Sufficient alkaline phosphatase activity to hydrolyse pyrophosphate (a natural inhibitor of mineral deposition).
• Deficiency or disruption of any of these factors can impair hydroxyapatite formation, resulting in accumulation of unmineralised osteoid and mechanically weak bone tissue.
  
  

Vitamin D Metabolism and Its Central Role

• Vitamin D is essential for maintaining calcium and phosphate homeostasis. It can be acquired via dietary intake or endogenously synthesised in the skin under UV-B radiation.
• The precursor, 7-dehydrocholesterol, is converted to cholecalciferol (vitamin D3) in the skin, then hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D), also known as calcidiol.
• Calcidiol is further hydroxylated in the kidneys by 1-alpha-hydroxylase to yield 1,25-dihydroxyvitamin D (calcitriol), the biologically active form.
• Liver dysfunction impairs 25-hydroxylation, while renal disease reduces 1-alpha-hydroxylation, both contributing to reduced calcitriol levels.
  
  

Consequences of Calcitriol Deficiency

• Calcitriol facilitates active calcium absorption from the intestines.
• Deficiency results in decreased serum ionised calcium, stimulating parathyroid hormone (PTH) secretion (secondary hyperparathyroidism).
• PTH attempts to maintain calcium levels by increasing renal calcium reabsorption and mobilising calcium from bone, but simultaneously induces renal phosphate wasting.
• The combined effect is persistent hypophosphataemia, further undermining bone mineralisation.
• In parallel, chronic hypocalcaemia promotes osteoclastic activity, leading to increased bone resorption and osteopenia.
  
  

Disrupted Feedback Mechanisms in Renal and Endocrine Pathology

• The synthesis of calcitriol is tightly regulated by feedback loops:
  • Stimulated by: PTH and low serum phosphate
  • Inhibited by: Fibroblast growth factor 23 (FGF23) from osteocytes, and high serum levels of calcitriol itself.
• FGF23 downregulates 1-alpha-hydroxylase and inhibits renal phosphate reabsorption, which is particularly relevant in tumour-induced osteomalacia and genetic phosphate-wasting syndromes.
  
  

Impact of Chronic Kidney Disease (CKD)

• CKD impairs 1-alpha-hydroxylase activity, leading to reduced calcitriol production.
• Simultaneously, phosphate retention due to decreased renal clearance causes hyperphosphataemia, which suppresses calcitriol synthesis and exacerbates hypocalcaemia.
• The resultant secondary hyperparathyroidism accelerates bone turnover, resorption, and mineral loss.
  
  

Pharmacological Interference with Vitamin D Pathways

• Certain drugs can increase the metabolic breakdown of vitamin D, decreasing the availability of both 25[OH]D and 1,25[OH]2D:
  • Induction of cytochrome P450 enzymes by antiepileptics (e.g., phenytoin, phenobarbital), rifampicin, and theophylline
  • Inhibition of hydroxylation enzymes by antifungals like ketoconazole
  • Increased 24-hydroxylase activity by chronic glucocorticoid exposure, leading to increased conversion of calcitriol to inactive 24,25-dihydroxyvitamin D.
    
    

Resultant Biochemical Profile and Structural Consequences

• The net outcome of these metabolic disruptions includes:
  • Low serum calcium and phosphate
  • Elevated alkaline phosphatase (from increased osteoblastic activity)
  • Elevated PTH (secondary hyperparathyroidism)
• Histologically, bone biopsies show widened unmineralised osteoid seams and decreased tetracycline labelling, confirming delayed mineral apposition.
  
  
  
  

Global Prevalence and Distribution

• Vitamin D deficiency is the predominant cause of osteomalacia worldwide. More than 40% of the adult population in the United States, Europe, and East Asia exhibit vitamin D deficiency, with many individuals experiencing subclinical or overt manifestations of bone demineralisation.
• Postmortem studies have shown histological evidence of osteomalacia in up to 25% of European adults, suggesting underdiagnosis during life.
• Despite food fortification strategies in many high-income nations, cases continue to be reported, especially among individuals with poor dietary intake or limited sun exposure.
  
  

Geographic and Cultural Factors

• In developing regions such as Tibet and Mongolia, clinical rickets—closely related pathophysiologically to osteomalacia—is reported in up to 60% of infants due to vitamin D deficiency.
• In the Middle East, high rates of osteomalacia have been reported among Muslim women and their children, largely due to cultural practices involving extensive clothing coverage, which limits sunlight exposure and cutaneous synthesis of vitamin D.
• Fortification efforts have reduced the incidence of vitamin D deficiency in Western countries, but osteomalacia still occurs in individuals consuming unfortified foods, particularly those who are housebound or live in northern latitudes.
  
