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International Journal of Clinical and Experimental Pathology logoLink to International Journal of Clinical and Experimental Pathology
. 2014 Apr 15;7(5):2113–2122.

Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis

Zhenyu Zhou 1,*, Chen Chen 1,*, Jun Zhang 1,*, Xinran Ji 2,*, Lifeng Liu 1, Guichun Zhang 1, Xuecheng Cao 1, Pingshan Wang 1
PMCID: PMC4069896  PMID: 24966919

Abstract

Purpose: The aim of this meta-analysis was to assess the safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density (BMD). Methods: Safety of denosumab was compared with placebo or bisphosphonates. A systematic literature search without language restriction was conducted up to January, 2014. The RevMan 5.1 software was used for statistical analysis. Results: A total of 11 English literatures were eventually identified. The pooled data in the overall analysis revealed that there was no significant difference when compared denosumab with placebo or bisphosphonates in any adverse events (AAE) (RR=0.99, 95% CI=0.98-1.01, p=0.29), serious adverse event (SAE) (RR=1.05, 95% CI=0.98-1.13, p=0.18), neoplasm/cancer (RR=1.14, 95% CI=0.95-1.37, p=0.16) and deaths (RR=0.77, 95% CI=0.57-1.04, p=0.09). However, significant differences were found when compared denosumab with placebo or bisphosphonates in SAE related to infection (RR=1.23, 95% CI=1.00-1.52, p=0.05) and non-vertebral fracture (RR=0.86, 95% CI=0.74-1.00, p=0.05). Subgroup analysis was performed by the type of drugs which was used in the control group. The results of subgroup analysis did not demonstrate the differences between denosumab and bisphosphonates in SAE related to infection (RR=1.13, 95% CI=0.63-2.03) and non-vertebral fracture (RR=1.31, 95% CI=0.87-1.98). Conclusions: Compared to placebo, denosumab treatment significantly decreased the risk of non-vertebral fracture but increased the risk of SAE related to infection in the postmenopausal women with osteoporosis or low BMD. However, no difference between the safety of denosumab and bisphosphonates was found.

Keywords: Denosumab, osteoporosis, postmenopausal women, meta-analysis

Introduction

Osteoporosis is a common disease characterized by a systemic impairment of bone mass, strength, and microarchitecture which increases the propensity of fragility fractures [1]. There is higher prevalence of osteoporosis among postmenopausal women and the elderly [2]. Approximately 30% of all postmenopausal women in the United States and Europe have osteoporosis [3]. In Korea, the prevalence of osteoporosis has been reported to be 31% in postmenopausal women aged 45-64 years, 53% in those aged 65-74 years [4]. Shao et al. [5] reported that the prevalence of osteoporosis was as much as 60% in postmenopausal Chinese women.

The treatment of osteoporosis and prevention of osteoporotic fractures consist of non-drug and drug therapy [6]. Drug therapy of osteoporosis is based on the knowledge of mechanisms of bone turnover and the manipulation of the cellular components of bone turnover in recruitment, activation and apoptosis [7]. Bisphosphonates is one of the drugs that are currently available for postmenopausal osteoporosis by inhibiting bone turnover [8].

Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor-κB ligand (RANKL) [9]. RANKL is a cytokine member of the tumour necrosis factor family that is the principal final mediator of osteoclastic bone resorption [10]. It is the key molecule responsible for the bone loss observed in osteoporosis [11]. By binding to RANKL and preventing its binding to the RANK receptors on the surface of osteoclasts and osteoclast precursors, denosumab inhibits the development, activation and survival of osteoclasts [12]. Although denosumab had been recommended as one of the clinical medicines by American Association of Clinical Endocrinologists (AACE) [13], it is lack of large sample size studies to perfectly evaluate the effectiveness and safety of denosumab. Therefore, we performed a meta-analysis to assess the safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density (BMD).

