EndocrinologyTier 2Disease (DEADMAN)

Bone metabolism disorders - vitamin D deficiency

Description

25(OH)D is the storage form and the one you measure (t1/2 ~2-3 weeks)
1,25(OH)2D is the active hormone - t1/2 ~4-6 hr, tightly regulated, normal even in severe deficiency
- -> *never order 1,25(OH)2D to diagnose deficiency*
- Order it only for: granulomatous hypercalcaemia, lymphoma, rickets subtypes, CKD-MBD

Australian thresholds - 25(OH)D

nmol/L
>=50 (end of winter)	Sufficient
30-49	Mild deficiency
12.5-29	Moderate
<12.5	Severe - rickets/osteomalacia risk

Aim >=50 at the end of winter/early spring - i.e. ~10-20 nmol/L higher at the end of summer

Currency caveat

Endocrine Society 2024 declined to endorse any specific 25(OH)D threshold and recommends against routine testing in healthy adults <75
- Australian practice (Healthy Bones Australia, MBS rules) still uses the >=50 nmol/L target
- The direction of travel is clear: test fewer people, supplement by risk rather than by number

~23% of Australian adults have 25(OH)D <50 nmol/L
- >50% in southern states at the end of winter
High-risk groups
- Dark skin - needs 3-6x the UV exposure
- Veiling or concealing dress; institutionalised, housebound, hospitalised
- Obesity (sequestration in adipose -> low levels, higher dose requirement)
- Malabsorption - coeliac, IBD, bariatric surgery, pancreatic insufficiency
- CKD, liver disease
- Anticonvulsants, rifampicin (CYP induction -> inc catabolism), glucocorticoids, antiretrovirals
- Exclusively breastfed infants of deficient mothers
Australia has one of the highest skin cancer rates in the world - the advice is incidental, not deliberate, sun exposure

Synthesis pathway

7-dehydrocholesterol in skin + UVB -> cholecalciferol (D3)
Liver 25-hydroxylase (CYP2R1) -> 25(OH)D
Kidney 1-alpha-hydroxylase (CYP27B1) -> 1,25(OH)2D
- Stimulated by PTH and hypophosphataemia; inhibited by FGF23 and 1,25(OH)2D itself
Catabolism by 24-hydroxylase (CYP24A1)
- Loss-of-function CYP24A1 -> idiopathic infantile hypercalcaemia, hypercalcaemia in adults after vitamin D loading

Consequences of deficiency

dec intestinal Ca and PO4 absorption
- -> low/low-normal Ca -> secondary hyperparathyroidism
  - -> inc bone resorption, inc cortical porosity
  - -> phosphaturia -> low PO4
- -> impaired mineralisation of osteoid -> osteomalacia (rickets if growth plates open)
Proximal myopathy - direct muscle receptor effect -> falls

Vitamin D-dependent rickets

Type	Defect	1,25(OH)2D	Treatment
1A	CYP27B1 (1-alpha-hydroxylase)	low	Calcitriol
2A	VDR (receptor resistance)	very high	High-dose calcitriol + Ca; alopecia

Contrast X-linked hypophosphataemic rickets: FGF23 excess -> low PO4, normal Ca, normal PTH, inappropriately normal 1,25(OH)2D -> burosumab

Who to test

Do not screen the general population. Test only if:
- Symptomatic bone pain or proximal myopathy
- Osteoporosis, fragility fracture, or before starting an antiresorptive
- Malabsorption, CKD, chronic liver disease, hyperparathyroidism, hypocalcaemia
- Dark skin, veiling, housebound, institutionalised
- Anticonvulsants, glucocorticoids
- Pregnancy in a high-risk woman
MBS restricts rebated 25(OH)D testing to these indications - a "tired, check vitamin D" request is not one

Biochemistry of osteomalacia

Low or low-normal Ca, LOW PO4, HIGH ALP, HIGH PTH, LOW 25(OH)D
A normal ALP does not exclude it, but a raised ALP with low PO4 is the classic pattern

Imaging / other

Looser zones (pseudofractures) - pubic rami, scapula, femoral neck, ribs - pathognomonic of osteomalacia
Rickets: widened, cupped, frayed metaphyses; rachitic rosary; genu varum; craniotabes
DEXA - low BMD (osteomalacia can be misread as osteoporosis)
Bone biopsy with tetracycline labelling - definitive, rarely needed

Look for the cause

Replacement - by severity

	Regimen
Mild (30-49)	Cholecalciferol 1000-2000 IU/day
Moderate-severe (<30)	3000-5000 IU/day for 6-12 weeks, then 1000-2000 IU/day maintenance
Malabsorption/obesity	3-5x the usual dose, or parenteral

Ensure adequate calcium intake (~1000-1300 mg/day, diet preferred) - vitamin D alone will not heal osteomalacia
Recheck 25(OH)D at 3 months (earlier is uninterpretable - the analyte has not plateaued)

Do NOT use annual mega-doses

Single annual 500,000 IU cholecalciferol paradoxically INCREASES falls and fractures in older people
- Excess risk concentrated in the first 3 months after the dose
- Similar signal with high-dose monthly regimens (VITAL, D-Health, ViDA)
-> daily or monthly lower dosing is the standard

Use calcitriol, not cholecalciferol, when 1-alpha-hydroxylation is the problem

Prevention

Osteomalacia responds

Bone pain and myopathy improve in weeks; ALP may rise transiently as mineralisation resumes
Watch for hungry bone-like hypocalcaemia and hypophosphataemia on treatment of severe deficiency

Coeliac disease, IBD, cystic fibrosis, pancreatic insufficiency, bariatric surgery
CKD-MBD; chronic liver disease, cholestasis
Anticonvulsants (phenytoin, carbamazepine, phenobarbitone), rifampicin, glucocorticoids, antiretrovirals, cholestyramine, orlistat
Obesity; sarcopenia and falls
Primary hyperparathyroidism (deficiency worsens it; replete cautiously)
Granulomatous disease - hypercalcaemia from unregulated extrarenal 1-alpha-hydroxylase (supplementation can precipitate it)
Tumour-induced osteomalacia (FGF23-secreting mesenchymal tumour)
Dark skin, veiling, high-latitude residence, institutional care

Biochemical correction in 6-12 weeks; secondary hyperparathyroidism takes 3-6 months to normalise
Osteomalacia heals over 6-12 months; Looser zones resolve radiologically
Long-standing rickets -> permanent bony deformity
Supplementation in a vitamin D-replete population does not reduce fractures, falls, cancer or cardiovascular events (VITAL, D-Health)
- The benefit is confined to the genuinely deficient

Complications

Fragility fracture, osteomalacia, rickets
Proximal myopathy and falls
Hypocalcaemia, tetany, seizures (infants)
Toxicity: 25(OH)D >220-250 nmol/L -> hypercalcaemia, hypercalciuria, nephrocalcinosis, AKI
- Almost always from supplements, never from sun
- Consider CYP24A1 mutation if hypercalcaemia follows ordinary doses

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