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Effect of Bisphosphonates on Periprosthetic Bone Mineral Density After Total Joint ArthroplastyA Meta-Analysis
Mohit Bhandari, MD, MSc, FRCSC1; Sohail Bajammal, MD1; Gordon H. Guyatt, MD, MSc1; Lauren Griffith, MSc1; Jason W. Busse, DC, MSc1; Holger Schünemann, MD, PhD1; Thomas A. Einhorn, MD2
1 Department of Clinical Epidemiology and Biostatistics, McMaster University Health Sciences Center, Room 2C9, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. E-mail address for M. Bhandari: bhandam@mcmaster.ca
2 Department of Orthopaedic Surgery, Boston University Medical Center, 720 Harrison Avenue, Suite 808, Boston, MA 02118
View Disclosures and Other Information
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from a Canadian Institutes of Health Research Fellowship Award. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from commercial entities (Merck and Novartis). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada, and the Department of Orthopaedic Surgery, Boston University Medical Center, Boston, Massachusetts

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2005 Feb 01;87(2):293-301. doi: 10.2106/JBJS.D.01772
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Abstract

Background: Periprosthetic bone loss following total joint arthroplasty may threaten the survival of the implant. Bisphosphonates are effective in reducing bone loss in conditions associated with accelerated bone turnover. To determine the current understanding of the effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty, we conducted computerized searches for randomized controlled trials evaluating the use of bisphosphonates in patients treated with primary total joint arthroplasty.

Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the web site of the United Kingdom National Research Register, and the archives of the American Academy of Orthopaedic Surgeons annual meetings (1989 through 2003), and we conducted hand searches of the bibliographies of relevant articles. We assessed methodological quality and abstracted relevant data. When necessary, we contacted authors to provide additional information.

Results: Of 386 citations that were initially identified, six (five complete papers and one abstract), which included a total of 290 patients, met our inclusion criteria. Those papers showed that significantly less periprosthetic bone loss had occurred in the bisphosphonate-treated patients than in the control patients at three months (152 patients; weighted mean difference, 3.3%; 95% confidence interval, 1.9% to 4.7%; p < 0.01), six months (248 patients; weighted mean difference, 4.5%; 95% confidence interval, 1.6% to 7.4%; p < 0.001), and twelve months (197 patients; weighted mean difference, 4.2%; 95% confidence interval, 1.5% to 6.9%; p = 0.03). Bisphosphonates appeared to have a larger effect on bone loss following arthroplasties with cement than on bone loss following arthroplasties without cement (difference, 0.1%, 5%, and 5.4% at three, six, and twelve months; significant difference [p < 0.001] at one year only) and a larger effect on bone loss following total knee arthroplasties than on bone loss following total hip arthroplasties (difference, 4.1%, 11.5%, and 7.1% at three, six, and twelve months; significant difference [p < 0.001] at six months only). None of the studies related the effects of bisphosphonates on bone mineral density to clinically relevant outcomes.

Conclusions: A meta-analysis of six randomized controlled trials suggested that bisphosphonates have a beneficial effect with regard to maintaining more periprosthetic bone mineral density than that in controls. However, the limitations of the available studies and the lack of analyses of clinically relevant outcomes (functional outcomes, revision rates, and quality of life) necessitate the planning and conduct of a sufficiently sized, methodologically sound study with clinically relevant end points. Until this has been done, the current evidence regarding the beneficial effects of bisphosphonates on periprosthetic bone after total joint arthroplasty should be interpreted with caution.

Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Mohit Bhandari, M.D.
    Posted on May 26, 2005
    Dr. Bhandari and colleagues respond to Dr Shetty et al
    McMaster University

    ID: 87/2/293

    We read with great interest the comments raised by Shetty and colleagues on our paper ““Effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty. A meta-analysis” by Bhandari et al (2005; 87(2): 293-301).

    We have indicated in the discussion section of the paper that “Our subgroup analyses should be interpreted with caution. These analyses are inherently underpowered, and differences may be the result of chance alone. Investigators have suggested that tests of interaction between different subgroups can limit erroneous conclusions; however, tests of interaction are often underpowered. Thus, our findings that bisphosphonates exert a differential effect on total knee arthroplasties and arthroplasties with cement should be considered exploratory.” We agree, with Shetty and colleagues that the effect of cementation could be confounded by the site of arthroplasty. Meta-regression analysis could potentially answer this question. However, the limited number of studies make such an analysis difficult.

