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21 February 2006, Vol 144, No. 4>
Articles | 21 February 2006

Zoledronic Acid Prevents Bone Loss after Liver Transplantation: A Randomized, Double-Blind, Placebo-Controlled Trial

Bronwyn A.L. Crawford, MBBS, PhD; Cherie Kam, MPH, GDipScMed; Julie Pavlovic, RN; Karen Byth, PhD, DIC, CStat RSS; David J. Handelsman, MBBS, PhD; Peter W. Angus, MBBS, MD; and Geoffrey W. McCaughan, MBBS, PhD
[+] Article and Author 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.


Ann Intern Med. 2006;144(4):239-248. doi:10.7326/0003-4819-144-4-200602210-00005
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This study suggests that bisphosphonate therapy inhibits bone loss after liver transplantation, a finding that may have implications for other forms of solid organ transplantation. The positive effect of zoledronic acid on bone density was seen despite more glucocorticoid therapy being required for treatment of acute rejection in this group. Evidence of the antiresorptive effect of zoledronic acid was seen in the development of secondary hyperparathyroidism, presumably as a response to the inhibition of calcium release from bone into the circulation by zoledronic acid. In addition, patients treated with zoledronic acid maintained a higher degree of suppression of bone-specific ALP than those treated with placebo.

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Figures

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Figure 1.
Study flow diagram.BMD

Patients were recruited from 2 liver transplantation centers in Australia over a 3-year period. The total number of adult patients having liver transplantations during this time was 110 in Sydney and 78 in Melbourne. The timing and number of infusions of either zoledronic acid or saline (placebo) are shown. The number of bone mineral density ( ) measurements that were analyzed included data collection on 6 of the 9 patients who withdrew from the study and some isolated missing data points (for BMD at baseline and at 3, 6, and 12 months after liver transplantation, the numbers of patients were 32, 32, 26, and 29, respectively, for the zoledronic acid group and 30, 27, 28, and 25, respectively, for the placebo group).

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Figure 2.
Bone density change.BMDPPP

The percentage change from baseline (means and 95% CIs) in bone mineral density ( ) at the lumbar spine, femoral neck, and total hip for the zoledronic acid and the placebo groups (  = 0.032, 0.002, 0.001, respectively, for treatment effect; unadjusted analyses) is shown. The zero time point represents baseline data collected before liver transplantation; the subsequent time points are the number of months after transplantation. At 0, 3, 6, and 12 months, respectively, the numbers of patients were 32, 32, 26, and 29, respectively, for the zoledronic acid group and 30, 27, 28, and 25 for the placebo group. Estimated effects are based on models fitted to log-transformed BMD data. *  < 0.05. †  < 0.001 for individual time points, zoledronic acid versus placebo.

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Appendix Figure 1. Serum parathyroid hormone, 1,25-hydroxyvitamin D, and 25-hydroxyvitamin D (means and 95% CIs) after liver transplantation are shown for the zoledronic acid and placebo groups. The normal reference ranges are 2.5 to 6.5 pmol/L for parathyroid hormone; 36 to 120 pmol/L for 1,25-hydroxyvitamin D; and 39 to 120 nmol/L for 25-hydroxyvitamin D. At 0, 1, 3, 6, 9, and 12 months, respectively, the numbers of patients were 30, 32, 31, 30, 30, and 30 for the zoledronic acid group and 28, 24, 27, 28, 26, and 24 for the placebo group. The zero time point represents baseline data collected before liver transplantation; the subsequent time points are the number of months after transplantation. *  < 0.05. †  < 0.001 for individual time points, zoledronic acid versus placebo.
Levels of vitamin D and parathyroid hormone.PP
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Appendix Figure 2. Urinary deoxypyridinoline/creatinine ratio and serum bone-specific alkaline phosphatase ( ) levels (means and 95% CIs) after liver transplantation are shown for the zoledronic acid and the placebo groups. The normal reference ranges are 3.0 to 7.4 nmol/mmol for deoxypyridinoline and 4 to 21 µg/L for bone-specific ALP. At 0, 1, 3, 6, 9, and 12 months, respectively, the numbers of patients were 25, 30, 30, 28, 30, and 27 for the zoledronic acid group and 23, 24, 25, 25, 25, and 21 for the placebo group for urinary deoxypyridinoline and 25, 28, 28, 26, 28, and 29 for the zoledronic acid group and 23, 23, 22, 26, 21, and 16 for the placebo group for bone-specific ALP. The zero time point represents baseline data collected before liver transplantation; the subsequent time points are the number of months after transplantation. *  < 0.01. †  < 0.05 for individual time points, zoledronic acid versus placebo.
Bone turnover markers.ALPPP
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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general jounals
BMJ 2010;341:c5893-c1494.

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Summary for Patients

Zolendronic Acid Prevents Bone Loss after Liver Transplantation

The summary below is from the full report titled “Zoledronic Acid Prevents Bone Loss after Liver Transplantation. A Randomized, Double-Blind, Placebo-Controlled Trial.” It is in the 21 February 2006 issue of Annals of Internal Medicine (volume 144, pages 239-248). The authors are B.A.L. Crawford, C. Kam, J. Pavlovic, K. Byth, D.J. Handelsman, P.W. Angus, and G.W. McCaughan.

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