Materials and methods

Search strategy

A systematic literature search without language restriction was conducted up to January, 2014 by using the electronic databases such as PubMed, Embase, Springer link, Cochrane library. The key words included “denosumab”, “osteoporosis”, “postmenopausal women”, and “low bone mineral density”. Furthermore, paper literatures were retrieved by manual search. Review articles and reference lists of retrieved Figure 1. Literature search and study selection.articles were also inspected to find additional eligible studies.

Figure 1.

Figure 1

Literature search and study selection.

Study selection

Studies that met the following criteria were included in the meta-analysis: (1) the studies were randomized controlled trials; (2) the subjects were the postmenopausal women with osteoporosis or low BMD; (3) the studies were designed to compare the safety of denosumab with placebo or bisphosphonates; (4) one of the following risk indicators must be included: any adverse events (AAE), serious adverse event (SAE), SAE related to infection, non-vertebral fracture, neoplasm/cancer and deaths. Studies were excluded if they were (1) animal studies; (2) studies that had unavailable data or lack of enough data; (3) reviews, letters and comments; (4) repeated publication articles.

Data extraction and quality assessment

Two evaluators independently selected studies and extracted data. Discrepancies were resolved by discussion with a third investigator. For each study, the following information was extracted: the first author name, year of publication, region, age of subjects, number of subjects, dosage of denosumab and outcomes.

Study quality was assessed using the 6-item instrument developed by Jadad et al [13]. The studies with the score from 3 to 5 are high quality studies. According to Cochrane Library Handbook [14], risk assessment tool in RevMan 5.1 was used to evaluate the risk of bias in the following factors: random sequence generation, allocation concealment, blinding of participants and staff, blinding of outcome assessment, incomplete data of outcome, selective reporting and so on.

Statistical analysis

The risk indicators of AAE, SAE, SAE related to infection, fractures, neoplasm/cancer and deaths were used to assess the safety of denosumab in the postmenopausal women with osteoporosis or low BMD. Placebo or bisphosphonates were regarded as control. The RevMan 5.1 software was used for statistical analysis and risk ratio (OR) and 95% confidence intervals (CIs) as summary statistics were calculated. Heterogeneity of effect size across studies was assessed by using Cochran’s Q and the I2 statistic [15]. A Random-effects model was applied if there was significant heterogeneity (p<0.05, I2>50%). Otherwise, a fixed-effects model was used. Subgroup analysis was performed by the type of drugs which was used in the control group. Publication bias was observed with the funnel plot. Sensitivity analysis was performed by omitting special studies to test the stability of pooled results.

Result

Search results

A total of 1059 potential relevant articles were identified by initial literature research. After removing duplicated articles, 735 literatures were remained. Then, 704 obviously irrelevant literatures were excluded. Finally, 20 literatures were omitted from the remaining 31 literatures. The 20 literatures included three reviews, one animal study, four studies with the same population, six studies without related risk indicators, and seven studies lack of data about the comparison between the denosumab and control group. Finally, based on the included criteria and excluded criteria, 11 literatures [16-26] were included in this meta-analysis. The flow diagram of the search process is shown in Figure 1.

Characteristic of included studies

The characteristics of the included studies are summarized in Table 1. The included literatures were published from 2007 to 2014 in this meta-analysis. The 11 literatures contained 13 studies. The safety of denosumab was compared to placebo in seven [16,17,19-21,24,25] out of the thirteen studies with 4390 patients in placebo group and comparison between bisphosphonates and denosumab was shown in the other six studies [18,20,22-24,26] with 4390 patients in bisphosphonates group. Among the patients in all studies, 6483 were assigned to the denosumab group. Length of the follow-up time was from 9 months to 3 years. All the included literatures were high quality studies with the Jadad scores from 3 to 5. Assessment of risk of bias is shown in Figure 2. There was no high risk of bias in the studies except the study of Kumagai et al. [19], Recknor et al. [22] and Roux et al. [23].

Table 1.

