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Electronic letters published:
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The authors' reply
Non-skeletal Effects of Osteoporosis Treatments: Does the evidence support the conclusions?
Comment
Musculoskeletal adverse effects of bisphosphonate therapy
Calcium an orphan treatment
MacLean et al. 2008; Ann Intern Med. 2008; 148:197-213.
Meta-analysis of Osteoporosis Therapies
All the data that doesn't FIT
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Catherine H MacLean, MD, PhD RAND, Greater Los Angeles Health Care System, UCLA, Margaret Maglione, Marika Suttorp
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catherine.maclean{at}wellpoint.com Catherine H MacLean, et al.
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Dr. Rosen is correct. The study he references (1) was included in our analysis but not called out in the section on renal insufficiency. This trial reported the effect of risedronate on fractures among subjects with varying degrees of renal insufficiency. This study, which combined data from nine randomized, double-blind, placebo controlled trials, reported a reduced incidence of vertebral fractures for subjects treated with risedronate relative to placebo for subjects with severe, moderate and mild renal insufficiency. Although not reported in our Annals manuscript, we did collect data and calculate pooled estimates for all adverse events reported in all studies reviewed. Details on musculoskeletal and other adverse events can be found in the appendices to the full report (2). We identified between 1 and 3 studies that compared the effect of alendronate, ibandronate, pamidronate, risedronate and/or zoledronic acid on myalgias, cramps or leg pain. Relative to placebo, significant risks were observed for ibandronate 2.25(1.57, 3.29) and zoledronic acid 3.67(2.01, 7.18). As pointed out by Stock et al., a limitation of our methods is that we did not specifically search for adverse events, but rather collected data on the adverse events that were reported in the context of our defined search strategy. However, data from the MORE trial (3) and the referenced study by Vogel, et al. (4) are included our analyses. Regarding questions about the use of previously published meta- analyses our methods do not describe pooling across meta-analyses because we did not pool across meta-analyses. All meta-analyses relevant to the study questions were sought and pooled estimates from these meta-analyses were described as reported by the original authors. Where no meta- analyses were available, we pooled data if there were at least three studies, otherwise we reported the results of one or two studies identified. Also, as stated in the methods section of the manuscript, the studies included in each of the meta-analyses are enumerated in the complete report.(2) Black et al. erroneously state that we assigned a ratings of "good efficacy” and “fair efficacy” for the prevention of hip fractures to alendronate and zoledronic acid, respectively. We reported that each of these agents reduced the risk of hip fracture and that the level of evidence to support this assessment was good for alendronate and fair for zoledronic acid. The criteria used to define the level of evidence are detailed in the methods section of the manuscript. Per these criteria, however, the level of evidence for both alendronate and zoledronic acid is good and we thank Black et al for bringing this error to our attention. With regard to the data reported in the figures for ‘high risk’ populations included in the manuscript and the data reported in the appendix figures for populations not described as high risk we would like to point out that these categories are not necessarily mutually exclusive. Additionally, some meta-analyses included in this systematic review reported risk estimate for different risk groups that are not mutually exclusive. Such is the case with the Stevenson meta-analysis.(5) The risk estimates from this meta-analysis for high risk groups are included in the ‘high risk’ figures; those for other groups in the ‘not described as high risk’ group. It is possible that some of the same patients were included in the various overlapping risk groups described in the Stevenson report. However, we do not feel that it was inappropriate for the Stevenson meta-analysis or our review to include data from the same patients in the non-mutually exclusive risk groups. This approach simply provides several different ways to look at the data. 1. Miller PD, Roux S, Barton IP, Dunlap LE, Burgio DE. Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. Journal of Bone and Mineral Research 2005;20:2105 -2115. 2. MacLean C, Alexander A, Carter J, Chen S, Desai SB, Grossman J, et al. Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis. Comparative Effectiveness Review No. 12. (Prepared by the Southern California/RAND Evidence-based Practice Center under contract 290-02-0003). Rockville, MD: Agency for Healthcare Research and Quality; December 2007. Available at http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. 3. Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, Cummings S; Multiple Outcomes of Raloxifene Evaluation Investigators. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004;104:837-44. 4. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727- 41. 5. Stevenson M, Lloyd Jones M, De Nigris E, et al. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess 2005;9(22):1-160. Conflict of Interest:None declared |
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Laura N Kuhl, BA Maine Medical Center Research Institute, Bruce Ettinger, Clifford J. Rosen, and Nananda F. Col
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kuhll{at}mmc.org Laura N Kuhl, et al.