  
  

Emerging Trends in High-Income Countries

• Paradoxically, nutritional osteomalacia is increasingly reported in high-income countries. Hospitalisation rates for rickets and osteomalacia have risen in recent decades, particularly among immigrant and ethnic minority populations.
• Contributing factors include dark skin pigmentation (which reduces UVB absorption), dietary restrictions, indoor lifestyles, and the use of sunscreen.
• Vitamin D-related bone disease also persists in populations with low socioeconomic status and restricted healthcare access.
  
  

High-Risk Populations

• Individuals most at risk include:
  • Older adults, especially those who are institutionalised or homebound
  • Patients with malabsorptive disorders (e.g. coeliac disease, Crohn disease, post-bariatric surgery)
  • People with chronic kidney or liver disease impairing vitamin D metabolism
  • Those with hereditary forms of vitamin D resistance or phosphate-wasting syndromes
  • Populations with full-body clothing traditions or photosensitive skin conditions
• Inherited phosphate-wasting disorders (e.g. X-linked or autosomal dominant hypophosphataemic rickets) often manifest in childhood but may continue into or re-emerge in adulthood.
• Acquired causes such as tumour-induced osteomalacia or drug-induced Fanconi syndrome are rare but important contributors in adults.

Diagnostic and Public Health Implications

• The true global burden of osteomalacia is likely underestimated due to subclinical disease and non-specific presentations.
• Increasing recognition of risk factors should guide public health strategies, including:
  • Expanded vitamin D supplementation programmes
  • Dietary fortification policies tailored to at-risk groups
  • Awareness campaigns targeting clinicians to consider osteomalacia in differential diagnosis for bone pain and muscle weakness, especially in vulnerable populations.
    
    
    
    

Overview and Symptom Onset

• Osteomalacia often presents insidiously, with early stages being asymptomatic or manifesting vague complaints.
• As the disease progresses, patients may experience multiple musculoskeletal symptoms that are non-specific and easily mistaken for other rheumatological or systemic disorders.
• A detailed history is essential, particularly in populations at risk, to prompt consideration of osteomalacia and avoid delays in diagnosis.
  
  

Key Symptoms to Elicit from the History

• Dull, aching pain often localised to weight-bearing areas such as the pelvis, hips, lumbar spine, and lower limbs.
• Pain may be exacerbated by activity or ambulation and can be associated with localised tenderness.
• Unlike osteoporosis, osteomalacia typically produces symptomatic bone pain even in the absence of fractures.
  
  

• Predominantly proximal muscle weakness, often affecting the pelvic girdle and thighs.
• Patients may describe difficulty climbing stairs, rising from a seated position, or walking long distances.
• A waddling gait may be reported in more advanced cases and is associated with both vitamin D deficiency and phosphate metabolism disorders.
  
  

• History may reveal fractures occurring with minimal or no trauma, particularly affecting ribs, vertebrae, long bones, or the pelvis.
• In hypophosphatasia, atypical fracture patterns—especially slow-healing metatarsal or femoral shaft fractures—should raise suspicion.
• Delayed or poor fracture healing may also be noted.
  
  

• Patients may report reduced mobility, falls, or increased fatigue during physical tasks.
• Long-standing proximal myopathy may lead to altered gait or inability to ambulate independently.
  
  

• In cases of prolonged or severe osteomalacia, patients may report gradual changes in posture or stature due to spinal curvature, pelvic tilt, or thoracic deformities.
• These deformities develop over time and are rarely the presenting feature.
  
  

• Depending on the underlying cause, history may reveal cramping, paresthesias (tingling or numbness), and episodes suggestive of tetany.
• In some cases, patients may recall previous positive Trousseau or Chvostek signs or episodes of seizures.

• In those with hypophosphatasia or hereditary forms of osteomalacia, early loss of deciduous or adult teeth may be part of the patient history.
• This may be associated with a family history of similar dental or skeletal issues.
  
