Osteomalacia and Rickets

• Cause is usually vitamin D deficiency: inadequate sunlight or intake, malabsorption (coeliac disease, bariatric surgery, cholestasis), chronic kidney disease (impaired 1-alpha-hydroxylation), liver disease, and anticonvulsants that induce vitamin D catabolism. Hypophosphataemic causes include X-linked hypophosphataemia and tumour-induced osteomalacia (FGF23).
• Biochemistry is the exam anchor: low or low-normal calcium, low phosphate, raised alkaline phosphatase, raised PTH (secondary hyperparathyroidism), low 25-hydroxyvitamin D.
• Rickets shows craniotabes, frontal bossing, a rachitic rosary at the costochondral junctions, widened wrists, genu varum (bowing), and delayed fontanelle closure and dentition.
• Osteomalacia presents with diffuse bone pain, proximal myopathy with a waddling gait, and fragility fractures. Radiographs may show Looser zones (pseudofractures) — lucent bands perpendicular to the cortex.
• Treatment replaces vitamin D and ensures adequate calcium and phosphate, with the specific form (cholecalciferol versus calcitriol) determined by the underlying cause.

Calciopenic (vitamin D–pathway) causes — the common exam mechanism

• Inadequate substrate: limited UVB exposure (high latitude, winter, veiling, institutionalisation, sunscreen use), exclusive breastfeeding without supplementation (breast milk is a poor vitamin D source), and strict vegan or milk-free diets.
• Malabsorption of fat-soluble vitamin D: coeliac disease, Crohn disease, cystic fibrosis, cholestatic liver disease, pancreatic insufficiency, and Roux-en-Y gastric bypass.
• Impaired hydroxylation: liver disease blocks 25-hydroxylation (CYP2R1); chronic kidney disease blocks 1-alpha-hydroxylation (CYP27B1), so 25-OH-D may be adequate while calcitriol is low.
• Accelerated catabolism: enzyme-inducing anticonvulsants (phenytoin, phenobarbital, carbamazepine), rifampin, and glucocorticoids.
• Genetic: vitamin D–dependent rickets type 1 (CYP27B1 loss — low calcitriol) and type 2 (vitamin D receptor mutation — high calcitriol with alopecia).

Phosphopenic causes

• FGF23-mediated renal phosphate wasting: X-linked hypophosphataemia (PHEX mutation, X-linked dominant — the classic non-nutritional childhood rickets) and tumour-induced osteomalacia from a small mesenchymal tumour secreting FGF23.
• Proximal tubular dysfunction: Fanconi syndrome, type 2 (proximal) renal tubular acidosis, tenofovir, ifosfamide, and heavy-metal exposure.
• Dietary/iatrogenic phosphate loss: prolonged antacid (aluminium/magnesium) use binding gut phosphate; preterm infants on unfortified feeds.

Modifiable versus non-modifiable

• Modifiable: sun avoidance, supplement non-adherence, diet, bariatric surgery follow-up, drug choice, obesity (vitamin D sequestration in adipose tissue).
• Non-modifiable: darkly pigmented skin (melanin absorbs UVB), age extremes, genetic tubulopathies, and CKD stage. The AAP recommends 400 IU/day of vitamin D for all breastfed and partially breastfed infants — its absence is the planted detail in paediatric stems.

• Normal mineralisation requires a sufficient calcium × phosphate product at the mineralisation front. Osteoblasts lay down osteoid (type I collagen plus non-collagenous proteins) normally in this disease; what fails is nucleation and growth of hydroxyapatite crystals within it. The result is a widened, unmineralised osteoid seam — soft bone with normal or even increased matrix volume, which is why this is not osteoporosis.
• The vitamin D axis: 7-dehydrocholesterol in skin is converted by UVB to cholecalciferol, 25-hydroxylated in the liver (CYP2R1) to the storage form measured clinically, then 1-alpha-hydroxylated in the proximal tubule (CYP27B1) to calcitriol. Calcitriol drives intestinal absorption of both calcium (TRPV6/calbindin) and phosphate.
• The calciopenic cascade: low calcitriol → reduced gut calcium absorption → falling ionised calcium → secondary hyperparathyroidism. PTH restores serum calcium by bone resorption and distal tubular reabsorption, which is why calcium is often only low-*normal*, but PTH simultaneously inhibits proximal tubular NaPi-2a cotransporters, causing phosphaturia and frank hypophosphataemia. The calcium × phosphate product falls below the threshold for mineralisation.
• Alkaline phosphatase rises because osteoblasts, stimulated by PTH and expanding osteoid surfaces, are hyperactive — ALP is a marker of osteoblast work, not of mineralisation success.
• At the growth plate (rickets only), hypertrophic chondrocytes normally undergo phosphate-dependent apoptosis before vascular invasion. Hypophosphataemia blocks that apoptosis, so the hypertrophic zone accumulates: the physis widens and the metaphysis becomes cupped, splayed and frayed. Cartilage overgrowth at costochondral junctions produces the rachitic rosary.
• Soft bone deforms under load — bowing of weight-bearing long bones, craniotabes in the non-weight-bearing infant skull, and Looser zones where nutrient arteries or muscular pull stress the cortex in adults.
• Proximal myopathy reflects vitamin D receptor signalling in muscle plus hypophosphataemia limiting ATP generation.
• In FGF23 excess, FGF23 both wastes phosphate and suppresses CYP27B1, so phosphate is low while calcium and PTH stay normal.