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Because the choice of osteoporosis drugs often centers around their non-skeletal effects, it is important that clinicians have access to accurate information about their benefits and risks. In this regard the article, “Systematic Review: Comparative Effectiveness of Treatments to Prevent Fracture in Men and Women with Low Bone Density or Osteoporosis” fails in several respects. The paper reports that ibandronate protects against upper gastrointestinal perforations, ulcers, or bleeding (OR 0.33 [CI 0.14- 0.74]). This finding is based on two studies (1,2), neither of which reports a difference between ibandronate and placebo. Additionally, the authors fail to include important benefits and risks of some drugs. The paper does not mention that raloxifene has been shown to reduce breast cancer risk. The technical report leading to this conclusion (3) cites only two studies (4,5), one of which does not specifically report on breast cancer (4), and omits data from the pivotal MORE (6), RUTH (7), and STAR (8) trials. The paper also omits any mention of the risk of endometrial cancer associated with tamoxifen. Here too, the technical report erroneously concludes that endometrial cancer is not an adverse effect for tamoxifen, citing Fisher (9). However, Fisher reported an increased risk of endometrial cancer associated with tamoxifen (RR 2.53 [CI 1.35-4.97]). Additionally, neither the paper nor the technical report provide any mention of the increased risk of hot flashes that have been conclusively demonstrated for tamoxifen (9) and raloxifene (6). Although not mentioned in the Annals paper, the technical report concludes that risedronate protects against musculoskeletal events, citing ten studies. However, only four are listed as having a protective effect in the appendix of the report. In the largest of these studies (10), the direction of the effect listed in the appendix is opposite that listed in the original article. Additionally, the technical report concludes that teriparatide reduces cancer risk. Two of the 3 studies cited have identical incidence rates between treatment and placebo, while the third (11) shows a barely significant difference (p=0.05). This makes it improbable that a pooled estimate could be statistically significant. This paper is based on a technical report that is in the public domain (3). We urge the authors of the paper and technical report, as well as other interested scientists, to carefully review these materials and their conclusions. Making appropriate corrections should be a priority. References 1. Chesnut III CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbridge J, Schimmer RC, Delmas PD. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. Journal of bone and mineral research. 2004;19(8):1241-9. 2. McClung MR, Wasnich RD, Recker R, Cauley JA, Chesnut III CH, Ensrud KE, Burdeska A, Mills T. Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis. J Bone Miner Res 2004;19(1):11-8. 3. MacLean C, Alexander A, Carter J, Chen S, Desai SB, Grossman J, et al. Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis. Comparative Effectiveness Review No. 12. (Prepared by the Southern California/RAND Evidence-based Practice Center under contract 290-02-0003). Rockville, MD: Agency for Healthcare Research and Quality; December 2007. Available at www.effectivehealthcare.ahrq.gov/reports/final.cfm. 4. Grady D, Ettinger B, Moscarelli E, Plouffe L, Sarkar S, Ciaccia A, Cummings S. Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol 2004;104(4):837 -44. 5. Johnston CC Jr, Bjarnason NH, Cohen FJ, et al. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch Intern Med 2000;160(22):3444- 50. 6. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999; 282(7):637-45. 7. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, McNabb MA, Wenger NK. Effects of Raloxifene on Cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006; 355; 2: 125-137. 8. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER, Wade JL, Robidoux, A, Margolese RG, James J, Lippman, SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295(23):2727-41. 9. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90 (18):1371-88. 10. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, Eusebio RA, Devogelaer JP. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. J Bone Miner Res 2000;15(6):1006-13. 11. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Erikson EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344(19):1434- 41. Conflict of Interest:Bruce Ettinger has received honoraria or consultation fees in the past two years from: Berlex, Duramed-Barr, Eli Lilly, Glaxo-Smith Kline, Novartis, Proctor&Gamble, Roche, and Schering Plough. |
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Harold Rosen, MD Harvard
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hrosen{at}bidmc.harvard.edu Harold Rosen
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I greatly enjoyed reading the systematic review by MacLean et al (1) of treatments for osteoporosis. However, I take exception with one point. While it is true that they, “identified one trial on the efficacy of alendronate for prevention of fractures in patients with renal insufficiency (2)”, they did not mention another similar analysis documenting the efficacy of risedronate for prevention of fractures in patients with renal insufficiency (3). The paper documenting efficacy of risedronate in patients with CKD is especially important, since it documented fracture efficacy of risedronate in patients with GFR <30, or Stage 4 CKD, while the paper that the authors cited reported on patients with GFR as low as 30-45. Sincerely yours, Harold Rosen, MD Director – Osteoporosis Prevention and Treatment Center Beth Israel Deaconess Medical Center 1. MacLean C, Newberry S, Maglione M, McMahon M,Ranganath V,Suttorp M et al. Ann Intern Med 2008;148-197 2. Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, IshaniA, et al. . J Bone Miner Res 2007;22:503-8 3. Miller P, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. J Bone Miner Res 2005;20:2105-2115 Conflict of Interest:None declared |