  

Supporting History to Clarify Aetiology

• Diet low in vitamin D and calcium-rich foods (e.g. dairy, fortified cereals)
• History of restrictive diets, food intolerances, or eating disorders
• Long-term vegetarian or vegan diets without supplementation
  
  

• Limited outdoor activity, especially in colder months or in individuals living at high latitudes
• Use of full-body covering clothing for cultural or dermatological reasons
• Regular sunscreen use or skin conditions necessitating sun avoidance
  
  

• History of gastrointestinal surgery (e.g. gastrectomy, bariatric surgery)
• Known malabsorptive conditions (e.g. coeliac disease, Crohn disease, chronic pancreatitis)
• Renal or liver disease
• Chronic use of anticonvulsants, corticosteroids, or other medications affecting vitamin D metabolism

• Relatives with rickets, frequent fractures, early tooth loss, or bone deformities
• X-linked or autosomal recessive conditions affecting vitamin D or phosphate handling
  
  

Prevalence of Symptoms 

• Bone pain and muscle weakness: 94%
• Localised bone tenderness: 88%
• Fractures: 76%
• Difficulty walking or waddling gait: 24%
• Muscle cramps, Chvostek’s sign, paresthesia, or immobility: 6–12%

General Considerations

• Physical findings in osteomalacia are often non-specific and may be absent in early stages.
• Examination features typically emerge once the disease has progressed and are often subtle or attributed to ageing, inactivity, or other musculoskeletal conditions.
• Findings reflect the underlying disturbances in mineralisation and bone turnover, and may vary depending on the duration of disease and underlying aetiology (e.g. vitamin D deficiency, phosphate-wasting disorders, hypophosphatasia).
  
  

Key Examination Findings

• Most pronounced in the pelvic girdle and shoulders.
• Weakness is symmetrical and may be associated with discomfort or hypotonia.
• Can manifest as difficulty rising from a seated position, climbing stairs, or lifting arms overhead.
• May progress to noticeable muscle wasting in chronic cases.
  
  

• A characteristic waddling gait may be observed, often secondary to proximal myopathy.
• This is especially prominent in vitamin D deficiency and phosphate metabolism disorders.
• In severe cases, patients may require assistance or experience falls due to poor muscular control and weakness.

• Diffuse tenderness over weight-bearing bones such as the tibiae, pelvis, and lumbar spine.
• Localised pain on palpation of suspected fracture sites is common, especially in the ribs, long bones, or pelvis.
• Tenderness often precedes radiological findings.
  
  

• Present only in advanced or longstanding disease.
• May include thoracic kyphosis, pelvic asymmetry, and bowed legs (genu varum), especially in adults with uncorrected disease from childhood.
• Spinal curvature abnormalities can also develop due to vertebral fractures and soft bone support.
  
  

• Physical signs may include pain or swelling at sites of incomplete fractures.
• Commonly affected sites include the ribs, pelvis, femoral necks, and vertebrae.
• Unlike traumatic fractures, these may be bilateral and symmetrical with minimal trauma.
  
  

• In patients with concurrent hypocalcaemia, features of neuromuscular irritability may be seen, including:
  • Positive Chvostek’s sign (facial twitching with tapping over facial nerve)
  • Positive Trousseau’s sign (carpal spasm with blood pressure cuff inflation)
  • Muscle spasms and cramps
  • Paresthesias (tingling and numbness of extremities or face)
  • In severe cases, hypocalcaemic tetany or seizures may occur.

• Premature loss of deciduous or adult teeth.
• Associated with abnormal mineralisation of cementum.
• May coexist with chondrocalcinosis or pseudogout features on joint examination.

Initial Laboratory Assessment

• Serum calcium
  • Low or low-normal in vitamin D deficiency or secondary hyperparathyroidism.

• Serum phosphate
  • Commonly low in phosphate-wasting disorders and in secondary hyperparathyroidism.

• Serum alkaline phosphatase (ALP)
  • Elevated in most patients due to increased osteoblastic activity.
  • Characteristically low in hypophosphatasia.

• 25-hydroxyvitamin D [25(OH)D]
  • Best marker of vitamin D status.
  • Severely reduced (<25 nmol/L or <10 ng/mL) in nutritional osteomalacia.

• Parathyroid hormone (PTH)
  • Typically elevated in response to hypocalcaemia or phosphate imbalance.

• 24-hour urinary calcium
  • Low in vitamin D deficiency-related osteomalacia.

• Renal function tests (urea and creatinine)
  • May be elevated in chronic kidney disease (CKD)–related osteomalacia.
    
    

Radiological Investigations

• Plain radiographs (X-rays)
  • Looser zones (pseudofractures): radiolucent bands perpendicular to bone cortex, often bilateral and symmetrical.
  • Codfish vertebrae: biconcave appearance of vertebral bodies.
  • Bowing of long bones, cortical thinning, and coarse trabeculae in advanced disease.
  • Subperiosteal bone resorption in cases with longstanding secondary hyperparathyroidism.

• Dual-energy X-ray absorptiometry (DXA)
  • Shows reduced bone mineral density.
  • Cannot distinguish osteomalacia from osteoporosis.
    
    
• Skeletal scintigraphy
  • Increased radiotracer uptake at sites of pseudofractures or high turnover.
  • Useful when X-rays are inconclusive or in suspected tumour-induced osteomalacia.
    