Characteristics of 11 studies included in meta-analysis

Author Year length of study (years) Location n, age trial mean (SD) Treatment of trial n, age control Treatment of control lumbar spine BMD T-scores Outcomes Jadad Score
Bone 2008 2 North America 166 60 mg every 6 months 166 placebo (-2.5, -1.0)+ SAE; AAE; SAE related to infection; Neoplasm; Deaths; Non-vertebral fracture. 4
59.8 (7.4) 58.9 (7.5)
Cummings 2009 3 multicenter, international 3902 60 mg every 6 months 3906 placebo (-4.0, -2.5) SAE; SAE related to infection; Neoplasm; Deaths; Non-vertebral fracture. 4
72.3 (5.2) 72.3 (5.2)
Ellis 2008 2 North America 127 60 mg every 6 months 125 placebo (-2.5, -1.0) SAE; SAE related to infection; Neoplasm; Deaths. 4
59.7 (9.7) 89.2 (8.9)
Kumagai 2011 9 months Japan 30 0.03, 0.1, 0.3, 1.0, 3.0 mg/kg 10 placebo NP AAE 3
40-66* 59.6 (3.1)
Lewiecki 2007 2 United States 319 6, 14, 30 mg/ 3 months; 14, 60, 100, 210 mg/6 months 46 placebo (-4.0, -1.5) SAE; SAE related to infection; Neoplasm; Deaths; AAE 4
63.7 (9.1)
62.3 (8.0) 47 Alendronate 70 mg/week
62.8 (8.2)
Nakamura 2012 1 Japan 157 60 mg every 6 months 55 placebo (-4.0, -2.5) SAE; SAE related to infection; Neoplasm; AAE 4
65.2 (6.8) 64.6 (7.0)
Seeman 2010 1 multicenter, international 83 60 mg every 6 months 82 placebo (-3.0, -2.0) AAE; SAE 5
60.8 (5.2)
60.3 (5.9) 82 Alendronate 70 mg/week
60.7 (5.2)
Brown 2009 1 multicenter, international 594 60 mg every 6 months 595 Alendronate 70 mg/week ≤2.0 SAE; AAE; SAE related to infection; Neoplasm; Non-vertebral fracture. 3
64.1 (8.6)
Kendler 2010 1 multicenter, international 253 60 mg every 6 months 251 Alendronate 70 mg/week (-4.0, -2.0) SAE; AAE; SAE related to infection; Neoplasm; Deaths; Non-vertebral fracture. 5
66.9 (7.8) 68.2 (7.7)
Recknor 2013 1 United States and Europe 417 60 mg every 6 months 416 ibandronate 150 mg/month (-4.0, -2.0) AAE; SAE; SAE related to infection; Neoplasm; Non-vertebral fracture; Deaths. 3
67.2 (8.1) 66.2 (7.8)
Roux 2014 1 multicenter, international 435 60 mg every 6 months 435 risedronate 150 mg/month -2.3 (1.1)&, SAE; AAE; SAE related to infection; Deaths; Non-vertebral fracture. 3
67.8 (7.0) 67.7 (6.8) -2.2 (1.2)
*

range of age;

+

range of lumbar spine BMD T-scores;

&

mean (SD) of lumbar spine BMD T-scores;

AE: adverse events; SAE: Serious adverse events; AAE: any adverse events; NP: not provided.

Figure 2.

Figure 2

Risk of bias of 11 studies included in meta-analysis.

Comparison of safety

For the six risk indicators, no significant heterogeneity (p>0.05, I2<50%) was detected among the included studies. A fixed-effects model was used to calculate RR and 95% CI. Relevant forest plots are presented in Figures 3, 4. No significant difference between denosumab and control group was demonstrated in AAE (RR=0.99, 95% CI=0.98-1.01, p=0.29), SAE (RR=1.05, 95% CI=0.98-1.13, p=0.18), neoplasm/ cancer (RR=1.14, 95% CI=0.95-1.37, p=0.16) and deaths (RR=0.77, 95% CI=0.57-1.04, p=0.09) (Figure 3). Subjects assigned to denosumab demonstrated evidence of significant risk of SAE related to infection (RR=1.23, 95% CI=1.00-1.52, p=0.05) when compared to controls. Denosumab treatment significantly decreased the risk of non-vertebral fracture (RR=0.86, 95% CI=0.74-1.00, p=0.05) in the postmenopausal women with osteoporosis or low BMD (Figure 4).

