• Osteomalacia is prevalent worldwide but particularly common in regions with limited sunlight exposure, cultural practices involving extensive body coverage, or dietary vitamin D deficiency.
• In Western countries, the prevalence has decreased since the introduction of vitamin D food fortification programmes, but it remains significant among the elderly, institutionalised patients, and immigrant populations from South Asia and the Middle East.
• Estimated prevalence of vitamin D deficiency (25(OH)D < 25 nmol/L or < 10 ng/mL) ranges from 5–25% in the general population of developed countries, with subclinical osteomalacia being much more common than overt disease.

• Vitamin D insufficiency is highly prevalent in Hong Kong, particularly among:
  • Elderly institutionalised patients: Studies have shown > 70% of elderly nursing home residents in Hong Kong have vitamin D deficiency ^[4].
  • Post-menopausal women: Already at risk of osteoporosis, compounded by vitamin D deficiency.
  • Indoor workers and individuals with limited outdoor activity due to Hong Kong's urban lifestyle.
  • Chronic kidney disease (CKD) patients: Hong Kong has a high burden of CKD (often secondary to diabetes and hypertension), leading to renal osteodystrophy including osteomalacia ^[5].
• Chronic liver disease (particularly hepatitis B-related, which is endemic in Hong Kong) can impair 25-hydroxylation of vitamin D, contributing to osteomalacia ^[6].
• Drug-induced osteomalacia: use of anticonvulsants (phenytoin, carbamazepine) — relevant given Hong Kong's ageing population with comorbid epilepsy.

• Sex: Slightly more common in females (due to lower baseline vitamin D stores, pregnancy/lactation demands, and cultural factors such as sun avoidance).
• Age: Can occur at any adult age, but most commonly affects the elderly.
• Ethnicity: Higher in darker-skinned individuals (melanin reduces cutaneous vitamin D synthesis) and those with dietary restrictions (e.g., vegans, lactose intolerance).

• Inadequate sunlight exposure (institutionalised, indoor lifestyle, extensive clothing coverage)
• Dietary deficiency (low intake of oily fish, egg yolks, fortified foods)
• Darker skin pigmentation
• Obesity (vitamin D is fat-soluble and sequestered in adipose tissue)

• Chronic liver disease → impaired 25-hydroxylation (Hong Kong: hepatitis B) ^[6]
• Chronic kidney disease (CKD) → impaired 1α-hydroxylation → reduced active 1,25(OH)₂D₃ ^[5]
• Drugs that induce hepatic CYP450 enzymes and accelerate vitamin D catabolism: phenytoin, carbamazepine, rifampicin, phenobarbital
• Nephrotic syndrome → urinary loss of vitamin D-binding protein (and bound 25(OH)D)

• Coeliac disease (can cause both osteoporosis and osteomalacia) ^[7]
• Crohn's disease (particularly terminal ileum involvement → bile salt malabsorption → fat-soluble vitamin malabsorption) ^[8]
• Chronic pancreatitis / pancreatic insufficiency
• Post-gastrectomy / bariatric surgery (particularly Roux-en-Y gastric bypass)
• Cholestatic liver disease (reduced bile salts → impaired fat/vitamin D absorption)

• Renal phosphate wasting (X-linked hypophosphataemia, tumour-induced osteomalacia via FGF-23 excess)
• Fanconi syndrome (generalised proximal tubular dysfunction → phosphaturia, glycosuria, aminoaciduria, bicarbonaturia) ^[3]
• Chronic antacid use (aluminium-containing antacids bind dietary phosphate in the gut)

• Aluminium toxicity (historically from dialysate water; aluminium deposits on mineralisation front and directly poisons osteoblasts)
• Hypophosphatasia (inherited deficiency of tissue non-specific alkaline phosphatase → cannot generate inorganic phosphate for mineralisation)
• Fluoride excess (fluorosis)
• Bisphosphonate overuse (extremely rare, mainly at very high doses used in Paget's disease)
• Etidronate (first-generation bisphosphonate — known to directly inhibit mineralisation; newer bisphosphonates like alendronate and zoledronate do not have this effect at therapeutic doses)

