Meta analysis of zoledronic acid on the bone markers among osteoporosis patients

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1 Scientific Research and Essays Vol. 7(23), pp , 21 June, 2012 Available online at DOI: /SRE ISSN Academic Journals Full Length Research Paper Meta analysis of zoledronic acid on the bone markers among osteoporosis patients Liu Ming, Pan Wei, Chen Yan and Chen Decai* Department of Endocrinology, the West China Hospital, Sichuan University, Chengdu , China. Accepted 30 May, 2012 Osteoporosis is a skeletal disease that is characterized by compromised bone strength predisposing a person to an increased risk of fracture. Zoledronic acid (ZOL) is an aminobisphosphonate with a high affinity for mineralized bone. This review of relevant meta-analysis aimed to clarify the effect of ZOL in treatment and prevention of osteoporosis. Random control trials that investigated the evidence for the role of ZOL in treatment of osteoporosis was obtained through a comprehensive literature search for the database of MEDLINE, EMBASE and the Chinese Biomedical Database up to September The RevMan software was used for all of the statistical analysis. A total of 6 trials were included in this meta-analysis. The pooled percentage changes of bone mineral density (BMD) for ZOL experimental group were improved by 215% compared with the placebo, and reduce the rate of fracture in patients by 48%. We also found the ZOL intervention may induce less adverse effects by 13% compared with placebo. From the subgroup analysis we found the long term intervention of ZOL could gain a high BMD and could prevent more fracture compared with placebo. Additionally, ZOL improved more BMD among patients above 50 years of age. In conclusion, our findings showed that ZOL is a well and effective approach in the prevention of osteoporosis, especially more effective in high risk group of osteoporosis. Key words: Meta-analysis, intravenous zoledronic acid, osteoporosis, bone mineral density, fracture. INTRODUCTION Osteoporosis is a skeletal disease that is characterized by compromised bone strength predisposing a person to an increased risk of fracture (NIHCDPOP, 2001). According to the World Health Organization (WHO) data, osteoporosis affects approximately 75 million people throughout Europe, the US, and Japan (Eastell et al., 2009). In the US, osteoporosis occurs in 55% of the population aged 50 years and above (Hanley and Josse, 1996). Osteoporosis occurs more in women than in men. One in four women above the age of 50 years has osteoporosis in Canada (Papadimitropoulos et al., 1997). Increasing life expectancy means that the prevalence of the disease is likely to increase. It is estimated that, for example, in Canada, by 2041, 25% of the population will be aged 65 years and over 4. Osteoporosis affects an *Corresponding author. liuminghuaxi@yahoo.com.cn or linadr2011@yahoo.com.cn estimated 75 million persons in Europe, the United States, and Japan and is associated with an estimated 9 million new fractures every year worldwide (IOF, 2011), including more than 2 million fractures per year in the United States (Burge et al., 2007). Osteoporosis-related fractures are associated with significant morbidity, increased mortality and enormous financial costs (IOF, 2011). Oral nitrogen-containing bisphosphonates (e.g, alendronate, risedronate, and ibandronate) are the standard of care in osteoporosis (Chapurlat and Delmas, 2006). These bone-specific agents inhibit farnesyl diphosphate synthase, a key branch point of the mevalonate pathway, and thus, inhibit protein prenylation in osteoclasts (Kavanagh et al., 2006). This activity makes bisphosphonates potent inhibitors of bone resorption and remodeling activity (Kimmel, 2007). Oral bisphosphonates have been shown to increase bone mineral density (BMD) and reduce fracture risk. However, the real world effectiveness of oral treatment is compromised by suboptimal patient compliance and persistence with