Rickets (before physeal closure)

• Craniotabes: ping-pong-ball softening of the parietal/occipital skull in the first months, from unmineralised membranous bone.
• Frontal bossing and delayed fontanelle closure: osteoid accumulation at the frontal and parietal eminences.
• Rachitic rosary: palpable beading at the costochondral junctions from hypertrophic cartilage overgrowth. The adjacent Harrison sulcus is a horizontal groove where the diaphragm pulls on soft ribs.
• Widened wrists and ankles: metaphyseal flaring at the distal radius/ulna and knee, the most rapidly growing physes.
• Genu varum in the newly walking toddler, genu valgum in older children, plus a waddling gait and delayed motor milestones.
• Delayed dentition, enamel hypoplasia, growth failure and short stature.
• Hypocalcaemic manifestations: tetany, carpopedal spasm, Chvostek and Trousseau signs, stridor from laryngospasm, and seizures — most often in infancy and in vitamin D–dependent rickets.

Osteomalacia (after physeal closure)

• Diffuse, dull, aching bone pain that is worse with weight-bearing and reproducibly tender to sternal, rib and tibial pressure — this focal bone tenderness distinguishes it from fibromyalgia.
• ***Proximal myopathy* with a waddling gait**: difficulty rising from a chair or climbing stairs, with preserved sensation and normal or only mildly raised creatine kinase.
• Fragility fractures, classically femoral neck, pubic rami and ribs, often with minimal trauma.

Initial laboratory panel — order together

• Serum calcium, phosphate, alkaline phosphatase, PTH, creatinine, magnesium and 25-hydroxyvitamin D. The single most useful first test is 25-OH-D, the storage form; it is the correct measure of vitamin D status.
• Classic nutritional pattern: low or low-normal calcium, low phosphate, markedly raised alkaline phosphatase, raised PTH, and low 25-OH-D. The 2016 Global Consensus on Nutritional Rickets treats a 25-OH-D below roughly 12 ng/mL (30 nmol/L) as deficiency; the Endocrine Society has used a higher sufficiency threshold near 30 ng/mL.
• Do not order 1,25-dihydroxyvitamin D as the screening test — secondary hyperparathyroidism upregulates CYP27B1, so calcitriol is often normal or high despite severe deficiency. Reserve it for suspected vitamin D–dependent rickets, CKD, or FGF23 disorders.
• If phosphate is low with normal calcium and normal PTH, quantify renal phosphate handling (fractional excretion of phosphate, TmP/GFR) and measure FGF23 — inappropriately elevated FGF23 with renal phosphate wasting indicates X-linked hypophosphataemia or tumour-induced osteomalacia. Localise an occult tumour with functional somatostatin-receptor imaging.

Imaging

• Plain radiographs of the wrist and knee in children: widened physis, cupping, splaying and fraying of the metaphysis, coarse trabeculae and bowing — enough to make the diagnosis in the right clinical setting.
• Adults: generalised osteopenia with Looser zones (Milkman pseudofractures) — lucent bands perpendicular to the cortex at the medial femoral neck, pubic rami, scapular margins and ribs. Bone scan shows multiple symmetric hot spots. DXA underestimates the problem and does not distinguish osteomalacia from osteoporosis.

Confirmatory

• Tetracycline double-labelled transiliac bone biopsy is the histologic gold standard — increased osteoid volume and thickness with a prolonged mineralisation lag time — but is rarely needed outside atypical or research cases.
• **A low alkaline phosphatase points away from rickets to *hypophosphatasia*** (tissue-nonspecific ALP mutation) — a key discriminator.

Immediate stabilisation

• Symptomatic hypocalcaemia (tetany, laryngospasm, seizure) is treated first with IV calcium gluconate on a cardiac monitor, followed by oral calcium; correct hypomagnesaemia simultaneously, since low magnesium causes functional PTH resistance and refractory hypocalcaemia.

First-line — nutritional (calciopenic) disease

• Native vitamin D: cholecalciferol (D3) or ergocalciferol (D2), given daily or as intermittent high-dose stoss therapy. The 2016 Global Consensus on Nutritional Rickets recommends a treatment course of at least 2000 IU/day for a minimum of three months, always with adequate oral elemental calcium (roughly 500 mg/day), because vitamin D alone will not mineralise bone without substrate.
• Transition to maintenance supplementation afterwards; the AAP advises 400 IU/day for infants, with higher daily maintenance in older children and adults per Institute of Medicine dietary reference intakes.
• Expect ALP to fall and radiographs to heal over weeks to months; persistent elevation means non-adherence, malabsorption, or a wrong diagnosis.

