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Bisphosphonates can prevent recurrent hip fracture and reduce the mortality in osteoporotic patient with hip fracture: A meta-analysis.

Byline: Jing Peng, Yong Liu, Long Chen, Kun Peng, Zhao Xu, Dagang Zhang and Zhou Xiang

ABSTRACT

Objective: This meta-analysis was conducted to investigate the efficacy of bisphosphonates for preventing recurrent hip fracture and reducing the mortality of elderly patient with hip fracture.

Methods: The databases of Pubmed, Embase and Cochrane Library were searched. All randomized or prospective matched controlled trials that assessed the efficacy of bisphosphonate for elderly patients with hip fracture were included. Two researchers independently extracted data of the included articles and assessed the methodological quality which was assessed based on Jadad scoring system or Newcastle-Ottawa scale. The second hip fracture incidence, mortality and complications were compared between bisphosphonates and control groups.

Results: Four studies including 3088 patients were included. Results showed that there were significant difference of second hip fracture (Pless than 0.05) and mortality (Pless than 0.05) between bisphosphonates group and control group. While no significant intergroup difference were observed for all complications. Conclusions: Bisphosphonates can prevent subsequent hip fracture, reduce the mortality, and does not increase the overall complications in elderly patients with hip fracture.

KEY WORDS: Bisphosphonate, Osteoporosis, Hip fracture.

INTRODUCTION

Hip fracture represents the most serious consequence of osteoporosis, which is related to increased mortality,1-3 diminished function of extremity and quality of life.4,5 With the aging of the world population, the incidence of fragility fracture will significantly increase, and the annual number of hip fracture may double during the first half century.6,7 However, prior hip fracture is a risk factor for subsequent fracture, which is associated with a more than 2.0-fold increased risk of subsequent fracture.8,9 with the incidence range from 1% to 14.8%.10-12 In addition, the high rate of recurrent hip fracture, which is also related to high rate of bone loss,13 accompany greatly increase of mortality.9

Considering the grave consequences, measures must be initiated to prevent the second hip fracture occurrence. Unfortunately, osteoporosis is usually under-diagnosed and undertreated in elderly hip fracture patients.14 In recent years, bisphosphonates are widely used for treatment of osteoporosis, such as Alendronate, Risedronate and Zoledronic et al., as those agents have been approved to reduce the incidences of vertebral and hip fracture in elderly patients.15-17 However, whether the bisphosphonates can reduce the risk of second hip fracture is unknown. Although a few studies had focused on the issue, it is still controversial because of the small sample and inconformity of the outcome. In order to acquire a reliable conclusion, we compiled all available data from a few prospective or randomized researches and carried out a meta-analysis to assess the efficacy of biphosphonates on the subsequent hip fracture in the elderly patients with hip fracture.

METHODS

Systematic literature search: The databases of Pub-med, Embase and Cochrane Library were searched from inception to January 2015. The search strategy was based on combination of medical subject headings (MeSH) or keywords "bisphosphonates", "osteoporosis", "hip fracture". Two researchers independently identified the titles and abstracts related to effect of bisphosphonates for elderly patient with hip fracture, and full text of all potentially relevant studies were obtained to identify whether it can be included. References of all included articles were also manually browsed to identify potentially relevant studies which were not searched in the databases. Inclusion and exclusion criteria

Types of studies: Randomized control trial (RCT) and prospective non-randomized concurrent controlled trials were considered for this meta-analysis. Types of participants: Osteoporotic patients with age more than 50 years who had undergone hip fracture were included in this research. Patients with secondary osteoporosis were excluded.

Types of interventions: Trials that compared oral bisphosphonate with placebo or blank control in older patients with hip fracture were included. Types of outcome measures: The primary outcomes were second hip fracture, mortality. The second hip fracture was related to the recurrent hip fracture. Secondary outcomes were the all complications, other complications. Other complications refer to the complications that excluded the mortality and the second hip fracture.