    

Further Biochemical Investigations

• 24-hour urinary phosphate
  • Elevated in Fanconi syndrome and tumour-induced osteomalacia.
    
    
• Serum fibroblast growth factor 23 (FGF23)
  • Elevated in FGF23-mediated phosphate-wasting syndromes.
  • Inappropriately normal levels with low phosphate suggest FGF23 excess.
    
    
• Bone-specific alkaline phosphatase
  • More specific indicator of bone turnover.
    
    
    

Bone Biopsy (Gold Standard, Rarely Performed)

• Indications
  • Diagnostic uncertainty despite laboratory and imaging findings.
  • Suspected mixed bone disease (e.g., CKD-mineral bone disorder).
  • Suspicion of rare matrix disorders such as fibrogenesis imperfecta.
    
    
• Histological Features
  • Increased osteoid volume.
  • Widened unmineralised osteoid seams.
  • Prolonged mineralisation lag time.
  • Absence of tetracycline uptake in osteoid.
    
    

Diagnostic Frameworks

• Hypophosphataemia or hypocalcaemia.
• Elevated ALP.
• Bone pain or proximal muscle weakness.
• BMD <80% of young adult mean.
• Radiographic pseudofractures or multiple hotspots on scintigraphy.
  
  

• Elevated PTH.
• Elevated ALP.
• Low urinary calcium.
• Low dietary calcium or 25(OH)D <30 nmol/L.
  
  
  

Differential Diagnostic Clues

• Osteoporosis
  • Normal labs, no bone pain or pseudofractures.
    
    
• Paget disease
  • Localised bone pain, very high ALP, typical radiographic features.
    
    
• Hypophosphatasia
  • Low ALP, normal calcium and phosphate, elevated PLP or phosphoethanolamine.
    
    
• CKD-related osteomalacia
  • Mixed lab picture with high PTH, low 1,25(OH)₂D, phosphate retention.
    
    
• Tumour-induced osteomalacia
  • Low phosphate, high FGF23, suppressed 1,25(OH)₂D.

• Fanconi syndrome
  • Hypophosphataemia with glucosuria, aminoaciduria, and metabolic acidosis.
    
    

Osteoporosis

• Clinical clues: Common in postmenopausal women, older adults, and patients on chronic glucocorticoid therapy.
• Symptoms: Typically painless until a fracture occurs. In contrast, osteomalacia presents with bone pain and muscular weakness even in the absence of fracture.
• Biochemistry: Normal serum calcium, phosphate, ALP, and PTH. Vitamin D may be mildly low, but not severely reduced.
• Imaging: Both conditions show low BMD on DXA. However, Looser zones (pseudofractures) and coarse trabeculae on radiographs are specific to osteomalacia.
• Other clues: Urinary calcium is often normal in osteoporosis but reduced in osteomalacia.
• Importance: Misdiagnosis can be harmful—bisphosphonates, used for osteoporosis, may worsen osteomalacia and cause hypocalcaemia.

Paget Disease of Bone

• Clinical clues: Often asymptomatic. If symptomatic, patients present with localised bone pain and deformities.
• Biochemistry: Markedly elevated ALP; calcium and phosphate usually normal.
• Imaging: Shows cortical thickening, bone expansion, coarse trabeculae, and mixed radiolucent and sclerotic areas.
• Differentiation: Looser zones and generalised tenderness suggest osteomalacia. Paget's disease tends to be localised and deforming.
  
  

Multiple Myeloma

• Clinical clues: Presents with fatigue, weight loss, diffuse bone pain, and frequent fractures.
• Biochemistry: May include anaemia, hypercalcaemia, and renal impairment. ALP is usually normal.
• Imaging: Classic findings include lytic bone lesions and diffuse osteopenia.
• Overlap: Can lead to Fanconi syndrome, which results in renal phosphate wasting and osteomalacia.
• Distinction: Osteomalacia typically shows normal kidney function unless due to underlying CKD or drug toxicity.
  
  

Primary Hyperparathyroidism

• Clinical clues: May be asymptomatic or present with bone pain, kidney stones, or abdominal symptoms.
• Biochemistry: Elevated PTH and calcium; phosphate often low.
• Differentiation: Osteomalacia usually shows low or normal calcium with elevated PTH due to secondary causes.
• Imaging: May show subperiosteal bone resorption, which can overlap with long-standing osteomalacia but occurs in different distribution.
  
