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Int J Clin Exp Med 2019;12(9):11037-11048www.ijcem.com /ISSN:1940-5901/IJCEM0094322

Review ArticleDenosumab versus bisphosphonates for treatment of postmenopausal osteoporosis: a meta-analysis

Xiaoyong Lan1, Haiping Ma2, Zhiping Zhang3, Dong Ye3, Jun Min4, Feng Cai3, Jun Luo1

1Department of Rehabilitation, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; 2Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; 3Department of Orthopedics, The Third Affiliated Hospital of Nanchang University, Jiangxi, China; 4Department of Rehabilitation, The Third Affiliated Hospital of Nanchang University, Jiangxi, China

Received March 24, 2019; Accepted July 24, 2019; Epub September 15, 2019; Published September 30, 2019

Abstract: Bisphosphonate is a first-line treatment for osteoporosis. Denosumab is a monoclonal antibody against human IgG-2 that has become common for the treatment of osteoporosis in postmenopausal women. Their efficacy is in controversy. We thus performed a systematic review and meta-analysis to compare the efficacy and safety of denosumab with bisphosphonates to treat osteoporosis. EMBase, PubMED, CNKI and Cochrane Clinical Controlled Experiment Center databases were searched from inception to March 2019. Randomized controlled trials (RCTs) comparing denosumab with bisphosphonates to treat osteoporosis were included. Both random-effect/fixed effect models were used for meta-analysis. Revman 5.3 was used for meta-analysis. Twelve studies depicting 11 RCTs with a total of 6392 patients were collected in the final meta-analysis. As for changes in bone mineral density (BMD) of the lumbar spine, total hip and femoral neck, the pooled outcomes all favored Denosumab (P < 0.00001). In terms of adverse events and severe adverse events, no significant difference was observed. Similar outcomes were detected in the incidences of fractures and mortality, and the pooled RRs were 1.06 (95% CI: 0.81, 1.39; I2 = 0%, P = 0.68) and 0.64 (95% CI: 0.20, 2.06; I2 = 0%, P = 0.45), respectively. Conclusions: This meta-analysis suggests that compared with bisphosphonates, denosumab can significantly increase BMD of hip, lumbar vertebra, femoral neck and other places in postmenopausal osteoporotic women; and the safety of the two drugs is similar, with no significant difference.

Keywords: Bisphosphonates, denosumab, postmenopausal osteoporosis

Introduction

Osteoporosis is a metabolic bone disease char-acterized by a decrease in bone mass per unit volume. In most cases, the decrease of bone tissue is mainly due to the increase of bone absorption, accompanied by bone pain and easy fracture. According to current statistics, when adults are older than 50 years old, about half of them suffer from osteoporosis of varying degrees, of which 70% are postmenopausal women [1-4]. In Europe and America, an aver-age of 2,300,000 fractures occurs every year due to osteoporosis [5, 6]. Once the fracture occurs; the quality of life of patients will be seri-ously affected, wasting unnecessary medical expenses, and even leading to death. With the progress of society and the extension of life expectancy, osteoporosis has become a glob- al public health problem. Therefore, active pre-

vention and treatment of osteoporosis has become an urgent task.

At present, the clinical anti-osteoporosis drugs are mainly divided into three kinds; parathyroid hormone as the representative of bone forma-tion drugs, bisphosphonates as the representative of anti-bone resorption drugs, and calci-um and vitamin D and its analogues as the rep-resentative of the basic supplements [7-9]. Bi- sphosphonate is a first-line treatment for osteoporosis. Bisphosphonates can be classified into two broad categories based on their structural and functional mechanisms. The first includes pyrophosphates like bisphosphonates, such as etidronates and chlorophosphonates, which are metabolically bound to nonhydroly- tic adenosine triphosphate (ATP) analogues as ATP dependent enzyme inhibitors. The second group is nitrogen-containing bisphosphonates,

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Denosumab vs bisphosphonates for postmenopausal osteoporosis