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Lionel S Lim, MD, MPH Griffin Hospital
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lionel_lim{at}hotmail.com Lionel S Lim
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MacLean et al did not mention musculoskeletal adverse effects associated with bisphosphonates in their review of osteoporosis treatments. Although the majority of adverse effects are gastrointestinal related, bisphosphonate use may also induce musculoskeletal side effects. Postmarketing reports describe severe disabling and incapacitating musculoskeletal pain which may occur up to 4 years after taking alendronate or risedronate (1). Retrospective cohort studies have examined the prevalence of musculoskeletal adverse effects of alendronate and risedronate (2, 3). Among 840 patients receiving the above bisphosphonates (84.5% alendronate users), the prevalence of musculoskeletal adverse effects (bone pain, arthralgias, and myalgias) was 2.3% for alendronate and 3.1% for risedronate (2). Another study of 612 patients in an osteoporosis clinic revealed that 5.6% experienced musculoskeletal adverse effects with alendronate and risedronate therapies, including myalgia, arthralgia, back pain, and generalized bone pain (3). Unlike the former study, it was observed that all cases of musculoskeletal adverse effects occurred in patients whose treatment was commenced with once-weekly formulations of the above bisphosphonates: 20.1% and 25% of alendronate and risedronate users respectively. Although not as frequent as gastrointestinal side effects, clinicians need to be aware of and counsel patients regarding possible musculoskeletal adverse effects associated with oral bisphosphonate therapy. References 1. Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med. 2005;165(3):346-7. 2. Anastasilakis AD, Goulis DG, Kita M, Avramidis A. Oral bisphosphonate adverse effects in 849 patients with metabolic bone diseases. Hormones (Athens). 2007;6(3):233-41. 3. Bock O, Boerst H, Thomasius FE, et al. Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention. J Musculoskelet Neuronal Interact. 2007;7(2):144-8. Conflict of Interest:None declared |
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Richard L Prince, MD FRACP Univ of Western Australia, Sir Charles Gairdner Hospital
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rlprince{at}cyllene.uwa.edu.au Richard L Prince
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The latest omnibus attempt at meta analysis of treatments for osteoporosis leaves the authors open to the charge of data being lost in translation (1). We note that other correspondents are concerned about their favourite therapy, ours is calcium (2) an orphan treatment that does not have it's RCT's regulated by a single organisation. As such the quality of the studies may be open to question. In the current meta analysis the effects of the RECORD trial must have had a disproportionate effect because of its size (3). However it must be pointed out to all interested in such studies that the RECORD investigators did not meet the patients in the study face to face nor confirm compliance by tablet counting, a critical if undervalued aspect of clinical trialling. Despite the patients best intentions medications are often missed. Our study emphasised the importance of compliance with calcium therapy, which has a short duration of action to suppress PTH, the probable mechanism of action, due to the continual renal leak of calcium associated with gonadal failure (4, 5). Despite the shortcomings of some trials of calcium and vitamin D another recent meta analysis concentrating on calcium with or without vitamin D concluded that there was a 12% risk reduction of all fracture types (6). 1. MacLean C, Newberry S, Maglione M, McMahon M, Ranganath V, Suttorp M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148(3):197-213. 2. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5- year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006;166(8):869-75. 3. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low- trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365(9471):1621-8. 4. Dick IM, Liu J, Glendenning P, Prince RL. Estrogen and androgen regulation of plasma membrane calcium pump activity in immortalized distal tubule kidney cells. Molecular and Cellular Endocrinology 2003;212(1-2):11 -8. 5. Dick IM, Devine A, Beilby J, Prince RL. Effects of endogenous estrogen on renal calcium and phosphate handling in elderly women. Am J Physiol Endocrinol Metab 2005;288(2):E430-435. 6. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370(9588):657-66. Conflict of Interest:None declared |
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John L Stock, MD Eli Lilly and Company, Indianapolis, IN, John L. Mershon and Michael Jay Schoenfeld
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jlstock{at}lilly.com John L Stock, et al.