  

Metastatic Bone Disease

• Clinical clues: Known primary malignancy, unexplained weight loss, or severe persistent pain.
• Biochemistry: Variable; may include elevated ALP or calcium depending on tumour type.
• Imaging: Can mimic osteomalacia with multiple areas of increased uptake on bone scan, but often shows lytic or blastic lesions not typical of osteomalacia.
• Red flags: Requires exclusion through history and appropriate oncological imaging.
  
  

Renal Osteodystrophy (CKD-MBD)

• Clinical clues: Occurs in patients with chronic kidney disease.
• Biochemistry: Elevated phosphate, low or normal calcium, and elevated PTH; reduced 1,25(OH)₂D levels.
• Imaging: Mixed patterns including osteomalacia, osteitis fibrosa, and adynamic bone disease.
• Note: Bone biopsy may be required to differentiate among subtypes of renal osteodystrophy.
  
  

Key Diagnostic Distinctions

• Osteomalacia is defined by defective bone mineralisation and typically shows a biochemical pattern of low calcium, low phosphate, elevated ALP, and elevated PTH.
• Looser zones on imaging and characteristic muscle weakness help differentiate it from osteoporosis, which lacks pain and typically has normal biochemistry.
• Paget disease and malignancy-related bone disease present with distinct imaging patterns and lab profiles.
• Primary hyperparathyroidism involves hypercalcaemia, whereas osteomalacia does not.
  
  
  
  

General Principles

• Treatment must be aetiology-specific and includes reversing vitamin D deficiency, correcting calcium and phosphate imbalances, and addressing any underlying renal, hepatic, or genetic disorders.
• Nutritional deficiencies are the most common and most easily corrected, but malabsorptive, renal, and genetic causes often require targeted therapy and long-term monitoring.
• All patients should achieve adequate elemental calcium intake based on age and risk category, ideally from both dietary sources and supplementation when required.
  
  

Nutritional Vitamin D Deficiency

• Initial therapy:
  • Administer 25,000 to 50,000 IU of vitamin D2 or D3 weekly for 6 to 8 weeks.
  • In cases of profound deficiency, doses may be increased to 50,000 IU two to three times weekly for 6 to 8 weeks.
• Maintenance therapy:
  • Following correction, maintain with 600 to 2000 IU of vitamin D3 daily.
• Clinical response:
  • Marked improvement in proximal muscle strength and bone tenderness usually within weeks.
  • BMD improves within 3–6 months but may take up to a year for full mineralisation recovery.
• Calcium intake:
  • Aim for 1000–1200 mg/day in most adults.
  • Use higher doses (up to 4 g/day) in patients with malabsorption or severe deficiency.
    
    

Gastrointestinal Malabsorption

• Examples: Coeliac disease, Crohn disease, bariatric surgery, cystic fibrosis.
• Oral vitamin D dosing:
  • May require 10,000 to 50,000 IU daily due to poor absorption.
• Second-line treatment:
  • If 25(OH)D fails to improve, switch to hydroxylated forms such as calcidiol or calcitriol.
• Calcium supplementation:
  • Consider divided doses to improve absorption and reduce gastrointestinal side effects.
  • Monitor for hypercalciuria and adjust dose accordingly.
    
    

Chronic Liver Disease

• Pathophysiology: Impaired hepatic 25-hydroxylation leads to low 25(OH)D levels.
• Preferred therapy:
  • Calcidiol (25[OH]D) at 20–40 µg/day; higher doses up to 200 µg/day in severe disease.
  • If unavailable, calcitriol may be used.
• Monitoring: Assess 25(OH)D, calcium, and PTH regularly to avoid overtreatment and hypercalcaemia.
  
  

Chronic Kidney Disease (CKD)

• Pathophysiology: Decreased 1-alpha hydroxylase activity leads to impaired 1,25(OH)₂D production.
• Treatment:
  • Calcitriol or other activated vitamin D analogues.
  • Available in oral or intravenous formulations.
• Additional therapy:
  • Use non-aluminium phosphate binders for phosphate control.
  • Address secondary hyperparathyroidism as per CKD-MBD guidelines.
• Monitoring: Regular checks of serum calcium, phosphate, and PTH to guide therapy and prevent adynamic bone disease or vascular calcification.
  
  

Phosphate-Wasting Disorders

• Indications for treatment:
  • Symptomatic hypophosphataemia or biochemical evidence of chronic phosphate loss.
• Therapy:
  • Oral phosphate divided into multiple daily doses.
  • Combine with active vitamin D analogues to prevent hypocalcaemia from phosphate therapy.
• Goals:
  • Alleviate symptoms (e.g., bone pain, weakness), improve BMD, and reduce fracture risk—not necessarily to fully normalise phosphate.