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which are the latest and most effective drugs, such as ibandronate, pamidronate, alendro-nate, risedronate and zoledronic acid [10]. De- nosumab is a monoclonal antibody against human IgG-2, targeting osteoclast-regulating fac-tor. It has high specificity and affinity for human nuclear factor-κB receptor-activated ligand (RANKL). Its binding to RANKL can significantly reduce bone resorption and thus improve bone density and reduce fractures. This opens up new ideas for the treatment of osteoporosis [11]. In 2009, the Food and Drug Administrati- on officially approved denosumab for the treat-ment of osteoporosis in postmenopausal women. Similarly, the American Society of Clinical Endocrinologists listed denosumab as a first-line drug in the osteoporosis guidelines for postmenopausal women in 2010 [12, 13]. Al- though denosumab and bisphosphonates have different mechanisms of action, the indications are very similar. To further compare the efficacy and safety of the two drugs, international schol-ars have conducted a number of multicenter randomized controlled trials (RCTs) in recent years. The purpose of this article is to analyze the efficacy and safety of the two drugs in the treatment of postmenopausal women with osteoporosis by meta-analysis, and to provide ref-erences for clinical treatment.

Methods

Literature retrieval strategy

The retrieval method was formulated according to the requirements of Cochrane collaboration system evaluation. Search in the following data-bases: EMBase, PubMED, CNKI and Cochrane Clinical Controlled Experiment Center databas-es. Retrieve “osteoporosis, bone mineral den-sity, bisphosphonates, and denosumab” and so on. The retrieval time period was from incep-tion to March 2019. In order to ensure that the included studies were fully searched, a manual retrieval approach was adopted.

Literature inclusion and exclusion criteria

Inclusive criteria: (1) Literature on postmeno-pausal osteopenia or osteoporosis has been reported, with bisphosphonates group and denosumab group included in the literature. (2) The main outcome measures were the eleva-tion of bone mineral density relative to baseline

and the presence of fracture at follow-up. (3) Follow-up time was more than 1 years. (4) Sample size exceeds 50 cases. Exclusion crite-ria: (1) Articles with identical data or samples are used in cross references. (2) Literature on nonstandard randomized controlled design and errors in diagnosis or efficacy evaluation. (3) Patients with metastatic bone disease in the past.

Data extraction and study quality evaluation

Two researchers independently searched the literature and selected data according to rele-vant criteria. The main contents of the collect-ed literature included topics, research groups, first authors, publication time, sample size, controlled trials, follow-up time, statistical char-acteristics of the subjects, changes in bone mineral density (BMD), intervention and control methods, fractures and adverse reactions. If the literature data is incomplete or there is no original data, the author of the literature was contacted to obtain relevant information, or the literature charts. The quality of the included lit-erature was assessed using the “Cochrane col-laboration bias assessment criteria”, such as randomization, allocation concealment, imple-mentation of blindness, measurement blind-ness, and completeness of results, with the 0-2/3-5/5-7 score as low/medium/high quality, respectively. In case of disagreement, two researchers discussed and resolved the matter, and if no decision was reached, they sou- ght the advice of a third-party senior expert [14, 15].

Data analysis

Meta-analysis was carried out by RevMan 5_3 Software [16]. We explored heterogeneity by utilizing the chi-square (χ2) test, with signifi-cance set at p value less than 0.100. For the quantification, we used the I2 test, with the sig-nificant values of less than 25% indicating low heterogeneity, less than 50% indicating moder-ate heterogeneity, and greater than 50% indi-cating substantial heterogeneity. If the hetero-geneity was significant, we selected a random effect model (DerSimonian and Laird method) [15] and a subgroup analysis was performed for the used literature to minimize the influen- ce of heterogeneity on the results. Sensitivity analysis was performed to evaluate the stabili-


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ty of the results. The intervention effect was expressed as a risk ratio (RR) and correspond-ing confidence intervals (CI). Continuous data were meta-analyzed in terms of the weighted mean difference (WMD) and associated 95% CI, and the results of Meta-analysis were dis-played by forest plots. Publication bias was assessed by funnel plot.