To understand osteomalacia, you must understand how bone is normally built:

1. Osteoid: The organic matrix secreted by osteoblasts, composed primarily of type I collagen (~90%) plus non-collagenous proteins (osteocalcin, osteonectin, bone sialoprotein).
2. Mineralisation: After osteoid is laid down, there is a "mineralisation lag time" of ~10–20 days during which hydroxyapatite crystals [Ca₁₀(PO₄)₆(OH)₂] are deposited within and around the collagen fibrils.
3. Requirement for mineralisation: Adequate concentrations of:
   • Calcium (maintained by PTH, vitamin D, calcitonin)
   • Phosphate (maintained by vitamin D, PTH, FGF-23)
   • Alkaline phosphatase (hydrolyses pyrophosphate, which is a natural inhibitor of mineralisation, and generates free inorganic phosphate)
   • Appropriate pH (acidosis inhibits mineralisation)

• Trabecular (cancellous) bone: 20% of skeletal mass but 80% of bone turnover. Spongy interior of vertebral bodies, pelvis, metaphyses of long bones. High surface area means it is metabolically very active — osteomalacia affects trabecular bone readily ^[9].
• Cortical (compact) bone: 80% of skeletal mass but only 20% of bone turnover. Dense outer shell of long bones. Less metabolically active but still affected in severe osteomalacia.

Understanding this pathway is critical because vitamin D deficiency is the most common cause of osteomalacia ^[1][2]:

Key regulation points:

• 1α-hydroxylase in the kidney is stimulated by PTH and inhibited by FGF-23 and by 1,25(OH)₂D₃ itself (negative feedback).
• PTH secretion is stimulated by low ionised calcium and high phosphate ^[10].
• FGF-23 (fibroblast growth factor 23) is secreted by osteocytes; it causes renal phosphate wasting and suppresses 1α-hydroxylase, reducing calcitriol synthesis. This is the hormone that is pathologically elevated in tumour-induced osteomalacia and X-linked hypophosphataemia.

The aetiologies of osteomalacia can be systematically classified into two broad categories based on the fundamental requirement that is deficient:

This is by far the most common cause ^[1][2]:

1. Calcipenic (low calcium ± low phosphate) — most commonly from vitamin D deficiency
2. Phosphopenic (isolated low phosphate, calcium usually normal) — renal phosphate wasting, FGF-23 excess
3. Direct mineralisation defect (calcium and phosphate may be normal) — aluminium, hypophosphatasia, fluoride

1. Nutritional (most common globally)
2. Malabsorptive
3. Renal (CKD-related — part of renal osteodystrophy spectrum)
4. Drug-induced
5. Hereditary (XLH, hypophosphatasia)
6. Tumour-induced (TIO)

In CKD, the bone disease is complex and classified as renal osteodystrophy (now termed CKD-MBD: CKD-Mineral and Bone Disorder). The spectrum includes:

• High-turnover disease: Secondary hyperparathyroidism → osteitis fibrosa cystica (excess PTH drives bone resorption)
• Low-turnover disease:
  • Osteomalacia (impaired mineralisation due to low calcitriol ± aluminium toxicity)
  • Adynamic bone disease (over-suppression of PTH, often iatrogenic from excess calcium/vitamin D supplementation or calcimimetics)
• Mixed ^[5]

The hallmark is insidious onset — osteomalacia develops slowly over months to years:

"Osteoporosis is silent until it fractures; osteomalacia is painful even before it fractures." — This clinical pearl helps differentiate the two at the bedside.

Why is this the most common cause?