Data extraction and quality assessment: Two researchers independently extracted data from the eligible articles, and performed the assessment of the methodological quality. Any disagreement was resolved by discussion to reach final consensus. If more than one paper with the same data were identified, only the one containing definitive data were included. Extracted data included demographics, methodology, details of intervention, and the interest outcomes (such as the second hip fracture cases, mortality and complications).If there were no exact records about the second fracture cases, an email was sent to the authors in order to obtain the accurate cases. The quality of RCTs were assessed by the Jadad score,18 with a cumulative score >3 indicating high quality. While the quality of non-randomized trials were assessed by the Newcastle-Ottawa scale,19 a score [greater than or equal to]5 indicating high quality.

Data analyses: All data analysis was conducted with the Review Manager 5.1 software. The weighted mean difference was measured for continuous variables, and relative risk (RR) was calculated for dichotomous outcomes. Pless than 0.05 were considered statically significant, and the 95% confidence intervals (CIs) were reported. Statistical heterogeneity among researches was assessed by I-square (I2) and Chi-square (kh) test. If there was no statistical heterogeneity (I2less than 50% or kh2 test P[greater than or equal to]0.1), a fixed effect model was adopted, or a random effect model was used. Funnel plots were not created because the included trials were only four.

Table-I: Characteristics of included studies.

Included###Design###Samples###Age(years)###Men(%)###Intervention###Follow-up

studies###(month)

###Bisphosphonate Control Bisphosphonate Control###Bisphosphonate Control

Lyles###RCT###1054###1057###749.48###74.69.86###23.3%###24.5%###Zoledronic###36

et al.[20]###acid

Beaupre###Prospective###101###108###56% patients###44%patients 27%###43%###Alendronate,###24

et al.[22]###control###> 75 years###> 75 years###Risedronate

Etidronate

Cecilia###RCT###119###120###817###817###20.2%###21.6%###Alendronate###12

et al.[21]

Osaki###Prospective###173###356###80.27.9###81.98###0###0###Risedronate###36

et al.[23]###control

RESULTS

Characteristics of studies: A total of 912 studies were retrieved from the database after removing the duplication. After carefully screening of the titles and abstracts by two reviewers, another 702 papers were excluded because they were not found relevant. Then the two reviewers reviewed the full article, and 108 articles were excluded, leaving 4 articles20-23 which matched the inclusion criteria for data extraction and analysis. In the 4 researches, a total of 3088 patients over 50 years were enrolled in this meta-analysis (Fig.1). The baseline charac-teristics were comparable between the bisphosphonate group and control group, and the intervention contained zoledronic acid, Alendronate, Risedronate, Etidronate (Table-I). Outcomes of interest, such as second hip fracture, mortality, complications, are involved in those researches (Table-II). The outcomes of the quality assessment of the included researches were displayed in Table III and IV.

Second hip fracture: The second hip fracture incidences were mainly compared in two researches.20,23 Three researches showed the cases of second hip fracture of bisphosphonate group and control group. Another research22 revealed the total second hip fracture patients, and the specific numbers in each group was obtained by an email from the authors. Overall, the four studies involved 3088 patients to compare the incidences of second hip fracture between the bisphosphonate group and control group. The heterogeneity test showed there was no statistical heterogeneity (kh2=4.63, df=3, P=0.20, I2=35%). Data pooled by the fixed effect model revealed significant difference of second hip fracture between bisphosphonate group and control group (mean difference: 0.60, 95% CI 0.39 to 0.93, P=0.02) (Fig.2).

Mortality: Two articles evaluated the mortality of bisphosphonate group and control group; although the other two studies did not directly assess the effect of bisphosphonate on the mortality, we can extract the cases of death of each group from the article. The heterogeneity test indicated there was no statistical heterogeneity (kh2=2.24, df=3, P=0.52, I2=0%). A fixed effect model was adopted and the analytic data showed that there was significant difference between bisphosphonate group and control group (mean difference: 0.66, 95% CI 0.52 to 0.85, P=0.001) (Fig.3).