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We read with interest the recent comprehensive AHRQ systematic review on osteoporosis therapies by MacLean et al (1), and would like to bring 3 issues to your attention. The paper describes an increased risk of “mild cardiac events” with raloxifene, based on a combination of 4 events (tachycardia, chest pain, palpitations and vasodilatation) across 6 studies [total N=2686]. Criteria for selecting these particular events and trials are not given. Importantly, the trials selected do not include the pivotal randomized, placebo-controlled trials, such as the Multiple Outcomes of Raloxifene Evaluation [MORE, N=7705] (2) and Raloxifene Use for the Heart [RUTH, N=10,101] (3) trials, which form the basis of the FDA-approved indications and safety profile for raloxifene. In addition, the term “vasodilatation” corresponds to hot flashes or flushes, which are not mild cardiac events. If the term “vasodilatation” is not included, only 8 “mild cardiac events” remain across the 6 trials, all of which were reported as “chest pain”, with 4 events in the raloxifene and placebo groups respectively. If “mild cardiac events” includes only the adverse events of tachycardia, chest pain, and palpitations, then the numbers of these events are not different between the raloxifene and placebo groups in the pivotal MORE and RUTH studies (Data on file, Eli Lilly and Company). Secondly, while the focus of the systematic review is bone agents, no mention is made of the primary efficacy and safety trials (2, 3, 4), with a total of 37,000 subjects, which support the more recent FDA-approved indications for raloxifene: the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and the reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer, in addition to postmenopausal osteoporosis prevention and treatment. Lastly, the authors conclude that the available data are insufficient to determine the relative efficacy or safety of osteoporosis agents due to few head-to-head comparisons. One such comparative study was published on 15 November 2007, 5 days after the end of the specified literature search period. This 18-month randomized, double-blind trial compared teriparatide with alendronate in 428 patients with glucocorticoid-induced osteoporosis, with a change in lumbar spine BMD as the primary outcome, and safety and incidence of fractures as secondary outcomes (5). We want to bring these 3 points to your readers’ attention so that they are aware of the current available efficacy and safety data. Potential Financial Conflicts of Interest: All employees of Eli Lilly and Company. Current Author Addresses: John L. Stock, MD, Medical Fellow, Women’s Health, Osteoporosis, and Urology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, e-mail: jlstock@lilly.com; John L. Mershon, MD, Medical Advisor, Women’s Health, Osteoporosis, and Urology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, e- mail: jlmershon@lilly.com; Michael Jay Schoenfeld, MA, Outcome Liaison Consultant, Women’s Health, Osteoporosis, and Urology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, e-mail: michael_jay@lilly.com. 1. MacLean C, Newberry S, Maglione M, McMahon M, Ranganath V, Suttorp M, et al. Systematic Review: Comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med. 2008;148:197-213. 2. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-45. 3. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-37. 4. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727- 41. 5. Saag KG, Shane E, Boonen S, Marin F, Donley DW, Taylor KA, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357:2028-39. Conflict of Interest:None declared |
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Dennis M. Black, PhD University of California, San Francisco, Steven Boonen, Pierre Delmas, Kenneth W.Lyles
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dblack{at}psg.ucsf.edu Dennis M. Black, et al.