• Vitamin D is unique — it is both a "vitamin" (dietary) and a "hormone" (synthesised endogenously in skin). Most people rely heavily on cutaneous synthesis (80% of vitamin D), so any factor reducing sun exposure dramatically reduces vitamin D status.
• Groups at highest risk in Hong Kong:
  • Elderly nursing home residents (limited outdoor time, reduced skin synthesis capacity with age — the amount of 7-dehydrocholesterol in aged skin is ~25% of that in young adults)
  • CKD patients (impaired 1α-hydroxylation)
  • Hepatitis B/C cirrhosis patients (impaired 25-hydroxylation) ^[6]
  • Post-gastrectomy / bariatric surgery patients
  • Patients on anticonvulsants (phenytoin, carbamazepine)

Pathophysiology cascade: Low vitamin D → low calcitriol → ↓ intestinal Ca/PO₄ absorption → ↓ serum Ca → parathyroid glands sense low Ca → secondary hyperparathyroidism → PTH attempts to restore calcium by (a) mobilising calcium from bone, (b) increasing renal Ca reabsorption, (c) increasing renal PO₄ excretion → PO₄ drops further → Ca × PO₄ product falls below mineralisation threshold → osteomalacia.

• As GFR falls below ~30 mL/min (CKD Stage 3b–5):
  • Loss of functioning renal tubular cells → reduced 1α-hydroxylase activity → low calcitriol
  • Impaired phosphate excretion → hyperphosphataemia
  • Hyperphosphataemia directly stimulates PTH secretion + suppresses 1α-hydroxylase
  • Low calcitriol removes negative feedback on PTH → secondary hyperparathyroidism
  • Net effect: High-turnover bone disease (osteitis fibrosa) ± osteomalacia ^[5]
• Aluminium-related osteomalacia: historically seen in dialysis patients exposed to aluminium in dialysate water or aluminium-containing phosphate binders. Now rare due to improved water purification and use of non-aluminium binders (calcium carbonate, sevelamer, lanthanum).

• Generalised proximal renal tubular dysfunction → loss of phosphate, glucose, amino acids, uric acid, bicarbonate in urine ^[3].
• Causes: inherited (cystinosis in children, Wilson's disease) or acquired (multiple myeloma, heavy metals, tenofovir, ifosfamide).
• Hypophosphataemic rickets (in children) and osteomalacia (in adults) are characteristic bone manifestations ^[3].
• Biochemical clue: type II (proximal) renal tubular acidosis with hypokalaemia + hypophosphataemia + glycosuria with normal blood glucose.

• Caused by mesenchymal tumours (often small, benign, difficult to locate) that secrete excess FGF-23.
• Presentation: adult with insidious bone pain, proximal weakness, refractory hypophosphataemia, normal calcium, low calcitriol, elevated FGF-23.
• Localisation: whole-body ⁶⁸Ga-DOTATATE PET/CT or octreotide scan → surgical resection is curative.
• If tumour cannot be found or resected: treat with oral phosphate + calcitriol replacement; burosumab (anti-FGF-23 monoclonal antibody) is a newer treatment option.

• Most common inherited cause of rickets/osteomalacia.
• PHEX gene mutation (X-linked dominant) → impaired degradation of FGF-23 → FGF-23 excess → renal phosphate wasting + impaired calcitriol synthesis.
• Children present with rickets (bowed legs, growth retardation); adults present with osteomalacia (bone pain, insufficiency fractures, dental abscesses, enthesopathy).
• Treatment: oral phosphate + calcitriol; burosumab (approved for XLH in 2018) is now recommended as first-line in children and is available for adults with active disease.

This is the most important differential because both are metabolic bone diseases that cause fractures and can coexist:

Both cause reduced bone mass, but in osteoporosis the ratio of bone mineral to bone matrix is normal, whereas in osteomalacia the ratio of bone mineral to bone matrix is low ^[1]. ALP is normal in osteoporosis but raised in osteomalacia (because osteoblasts upregulate ALP trying to mineralise the excess osteoid) ^[1].