Table-II: Outcomes of two groups in the included studies

Included studies###Second hip fracture###BMD of TH###Death###Other complications

###Bisphosphonate###Control###Bisphosphonate###Control###Bisphosphonate###Control###Bisphosphonate###Control

Lyles et al.[20]###23/1054###33/1057###+2.6%###-1.0%###101/1054###141/1057###743/1054###678/1057

Beaupre et al.[22]###3/101###1/108###NA###NA###7/101###17/108###NA###NA

Cecilia et al.[21]###2/119###2/119###+0.79%###-1.78%###13/119###15/120###10/119###12/120

Osaki et al.[23]###5/173###32/356###NA###NA###NA###NA###32/173###55/356

Table-III: Quality assessment of the included RCTs in term of the Jadad scoring system.

Study###Randomized###Appropriate###Appropriate###Description of###Jadad score###Study quality

###randomization###double blinded###withdrawals

Lyles et al.[20]###Yes###Yes###Yes###Yes###5###High

Cecilia et al.[21]###Yes###Yes###No###Yes###3###Low

Table-IV: Quality assessment of the non-randomized controlled trials in term of the Newcastle-Ottawa scale.

Study###Selection star###Comparability star###Outcome star###Total star###Study quality

Beaupre et al.[22]###4###1###3###8###High

Osaki et al.[23]###4###1###3###8###High

Other complications: The other complications, which refer to the complications excluded the second hip fracture and death, included renal event, myalgia, influenza-like symptoms, headache, arthralgia, pyrexia, cardiovascular or cerebrovascular event, gastric symptoms, other sites fracture, etc.

Three studies compared the other complications between two groups. The heterogeneity test indicated there was no statistical heterogeneity (kh2=1.14, df=2, P=0.57, I2=0%). The other complications were significant different between bisphosphonate group and control group (mean difference: 1.3, 95% CI 1.10 to 1.54, P=0.002) (Fig.4).

All complications: Data of all complications was extracted from the three studies and was analyzed. The heterogeneity test indicated there was no statistical heterogeneity (kh2=2.49, df=2, P=0.29, I2=20%). Data pooled by a fixed effect model revealed no statistical significant difference between the two groups (mean difference: 1.02, 95% CI 0.84 to 1.22, P=0.87) (Fig.5).

DISCUSSION

Because of the subsequently increasing morbidity and mortality results from fragile hip fracture in elderly patient, measures must be carried out to prevent hip fracture. Antiosteoporosis therapy-pharmacological treatment is one of the most important methods which is now widely adopted presently. Bisphosphonates, such as alendronate, risedronate, zoledornic acid, recommended as firstline drug for primary prevention of osteoporotic fracture, are widely prescribed medicines for osteoporotic therapy, which were proved to be effective and can reduce the vertebral fracture, non-vertebral fracture and mortality.15,16,24-26 In addition, bisphosphonates also possessed a preventive effect on hip fracture in elderly osteoporotic patients.27 However, these researches mainly target the patients without hip fracture.

As hip fracture in elderly osteoporotic patient indicated serious osteoporosis, and the prior fracture also is a risk factor for new fracture, whether the bisphosphonate can also hold the efficacy for preventing second hip fracture in elderly patients with hip fracture is under discussion.

The research focusing on the efficacy of preventing second hip fracture was very few. Although a few retrospective studies showed that adherent use of bisphosphonate could significantly reduce the risk of second hip fracture.12,28 However, retrospective studies may affect the validity, and randomized control trial or prospective matched studies also needed to certify the efficacy of bisphosphonate on second hip fracture protection. In this metaanalysis, four articles were included, which contain two randomized control trials and two prospective studies. In general, only randomized control trial can be included in meta-analysis, but the researches that focused on the elderly patients with hip fracture and put the second hip fracture or mortality as the first outcome were so few that we included the other two prospective studies, in order to avoid losing the valid data.

In the four researches, the baseline characteristics (such as age, BMD) between the bisphosphonate and control group were relatively comparable, which can reduce the selection bias. Finally, a total of 3088 patients were included in this analysis, and the outcomes revealed that there was significant difference of second hip fracture (mean difference: 0.60, 95% CI 0.39 to 0.93) and mortality (mean difference: 0.66, 95% CI 0.52 to 0.85) between bisphosphonate group and control group. The reduction of second hip fracture may be partly ascribed to the improved BMD produced by bisphosphonate, as a few researches showed than bisphosphonate can increase the BMD in patients with low trauma fracture.20,29

The all complications were comparable between bisphosphonate group and control group (mean difference: 1.02, 95% CI 0.84 to 1.22), while the other complications (excluding the second hip fracture and mortality) were more common in the bisphosphonate group ((mean difference: 1.3, 95% CI 1.10 to 1.54). The results showed that constituent ratio of complications may be transformed by bisphosphonate-the rate of serious adverse events (such as death, second hip fracture) was reduced and some mild symptoms (such as gastric symptoms, headache, myalgia, influenza-like symptoms) increased.

