Osteomalacia in Chronic Kidney Disease

Osteomalacia in chronic kidney disease is defective mineralisation of newly formed bone matrix, producing excess unmineralised osteoid and low bone strength; the childhood equivalent is rickets.

Causes in chronic kidney disease are vitamin D deficiency (nutritional, low sun exposure, proteinuria, loss of 25-hydroxyvitamin D binding protein), reduced calcitriol, metabolic acidosis, phosphate depletion (tubulopathies, excess binders), aluminium deposition at the mineralisation front, anticonvulsants, malabsorption, and FGF23-mediated phosphate wasting. With the decline of aluminium exposure, vitamin D deficiency and acidosis now dominate.

Pathophysiology. Mineralisation requires adequate calcium and phosphate at the bone surface and alkaline phosphatase activity. Deficiency of either, or toxic inhibition (aluminium), delays mineralisation lag time and widens osteoid seams.

• Diffuse bone pain and tenderness (ribs, pelvis, spine, heels), proximal myopathy, waddling gait, difficulty rising from a chair.
• Fractures with minimal trauma; pseudofractures (Looser zones) in the femoral neck, pubic rami, scapula and ribs.
• Hypocalcaemia features: perioral paraesthesia, cramps, tetany.
• Children: rickets with delayed motor milestones, craniotabes, frontal bossing, rachitic rosary, Harrison sulcus, widened wrists, genu varum or valgum, bowing, delayed fontanelle closure, growth failure, hypocalcaemic seizures.
• Aluminium toxicity: microcytic anaemia, dementia and encephalopathy, proximal myopathy, bone pain.

Red flags

• Hypocalcaemic seizure or tetany.
• Corrected calcium under 1.9 mmol/L.
• Atraumatic fractures; progressive deformity in a child.
• Dialysis patient with unexplained bone pain and microcytosis: aluminium.

• Corrected calcium (low or normal), phosphate (low in tubular or nutritional causes, high in advanced chronic kidney disease), alkaline phosphatase (raised), parathyroid hormone (raised in vitamin D deficiency and secondary hyperparathyroidism; normal or low with aluminium), 25-hydroxyvitamin D (under 25 nmol/L is deficiency), 1,25-dihydroxyvitamin D, bicarbonate, magnesium.
• Urinary phosphate reabsorption (TmP/GFR), glycosuria, aminoaciduria and urinary pH for Fanconi syndrome and distal acidosis.
• FGF23 for suspected FGF23-mediated disease. Serum aluminium (above 60 microg/L in dialysis suggests toxicity; above 200 microg/L is toxic). Desferrioxamine challenge: deferoxamine 5 mg/kg during the last hour of dialysis, aluminium level 2 days later (rise above 150 microg/L supports toxicity).
• Radiographs: Looser zones, biconcave vertebrae, loss of cortical definition; in children, cupped and frayed metaphyses.
• Bone biopsy: widened osteoid seams (osteoid volume above 15% and osteoid thickness above 12.5 microm), prolonged mineralisation lag time over 100 days, stainable aluminium at the mineralisation front.

Differential diagnosis

• Osteoporosis, adynamic bone disease, hyperparathyroid bone disease, hypophosphatasia (low alkaline phosphatase), tumour induced osteomalacia, myeloma and bone metastases, fibromyalgia and polymyalgia (normal biochemistry).

First line: correct the deficiency

• Cholecalciferol 50 000 units weekly for 6 to 8 weeks when 25-hydroxyvitamin D is under 25 nmol/L, then 800 to 2000 units daily; repeat level after 3 months and maintain at least 50 nmol/L.
• Active vitamin D when advanced chronic kidney disease prevents activation: alfacalcidol 0.25 to 0.5 microg daily (up to 1 microg daily in Fanconi syndrome) or calcitriol 0.25 to 0.5 microg daily; check calcium and phosphate after 1 week and then monthly.
• Calcium: dietary intake 1000 mg daily; calcium carbonate 500 mg elemental calcium three times daily, between meals when phosphate is normal, with meals as a binder when phosphate is high; total elemental calcium from binders limited to 1.5 g daily.
• Acidosis: sodium bicarbonate 500 mg to 1 g orally two to three times daily to bicarbonate at least 22 mmol/L.
• Phosphate depletion: oral phosphate 500 to 1000 mg elemental phosphorus daily in divided doses with calcitriol to blunt parathyroid hormone rise.

Aluminium toxicity

• Remove all sources (check water treatment and dialysate, stop aluminium hydroxide and sucralfate). Deferoxamine 5 mg/kg intravenously once weekly during the last hour of dialysis for 2 to 3 months, with haemodiafiltration or high flux dialysis to clear the chelate. Watch for mucormycosis, visual and hearing loss. Transplantation if suitable.

Hypocalcaemic emergency. Calcium gluconate 10% 10 mL intravenously over 10 minutes with ECG monitoring, then an infusion of 100 mL of 10% in 1 litre of 5% glucose at 50 mL/hour titrated to corrected calcium 2.0 to 2.2 mmol/L.

Monitoring. Calcium, phosphate and alkaline phosphatase weekly after starting treatment, then monthly; healing shown by falling alkaline phosphatase over 3 to 6 months and radiological resolution of Looser zones.

Referral and escalation. Nephrology and metabolic bone service when 25-hydroxyvitamin D is replaced and alkaline phosphatase stays raised, or when aluminium toxicity or a tubulopathy is suspected.

Special groups

• Children: cholecalciferol 3000 to 6000 units daily for 8 to 12 weeks, calcium 500 mg elemental calcium daily or more, alfacalcidol 0.05 microg/kg daily (maximum 1 microg), orthopaedic review for deformity, and somatropin 0.045 to 0.05 mg/kg daily subcutaneously once mineral disorder is controlled.
• Pregnancy: cholecalciferol 800 to 2000 units daily and calcium 1000 mg daily; calcitriol with monitoring.
• Anticonvulsant treated patients: cholecalciferol 1000 to 2000 units daily.