Paget's disease is characterised by excessive abnormal bone remodelling at selected skeletal sites, resulting in structurally disorganised, enlarged bone ^[11].

Why the distinction matters: Paget's has normal calcium and phosphate but very high ALP. Osteomalacia has low calcium and/or phosphate with high ALP. Paget's is focal; osteomalacia is generalised.

Myeloma is a haematological malignancy of plasma cells that causes purely lytic bone lesions via osteoclast activation (RANKL overexpression by myeloma cells) ^[1].

Multiple myeloma must be considered in the differential of back pain and bone pain in the elderly ^[1]. The ALP pattern is the key biochemical discriminator — it is normal in myeloma (no osteoblast activation) but raised in osteomalacia.

Metastatic disease to bone is common (lung, breast, prostate, kidney, thyroid — "Lead Kettle" mnemonic or Lung, Breast, Prostate, Kidney, Thyroid) and must be excluded in any patient with bone pain, especially if:

• Pain is focal rather than diffuse
• Constitutional symptoms (weight loss, night sweats, anorexia) are present
• Fracture occurs above T5 (a suspicious level — most osteoporotic compression fractures occur at T6–L4) ^[12]

Primary hyperparathyroidism (pHPT) can cause bone pain, raised ALP, and fragility fractures. However:

Key discriminator: Calcium is high in pHPT (that's the defining feature) vs low in osteomalacia. Both have low phosphate and raised PTH, but the calcium direction is opposite.

PMR can mimic the proximal pain and stiffness of osteomalacia, particularly in elderly patients:

Can cause diffuse musculoskeletal pain but:

• Normal biochemistry (normal ALP, calcium, phosphate)
• No bone tenderness or fractures
• Associated with fatigue, sleep disturbance, cognitive difficulties ("fibro fog")
• Tender points at specific soft tissue locations (not over bone)

Not all vitamin D deficiency leads to osteomalacia. Mild to moderate vitamin D insufficiency (25(OH)D 25–50 nmol/L) may cause:

• Mild secondary hyperparathyroidism
• Muscle weakness
• Non-specific pain

But overt osteomalacia with defective mineralisation typically requires severe, prolonged deficiency (25(OH)D < 25 nmol/L or < 10 ng/mL).

In practice, osteomalacia is diagnosed when the following constellation is present:

1. Clinical features: Diffuse bone pain, proximal myopathy, bone tenderness ± insufficiency fractures
2. Biochemical pattern: ↓ Ca, ↓ PO₄, ↑ ALP, ↑ PTH (the classic tetrad for vitamin D deficiency type) ^[2]
3. Low 25(OH)D: Confirms vitamin D deficiency as the cause (most common scenario)
4. Radiological features: Looser zones (pathognomonic), generalised osteopenia
5. Response to treatment: Clinical and biochemical improvement with vitamin D ± calcium/phosphate supplementation provides retrospective diagnostic confirmation

The gold standard diagnosis of osteomalacia is bone biopsy with double tetracycline labelling — this is the only way to directly visualise and quantify defective mineralisation ^[1].

However, bone biopsy is rarely performed in routine clinical practice because:

• It is invasive (iliac crest biopsy under local anaesthesia)
• It requires a specialised pathologist experienced in undecalcified bone histomorphometry
• The clinical-biochemical-radiological picture is usually sufficient for diagnosis

When is bone biopsy indicated?

• Diagnostic uncertainty (atypical biochemistry, e.g., normal vitamin D with suspected osteomalacia)
• Suspected aluminium-related osteomalacia in dialysis patients
• Suspected hypophosphatasia
• Renal osteodystrophy classification (to distinguish osteomalacia from adynamic bone disease vs osteitis fibrosa)
• Research purposes

Histological criteria for osteomalacia on bone biopsy:

How double tetracycline labelling works (understanding from first principles):

