On 2014 Apr 05, Andrea Messori commented:

Incidence of new vertebral fractures in women treated with an antireabsorptive agent or placebo: re-analysis of 9 randomized trials

In the study of anti-reabsorptive agents for preventing vertebral fractures in women with post-menopausal osteoporosis, the systematic review published by Migliore et al[1] is the most recent contribution in this area and has also the merit that mixed treatment comparisons were carried out.

One limitation of the study by Migliore et al[1] is that, in studying the end-point of new vertebral fractures according to 9 randomized placebo-controlled trials [2-10], the crude event rates were not presented for individual trials. In fact, only the denominators of these rates were reported (see Table I of the publication by Migliore et al[1]). In addition, these denominators were affected by some typographical errors (eg. see the number of patients enrolled in the placebo arm of the trial by Lieberman et al. [3], N=42, which is erroneous and seems to be an inadvertent duplicate presentation of the age of the same patients).

We have previously stressed that the crude event rates extracted from individual trials should be reported in any meta-analysis study [11] because this presentation allows us to verify the quality of the extraction process and the reliability of the final results.

We have therefore re-extracted the event rates from the 9 trials [2-10] and we have reanalyzed these rates by redoing the same meta-analysis carried out by Migliore et al.[1] (see their Table II, first five comparisons vs placebo). Our analysis was based on the random-effect model as implemented in the OMA software [12]. We expressed our results as both odds-ratio and relative risk.

Figure 1 shows the results of this re-analysis. Our results are nearly identical to those published by Migliore et al. [1] and can therefore be seen as a useful confirmation of the findings of the referenced study.

Andrea Messori HTA Unit ESTAV Centro 50100 Firenze Italy

FIGURE 1 - Incidence of new vertebral fractures in women treated with an anti-reabsorptive agent or placebo.

The Forest plot shows the subgroup analysis for 5 treatments (alendronate, risedronate, zolendronate, ibandronate, and denosumab) compared with placebo. The original material was derived from 9 randomized trials [2-10]. The meta-analysis results are expressed as odds-ratio (Panel A) and relative risk (Panel B).<br> Abbreviations and symbols: horizontal black lines represent the 95CI% around the event rate (■); yellow diamonds represent the pooled (meta-analytical) rate with its 95%CI for the various subgroups, while the blue diamond represents the pooled overall rate across the two subgroups. The vertical dotted line (in red) represents the pooled rate from the overall series of 9 trials. I² is the index of heterogeneity and is accompanied by the p-value of its statistical significance. Abbreviations: RR, relative risk; Ev, number of events; Trt, number of patients in the treatment group; Ctrl, number of patient in the control group; ALE, alendronate; RIS, risedronate,; ZOL, zolendronate; IBA, ibandronate; DEN, denosumab.

This figure can be downloaded at the address: http://www.osservatorioinnovazione.net/papers/migliore2013fig1.jpg

References

1. Migliore A, Broccoli S, Massafra U, Cassol M, Frediani B. Ranking antireabsorptive agents to prevent vertebral fractures in postmenopausal osteoporosis by mixed treatment comparison meta-analysis. Eur Rev Med Pharmacol Sci. 2013 Mar;17(5):658-67.

2. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996 Dec 7;348(9041):1535-41. PubMed PMID: 8950879.

3. Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov 30;333(22):1437-43. PubMed PMID: 7477143.

4. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998 Dec 23-30;280(24):2077-82. PubMed PMID: 9875874.

5. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999 Oct 13;282(14):1344-52. PubMed PMID: 10527181.

6. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11(1):83-91. PubMed PMID: 10663363.

7. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007 May 3;356(18):1809-22. PubMed PMID: 17476007.

8. Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007 Nov 1;357(18):1799-809. Epub 2007 Sep 17. PubMed PMID: 17878149.

9. Chesnut III CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004 Aug;19(8):1241-9. Epub 2004 Mar 29. PubMed PMID: 15231010.

10. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11. Erratum in: N Engl J Med. 2009 Nov 5;361(19):1914. PubMed PMID: 19671655.

11. Messori A, Fadda V, Maratea D, Trippoli S. The need to know crude event rates in meta-analysis. Am Heart J. 2013 Sep;166(3):e17. doi: 10.1016/j.ahj.2013.06.016. Epub 2013 Jul 25. PubMed PMID: 24016516.