The compliance with bisphosphonate also influence the efficacy of pharmacotherapy, and some researches had confirmed that the refracture rate for patients with >80% compliance was significantly lower than that less than 80% compliance.12,28,30

In this meta-analysis, the compliance of patients in the four included researches was higher than 80%.The decreased mortality can be attributed to several reasons. First, the reduction in the risk of death may be partly related to the reduction of second hip fracture, as subsequent hip fracture were significantly associated with excess mortality. Second, bisphosphonate could provide protective effect against cardiovascular events, and patients with bisphosphonate therapy had a lower risk of acute myocardial infarction, which was proved by Kang's research.31 In addition, Colon-Emeric et al also reported that patients treated with zoledronic acid were less likely to die from cardiac arrhythmias than control group.32 Last, bisphosphonate may have effect on immunomodulatory effect, affecting both dendritic cells and T cells.33

Limitations: First, the drugs, doses, frequency, prescription time in each research were not perfectly same, which may influence the outcomes of interest, although the drugs all belong to bisphosphonate and the doses were the recommended dose. Second, the included studies were still relatively few-only four researches. Last, because the researches of bisphosphonate for elderly patients with hip fracture are so few that two prospective matched cohort researches were also included, which may result in selection bias in this meta-analysis.

In conclusion, this meta-analysis revealed that bisphosphonates can prevent subsequent hip fracture, reduce the mortality, and does not increase the overall complications in elderly patient with hip fracture. On the basis of this meta-analysis, bisphosphonate therapy for elderly patients with hip fracture was supported.

REFERENCES

1. Omsland TK, Emaus N, Tell GS, Magnus JH, Ahmed LA, Holvik K, et al. Mortality following the first hip fracture in Norwegian women and men (1999-2008). A NOREPOS study. Bone. 2014;63: 81-86.

2. Davidson CW, Merrilees MJ, Wilkinson TJ, McKie JS, Gilchrist NL. Hip fracture mortality and morbidity--can we do better? N Z Med J. 2001;114(1136): 329-332.

3. Pande I, Scott DL, O'Neill TW, Pritchard C, Woolf AD, Davis MJ. Quality of life, morbidity, and mortality after low trauma hip fracture in men. Ann Rheum Dis. 2006;65(1): 87-92.

4. Boonen S, Autier P, Barette M, Vanderschueren D, Lips P, Haentjens P. Functional outcome and quality of life following hip fracture in elderly women: a prospective controlled study. Osteoporos Int. 2004;15(2): 87-94.

5. Adachi JD, Loannidis G, Berger C, Joseph L, Papaioannou A, Pickard L, et al. The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada. Osteoporos Int. 2001;12(11): 903-908.

6. Rosengren BE, Karlsson MK. The annual number of hip fractures in Sweden will double from year 2002 to 2050: projections based on local and nationwide data. Acta Orthop. 2014;85(3): 234-237.

7. Friedman SM, Mendelson DA. Epidemiology of fragility fractures. Clin Geriatr Med. 2014;30(2): 175-181.

8. Colon-Emeric C, Kuchibhatla M, Pieper C, Hawkes W, Fredman L, Magaziner J, et al. The contribution of hip fracture to risk of subsequent fractures: data from two longitudinal studies. Osteoporos Int. 2003;14(11): 879-883.

9. Bliuc D, Alarkawi D, Nguyen TV, Eisman JA, Center JR. Risk of subsequent fractures and mortality in elderly women and men with fragility fractures with and without osteoporotic bone density: The dubbo osteoporosis epidemiology study. J Bone Miner Res. 2015;30(4): 637-646. doi: 10.1002/jbmr.2393.