• The patient takes oral tetracycline at two time points separated by a known interval (typically 10–14 days)
• Tetracycline binds to newly mineralising bone surfaces and fluoresces under UV light
• In normal bone: you see two distinct fluorescent lines at the mineralisation front, separated by a distance proportional to the rate of new bone formation
• In osteomalacia: the labels are absent, single, or diffuse/blurred — because mineralisation is not occurring or is severely delayed, so the tetracycline cannot bind to an advancing mineralisation front

As detailed above:

• Trans-iliac bone biopsy with prior double tetracycline labelling
• Undecalcified sections examined under UV light for fluorescent tetracycline labels
• Histomorphometric criteria: widened osteoid seams (> 12.5 μm), increased osteoid volume (> 5%), prolonged mineralisation lag time, absent/blurred tetracycline double labels
• This is the only investigation that directly demonstrates defective mineralisation — all other tests are indirect
• Indicated when: diagnostic uncertainty, suspected aluminium toxicity, classification of renal osteodystrophy, suspected hypophosphatasia, research

This requires a fundamentally different approach because the problem is impaired renal 1α-hydroxylation, not vitamin D deficiency per se ^[5][21].

Treatment Components (KDOQI/KDIGO Guidelines)

CKD-MBD treatment per KDOQI: (1) Dietary phosphate restriction, (2) Calcium-based and non-calcium-based phosphate binders, (3) Vitamin D for secondary hyperparathyroidism, (4) Calcimimetics (cinacalcet), (5) Parathyroidectomy ^[21].

Why not just give calcitriol alone? Calcitriol increases intestinal phosphate absorption along with calcium. In CKD where phosphate excretion is already impaired, giving calcitriol alone without phosphate control can worsen hyperphosphataemia → worsen vascular calcification → CKD-MBD progression. This is why the treatment is multimodal.

• Asfotase alfa (Strensiq) — recombinant tissue non-specific alkaline phosphatase
  • SC injection, typically 3–6 times per week
  • Provides the missing enzyme → hydrolyses pyrophosphate → removes the mineralisation inhibitor → allows mineralisation to proceed
  • FDA-approved for perinatal/infantile/juvenile-onset hypophosphatasia (2015); increasingly used in adults with severe disease
• Do NOT give bisphosphonates — they are pyrophosphate analogues and would worsen the mineralisation defect in hypophosphatasia

Monitoring is critical to ensure the osteomalacia is truly resolving:

ALP normalisation is the key marker: When ALP returns to normal, it indicates that the osteoblasts have successfully mineralised the excess osteoid and are no longer "overworking." If ALP remains elevated despite treatment, consider: (1) inadequate vitamin D dosing, (2) non-compliance, (3) persistent malabsorption, (4) wrong diagnosis (e.g., Paget's disease).

In clinical practice, particularly in elderly patients, osteomalacia and osteoporosis can coexist. For example, a post-menopausal woman with vitamin D deficiency has:

• Osteoporosis (oestrogen deficiency → accelerated bone loss)
• Osteomalacia (vitamin D deficiency → defective mineralisation)

Management approach:

1. Treat the osteomalacia first — replace vitamin D + calcium for at least 4–6 weeks
2. Reassess biochemistry — ALP should fall, calcium/phosphate normalise
3. Repeat DEXA after 6–12 months — the T-score may improve significantly (osteomalacia component resolved)
4. Then consider anti-resorptive therapy (bisphosphonate or denosumab) for the residual osteoporosis component if indicated

• Maternal osteomalacia → neonatal hypocalcaemia (the neonate is born with depleted calcium stores because the mother could not provide adequate calcium transfer across the placenta) → neonatal seizures
• Neonatal rickets — congenital rickets from severe maternal vitamin D deficiency
• Obstructed labour from pelvic deformity (triradiate pelvis) — may necessitate emergency caesarean section

• Higher mortality from hip fractures
• Increased susceptibility to pneumonia from rib fractures + kyphosis (restrictive lung pattern)
• Immobility → pressure sores, venous thromboembolism, deconditioning