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The meta-analysis by MacLean and colleagues 1 is interesting and comprehensive but we question one methodologic aspect: use of previous meta-analyses and their combination with individual trials. The methods are unclear as to how previous meta-analyses were chosen/combined and this may have led to inconsistent results. For example, for alendronate, 2 meta -analyses are listed for high risk patients (defined in Table 1) for hip fracture (table 4). One meta-analysis includes two trials in high risk patients. The other includes six trials, two overlap with the first meta- analysis while the other 4 do not meet the authors' high risk criteria. How were these two meta-analyses combined and the non-high risk studies incorporated in order to achieve the overall assessment? We suggest that greater consistency and clarity would be gained in building meta-analyses from relevant individual trials. This inconsistent use of meta-analyses and individiual trials could lead to inconsistent results. For example, for hip fractures in high risk patients, alendronate is assigned "good" efficacy while zolendronic acid is assigned "fair" efficacy. Both drugs have two trials in high risk patients as defined in table 1. The two alendronate studies had hip fracture as secondary outcomes with the first marginally significant (p=.047) and the second very small (4 hip fractures total) and not significant. For zoledronic acid, the first study 2 had hip fracture as a primary endpoint with very significant results (p=.002) and the second had a beneficial trend (with 56 hip fractures) 3. It is not clear how these two zoledronic acid studies were combined to yield the overall assessment since no meta-analysis yet exists but we performed a pooled analysis to yield a hazard ratio of 0.6, p<.01. Thus, evidence for hip fracture efficacy for zoledronic acid is at least as strong as alendronate and should support a similar overall efficacy. This inconsistency would have been alleviated by building the meta-analysis from individual studies. We would like to know what criteria were used to choose which meta- analyses were included and how they were combined with each other and with individual trials. We strongly believe that the use and combination of previous meta-analyses is confusing, is not always consistent with the authors stated methods and has led, at least in one case, led to an illogical efficacy assessment. We suggest that future meta-analyses rely solely on individual studies that meet their specific criteria. Sincerely, Dennis M. Black , PhD Steven Boonen, MD, PhD Pierre Delmas, MD, PhD Kenneth W.Lyles, MD 1. Maclean C, Newberry S, Maglione M, et al. Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis. Ann Intern Med 2007. 2. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356:1809-22. 3. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. N Engl J Med 2007. Conflict of Interest:Dennis Black has a Novartis Research Contract and is on the Merck Speaker's Bureau. Pierre Delmas consults for Novartis. Ken Lyles receives research support from Novartis, Alliance for Better Bone Health and Amgen, consults for Novartis, Procter & Gamble, Merck, Amgen, GTx, Lilly, GSK and Bone Medical Ltd. He is the a Use Patent Inventor of US Patent Application 20050272707: Methods for preventing or reducing secondary fractures after hip fracture, as well as the Provisional Patent Application Inventor for Medication Kits and Formulations for Preventing, Treating or Reducing Secondary Fractures After Previous Fracture. Steven Boonen receives research funding and/or consulting fees from Amgen, Aventis Pharma, Celtrix Pharmaceuticals, Eli Lilly & Company, GlaxoSmithKline, Insmed Pharmaceuticals, Institut de Recherches Internationales Servier, Merck Sharp & Dohme, Novartis Pharma, Nycomed, Pfizer, Procter & Gamble Pharmaceuticals, Roche Pharma, Sanofi-Aventis. |
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Robert Karis, M.D. none
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rckaris{at}gmail.com Robert Karis
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The review article by MacLean et al inappropriately uses the same data in two mutually exclusive categories, thereby increasing the statistical significance in both of these categories. Figure 4 in the article by MacLean et al concerns hip fractures in high risk patients. The data source for 3,021 of these patients is the review article by Stevenson et al (ref 22). In Table 15 of Stevenson et al, it is evident that the original data is found in the 1996 FIT study of 2027 patients (Lancet 1996:348:1535-41) and the 1995 study by Liberman et al of 994 patients (N Engl J Med 1995;333:1437-42). Figure 3 in the appendix of the article by MacLean et al addresses hip fractures in non-high risk patients. The data source for 5,426 of these patients is the review article by Stevenson et al. In Table 15 of Stevenson et al, it is seen that the original data comes from the 1998 FIT study of 4,432 patients AND the same 994 patients from the 1995 study by Liberman et al. The 994 patients mentioned above don't all belong in both the high risk and non-high risk categories. Furthermore, none of the three original articles are referenced in the article by MacLean et al, which I think is not a good practice. Conflict of Interest:None declared |
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