Figure 3.

Figure 3

Forest plots of the risk of any adverse events, serious adverse events, neoplasm/cancer and deaths. A: Forest plot of the risk of any adverse events, B: Forest plot of the risk of serious adverse events, C: Forest plots of the risk of neoplasm/cancer, D: Forest plots of deaths.

Figure 4.

Figure 4

Forest plots of the risk of SAE related to infection and non-vertebral fracture. A: Forest plot of the risk of SAE related to infection, B: Forest plot of the risk of non-vertebral fracture.

Subgroup analysis

In subgroup analysis, the pooled data (AAE: RR=1.00, 95% CI=0.99-1.01; SAE: RR=1.05, 95% CI=0.97-1.13; SAE related to infection: RR=1.25, 95% CI=1.00-1.56; non-vertebral fracture: RR=0.80, 95% CI=0.68-0.95; neoplasm/ cancer: RR=1.13, 95% CI=0.93-1.38; deaths: RR=0.77, 95% CI=0.57-1.05) of denosumab vs. placebo showed the consistent results with the overall analysis. The results of denosumab vs. bisphosphonates indicated that there was no evidence to prove the significant differences between denosumab and bisphosphonates group in all the risk indicators (AAE: RR=0.98, 95% CI=0.95-1.02; SAE: RR=1.06, 95% CI=0.84-1.34; SAE related to infection: RR=1.13, 95% CI=0.63-2.03; neoplasm/cancer: RR=1.17, 95% CI=0.73-1.87; non-vertebral fracture: RR=1.31, 95% CI=0.87-1.98; deaths: RR=0.72, 95% CI=0.20-2.59) (Table 2).

Table 2.

Summary of subgroup analysis and sensitivity analysis

Outcomes Overall effect Sensitivity analysis Subgroup analysis

Method 1 Method 2 Denosumab vs. placebo Denosumab vs. bisphosphonates
AAE 0.99 (0.98, 1.01) 0.99 (0.96, 1.02) 0.99 (0.98, 1.01) 1.00 (0.99, 1.01) 0.98 (0.95, 1.02)
SAE 1.05 (0.98, 1.13) 1.15 (0.94, 1.41) 1.05 (0.97, 1.13) 1.05 (0.97, 1.13) 1.06 (0.84, 1.34)
SAE related to infection 1.23 (1.00, 1.52) 1.45 (0.87, 2.41) 1.23 (1.00, 1.51) 1.25 (1.00, 1.56) 1.13 (0.63, 2.03)
Neoplasm (Cancer) 1.14 (0.95, 1.37) 1.20 (0.80, 1.81) 1.14 (0.95, 1.38) 1.13 (0.93, 1.38) 1.17 (0.73, 1.87)
Non-vertebral fracture 0.86 (0.74, 1.00) 1.12 (0.78, 1.61) 0.86 (0.74, 1.00) 0.80 (0.68, 0.95) 1.31 (0.87, 1.98)
Deaths 0.77 (0.57, 1.04) 0.72 (0.24, 2.13) 0.78 (0.58, 1.05) 0.77 (0.57, 1.05) 0.72 (0.20, 2.59)