Results

Literature review and quality evaluation

844 related literatures were retrieved initially in the databases (Figure 1). After preliminary screening, 813 articles were excluded, and the remaining 31 were retrieved for full-text read-ing. Finally, 12 studies depicting 11 RCTs with a total of 6392 patients were collected in the final meta-analysis [17-28].

Characteristics of the included studies

Table 1 lists the baseline clinicopathological characteristics for the included studies. Nine studies were compared between denosumab and alendronate [18, 21-28], one between denosumab and Ibandronate [20], one between risedronate [19] and the other zoledronate acid

Figure 2B, has the risk of bias of graph of the included RCTs. Overall, all the trials were cate-gorized as medium (3-5score) to high quality (5-7score).

Changes in BMD of lumbar spine, total hip and femoral neck

In the validity analysis for denosumab, BMD elevations in the lumbar spine, hip and femoral neck were compared with bisphosphonates after 1 year of treatment. The intervention in the denosumab group was subcutaneous injec-tion of 60 mg per 6 months. Figure 3A, shows nine RCTs reporting the degree of BMD eleva-tion in the lumbar spine after 12 months of treatment. A total of 5009 patients were enrolled. The results of the heterogeneity ex- amination included statistical values: I2 = 78%, P < 0.0001. It is suggested that there was het-erogeneity in the 9 studies, and the random effects model is used for analysis. The results showed that BMD increased by 1.33% (95% CI: 0.86%-1.81%) in the denosumab group, P < 0.01. After subgroup analysis with different treatment regimens, intra-group heterogeneity was significantly reduced (I2 = 0%), suggesting that the heterogeneity originated from different

Figure 1. Flow chart of publication search and selection.

[17]. Except for a very small number of elderly male patients (< 5%) in Nakamura et al’s RCT, the other 10 RCTs were all postmenopausal women with osteoporosis [18]. In McClung et al’s trial, a total of 412 women from 29 study centers in the United States, were randomly assigned to receive various dosage of denosumab (314 patients) [27]. In addition to intervention measures, all subjects were given calcium and VitD orally. Me- asured outcomes included the relative baseline elevation of BMD at each site, and were measured using Dual-energy X-ray absorptiometry. The fol-low-up period was 1-2 years.

Details of the risk of bias are summarized in Figure 2A, with the risk of bias summary for each included RCTs, and


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Table 1. Baseline characteristics of the included studies

Authors Study design Study location Primary outcomes* Comparisons No. of patients

Mean age (years)

BMD (T-score): lumbar spine/hip/femoral neck Medication Duration of

treatmentMiller et al [17]/(2016) RCT United States 1, 2, 3, 4, 5, 6, 7, 8 Denosumab 321 68.5 (7.1) -2.74/-1.93/NA 60 mg, q6m, sc 12 m

Zoledronic acid 322 69.5 (7.7) -2.64/-1.93/NA 5 mg, qy, iv

Nakamura et al [18]/(2014) RCT Japan 1, 2, 3, 4, 5, 6, 7 Denosumab 472 69.9 (7.4) -2.78/-2.01/-2.38 60 mg, q6m, sc 24 m

Alendronate 242 70.2 (7.3) -2.69/-1.96/-2.29 35 mg, q1w, po

Placebo 480 69.0 (7.7) -2.73/-1.95/-2.29 60 mg, q6m, sc

Roux et al [19]/(2014) RCT France 1, 2, 3, 4, 5, 6, 7, 8 Denosumab 435 67.8 (7.0) -2.20/-1.60/-1.90 60 mg, q6m, sc 12 m

Risedronate 435 67.7 (6.8) -2.30/-1.60/-1.90 150 mg, qm, po

Recknor et al [20]/(2013) RCT United States 1, 2, 3, 4, 5, 6, 7, 8 Denosumab 417 67.2 (8.1) -1.80/-2.10/-2.50 60 mg, q6m, sc 12 m

