Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Clinically important rapid bone loss occurs within 3 to 6 months after liver transplantation and may be associated with osteoporotic fractures. OBJECTIVE: To determine whether bisphosphonate treatment with zoledronic acid reduces transplant-related bone loss more than placebo in adults having liver transplantation for chronic liver disease. DESIGN: 12-month randomized, double-blind, placebo-controlled trial. SETTING: 2 large liver transplantation centers in Australia. PATIENTS: 62 adults having liver transplantation for chronic liver disease. INTERVENTIONS: Infusions of zoledronic acid, 4 mg (n = 32), or saline (n = 30) were given within 7 days of transplantation and again at months 1, 3, 6, and 9 after transplantation. All patients received supplementation with calcium carbonate, 600 mg/d, and ergocalciferol, 1000 U/d. MEASUREMENTS: The primary outcome was bone mineral density (BMD) measured by dual x-ray absorptiometry before transplantation and 3, 6, and 12 months later. Secondary outcomes included bone turnover markers that were measured before transplantation and 1, 3, 6, 9, and 12 months later. RESULTS: There were statistically significant interactions between treatment effects and time for BMD measurements at the lumbar spine (P = 0.002), femoral neck (P = 0.001), and total hip (P < 0.001). Differences in acute bone loss 3 months after transplantation favored zoledronic acid over placebo. Differences between groups in percentage change from baseline adjusted for baseline weight and serum parathyroid hormone (PTH) level were 4.0% (95% CI, 1.1% to 7.0%) for the lumbar spine, 4.7% (CI, 1.9% to 7.6%) for the femoral neck, and 3.8% (CI, 1.7% to 6.0%) for the total hip. At 12 months after transplantation, the difference in percentage change from baseline between the 2 groups adjusted for baseline weight and serum PTH level was 1.1% (CI, -2.1% to 4.4%) for the lumbar spine, 2.7% (CI, 0.0% to 5.4%) for the femoral neck, and 2.4% (CI, 0.1% to 4.7%) for the total hip. Treatment with zoledronic acid induced temporary secondary hyperparathyroidism and postinfusion hypocalcemia statistically significantly more often than did placebo. LIMITATIONS: The trial was not powered to assess fractures, and 10 of 62 (16%) patients were not included in adjusted analyses because of missing weight or serum PTH measurements. CONCLUSION: Treatment with zoledronic acid can prevent bone loss within the first year after liver transplantation.

The heterogeneity of bone disease in cirrhosis: a multivariate analysis.

This study aimed to assess the clinical, biochemical and hormonal factors contributing to low bone density in a large ambulatory group of patients with cirrhosis of diverse aetiology. Bone density of the lumbar spine, neck of femur, total hip, total body, as well as total body fat, was measured by dual X-ray (DEXA) absorptiometry in 81 men and 32 women (average age 50.3 years). Morning blood and urine samples were taken for hormonal and biochemical analysis. Viral hepatitis was the most common cause of cirrhosis (54%) and the severity of cirrhosis ranged from Child-Pugh A5-C14. Osteoporosis was most common in the lumbar spine but was present at any site in 31% of women and 22% of men, with osteopenia present in another 40% of both genders. Urinary deoxypyridinoline, a marker of bone resorption, was elevated in 56% of patients and was associated with increasing severity of cirrhosis and a higher prevalence of osteoporosis, particularly of the lumbar spine. Hip-bone density was primarily affected by low 25-hydroxyvitamin D levels and was associated with secondary hyperparathyroidism in one third of these patients. Additional important predictors for low bone density at all sites were age in women and testosterone in men. These findings indicate that, although the pathophysiology of osteoporosis in chronic liver disease is heterogeneous, high bone turnover may be the underlying pathophysiological mechanism in a significant subgroup of cirrhotic patients and may reflect metabolic effects of hypogonadism or secondary hyperparathyroidism on bone.

Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment.

Long-term glucocorticoid therapy in men is associated with loss of bone and muscle mass as well as a decrease in serum testosterone. We tested the effect of two androgens, testosterone and its minimally aromatizable analog nandrolone, on muscle mass (dual x-ray absorptiometry), muscle strength (knee flexion and extension by isokinetic dynamometry), bone mineral density (BMD), and quality of life (Qualeffo-41 questionnaire) in 51 men on a mean daily prednisone dose of 12.6 +/- 2.2 mg. Men were randomized, double blind, to testosterone (200 mg mixed esters), nandrolone decanoate (200 mg), or placebo given every fortnight by im injection for 12 months. At 12 months, both androgens increased muscle mass (mean change from baseline +3.5%, +5.8%, and -0.9% in testosterone, nandrolone, and placebo groups, respectively, P < 0.0001) and muscle strength (P < 0.05). Lumbar spine BMD increased significantly only in men treated with testosterone (4.7 +/- 1.1%, P < 0.01). There was no significant change in hip or total body BMD. Testosterone, but not nandrolone or placebo, improved overall quality of life (P < 0.001). These results suggest that androgen therapy may have a role in ameliorating adverse effects of glucocorticoid therapy such as muscle and bone loss and aromatization is necessary for androgen action on bone but not on muscle.