    Regarding the comment on the effect of pamidronate, we reported that in the context of discussing the potential influence of industry funding on study results. We stated “In the current review, one trial was funded by a commercial entity(1) and, in another trial, the drugs were given free by a commercial entity(2). The industry- funded trial demonstrated a significant benefit of the commercial entity’s product, but Wilkinson, et al, reported no significant effects of pamidronate at six months(2).” We indicated that pamidronate had no significant effects, eliminating the risk of bias of industry funding, without elaborating on the explanation of absence of effects, whether fall in bone mass in the pamidronate group or recovery in bone mass in the placebo group. We thank the authors for highlighting this point.

    Finally, we thank the authors for emphasizing our suggestion of the importance of further work in this field. As we indicated in the paper, “Whether improvements in bone mineral density improve quality of life and function and decrease the risk of revision surgery remains unknown. The current meta-analysis does, however, provide important hypotheses that suggest a biological rationale for the role of bisphosphonates in this patient population”. We look forward to hearing about a sufficiently sized, methodologically sound study to assess clinically relevant end points in this topic.

    Sincerely yours,

    Mohit Bhandari, M.D., Sohail Bajammal, M.D., Thomas Einhorn, M.D.

    References:

    1. Lyons A. Effects of alendronate in total hip arthroplasty (Abstractt) Journal of Bone and Joint Surgery-British Volume. Vol.81 Suppl 3, pp.313, 1999.

    2. Wilkinson JM, Stockley I, Peel NF, Hamer AJ, Elson RA, Barrington NA, Eastell R. Effect of pamidronate in preventing local bone loss after total hip arthroplasty: a randomized, double-blind, controlled trial. J.Bone Miner Res. 2001;16:556-64.

    Nitin. R Shetty
    Posted on May 05, 2005
    Effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty.
    Department of Orthopaedics, Northern General Hospital, Sheffied, U.K.

    To The Editor:

    We read with interest the paper, “Effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty. A meta-analysis” by Bhandari et al (1). We were intrigued by the finding that the effect size of bisphosphonate therapy was greater for cemented versus uncemented implants, and in total knee arthroplasty (TKA) versus total hip arthroplasty (THA). We note that both of the TKA studies were made using cemented implants, but that in half of the THA studies uncemented implants were used. Could the authors clarify whether cementation and joint site were independent predictors of drug efficacy, or might the greater effect in cemented implants be due to the common variable effect of TKA.

    The authors also state that in our study the effect of a single post- operative dose of pamidronate on femoral bone mineral density was lost at 6 months.(2) We feel that it is important to comment that this late loss of effect was due largely to a partial recovery in bone mass in the placebo group at this time-point, rather than a late fall in bone mass in the pamidronate group.

    Finally, we agree with the authors’ comments that studies to date have used small samples and not included clinically relevant outcome measures and that the clinical relevance of the results are, as yet, unclear. As bone mineral density is a major determinant of bone strength it seems plausible that pharmacological preservation of bone mass might influence the risk of periprosthetic fracture. Direct evidence for a relationship between regional bone loss, focal osteolysis, and aseptic loosening is lacking. We believe that further work is required to determine whether regional bone loss is an independent predictor of implant failure. If such a relationship were confirmed, this would justify the establishment of larger scale trials using clinically relevant outcomes such as development of osteolytic lesions or rates of implant survival.

    References:

    (1) Mohit Bhandari, Sohail Bajammal, Gordon H. Guyatt, Lauren Griffith, Jason W. Busse, Holger Schünemann, and Thomas A. Einhorn Effect of Bisphosphonates on Periprosthetic Bone Mineral Density After Total Joint Arthroplasty. A Meta-Analysis J Bone Joint Surg Am 2005; 87: 293-301

    (2) Wilkinson JM, Stockley I, Peel NFA, Hamer AJ, Elson RA, Barrington NA et al. Effect of pamidronate in preventing local bone loss after total hip arthroplasty: A randomized, double-blind, controlled trial. J Bone Miner Res 2001;16:556 -64.

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