2 2090 Sci. Res. Essays Table 1. Characteristics of the studies included in the meta-analysis. Study ID Country Follow-up Samples(Interventio n/controls) Age (years) Outcomes Adverse effects Hwang (2011) China 3 years 163/ ±0.4 BMD, fracture 11/52 Bubbear (2011) United Kingdom 1 year 7/7 28.6±14.4 BMD - Boonen (2010) Holland 3 years 2881/ ±11.5 Fracture - Black (2007) United States 3 years 275/ ±5.4 BMD Fracture 83/76 Lyles (2007) Holland 1.7 years 1065/1062 >50 Fracture 96/148 Reid (2002)l New Zealand 1 year 59/59 45 to 80 BMD 5/6 ZOL, Zoledronic acid; BMD, bone mineral density (mg/cm 2 ). prescribed regimens (Caro et al., 2004; Siris et al., 2006; Briesacher et al., 2007; Weycker et al., 2007; Rabenda et al., 2008). Zoledronic acid (ZOL) is an aminobisphosphonate with a high affinity for mineralized bone. Administered as an intravenous infusion over at least 15 min, it rapidly localizes to bone, where it inhibits osteoclastic bone resorption by inhibiting the action of the enzyme farnesyl pyrophosphate synthase in the mevalonate pathway. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity for bone mineral. In this regard, although recent reviews suggest that ZOL can be efficacious in increasing the bone mineral density (BMD), a quantitative summary of the degree of this effect is not available at present. Additionally, from a mechanistic standpoint, the possible effects of ZOL on the markers of bone turnover are not firmly established. Yet, the clinical evidence in the effect of ZOL on osteoporosis and its complication is conflicting. We therefore undertook a meta-analysis and a systematic review of the published randomized controlled clinical trials of ZOL in treatment and prevention of osteoporosis. METHODS Study selection Random control trials that investigated the evidence for the role of ZOL in treatment of osteoporosis was obtained through a comprehensive literature search. Trials had to be original data from RCTs regarding the evidence for the effect of ZOL on the osteoporosis. Randomization by clusters or individuals was acceptable. We used no language or publication status restrictions. The terms zoledronic acid and osteoporosis was used in MEDLINE, EMBASE and the Chinese Biomedical Database Databases. The data of the last search was September Inclusion and exclusion criteria Studies were included for systematic review if they met all of the following criteria: 1) must be clinic studies and research on humans; 2) evaluated effect of ZOL on the osteoporosis; 3) contained at least one relevant pair-wise comparison of intervention arms (that is, intravenous ZOL vs. placebo), and placebo used did not contain ZOL and was identical or similar in appearance and seemed to be comparative to ZOL. The usually placebo in studies were only calcium and vitamine D, or hormone therapy, raloxifene, calcitonin or tibolone along with calcium and vitamin D; 4) reported outcomes for the effects on the fracture or bone turnover markers; and 5) was a random control trial. A review of all matched eliminated duplicates, review articles, studies in patients with cancer-related condition, and studies did not have fracture or bone turnover markers as the endpoint. Searching strategy for identification of studies To determine the studies to be assessed further, two independent authors reviewed the titles, abstracts and keywords of all records retrieved to determine whether the studies were relevant to this review, and where the title and abstract did not provide adequate information, we assessed the full study and contact the authors of the study if additional information was required for further clarification. We also attempted to identify additional studies by searching the reference lists of relevant trials, and scrutinized author names, location, setting, number of participants, and study data to ensure that each trial would be included only once. Of the 99 articles identified, disagreement was resolved by discussion. 93 trials regarding role of ZOL on osteoporosis were excluded because 30 studies were studies regarded as animal models or studies conducted at a cellular level, 11 were reviews, 49 were not RCT studies, and 3 were duplicate publications. Ultimately, 6 articles were included (Table 1). By contracting the related authors of two studies to supplement the missing data, data from one article were obtained, and others did not respond or there was failure to contact these. Two independent reviewers independently extracted the data. Statistical analysis For dichotomous outcomes, we will express the measure of effect as odds ratio (OR), with 95% confidence intervals (CI). We analyzed measures using weighted mean difference (WMD) and the 95% CI in the analysis. We analyzed pooled results using either a fixed-effect or random-effects model, depending on the level of heterogeneity. The heterogeneity was tested with a Q-statistics with p-values < 0.05, and its possible sources were assessed by subgroup analysis as described below. The Egger s regression asymmetry test was taken to evaluate publication bias (p<0.1) and was considered representative of statistically significant publication bias. All statistical analyses were conducted using RevMan software.

3 Ming et al Table 2. Effect of intravenous ZOL on the BMD at lumbar spine. Study or sub group Experimental Standard Mean deviation Total Mean Control Standard Total deviation Weigh t (%) Black (2007) [3.77, 4.34] Bubbear (2011) [-0.90, 1.20] Hwang (2011) [6.95, 8.21] Reid (2002) [0.39, 1.14] Standard mean difference (IV, Random, 95% CI) Total (95% CI) [0.39, 5.92] Heterogeneity: Tau 2 = 7.85, χ 2 = , df = 3, (p< ), I 2 = 99%. Test for overall effect: Z = 2.24 (P = 0.03) Table 3. Effect of intravenous ZOL on the fracture. Study or sub Favour experimental Favour Control group Cases Total Cases Total Weight (%) Odds ratio (M-H, Random, 95% CI) Black (2007) [0.34, 0.72] Boonen (2010) [0.22, 0.28] Harkness (2004) [0.51, 1.23] Lyles (2002) [0.44, 0.76] Total (95% CI) [0.27, 0.86] Total cases Heterogeneity: Tau 2 = 0.33, χ 2 = 57.83, df = 3, (p< ), I 2 = 95%. Test for overall effect: Z = 2.45 (P = 0.01) RESULTS A total of 6 trials included in this meta-analysis are summarized in Table 1. Data for follow-up durations were ranged from 12 month to 3 years. Four of the trial groups included in this meta-analysis had assessed BMD at the lumbar spine; and four trials had studied the fracture of patients after intervention. Few numbers of studies assessed BMD at other sites, such as wrist, hip, trochanter, and whole body. Additionally, most of the studies were conducted for female patients due to the high incidence of osteoporosis in females. Serious adverse effect was also found in ZOL intervention group with the rate of 20 to 86%. Table 2 showed the effect of intravenous ZOL on the BMD at lumbar spine. The random effect model was used because of significant heterogeneity in the studies (I 2 = 99%). All the four trials resulted in a positive mean difference in percentage changes from baseline between ZOL experimental group and placebo control group. The pooled percentage changes of BMD for ZOL experimental group increased by 215%, which indicated the ZOL, could significantly increase the BMD of patients. Table 3 revealed the role of ZOL on the fracture of patients. The random effect model was used due to a substantial amount of heterogeneity (I 2 = 95%). All trials showed the ZOL could significantly decrease the rate of fracture, and the pooled results showed the fracture in patients could be reduced by 48%. The results showed studies of ZOL among patients at an older age could have high percentage changes of BMD, and a longer term of intervention of ZOL could gain a high BMD and reduce higher rate of fracture. Also, when the serious adverse effects of ZOL were analyzed in Table 4, we observed the ZOL intervention may induce less adverse effects by 13% compared with placebo, and no heterogeneity was found. Most of the serious adverse effects were renal event, pyrexia and cardiovascular or cerebrovascular events. The funnel plots did not show an obvious publication bias (Figure 1), and no evidence of publication bias was found in studies on the effect of ZOL for BMD and fracture (Egger s p=0.32 and for BMD and fracture studies, respectively). DISCUSSION Our results indicate that published randomized controlled

