Carolyn J. Crandall, MD, MS; Sydne J. Newberry, PhD; Allison Diamant, MD, MSHS; Yee-Wei Lim, MD, PhD; Walid F. Gellad, MD, MPH; Marika J. Booth, MS; Aneesa Motala, BA; Paul G. Shekelle, MD, PhD
Acknowledgment: The authors acknowledge Roberta Shanman, MLS, for conducting the update searches and Kanaka Shetty, MD, and Michael Scarpati, PhD, for the use of machine learning for the 2013 update searches. In addition, they acknowledge the guidance provided by the technical expert panel members, Roberta Biegel, MA; Bruce Ettinger, MD; Theodore Hahn, MD; Marc Hochberg, MD, MPH; Hau Liu, MD; Catherine MacLean, MD, PhD; Paul Miller, MD; Eric Orwoll, MD; Marcel E. Salive, MD, MPH; and Daniel Solomon, MD, MPH.
Grant Support: By the Agency for Healthcare Research and Quality (AHRQ) (HHSA290200710062I). No statement in this article should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Disclosures: All authors received grant support from AHRQ during the conduct of the study. Dr. Gellad reports grant support from Express Scripts outside the submitted work. Dr. Shekelle reports royalties from UpToDate outside the submitted work and was an author of an American College of Physicians guideline on this topic. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0317.
Requests for Single Reprints: Carolyn J. Crandall, MD, MS, Professor of Medicine, David Geffen School of Medicine, Division of General Internal Medicine & Health Services Research, University of California, Los Angeles, 911 Broxton Avenue, 1st Floor, Los Angeles, CA 90024; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Crandall and Diamant: David Geffen School of Medicine, Division of General Internal Medicine & Health Services Research, University of California, Los Angeles, 911 Broxton Avenue, 1st Floor, Los Angeles, CA 90024.
Dr. Newberry, Ms. Booth, and Ms. Motala: RAND Corporation, 1776 Main Street, Santa Monica, CA 90401.
Dr. Lim: Saw Swee Hock School of Public Health, National University of Singapore, Singapore MD3, 16 Medical Drive, Singapore 117597.
Dr. Gellad: Pittsburgh Veterans Affairs Medical Center and the Center for Health Equity Research and Promotion, University Drive, Pittsburgh, PA 15240.
Dr. Shekelle: Veterans Affairs Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073.
Author Contributions: Conception and design: C.J. Crandall, S.J. Newberry, A. Diamant, Y.W. Lim, P.G. Shekelle.
Analysis and interpretation of the data: C.J. Crandall, S.J. Newberry, A. Diamant, Y.W. Lim, W.F. Gellad, M.J. Booth, P.G. Shekelle.
Drafting of the article: C.J. Crandall, S.J. Newberry, A. Diamant, M.J. Booth, A. Motala, P.G. Shekelle.
Critical revision of the article for important intellectual content: C.J. Crandall, S.J. Newberry, A. Diamant, W.F. Gellad, P.G. Shekelle.
Final approval of the article: C.J. Crandall, S.J. Newberry, A. Diamant, W.F. Gellad, P.G. Shekelle.
Statistical expertise: M.J. Booth.
Obtaining of funding: P.G. Shekelle.
Administrative, technical, or logistic support: A. Motala, P.G. Shekelle.
Collection and assembly of data: S.J. Newberry, A. Diamant, Y.W. Lim, W.F. Gellad, A. Motala, M.J. Booth, P.G. Shekelle.
Crandall CJ, Newberry SJ, Diamant A, Lim Y, Gellad WF, Booth MJ, et al. Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures: An Updated Systematic Review. Ann Intern Med. 2014;161:711-723. doi: 10.7326/M14-0317
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Published: Ann Intern Med. 2014;161(10):711-723.
Osteoporosis is a major contributor to the propensity to fracture among older adults, and various pharmaceuticals are available to treat it.
To update a review about the benefits and harms of pharmacologic treatments used to prevent fractures in adults at risk.
Multiple computerized databases were searched between 2 January 2005 and 4 March 2014 for English-language studies.
Trials, observational studies, and systematic reviews.
Duplicate extraction and assessment of data about study characteristics, outcomes, and quality.
From more than 52 000 titles screened, 315 articles were included in this update. There is high-strength evidence that bisphosphonates, denosumab, and teriparatide reduce fractures compared with placebo, with relative risk reductions from 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. Raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use: atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs.
Few studies have directly compared drugs used to treat osteoporosis. Data in men are very sparse. Costs were not assessed.
Good-quality evidence supports that several medications for bone density in osteoporotic range and/or preexisting hip or vertebral fracture reduce fracture risk. Side effects vary among drugs, and the comparative effectiveness of the drugs is unclear.
Agency for Healthcare Research and Quality and RAND Corporation.
Summary of evidence search and selection.