Escalation and cause-specific therapy

• Malabsorption: high-dose oral vitamin D, parenteral dosing if needed, plus treatment of the underlying disease (gluten-free diet, pancreatic enzymes).
• CKD: 1-alpha-hydroxylation is lost, so give an active vitamin D analogue — calcitriol (or paricalcitol/doxercalciferol) with phosphate binders, following KDIGO CKD-MBD guidance.
• Vitamin D–dependent rickets type 1: calcitriol. Type 2 (receptor defect): very high-dose calcitriol and calcium, sometimes IV.
• X-linked hypophosphataemia: historically oral phosphate salts plus calcitriol; burosumab, an anti-FGF23 monoclonal antibody, is FDA-approved and now preferred in appropriate patients.
• Tumour-induced osteomalacia: surgical resection of the causative mesenchymal tumour is curative — the definitive management.
• Orthopaedic osteotomy only for residual deformity after biochemical healing.

Contraindicated / cautions

• Do not give plain cholecalciferol as sole therapy in advanced CKD — it cannot be activated.
• Do not give phosphate supplements without calcitriol in XLH: this provokes secondary and eventually tertiary hyperparathyroidism.
• Avoid unmonitored megadose vitamin D — hypercalcaemia, hypercalciuria and nephrocalcinosis follow.

Of the untreated disease

• Hypocalcaemic seizures, carpopedal spasm and laryngospasm — an emergency; signalled by stridor, tetany or a positive *Chvostek*/*Trousseau* sign in an infant with rickets. Requires IV calcium.
• Dilated cardiomyopathy and heart failure in infantile vitamin D deficiency — ionised hypocalcaemia impairs myocardial excitation–contraction coupling. An emergency; suspect it in a hypocalcaemic infant with tachypnoea, hepatomegaly and poor perfusion. It is largely reversible with calcium and vitamin D repletion.
• Fragility fractures and pseudofracture completion, especially femoral neck — soft, under-mineralised cortex fails under normal load.
• Permanent skeletal deformity: bowing, short stature, and a contracted rachitic pelvis that can cause obstructed labour later in life.
• Dental complications: enamel hypoplasia, delayed eruption, and dentine defects predisposing to caries and periapical abscess.
• Tertiary hyperparathyroidism: chronic PTH drive produces autonomous parathyroid nodules; suspect when calcium becomes high with a persistently raised PTH after repletion.
• Craniosynostosis and raised intracranial pressure have been described in poorly controlled hypophosphataemic rickets.

Of treatment

• Vitamin D toxicity: hypercalcaemia, hypercalciuria, nephrolithiasis and nephrocalcinosis with declining GFR — from excessive native or active vitamin D. Monitor serum calcium, urine calcium:creatinine ratio and creatinine during therapy.
• Phosphate supplementation in XLH: transient diarrhoea, and, more importantly, PTH stimulation leading to secondary then tertiary hyperparathyroidism and nephrocalcinosis when calcitriol is omitted.
• Burosumab: hyperphosphataemia and ectopic mineralisation; it is not used with concurrent oral phosphate and active vitamin D.
• Post-treatment hypocalcaemia and hypophosphataemia as avid remineralisation consumes mineral — the hungry bone phenomenon; watch electrolytes in the first weeks of therapy, particularly after correcting severe long-standing deficiency.

• The biochemical fingerprint is the answer to most stems: low/low-normal calcium, low phosphate, high alkaline phosphatase, high PTH, low 25-OH-D. Compare with osteoporosis (all labs normal) and Paget disease (isolated high ALP with normal calcium and phosphate).
• Order 25-hydroxyvitamin D, not 1,25-dihydroxyvitamin D, as the single best next step. Secondary hyperparathyroidism keeps calcitriol normal or high even in severe deficiency — measuring it is the classic distractor.
• Looser zones (pseudofractures) — lucent bands perpendicular to the cortex at the medial femoral neck, pubic rami and scapula — are the adult radiographic buzzword; metaphyseal cupping and fraying at the wrist and knee is the paediatric one.
• The exam patient: an exclusively breastfed, darkly pigmented infant given no vitamin D drops, or an adult years after Roux-en-Y gastric bypass with bone pain and a waddling gait. The AAP's 400 IU/day recommendation for breastfed infants is the omitted step.
• Proximal myopathy with normal CK and normal sensation plus focal bone tenderness distinguishes osteomalacia from polymyositis and fibromyalgia.
• Normal calcium and normal PTH with isolated hypophosphataemia and renal phosphate wasting = FGF23 excess — X-linked hypophosphataemia in a child (treat with burosumab), tumour-induced osteomalacia in an adult (resect the tumour). No tetany, because calcium is normal.
• **A low alkaline phosphatase in a rickets-like picture is hypophosphatasia**, not vitamin D deficiency — the deliberate trap.
• Alopecia plus rickets plus a very high calcitriol = vitamin D–dependent rickets type 2 (receptor defect); low calcitriol with the same picture = type 1 (1-alpha-hydroxylase defect).
• In CKD, give calcitriol, not cholecalciferol alone — the failing kidney cannot 1-alpha-hydroxylate (KDIGO CKD-MBD framing).