4 2092 Sci. Res. Essays Table 4. Serious adverse cases of ZOL intervention. Study or sub Experimental Control group Cases Total Cases Total Weight (%) Odds ratio (M-H, Random, 95% CI) Lyles (2007) [0.74, 1.05] Reid (2002) [0.19, 1.31] Hwang (2011) [0.32, 0.87] Bubbear (2011) Not estimable Boonen (2010) [0.81, 1.03] Black (2007) [0.73, 1.52] Total (95% CI) [0.75, 1.01] Total cases Heterogeneity: Tau 2 = 0.01, χ 2 = 6.45, df = 4, (p = 0. 71), I 2 = 38%. Test for overall effect: Z = 1.82 (P = 0.07) Figure 1. Funnel plot of role of ZOL on BMD. trials strongly support the use of ZOL for the treatment of osteoporosis in terms of the improved BMD and decreased fracture rate compared with placebo. Especially for old patients, the ZOL could play a more effective role in treatment and prevention of osteoporosis. Also, we found the long term use of ZOL for patients with high risk of osteoporosis, and a more improved BMD and less decreased fracture rate would be gained in our meta-analysis. Therefore, our meta-analysis showed that ZOL might be a good approach in prevention and treatment of osteoporosis. Previous studies reported that fracture risk increases as BMD decreases in untreated participants (Boivin et al., 2000; Reginster et al., 2008). In previous study, of the 158 fractures that occurred during the trial, 76 (48%) occurred in 48% of women with low bone mass and only 8% of fractures occurred in the 31% of the study population with normal BMD (Sornay-Rendu et al., 2005). In another prospective study of American women aged above 65 years, only 46% of incident hip fractures occurred in women with osteoporosis by BMD criteria whereas 54% occurred in women with higher BMD values (Wainwright et al., 2005). Furthermore, another study reported that women with low bone density had a 73% higher risk of fracture than women with normal BMD (Siris et al., 2001). Recent guidelines recommend that the pharmacological therapy be considered for postmenopausal women with osteoporosis and for women without osteoporosis at moderate to high fracture risk, based on a combination of BMD and clinical risk factors (McClung et al., 2007). In our

5 Ming et al study, we found that the ZOL could improve the BMD in individuals, especially increase higher BMD in high risk of osteoporosis, which showed the ZOL could be an effective way to approach the prevention of fracture. Our study also showed that the the long term use of ZOL would gain a more improved BMD and lower rate of fracture. As has been observed in the included study which showed the ZOL 5 mg treatment trials, the BMD were significantly increased at the end of the 12-month dosing interval. After the second infusion at month 12, the BMD increased in participants who received the active treatment (ZOL 2 5 mg group) (McClung et al., 2007) followed a similar pattern to that shown throughout the first year of the trial. Conversely, BMD levels continued to slowly increase in patients who switched from ZOL to placebo at month 12. This indicated only long term use of ZOL could prevent BMD effectively. In our study, we also found lower serious adverse effects in ZOL group compared with placebo, such as reneal event, pyrexia and cardiovascular or cerebrovascular events, which indicated the ZOL is safe and effective. The degree of safety of therapy in high risk group of osteoporosis for management of low bone mass has been inconclusive (Watts, 2006; Khosla and Melton, 2007; Schousboe et al., 2005; Meadows et al., 2007). Therefore, our study showed the safety of ZOL intervention compared to the traditional interventions. Conclusion Our findings revealed a better efficacy of ZOL for the treatment of osteoporosis in terms of the improved BMD and decreased fracture rate compared with placebo. Especially for patients above 50 years, the ZOL could play a more effective role in treatment and prevention of osteoporosis. ACKNOWLEDGEMENT We acknowledge the helps from Department of Endocrinology, Second West China Hospital, China. 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