Tumour-Induced Osteomalacia (TIO) and X-linked Hypophosphataemia

• Tumour-induced osteomalacia:
  • Caused by mesenchymal tumours secreting FGF23, leading to renal phosphate wasting.
• First-line:
  • Burosumab, a monoclonal antibody against FGF23, approved for TIO and X-linked hypophosphataemia.
  • Shown to improve serum phosphate, bone healing, and functional symptoms.
• Contraindications:
  • Severe renal dysfunction, hyperphosphataemia, and concurrent use of phosphate or active vitamin D analogues.
• Alternative:
  • Oral phosphate + calcitriol, used when burosumab is not accessible or contraindicated.
    
    

Medication-Induced Osteomalacia

• Examples: Phenytoin, carbamazepine, rifampicin, ketoconazole.
• Mechanism: Induce hepatic P450 enzymes, increasing vitamin D catabolism.
• Management:
  • Higher vitamin D dosing (to maintain serum 25(OH)D >75 nmol/L).
  • Consider switching to alternative medications if possible.
    
    

Monitoring Therapy

• Bone Mineral Density (BMD):
  • Baseline DXA scan and repeat at 12 months.
  • Improvement in BMD indicates adequate remineralisation.
• Biochemistry:
  • Monitor serum ALP, calcium, phosphate, PTH, and 25(OH)D every 1–3 months initially, then less frequently once stable.
• Urinary calcium excretion:
  • Periodic 24-hour urinary calcium monitoring helps detect excess supplementation and risk of nephrolithiasis.
• Treatment duration:
  • Full resolution of biochemical abnormalities and fracture risk reduction may take 6–12 months or longer, depending on severity.
    
    

Pregnancy

• Risk factors: Malnutrition, limited sun exposure, and malabsorption syndromes.
• Symptoms: Musculoskeletal pain, weakness, difficulty walking. Severe cases may present with fractures or cephalopelvic disproportion.
• Treatment:
  • Vitamin D3 2000–4000 IU daily, with dose escalation if 25(OH)D levels remain suboptimal.
  • Calcium 1000–1500 mg/day depending on dietary intake and urinary calcium levels.
• Monitoring:
  • Serum 25(OH)D, calcium, and 24-hour urinary calcium every 4–6 weeks.
• Safety:
  • High-dose vitamin D (e.g., 600,000 IU IM) has been used postnatally in case reports but is not routinely recommended during pregnancy due to limited safety data.
    
    

Rare and Genetic Causes

• Fanconi syndrome and proximal renal tubular acidosis:
  • Treat with vitamin D, bicarbonate replacement, and withdrawal of offending agents (e.g., heavy metals, medications).
• Hypophosphatasia:
  • Enzyme replacement may be considered; management is highly individualised.
• Bone matrix disorders (e.g., fibrogenesis imperfecta):
  • No standard treatment; rare case reports describe benefit with growth hormone.
    
    
    
    

Overall Outlook

• Favourable in most cases, especially when caused by nutritional vitamin D deficiency.
• Curable in the majority of patients when the underlying aetiology is identified and corrected.
• Delayed diagnosis or treatment may lead to prolonged bone pain, fractures, and functional impairment, but even these complications often improve significantly with appropriate therapy.
  
  

Response to Treatment

• Biochemical normalisation (e.g., calcium, phosphate, alkaline phosphatase, and 25-hydroxyvitamin D) can begin within weeks of starting treatment.
• Clinical improvement, such as reduced bone pain and improved muscle strength, is typically seen in parallel with biochemical recovery.
• Radiographic and histological healing (e.g., resolution of pseudofractures, increased bone density) may take several months to over a year, depending on:
  • Severity and duration of the deficiency
  • Underlying cause (nutritional, renal, genetic, etc.)
  • Patient adherence to treatment
  • Comorbidities such as chronic kidney disease or liver disease
    
    

Factors Influencing Prognosis

• Cause of osteomalacia:
  • Nutritional forms respond best.
  • Renal phosphate wasting syndromes and genetic conditions (e.g., X-linked hypophosphataemia, hypophosphatasia) may require lifelong treatment.
    
    
• Timeliness of diagnosis:
  • Earlier recognition leads to quicker resolution and prevents complications.
    
    
• Treatment adherence:
  • Consistent supplementation and monitoring are essential for recovery.
  • Non-compliance may lead to recurrence or progression.
    
    
• Response to therapy:
  • A rise in 25(OH)D, phosphate, and calcium, along with a fall in ALP, typically indicates improvement.
    
    
• Skeletal complications:
  • Existing deformities, fractures, or pseudofractures may require prolonged recovery time or supportive orthopaedic management.
    