Ibandronate 416 66.2 (7.8) -1.80/-2.10/-2.50 150 mg, qm, po

Freemantle et al [21]/(2012)# RCT United Kingdom 1, 2, 3, 4, 5, 6, 7 Denosumab 126 65.1 (7.6) -2.04/-1.60/-2.01 60 mg, q6m, sc 24 m


Kendler et al [22]/(2010) RCT Canada 1, 2, 3, 4, 5, 6, 7, 8 Denosumab 253 66.9 (7.8) -2.64/-1.79/NA 60 mg, q6m, sc 12 m

Alendronate 251 68.2 (7.7) -2.62/-1.81/NA 70 mg, qw, po

Seeman et al [23]/(2010) RCT Australia 4, 5, 6 Denosumab 83 60.3 (5.9) -2.40/-1.40/NA 60 mg, q6m, sc 12 m

Alendronate 82 60.7 (5.2) -2.50/-1.40/NA 70 mg, q1w, po

Palcebo 82 60.8 (5.2) -2.40/-1.10/NA 60 mg, q6m, sc

Brown et al [24]/(2009) RCT Spain 1, 2, 3, 4, 5, 6, 7, 8 Denosumab 594 64.1 (8.6) -2.57/-1.75/NA 60 mg, q6m, sc 12 m

Alendronate 595 64.6 (8.3) -2.57/-1.69/NA 70 mg, q1w, po

Beck et al [25]/(2008) RCT United States 1, 3 Denosumab 39 63.0 (8.0) NA/-1.42/NA 60 mg, q6m, sc 24 m

Alendronate 38 63.0 (8.0) NA/-1.46/NA 70 mg, q1w, po

Placebo 39 63.0 (9.0) NA/-1.37/NA 60 mg, q6m, sc

Lewiecki et al [26]/(2008) RCT United States 1, 2, 4, 5, 6, 7, 8 Denosumab 314 62.3 (8.0) -2.20/-1.40/-1.90 60 mg, q6m, sc 24 m


Placebo 46 63.7 (9.1) NA

McClung et al [27]/(2006) RCT United States 1, 2 Denosumab 47 62.8 (8.2) -2.00/-1.50/-2.00 60 mg, q6m, sc** 12 m

Alendronate 47 63.1 (8.1) -2.00/-1.60/-1.90 70 mg, qw, po

Placebo 46 63.7 (9.1) -2.20/-1.40/-1.90 60 mg, q6m, scValues were in means and standard deviations. Abbreviations: RCT, randomized controlled trials; BMD, bone mineral density; AE, adverse events; NA, not available. *Primary outcomes: 1, change in lumbar spine BMD; 2, change in total hip BMD; 3, change in femoral neck BMD; 4, AEs; 5, severe AEs; 6, withdrawn due to AEs; 7, risk of fracture; 8, mortality. **A total of 412 women from 29 study centers in the United States, were randomly assigned to receive Denosumab (314 patients) given subcutaneously either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label alendronate (at a dose of 70 mg) given orally once weekly, or placebo. #Enrolled patients were the same with Kendler er al’s RCT (2011) [28].


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treatment regimens in the bisphosphonates group. In detail, compared with bisphospho-nates of alendronate, denosumab for osteopo-rosis patients further increased the change in lumbar for spine BMD (WMD = 0.97%; 95% CI: 0.70% to 1.25%; P < 0.00001, I2 = 0%). Compared with other bisphosphonates such as zoledronic acid, risedronate and ibandronate, the results also favored the denosumab group (all P < 0.00001). We performed a sensitivity analysis by leaving out one study in turn and results showed that the overall effect size was not changeable, indicating a robustness of the results.

As for the total hip and femoral neck, BMDs of the denosumab group were 1.11% and 1.01% higher than that in the bisphosphonates group, respectively (95% CI: 0.97%-1.26%, P < 0.00001; and 95% CI: 0.81%-1.22%, P < 0.00001), as shown in Figure 3B and 3C.