10. Berry SD, Samelson EJ, Hannan MT, McLean RR, Lu M, Cupples LA, et al. Second hip fracture in older men and women: the Framingham Study. Arch Intern Med. 2007;167(18): 1971-1976.

11. Shen SH, Huang KC, Tsai YH, Yang TY, Lee MS, Ueng SW, et al. Risk analysis for second hip fracture in patients after hip fracture surgery: a nationwide population-based study. J Am Med Dir Assoc. 2014;15(10): 725-731.

12. Lee YK, Ha YC, Choi HJ, Jang S, Park C, Lim YT, et al. Bisphosphonate use and subsequent hip fracture in South Korea. Osteoporos Int. 2013;24(11): 2887-2892.

13. Karlsson M, Nilsson JA, Sernbo I, Redlund-Johnell I, Johnell O, Obrant KJ. Changes of bone mineral mass and soft tissue composition after hip fracture. Bone. 1996;18(1): 19-22.

14. Andrade SE, Majumdar SR, Chan KA, Buist DS, Go AS, Goodman M, et al. Low frequency of treatment of osteoporosis among postmenopausal women following a fracture. Arch Intern Med. 2003;163(17): 2052-2057.

15. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. 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;282(14): 1344-1352.

16. Schnitzer T, Bone HG, Crepaldi G, Adami S, McClung M, Kiel D, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging (Milano). 2000;12(1): 1-12.

17. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18): 1809-1822.

18. Jadad AR EMRCTn, ed. London UKBB, 2007.

19. Well GA SB, O'Connell D, Peterson J, Vwelch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [2015.06.18]. Available from: http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp.

20. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357(18): 1799-1809.

21. Cecilia D, Jodar E, Fernandez C, Resines C, Hawkins F. Effect of alendronate in elderly patients after low trauma hip fracture repair. Osteoporosis Int. 2009;20(6): 903-910.

22. Beaupre LA, Morrish DW, Hanley DA, Maksymowych WP, Bell NR, Juby AG, et al. Oral bisphosphonates are associated with reduced mortality after hip fracture. Osteoporosis Int. 2011;22(3): 983-991.

23. Osaki M, Tatsuki K, Hashikawa T, Norimatsu T, Chiba K, Motokawa S, et al. Beneficial effect of risedronate for preventing recurrent hip fracture in the elderly Japanese women. Osteoporosis Int. 2012;23(2): 695-703.

24. Fogelman I, Ribot C, Smith R, Ethgen D, Sod E, Reginster JY. Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. BMD-MN Study Group. J Clin Endocrinol Metab. 2000;85(5): 1895-1900.

25. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344(5): 333-340.

26. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002;346(9): 653-661.

27. Nguyen ND, Eisman JA, Nguyen TV. Anti-hip fracture efficacy of bisphosphonates: A Bayesian analysis of clinical trials. J Bone Miner Res. 2006;21(2): 340-349.

28. Lee YK, Ha YC, Yoon BH, Koo KH. Incidence of second hip fracture and compliant use of bisphosphonate. Osteoporos Int. 2013;24(7): 2099-2104.

29. Craig SJ, Youssef PP, Vaile JH, Sullivan L, Bleasel JF. Intravenous zoledronic acid and oral alendronate in patients with a low trauma fracture: experience from an osteoporosis clinic. Internal Med J. 2011;41(2): 186-190.

30. Soong YK, Tsai KS, Huang HY, Yang RS, Chen JF, Wu PCH, et al. Risk of refracture associated with compliance and persistence with bisphosphonate therapy in Taiwan. Osteoporosis Int. 2013;24(2): 511-521.

31. Kang JH, Keller JJ, Lin HC. Bisphosphonates reduced the risk of acute myocardial infarction: a 2-year follow-up study. Osteoporosis Int. 2013;24(1): 271-277.

32. Colon-Emeric CS, Mesenbrink P, Lyles KW, Pieper CF, Boonen S, Delmas P, et al. Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res. 2010;25(1): 91-97.

33. Conti L, Casetti R, Cardone M, Varano B, Martino A, Belardelli F, et al. Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells: role of CD86 and inflammatory cytokines. J Immunol. 2005;174(1): 252-260.
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Date:Apr 30, 2016
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