    

Overview

• Untreated osteomalacia results in defective mineralisation of osteoid, leading to both skeletal and metabolic complications.
• Many complications are preventable or reversible with timely treatment.
• The nature and severity of complications depend on the underlying aetiology, duration of disease, and adequacy of therapeutic intervention.
  
  

Skeletal Complication

• Occur due to mechanical stress on poorly mineralised bone.
• Appear as radiolucent bands perpendicular to the cortex on radiographs.
• Most common sites: femoral neck, pubic rami, ischial rami.
• Less common locations: ribs, scapulae, clavicles.
• Often bilateral and symmetrical.
• Associated with bone pain, especially during weight-bearing.
• Termed "Milkman’s fractures" when multiple pseudofractures are present.
  
  

• Observed in long-standing cases with severe deformity and vertebral weakness.
• May result from chronic spinal instability or imbalance due to multiple vertebral deformities.
  
  

• Rare in isolated osteomalacia but may occur when coexisting with osteoporosis.
• Lead to loss of height, vertebral wedging, and kyphotic posture.
  
  

Metabolic and Treatment-Related Complications

• May occur due to chronic phosphate depletion or as a compensatory response to hypocalcaemia.
• Long-term phosphate supplementation, especially without concurrent vitamin D analogues, increases PTH secretion.
• Elevated PTH further increases phosphate loss and worsens osteomalacia unless addressed.
  
  

• Arises when calcium-phosphate product exceeds 70 mg²/dL².
• Risk is increased in patients receiving calcium and phosphate replacement, particularly those with CKD.
• Calcification may involve soft tissues, vasculature, and internal organs.
  
  

• Caused by over-replacement with vitamin D or calcium supplements.
• Symptoms include confusion, abdominal pain, polyuria, and arrhythmias.
• Management includes withholding supplements, hydration, and loop diuretics if needed.

• Prolonged high-dose calcium or vitamin D can elevate urinary calcium excretion.
• Increases the risk of renal calculi (kidney stones).
• Preventable by periodic monitoring of 24-hour urinary calcium or calcium-to-creatinine ratio.
  
  
  

Prevention and Monitoring

• Monitor serum calcium, phosphate, and PTH to avoid over-replacement complications.
• Regular 24-hour urinary calcium assessments in high-risk patients help prevent kidney stones.
• Ensure phosphate supplementation is combined with active vitamin D analogues to reduce the risk of secondary hyperparathyroidism.
  
  
  
  