Adverse events

In the safety analysis, the adverse events, severe adverse events, fractures, withdrawal and death caused by adverse events occurring within one year after the start of the trial were studied by meta-analysis. Severe adverse events refer to major complications of tumors, infections, comorbidities from digestive, respi-ratory or circulatory systems. The RR of adverse events was 0.99 (95% CI: 0.96, 1.02), P = 0.62 (Figure 4A) of denosumab versus bisphospho-nates. In terms of severe adverse events, no significant difference was observed between the two groups (RR = 1.03, 95% CI: 0.85, 1.24; P = 0.76, I2 = 0%) (Figure 4B). The withdrawal rate of patients with adverse events in the denosumab group was lower than that in bisphosphonates group, and the difference was statistically significant (RR = 0.53, 95% CI: 0.37, 0.76; P = 0.0006, I2 = 0%) (Figure 4C).

Figure 2. Quality assessment based on Cochrane Collaboration’s tool. The risk of bias summary A. +, no bias; -, bias; ?, bias unknown; B. Risk of bias of graph of the included randomized controlled trials.


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Fractures and mortality

Figure 5A and 5B show no significant differ-ences were observed between denosumab and bisphosphonates in the pooled estimates, and the pooled RRs were 1.06 (95% CI: 0.80, 1.39; P = 0.68, I2 = 0%) and 0.64 (95% CI: 0.20, 2.06; P = 0.45, I2 = 0%) respectively.

Publication bias

Begg’s funnel plot was employed to assess the publication bias. As shown in Figure 6, the fun-

nel plots failed to reveal any obvious asymme-try except in the change in total lumbar spine BMD, and in the withdrawn due to adverse events of denosumab versus bisphosphonates.

Discussion

Based on the current available literature, the present systematic review and meta-analysis has confirmed that denosumab, a fully human monoclonal antibody against the RANKL, could potently reduce bone resorption with an accom-

Figure 3. Forest plots depicting the change in total lumbar spine BMD (A), the change in hip BMD (B), and the change in femoral neck BMD (C) of denosumab versus bisphosphonates. Abbreviations: BMD, bone mineral density.


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panying increase in BMD. Compared with the traditional bisphosphonates for bone loss in postmenopausal osteoporosis patients, deno-sumab significantly increased changes in lum-bar spine, total hip and femoral neck BMD. The results were robust as confirmed by the sensi-

tivity analysis. As for the safety concern, both the adverse events and severe adverse events were comparable between the two groups, as well as the rates of withdraw due to adverse events. Moreover, compared with bisphospho-nates, denosumab has no benefit in reducing

Figure 4. Forest plots depicting the AEs (A), severe AEs (B), and withdraw due to AEs (C) of denosumab versus bisphosphonates. Abbreviations: AE, adverse event.


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the risk of fracture. The pooled results also showed similarly in terms of mortality outcomes.

As an antiresorptive mechanism, the direct combination of the RANKL and the inhibiting effect for the osteoclasts’ survival and differen-tiation simultaneously makes denosumab a more powerful drug than bisphosphonates, in theory. In fact, we did observe a significant dif-ference between denosumab and bisphospho-nates for clinical outcomes that were changes in the skeletal BMD. It might be reasonable that BMD increasing leads to a reduced fracture rate for postmenopausal osteoporosis patients. However, no significant changes in fracture occurrence were detected in the present study. In a network meta-analysis the different phar-macological agents in reducing the risk of fra-gility fractures were investigated. Although both denosumab and bisphosphonates were most effective in reducing the risk of fragility frac-tures, the differences in denosumab, zoledro-

nate, risedronate, ibandronate, and alendro-nate were not statistically significant [29]. We speculate that the reason may be that the occurrence of fracture is the outcome of multi-ple factors, and the increase of BMD in a short time is not enough to reduce the risk of fracture.

