Zoledronic Acid Prevents Bone Loss after Liver Transplantation

A Randomized, Double-Blind, Placebo-Controlled Trial

21 February 2006 | Volume 144 Issue 4 | Pages 239-248

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.

Editors' Notes Context Rapid bone loss occurs in the first few months after liver transplantation and may be associated with fractures. Contribution This randomized, double-blind trial found that infusing zoledronic acid within 1 week of liver transplantation and again 1, 3, 6, and 9 months after transplantation prevented bone loss more effectively than did placebo infusions. Differences between groups lessened over time as some patients receiving placebo regained bone after several months. Zoledronic acid sometimes caused postinfusion hypocalcemia and temporary secondary hyperparathyroidism. Cautions The trial was not powered to assess differences in fracture outcomes. Implications Zoledronic acid infusions can prevent bone loss after liver transplantation. —The Editors

 

Author and Article Information

From Royal Prince Alfred Hospital, University of New South Wales, NHMRC Clinical Trials Centre, and University of Sydney, New South Wales, Australia; and Austin Health, Victoria, Australia.

Clinicaltrials.gov Identifier: NCT00114556.

Acknowledgments: The authors thank Dr. Sally Duke for data management.

Grant Support: Novartis Pharmaceuticals Pty Ltd. supplied zoledronic acid and some financial support.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Geoffrey W. McCaughan, MBBS, PhD, Liver Unit E9, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia.

Current Author Addresses: Dr. Crawford: Department of Endocrinology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia.

Ms. Kam: National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.

Ms. Pavlovic and Professor Angus: Victorian Liver Transplant Unit, Austin Health, Heidelberg, Victoria 3084, Australia.

Dr. Byth: NHMRC Clinical Trials Centre, University of Sydney, Mallett Street, Camperdown, New South Wales 2050, Australia.

Professor Handelsman: Department of Andrology, Concord Hospital, University of Sydney, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.

Professor McCaughan: The AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.

Author Contributions: Conception and design: B.A.L. Crawford, D.J. Handelsman, G.W. McCaughan.

Analysis and interpretation of the data: B.A.L. Crawford, K. Byth, D.J. Handelsman, G.W. McCaughan.

Drafting of the article: B.A.L. Crawford, D.J. Handelsman, P.W. Angus, G.W. McCaughan.

Critical revision of the article for important intellectual content: B.A.L. Crawford, K. Byth, D.J. Handelsman, P.W. Angus, G.W. McCaughan.

Final approval of the article: B.A.L. Crawford, D.J. Handelsman, P.W. Angus, G.W. McCaughan.

Provision of study materials or patients: P.W. Angus, G.W. McCaughan.

Statistical expertise: K. Byth, D.J. Handelsman.

Obtaining of funding: G.W. McCaughan.

Administrative, technical, or logistic support: C. Kam, J. Pavlovic, G.W. McCaughan.

Collection and assembly of data: B.A.L. Crawford, C. Kam, J. Pavlovic.