Sensitivity analysis

Based on the characteristic of the included studies, two methods were used to do sensitivity analysis. First, the study of Cummings et al. [17] was eliminated because of great weight (66.3%~92.5%) (Figures 3, 4). After eliminating the study of Cummings et al., the pooled data showed an inconsistent result with the result of the overall analysis in non-vertebral fracture (RR=1.12, 95% CI=0.78-1.61). The result indicated no significant difference between denosumab and control group. For the other risk indicators (AAE: RR=0.99, 95% CI=0.96-1.02; SAE: RR=1.15, 95% CI=0.94-1.41; SAE related to infection: RR=1.45, 95% CI=0.87-1.41; neoplasm/ cancer: RR=1.20, 95% CI=0.80-1.81; deaths: RR=0.72, 95% CI=0.24-2.13), the results were similar with the results of the overall analysis. Second, the study of Kumagai et al. [19] and Lewiecki et al. [20] were omitted to detect the stability of the results. Because multiple doses of denosumab were used in the two studies, while single-dose (60 mg/6 month) was used in the other studies. After omitting the study of Kumagai et al. and Lewiecki et al., the similar results (AAE: RR=0.99, 95% CI=0.98-1.01; SAE: RR=1.05, 95% CI=0.97-1.13; SAE related to infection: RR=1.23, 95% CI=1.00-1.51; non-vertebral fracture: RR=0.86, 95% CI=0.74-1.00; neoplasm/cancer: RR=1.14, 95% CI=0.95-1.38; deaths: RR=0.78, 95% CI=0.58-1.05) with overall analysis was obtained (Table 2).

Statistically similar results with overall analysis were obtained in sensitivity analysis. It evinced the stability of this meta-analysis.

Publication bias

In this meta-analysis, no evidence of publication bias was detected in the risk indicator of SAE related to infection by the funnel plot in Figure 5.

Figure 5.

Figure 5

Funnel plot of detection of publication bias.

Discussion

In this meta-analysis, we pooled data from 11 studies. Based on the results of statistical analysis, we concluded that there was no significant difference in AAE, SAE, neoplasm/cancer and deaths between denosumab and control group. Compared to control group, denosumab treatment increased the risk of SAE related to infection but reduced the risk of non-vertebral fracture. Nevertheless, the increase in the risk of SAE related to infection and the reduction in the risk of non-vertebral fracture were not demonstrated in the results of denosumab vs. bisphosphonates in the subgroup analysis.

At present, the phase III studies of denosumab were carried on [27]. Although many studies reported that denosumab was well tolerated [28-30], there were many potential theoretical safety concerns. A concern regarding the long-term use of denosumab relates to its possible effects on the immune system, increasing the risk of infections and cancer [27,31]. In this meta-analysis, the result showed the increase in the risk of SAE related to infection. However, no significant effect on the risk of cancer was found. Another theoretical safety concern was that over-suppression of bone remodeling might increase fracture [32]. However, the risk of non-vertebral fracture was reduced when patients were treated by denosumab in this meta-analysis. Further studies need to be done to verify the result of this meta-analysis and explain the reason that why the results were inconsistent with the theoretical speculation.

Bisphosphonates have been widely, efficiently, and safely used for the treatment of osteoporosis [33]. No difference was found between the safety of denosumab and bisphosphonates in this meta-analysis. Thus, denosumab was safe as bisphosphonates in treating osteoporosis.

Anastasilakis et al. [34] reported a similar meta-analysis in 2009. Compared to that one, there were basically three reasons that constitute the primary advantages of this meta-analysis. First, the included studies were updated. Eight studies [17-19,21-24,26] that published after 2009 were included. Second, the safety of denosumab was assessed by comparing with placebo in the study of Anastasilakis et al. However, in this meta-analysis, the safety of denosumab was assessed by comparing with placebo or bisphosphonates in the overall analysis, and subgroup-analysis by the type of drugs used in the control group was performed. Third, there was no heterogeneity among the included studies in this meta-analysis.

Some limitations of this meta-analysis should be paid attention to. First, the sample size in the included studies was small except the study of Cummings et al. Thus, the stability and reliability of the result in this meta-analysis need to be verified by large sample studies. Second, the efficacy of denosumab for increasing BMD did not analysis in this meta-analysis due to the limitation of the data in the included studies. The following study need to be done to perfect the study of denosumab.

In conclusion, compared to placebo, denosumab treatment significantly reduced the risk of non-vertebral fracture but increased the risk of SAE related to infection in the postmenopausal women with osteoporosis or low BMD. However, there was no difference between the safety of denosumab and bisphosphonates. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women and may be used as a first-line treatment in future. However, due to the existence of the unstable factors, furthermore studies need to be done to verify the result of this study.

Disclosure of conflict of interest

The authors have declared that no competing interests exist.

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