1. Adamson BB, Gallacher SJ, Byars J, et al. Mineralisation defects with pamidronate therapy for Paget's disease. Lancet. 1993;342:1459.
2. Al-Shoha A, Qiu S, Palnitkar S, Rao DS. Osteomalacia with bone marrow fibrosis due to severe vitamin D deficiency after a gastrointestinal bypass operation for severe obesity. Endocr Pract. 2009;15(5):528–533.
3. Arboleya L, Braña I, Pardo E, et al. Osteomalacia in adults: a practical insight for clinicians. J Clin Med. 2023;12(7):1457.
4. Ashwell M, Stone EM, Stolte H, et al. UK Food Standards Agency Workshop Report: an investigation of the relative contributions of diet and sunlight to vitamin D status. Br J Nutr. 2010;104(4):603–611.
5. Bhadada SK, et al. Fibrogenesis imperfecta ossium. Calcif Tissue Int. 2019;104(6):561–567.
6. Bianchi ML, Bishop NJ, Guañabens N, et al. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020;31(7):1445–1460.
7. Bishay RH, et al. Long-term iron polymaltose infusions associated with hypophosphataemic osteomalacia. Ther Adv Endocrinol Metab. 2017;8(1):14–20.
8. Brandi ML, Clunie GPR, Houillier P, et al. Challenges in tumour-induced osteomalacia. Bone. 2021;152:116064.
9. Cashman KD, Dowling KG, Škrabáková Z, et al. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr. 2016;103(4):1033–1044.
10. Cianferotti L. Osteomalacia is not a single disease. Int J Mol Sci. 2022;23(23):14589.
11. Clarke BL, et al. Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features. Clin Endocrinol (Oxf). 1995;43(4):479–484.
12. Dedeoglu M, Garip Y, Bodur H. Osteomalacia in Crohn's disease. Arch Osteoporos. 2014;9:177.
13. Dempster DW, Compston JE, Drezner MK, et al. Standardised nomenclature, symbols, and units for bone histomorphometry. J Bone Miner Res. 2013;28(1):2–17.
14. Fukumoto S, Ozono K, Michigami T, et al. Pathogenesis and diagnostic criteria for rickets and osteomalacia. J Bone Miner Metab. 2015;33(5):467–473.
15. Fukumoto S, et al. Regulation of renal 1α-hydroxylase by fibroblast growth factor 23. J Bone Miner Res. 2004;19(3):429–435.
16. Fulop M, Mackay M. Renal tubular acidosis, Sjögren syndrome, and bone disease. Arch Intern Med. 2004;164(8):905–911.
17. Haffner D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2025.
18. Hill TR, Aspray TJ. The role of vitamin D in maintaining bone health in older people. Ther Adv Musculoskelet Dis. 2017;9(4):89–95.
19. Holick MF. Vitamin D deficiency: clinical implications. N Engl J Med. 2007;357(3):266–281.
20. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press; 2011.
21. Jan de Beur SM, et al. Global guidance for the recognition, diagnosis, and management of tumour-induced osteomalacia. J Intern Med. 2023;293(3):309–328.
22. Karefylakis C, Näslund I, Edholm D, et al. Vitamin D status 10 years after primary gastric bypass: gravely high prevalence of hypovitaminosis D and raised PTH levels. Obes Surg. 2014;24(3):343–348.
23. Khan AA, Brandi ML, Appelman-Dijkstra NM, et al. Hypophosphatasia: diagnostic criteria and emerging therapies. Osteoporos Int. 2024;35(3):431–447.
24. Khan MA, et al. Impact of vitamin D status in chronic liver disease. J Clin Exp Hepatol. 2019;9(5):574–580.
25. Kurland ES, et al. Recovery from skeletal fluorosis. J Bone Miner Res. 2007;22(2):163–171.
26. Lang R, et al. Fibrogenesis imperfecta ossium with early onset: observations after 20 years. Bone. 1986;7(4):237–243.
27. Lips P, van Schoor NM. The role of vitamin D in bone health. Best Pract Res Clin Endocrinol Metab. 2011;25(4):585–591.
28. Liu S, et al. Fibroblast growth factor 23: regulation of phosphate homeostasis and beyond. Curr Opin Nephrol Hypertens. 2007;16(4):329–335.
29. Manson JE, Brannon PM, Rosen CJ, et al. Is there really a pandemic of vitamin D deficiency? N Engl J Med. 2016;375(19):1817–1820.
30. Minisola S, et al. Tumour-induced osteomalacia: a comprehensive review. Endocr Rev. 2023;44(2):323–353.
31. Munns CF, Shaw N, Kiely M, et al. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab. 2016;101(2):394–415.
32. Pettifor JM. Nutritional rickets: deficiency of vitamin D, calcium, or both? Am J Clin Nutr. 2004;80(6 Suppl):1725S–1729S.
33. Prentice A. Nutritional rickets around the world. J Steroid Biochem Mol Biol. 2013;136:201–206.
34. Reginster JY. The high prevalence of inadequate serum vitamin D levels and implications for bone health. Curr Med Res Opin. 2005;21(4):579–586.
35. Rendina D, Abate V, Cacace G, et al. Tumour-induced osteomalacia: a systematic review and individual patient analysis. J Clin Endocrinol Metab. 2022;107(8):e3428–e3436.
36. Rigante M, et al. Oncogenic osteomalacia with elevated fibroblast growth factor 23: a rare case of paranasal sinus tumour onset. Cureus. 2019;11(6):e4919.
37. Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med. 2011;364(3):248–254.
38. Seefried L, Genest F, Hofmann C, et al. Diagnosis and treatment of hypophosphatasia. Calcif Tissue Int. 2025;116(1):46–64.
39. Shikino K, Ikusaka M, Yamashita T. Vitamin D-deficient osteomalacia due to excessive self-restrictions for atopic dermatitis. BMJ Case Rep. 2014;2014.
40. Thacher TD, Fischer PR, Pettifor JM, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med. 1999;341(8):563–568.
41. Uday S, Högler W. Nutritional rickets and osteomalacia in the twenty-first century: revised concepts and prevention strategies. Curr Osteoporos Rep. 2017;15(4):293–302.
42. Vilaca T, Velmurugan N, Smith C, et al. Osteomalacia as a complication of intravenous iron infusion: a systematic review of case reports. J Bone Miner Res. 2022;37(6):1188–1199.
43. Weaver CM, Gordon CM, Janz KF, et al. The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos Int. 2016;27(4):1281–1386.
44. Whyte MP. Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12:233–246.
45. Whyte MP. Sclerosing bone disorders. In: Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 7th ed. American Society of Bone and Mineral Research; 2008:412.
46. Zittermann A, Gummert JF, Börgermann J. Vitamin D deficiency and mortality. Curr Opin Clin Nutr Metab Care. 2009;12(6):634–639.