Renal Osteodystrophy

Renal osteodystrophy is the term for the bone histological abnormalities of chronic kidney disease, a quantifiable component of chronic kidney disease mineral and bone disorder. Diagnosis rests on bone biopsy classified by turnover, mineralisation and volume.

The spectrum is: high turnover (osteitis fibrosa from secondary hyperparathyroidism); low turnover (adynamic bone disease, with few osteoblasts and osteoclasts); osteomalacia (defective mineralisation, with excess unmineralised osteoid); and mixed uraemic osteodystrophy (high turnover with a mineralisation defect).

Dialysis related amyloidosis (beta-2 microglobulin deposition) adds bone cysts, arthropathy and carpal tunnel syndrome after more than 5 to 10 years on dialysis.

Mechanisms

• High turnover: raised parathyroid hormone and FGF23, hypocalcaemia, phosphate retention.
• Low turnover: over suppression of parathyroid hormone (calcium load, vitamin D analogues, calcimimetics, parathyroidectomy), diabetes, ageing, uraemic toxins, malnutrition, inflammation.
• Osteomalacia: vitamin D deficiency, acidosis, hypophosphataemia, aluminium deposition at the mineralisation front.

Consequences: fractures (hip fracture rates in dialysis are 4 times those of the general population), bone pain, deformity, myopathy, growth failure, and associated vascular calcification.

• Bone pain (low back, hips, ribs, heels), worse with weight bearing; proximal muscle weakness; difficulty rising from a chair; waddling gait; fractures with minimal trauma; height loss and kyphosis; spontaneous tendon rupture (quadriceps, Achilles).
• Children: growth retardation, rickets (widened wrists, rachitic rosary, bowed legs or genu valgum), slipped capital femoral epiphysis, delayed puberty.
• Adynamic bone: frequently asymptomatic, associated with hypercalcaemia, vascular calcification and fractures.
• Aluminium bone disease: bone pain, proximal myopathy, fractures, microcytic anaemia, encephalopathy.
• Dialysis amyloid: carpal tunnel syndrome, shoulder pain, destructive spondyloarthropathy, bone cysts.

Red flags

• Atraumatic fracture (hip, vertebra, rib), pathological fracture, or new severe bone pain.
• Alkaline phosphatase above 3 times the upper limit of normal (osteomalacia, Paget disease or metastasis).
• Parathyroid hormone under 2 times the upper limit with hypercalcaemia (adynamic bone).
• Ulcerating painful skin lesions (calciphylaxis).

Biochemical markers

• Parathyroid hormone: values more than 9 times the upper limit usually indicate high turnover; below 2 times the upper limit in dialysis suggest low turnover. Intermediate values do not discriminate.
• Total or bone specific alkaline phosphatase: above 120 IU/L suggests high turnover; with normal parathyroid hormone suggests osteomalacia or liver disease. Calcium, phosphate, 25-hydroxyvitamin D, bicarbonate, aluminium (above 60 microg/L in dialysis patients suggests toxicity).

Imaging

• Radiographs: subperiosteal erosions, rugger jersey spine, pseudofractures (Looser zones) in osteomalacia, brown tumours, bone cysts of amyloid. DXA predicts fracture risk but does not distinguish turnover.

Bone biopsy (iliac crest, after double tetracycline labelling with demeclocycline 300 mg twice daily for 3 days, a 12-day gap, then a further 3 days, with biopsy 3 to 5 days later). Indicated when: unexplained fractures or bone pain, persistent hypercalcaemia or hypophosphataemia, suspected aluminium toxicity, before bisphosphonate or antiresorptive therapy in G4 to G5D, or when parathyroid hormone is intermediate and therapy is uncertain. Report turnover (T), mineralisation (M) and volume (V).

Differential diagnosis

• Age related and glucocorticoid osteoporosis; primary hyperparathyroidism; nutritional osteomalacia; Paget disease; myeloma and bone metastases; hypophosphatasia; tumour induced osteomalacia; dialysis amyloid versus infective arthritis.

Tailor therapy to the histological type or the best inference from biomarkers.

High turnover

• Lower parathyroid hormone and phosphate: sevelamer carbonate 800 mg three times daily with meals titrated to phosphate 1.1 to 1.7 mmol/L; correct 25-hydroxyvitamin D (cholecalciferol 50 000 units weekly for 6 to 8 weeks, then 800 to 2000 units daily); alfacalcidol 0.25 to 0.5 microg daily; cinacalcet 30 mg daily titrated to 180 mg when calcium is above 2.2 mmol/L; etelcalcetide 5 mg after dialysis, up to 15 mg.
• Parathyroidectomy for refractory disease (parathyroid hormone above 85 pmol/L with bone complications).

Low turnover (adynamic)

• Avoid over suppression: reduce or withdraw calcium based binders, vitamin D analogues and calcimimetics when parathyroid hormone falls below 2 times the upper limit of normal; use dialysate calcium 1.25 mmol/L; avoid calcium load above 1.5 g elemental daily. Correct malnutrition and acidosis. Antiresorptives are avoided. Anabolic therapy (teriparatide 20 microg subcutaneously daily for up to 24 months) has been used in selected patients under specialist supervision.

Osteomalacia

• Vitamin D replacement (cholecalciferol 50 000 units weekly for 6 to 8 weeks, then 800 to 2000 units daily); correct acidosis (sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L); correct phosphate (hypophosphataemia: oral phosphate 500 to 1000 mg elemental phosphorus daily).
• Aluminium toxicity: stop all aluminium exposure (water treatment, binders), then deferoxamine 5 mg/kg intravenously once weekly during the last hour of haemodialysis for 2 to 3 months, with aluminium level repeated 4 weeks after each course (risks: mucormycosis, and ocular and ototoxic effects).

Osteoporosis in G3 to G5D (when low turnover disease is excluded or unlikely)

• Alendronate 70 mg weekly with eGFR at least 35; risedronate 35 mg weekly with eGFR at least 30.
• Denosumab 60 mg subcutaneously every 6 months with calcium 500 mg elemental calcium three times daily and cholecalciferol, with calcium checked at 1 and 2 weeks after each dose; severe hypocalcaemia and rebound fractures after stopping are risks (arrange a bisphosphonate after cessation).
• Fall prevention, weight bearing exercise, stop smoking, minimise glucocorticoids, and treat acidosis and malnutrition.

Dialysis amyloid. High flux dialysis or haemodiafiltration, kidney transplant (pain relief within days), carpal tunnel release, analgesia.

Children. Cholecalciferol, alfacalcidol 0.25 to 0.5 microg daily, phosphate control, correction of acidosis, and somatropin 0.045 to 0.05 mg/kg daily subcutaneously when growth is under the 3rd centile and mineral control is achieved. Orthopaedic review for deformity.

Monitoring and escalation. Calcium, phosphate and parathyroid hormone monthly to 3-monthly; alkaline phosphatase and 25-hydroxyvitamin D 3-monthly to annually; imaging for fracture. Refer to nephrology and metabolic bone services for any fracture, bone pain with abnormal markers, or planned antiresorptive therapy; refer for bone biopsy where indicated.

Special groups

• Transplant recipients: bone loss is greatest in the first 6 to 12 months; use glucocorticoid sparing regimens, give cholecalciferol, and consider antiresorptives when eGFR allows.
• Women of child bearing potential: avoid bisphosphonates before pregnancy because of long skeletal retention.