FRAX = Fracture Risk Assessment Tool; HRT = hormone replacement therapy; LBD = low bone density.
* Original LBD report (4).
Table 1. Principal Conclusions About Drug Efficacy/Effectiveness and Adverse Events
Table 2. Principal Conclusions About Monitoring and Treatment Duration
Table 3. Selected Adverse Events, by Drug Compared With Placebo
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Alain Braillon, MD
October 10, 2014
Two issues are ignored. - The need for transparent access to data from clinical trials, detailed trial reports must be available to independent investigators: reliability of RCT published in medical journal by industrial sponsors is poor, specifically for this discipline. Accordingly the Crandall review should have mentioned this limitation. - The classification of half of all women over 50 as suffering from osteoporosis and osteopenia may be disease mongering and the importance of non-pharmacological interventions for fracture prevention should not have been ignored. Preventing wrist or even a hip fracture may be fine, however it should be balanced with the risk of serious potential harm such as esophageal cancer. Crandall et al must be commended for their robust and large review about the benefits and harms of pharmacologic treatments used to prevent fractures in adults at risk but this deserves comments.(1) First, data sources mainly rely on primary publications of controlled trials and reviews which are sponsored by the industry, therefore report reliability may be questioned. In the case of strontium (suspended because of an unfavorable risk/benefit profile) this is well documented with important differences between data for adverse events (venous thromboembolism, pulmonary embolism and myocardial infarction) in regulatory documents and those in primary publications.(2) Transparent access to data from clinical trials is mandatory, detailed trial reports must be available to independent investigators. Second, non-pharmacological interventions (healthy eating, smoking cessation, avoiding alcohol, exercising, assessing home for fall hazards ) must be the first approach to fracture prevention.(3) No information is available yet on the added value of pharmacological treatments when life style interventions are implemented as they should be. This is a serious case for concern. Crandall et al stressed they found low-strength signals of potential associations with various types of cancer, but additional data are needed. Eg. among two meta-analysis one found an increased odds (1.74) for esophageal cancer with pharmacologic treatment. I guess many would prefer a wrist or even a hip fracture. Last, in 1994, a small study group associated with WHO gave a definition of normal bone density which classified half of all women over 50 as suffering from osteoporosis and osteopenia but we must not forget that even high risk women are at low absolute risk and that the cut-off values were arbitrary.(4) Using osteoporosis and age (>60 years) as criteria for intervention reduces the population burden of fractures by 28% and but solutions to the prevention of the remaining 72% of fragility fractures remain unavailable.(5)
1 Crandall CJ, Newberry SJ, Diamant A et al. Comparative effectiveness of pharmacologic treatments to prevent fractures: An updated systematic review. Ann Intern Med 2014. Online Sep 9. doi: 10.7326/M14-0317
2 Bolland MJ, Grey G. A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record. BMJ Open 2014;4:e005787.
3 Pekkarinen T, Lyttyniemi E, Vlimki M. Hip fracture prevention with a multifactorial educational program in elderly community-dwelling Finnish women. Osteoporos Int 2013;24:2983-92.
4 Alonso-Coello P, Garca-Franco AL, Guyatt G, Moynihan R. Drugs for pre-osteoporosis: prevention or disease mongering? BMJ 2008;336:126-129.
5 Sanders KM, Nicholson GC, Watts JJ et al. Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone 2006;38:694-700.
1Servicio Navarro de Salud, Servicio de Prestaciones Farmacéuticas, Pamplona, Spain.
November 25, 2014
The conclusion about treatment duration “How long to treat is unknown, but high-risk patients may benefit from treatment longer than 5 y” is biased. It is the result of 'cherry picking' from several post hoc subgroup analysis (1-3). For example, it ignores the fact than in the FLEX trial, treatment duration longer than 5 years did not show benefits for patients with the higher risk, those with prevalent vertebral fracture, in terms of non-vertebral fractures and clinical vertebral fractures (1).Of note, it has been an improvement in the article over the original report of the evidence review in which the first statement about the key question 5b. How does the antifracture benefit vary with long-term continued use of pharmacotherapy? was: “One large RCT showed that after 5 years of initial alendronate therapy, vertebral fracture risk and nonvertebral fracture risk were lower if alendronate was continued for an additional 5 years instead of discontinued“ (4), that is simply false (1). 1. Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, et al, FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006; 296:2927-38.2. Schwartz AV, Bauer DC, Cummings SR, Cauley JA, Ensrud KE, Palermo L, et al, FLEX Research Group. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010; 25:976-82.3. Black DM, Bauer DC, Schwartz AV, Cummings SR, Rosen CJ. Continuing bisphosphonate treatment for osteoporosis—for whom and for how long? N Engl J Med. 2012; 366:2051-34. Crandall CJ, Newberry SJ, Diamant A, Lim YW, Gellad WF, Suttorp MJ, et al. Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update of a 2007 Report. Comparative Effectiveness Review no. 53. (Prepared by Southern California Evidence-based Practice Center under contract HHSA-290-2007-10062-I.) Rockville, MD: Agency for Healthcare Research and Quality; 2012. Accessed at http://effectivehealthcare.ahrq.gov/ehc/products/160/1007/CER53_LowBoneDensity_FinalReport_on 23 November 2014.
