Hepatic Osteodystrophy

Hepatic osteodystrophy is metabolic bone disease caused by chronic liver disease, and includes osteoporosis, osteopenia and, less often, osteomalacia. It raises the risk of fragility fractures and worsens quality of life.

Osteoporosis affects 12% to 55% of patients with cirrhosis and over 30% of those with cholestatic liver disease. Fracture risk is about double that of the general population. It is greatest in primary biliary cholangitis, haemochromatosis, alcohol related disease, and after liver transplantation.

Pathophysiology.

Causes are vitamin D deficiency from reduced synthesis and malabsorption, low sex steroids, raised bilirubin and bile acids that suppress osteoblasts, reduced insulin like growth factor 1, chronic inflammation, alcohol and tobacco use, malnutrition, and corticosteroid use.

Often silent until fracture. Back pain, loss of height, kyphosis, vertebral and rib fractures, bone pain and proximal muscle weakness (osteomalacia).

Red flags.

• New vertebral fracture.
• Hypocalcaemia or tetany.
• Bone pain with raised alkaline phosphatase.

Dual energy X-ray absorptiometry of the spine and hip (T-score of minus 2.5 or lower is osteoporosis) at diagnosis of cirrhosis or cholestatic disease. Vertebral imaging for suspected fracture. Measure calcium, phosphate, 25-hydroxyvitamin D, parathyroid hormone, testosterone or oestradiol, creatinine and alkaline phosphatase. Look for osteomalacia when vitamin D is very low.

Differential diagnosis.

• Primary osteoporosis.
• Hyperparathyroidism.
• Coeliac disease and malabsorption.
• Hypogonadism.
• Myeloma and metastatic bone disease.

Optimise nutrition, stop smoking and alcohol, and start weight bearing exercise. Replace vitamin D and calcium, then give an antiresorptive agent for osteoporosis or fragility fracture. Oral bisphosphonates are avoided with large varices or oesophageal disease, so an intravenous bisphosphonate or denosumab is used.

• Colecalciferol: 800 to 2,000 units orally once daily (loading of 50,000 units weekly for 8 weeks if 25-hydroxyvitamin D is under 25 nmol/L); maximum 4,000 units daily; monitor calcium and 25-hydroxyvitamin D at 3 months; reduce when level exceeds 100 nmol/L, and use calcifediol in severe cholestasis.
• Calcium: 1,000 to 1,200 mg total daily from diet and supplements; maximum 2,000 mg daily; monitor calcium and renal function; reduce in renal impairment and hypercalcaemia.
• Alendronate (no oesophageal varices, normal swallowing): 70 mg orally once weekly, taken fasting with water, upright for 30 minutes; for 3 to 5 years; maximum 70 mg weekly; monitor calcium and symptoms; avoid when creatinine clearance is under 35 mL/min.
• Zoledronic acid (varices or cholestasis): 5 mg IV over at least 15 minutes once yearly for 3 years; maximum 5 mg each year; monitor calcium, creatinine, and jaw and thigh pain; correct vitamin D first; avoid when creatinine clearance is under 35 mL/min.
• Denosumab (renal impairment): 60 mg subcutaneously every 6 months; maximum 60 mg every 6 months; monitor calcium (hypocalcaemia is a risk); do not stop abruptly, as rebound fractures occur.

Monitoring. Dual energy X-ray absorptiometry every 2 years (yearly if on corticosteroids or after transplant); calcium and vitamin D every 6 months.

Referral and escalation. Endocrinology or bone clinic for fractures or failed treatment.

Special groups. After liver transplantation, bone loss is fastest in the first 6 months, so start treatment before or at transplant.