Previous meta-analyses on this topic were associated several limitations. The differences between the current work and the previous ones should be highlighted. Lin et al conducted a head-to-head comparison of efficacy and safety profiles between 60 mg denosumab subcutaneously per 6 months and 70 mg alen-dronate orally per week for postmenopausal women with low BMD [30]. Of note was the observation that only four heterogeneous RCTs were included. The included studies were small and newly published ones have been published in recent years. Our meta-analysis added a sta-tistical power of 11 RCTs with a total of 6392 patients being collected. Another systematic

Figure 5. Forest plots depicting the incidence of bone fractures (A) and mortality (B) of denosumab versus bisphos-phonates.


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review and meta-analysis of denosumab com-pared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture, had nine studies including a total of 4890 post-menopausal women being identified [31]. How- ever, the real effects of denosumab for post-menopausal osteoporosis could not be accu-rately assessed as they included patients that were prescribed daily or weekly bisphospho-nates therapy for more than 1 month. What’s more, both the above meta-analyses were con-ducted to compare the efficacy and safety of denosumab over other pharmacological treat-ments for osteoporosis, except for bisphospho-nates, thus a larger heterogeneity was una- voidable.

In this study, meta-analysis of BMD elevation at different sites revealed some heterogeneity, possibly due to differences in basic character-istics and treatment options among the study groups. First, the baseline BMD of subjects in each study group was different (Table 1). There have been studies reporting that when the patient’s baseline BMD is low, the use of bisphosphonates would led to BMD increasing more significantly [32, 33]. Second, in ethnicity considerations, the subjects of Nakamura et al’s, were of different race and the control group was given alendronate 35 mg per week [18]. Third, different postmenopausal osteoporosis diagnostic criteria were applied for patients from different countries, and the dose

Figure 6. Funnel plots depicting the change in total lumbar spine, hip and femoral neck BMD (A-C); AEs (D), severe AEs (E) and with-drawn due to AEs (F), fractures (G) and mortality (H) of denosumab versus bisphosphonates. Abbre-viations: BMD, bone mineral den-sity; AE, adverse event.


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and duration of the medication were not con-sistent; as in the Recknor et al’s and Roux et al’s studies, all patients were treated with alen-dronate for more than 30 days prior to interven-tion [19, 20]. These differences might have contributed some effects on the heterogeneity, but in the sensitive analysis when removing these studies, the pooled results were similar. Moreover, severe complications might have been underestimated due to the relatively short follow-up duration of the included studies.

There are also some shortcomings in this study: (1) Most of the subjects are white, which may lead to distribution bias and selection bias, and affect the meta-analysis results. (2) Publicati- on bias, including the reported literature, the results of negative unreporting was not statisti-cally analyzed. (3) BMD changes in different parts of the body (lumbar spine, total hip and femoral neck BMD) before and after treatment were taken as the main observation index in all studies. The occurrence of fracture was only described as a secondary observation index in adverse reactions, and there was insufficient evidence to reflect the effectiveness of treat-ment. (4) Follow-up time was short, and only the data from 60 mg/6 months of subcutaneous injection of denosumab were analyzed. Its long-term effectiveness and safety need to be fur-ther studied. Nevertheless, in our study, strict inclusion and exclusion criteria were estab-lished, all of which were from RCTs. Most of the literature quality scores were medium to high level, and the reliability of the conclusion is strong.

Conclusion

In conclusion, compared with bisphospho-nates, denosumab can significantly increase bone mineral density of the hip, lumbar verte-bra, femoral neck and other places in post-menopausal osteoporotic women, and the safety of the two drugs is similar.

Disclosure of conflict of interest

None.

Address correspondence to: Dr. Jun Luo, Department of Rehabilitation, The Second Affiliated Hospital of Nanchang University, No.1 Minde Road, Donghu District, Nanchang 330006, Jiangxi, China. Tel: 83827855; E-mail: [email protected]

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review article denosumab versus bisphosphonates for ...ijcem.com/files/ijcem0094322.pdf · and...

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