Junwen Zhou, Tiansheng Wang, Suodi Zhai
1. Department of Pharmacy, Peking University Third Hospital, Beijing, China; 2. Department of Administrative Pharmacy and Clinical Pharmacy, Peking University Health Science Center, Beijing, China
December 14, 2014
Possible Overestimation of Evidence Strength and Inaccurate Report of Network Meta-Analysis Results
While I enjoyed reading the systematic review by Crandall et al. and agreed with the overall message, I wonder if the quality of evidence was overestimated and the NMA results were accurately reported. It’s great for Crandall et al. to use Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grade the strength of a body of evidence, but this method in their analysis is not without significant limitation due to the incomplete assessment for the risk of bias by Jadad scale . Cochrane tool  might work better in terms of risk of bias assessment in GRADE approach because it measures domains contributing to the overall assessment of risk of bias which were not assessed by Jadad scale: such as blinding for the outcome assessor, selective outcome reporting and “other sources” of bias. This limitation of Jadad scale might lead to less rigorous rating of bias of the randomized clinical trials (RCTs). One study  investigated the quality of 165 RCTs in endourology, and found out that 40 RCTs were assessed as high quality by Jadad scale, however, only 2 of them were low risk of bias according to Cochrane tool. The less rigorous assessment of risk of bias by Jadad scale might weaken the strength of the evidence comes from GRADE approach. Since Crandall assessed the evidence of most of the anti-fracture treatments preventing vertebral and non-vertebral fracture in women with osteoporosis as “strong” strength , which is considered that the evidence reflects the true effect and further research is very unlikely to change the confidence of estimate effect according to GRADE , one cannot help but doubt with the quality assessment for the body evidence. Significant limitations also exist in the comparative effectiveness. Crandall reported the Network Meta-Analysis (NMA) of Murad , however, Murad’s study evaluated several kinds of osteoporosis including cystic fibrosis patients, patients on glucocorticoid steroids, etc., which are not the focus of Crandall’s review. Moreover, Crandall did not report the significant results of denusomab  and zoledronic acid  from the NMAs sponsored by Amgen Inc. and Novartis Pharma., which is inappropriate as systematic reviews received industry funding are not necessarily unreliable. Additionally, discrepancies also existed between the results reported by Crandall and the original NMAs received no industry funding. For example, Migliore’s study  showed that zoledronic acid and denosumab could both significantly reduce the risk of vertebral fracture compared with risedronate and alendronate, respectively. However, Crandall reported that this study reported no significant difference among the included bisphosphonates. Besides the inaccuracy, it would be helpful if more NMA information could be provided. As GRADE working group has published the method of rating the quality of treatment effect estimates from NMA , the indirect evidence could “work” effectively as direct evidence. Furthermore, the ranking for medications of the same class from NMAs is very helpful for comparing efficacy. With the ranking of treatments and the strength of NMA evidence evaluated by the GRADE approach, NMA results could be extrapolated to clinical practice.  Jadad AR, Moore RA, Carroll D, et al, Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12.  Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions version 5.0.0. Cochrane Collaboration, 2008. Jo JK, Autorino R, Chung JH, et al. Randomized Controlled Trials in Endourology: A Quality Assessment. Journal of Endourology. 2013; 27: 1055-1060.  Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness of pharmacologic treatments to prevent fractures: An updated systematic review. Ann Intern Med. 2014; 161(10): 711-724. Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—agency for healthcare research and quality and the effective health-care program. J Clin Epidemiol. 2010; 63:513-23. Mohammad Hassan Murad, Matthew T. Drake, Rebecca J. Mullan et al. Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis. J Clin Endocrinol Metab. 2012; 97(6):1871–1880. Freemantle N, Cooper C, Diez-Perez A, Gitlin M, Radcliffe H, Shepherd S, et al. Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis. Osteoporos Int. 2013; 24:209-17. Jansen JP, Bergman GJ, Huels J, Olson M. The efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in osteoporosis: a network meta-analysis. Semin Arthritis Rheum. 2011; 40:275-84.e1-2. Migliore A, Broccoli S, Massafra U, Cassol M, Frediani B (2013) Ranking antireabsorptive agents to prevent vertebral fractures in postmenopausal osteoporosis by mixed treatment comparison meta-analysis. Eur Rev Med Pharmacol Sci. 17(5): 658-67. Milo A Puhan, Holger J Schünemann, Mohammad Hassan Murad, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 2014; 349:g563
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