12. OMA software (OMA, Open Meta-Analyst version 4.16.12, Tufts University, U.S., url http://tuftscaes.org/open_meta/)

On 2014 Apr 05, Andrea Messori commented:

Incidence of new vertebral fractures in women treated with an antireabsorptive agent or placebo: re-analysis of 9 randomized trials

In the study of anti-reabsorptive agents for preventing vertebral fractures in women with post-menopausal osteoporosis, the systematic review published by Migliore et al[1] is the most recent contribution in this area and has also the merit that mixed treatment comparisons were carried out.

One limitation of the study by Migliore et al[1] is that, in studying the end-point of new vertebral fractures according to 9 randomized placebo-controlled trials [2-10], the crude event rates were not presented for individual trials. In fact, only the denominators of these rates were reported (see Table I of the publication by Migliore et al[1]). In addition, these denominators were affected by some typographical errors (eg. see the number of patients enrolled in the placebo arm of the trial by Lieberman et al. [3], N=42, which is erroneous and seems to be an inadvertent duplicate presentation of the age of the same patients).

We have previously stressed that the crude event rates extracted from individual trials should be reported in any meta-analysis study [11] because this presentation allows us to verify the quality of the extraction process and the reliability of the final results.

We have therefore re-extracted the event rates from the 9 trials [2-10] and we have reanalyzed these rates by redoing the same meta-analysis carried out by Migliore et al.[1] (see their Table II, first five comparisons vs placebo). Our analysis was based on the random-effect model as implemented in the OMA software [12]. We expressed our results as both odds-ratio and relative risk.

Figure 1 shows the results of this re-analysis. Our results are nearly identical to those published by Migliore et al. [1] and can therefore be seen as a useful confirmation of the findings of the referenced study.

Andrea Messori HTA Unit ESTAV Centro 50100 Firenze Italy

FIGURE 1 - Incidence of new vertebral fractures in women treated with an anti-reabsorptive agent or placebo.

The Forest plot shows the subgroup analysis for 5 treatments (alendronate, risedronate, zolendronate, ibandronate, and denosumab) compared with placebo. The original material was derived from 9 randomized trials [2-10]. The meta-analysis results are expressed as odds-ratio (Panel A) and relative risk (Panel B).<br> Abbreviations and symbols: horizontal black lines represent the 95CI% around the event rate (■); yellow diamonds represent the pooled (meta-analytical) rate with its 95%CI for the various subgroups, while the blue diamond represents the pooled overall rate across the two subgroups. The vertical dotted line (in red) represents the pooled rate from the overall series of 9 trials. I² is the index of heterogeneity and is accompanied by the p-value of its statistical significance. Abbreviations: RR, relative risk; Ev, number of events; Trt, number of patients in the treatment group; Ctrl, number of patient in the control group; ALE, alendronate; RIS, risedronate,; ZOL, zolendronate; IBA, ibandronate; DEN, denosumab.

This figure can be downloaded at the address: http://www.osservatorioinnovazione.net/papers/migliore2013fig1.jpg

References

1. Migliore A, Broccoli S, Massafra U, Cassol M, Frediani B. Ranking antireabsorptive agents to prevent vertebral fractures in postmenopausal osteoporosis by mixed treatment comparison meta-analysis. Eur Rev Med Pharmacol Sci. 2013 Mar;17(5):658-67.

2. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996 Dec 7;348(9041):1535-41. PubMed PMID: 8950879.

3. Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov 30;333(22):1437-43. PubMed PMID: 7477143.

4. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998 Dec 23-30;280(24):2077-82. PubMed PMID: 9875874.

5. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999 Oct 13;282(14):1344-52. PubMed PMID: 10527181.

6. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11(1):83-91. PubMed PMID: 10663363.

7. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007 May 3;356(18):1809-22. PubMed PMID: 17476007.

8. Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007 Nov 1;357(18):1799-809. Epub 2007 Sep 17. PubMed PMID: 17878149.

9. Chesnut III CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004 Aug;19(8):1241-9. Epub 2004 Mar 29. PubMed PMID: 15231010.

10. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11. Erratum in: N Engl J Med. 2009 Nov 5;361(19):1914. PubMed PMID: 19671655.

11. Messori A, Fadda V, Maratea D, Trippoli S. The need to know crude event rates in meta-analysis. Am Heart J. 2013 Sep;166(3):e17. doi: 10.1016/j.ahj.2013.06.016. Epub 2013 Jul 25. PubMed PMID: 24016516.

12. OMA software (OMA, Open Meta-Analyst version 4.16.12, Tufts University, U.S., url http://tuftscaes.org/open_meta/)