Efficacy of statins for osteoporosis: a systematic review and meta-analysis

Abstract

Our meta-analysis assessed the efficacy of statins on the risk of fracture, bone mineral density (BMD), and the markers of bone metabolism by collecting data from 33 clinical trials. We found that statin treatment was associated with bone metabolism. And statins seemed to be more effective on male patients with osteoporosis. The efficacy of statins for the treatment of osteoporosis has been controversial in previous studies and meta-analyses. Our meta-analysis was conducted to examine in detail the efficacy of statins on osteoporosis. We searched PubMed, Embase, and the Cochrane Library databases for clinical trials from inception to May 2016. We included studies that described the effect of statins on the risk of fracture, BMD, or bone turnover markers. Moreover, we also conducted subgroup analyses according to the skeleton site, patient gender, and length of follow-up. A total of 33 studies which included 23 observational studies (16 cohort studies and 7 case-control studies) and 10 randomized controlled trials (RCTs) were evaluated. These 33 studies included 314,473 patients in statin group and 1,349,192 patients in control group. Statins decreased the risk of overall fractures (OR = 0.81, 95% CI 0.73–0.89) and hip fractures (OR = 0.75, 95% CI 0.60–0.92). Furthermore, the use of statins was associated with increased BMD at the total hip (standardized mean difference (SMD) = 0.18, 95% CI 0.00–0.36) and lumbar spine (SMD = 0.20, 95% CI 0.07–0.32) and improved the bone formation marker, osteocalcin (OC) (SMD = 0.21, 95% CI 0.00–0.42). However, there was no positive effect on vertebral fractures, upper extremity fractures, BMD at the femoral neck, bone-specific alkaline phosphatase (BALP), and serum C-terminal peptide of type I collagen (S-CTX). Also, compared with male subgroups, the effect on female subgroups was only slightly positive or of no statistical significance. Our meta-analysis indicates that statin treatment may be associated with a decreased risk of overall fractures and hip fractures, an increased BMD at the total hip, BMD at the lumbar spine, and OC. Moreover, our results also show that statin treatment may have a greater effect on male patients than on female patients.

Introduction

Osteoporosis, a systemic skeletal disease, is characterized by decreased bone density and microarchitectural disruption of bone tissue, with a consequent increased skeletal fragility and fracture [1]. Nowadays, osteoporosis is a major health problem worldwide [2], and most preventative and curative drugs for osteoporosis such as raloxifene, denosumab, bisphosphonates, and calcitonin work by the antiresorptive mechanism [36]. Although the most promising drug that promotes bone formation is teriparatide, teriparatide is given mainly by subcutaneous injection. In addition, the treatment of osteoporosis with teriparatide was associated with a high incidence of hypercalcemia [7]. So, it is essential to discover new drugs that promote bone formation.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become a mainstay in preventing and treating cardiovascular disease (CVD), and they appear to be potentially promising drugs for osteoporosis. The active mechanisms of the effect of statins on the bone have been examined by a number of researchers. The current literature demonstrates that the effects of statins on the bone may involve a number of mechanisms including proliferation, differentiation, protection of osteoblasts, and reducing osteoclastogenesis [8]. Consequently, statins which are both antiresorptive and anabolic agents may play a major role in the clinical management of osteoporosis. Also, if statins are proved to be beneficial for bone health, they will be the right choice for patients who are also at risk of cardiovascular disease.

In studies of the effects of statins on osteoporosis, the fracture risk, BMD, and the concentration of bone turnover markers have been reported in statin users and matched controls in case-control retrospective studies, prospective cohort studies, and randomized controlled trials (RCTs). Among the studies, there were widely varying results on the efficacy of statin therapy in osteoporosis. Our purpose was to comprehensively evaluate the effects of all statins on the fracture rates, BMD, and biochemical markers of bone metabolism. Previously published meta-analyses on the same topic have had inconsistent conclusions [911]. Recently, one meta-analysis [12] studied statin use and the risk of overall fracture; however, data about osteoporosis incompletely extracted. Consequently, we have conducted a meta-analysis which has added several different outcomes to investigate further the efficacy of statins on osteoporosis. We have made a detailed description of the distinctions among the studies.

Materials and methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for performing our systematic review and meta-analysis.

Data sources and searches

We searched studies from PubMed, Embase, and the Cochrane Library databases to identify relevant articles (from inception to May 2016) using text, medical subject headings (MeSH), and keywords: “bone mineral density”, “HMG-CoA reductase inhibitors” or “statins”, “osteoporosis”, “bone maker”, and “fracture”. References to reviews and eligible articles were also screened for additional articles.

Study selection

The studies were screened independently by two reviewers (TA and JFH). Studies that met the following criteria were included: (1) studies that were randomized controlled or observational human trials; (2) statin users who had taken any kind of statins at any therapeutic dose for at least 2 months; (3) patients in control groups who used drugs or placebo that did not influence bone anabolism; (4) studies that reported BMD data measured by dual-energy X-ray absorptiometry (DEXA) at included bone sites, the concentration of bone turnover markers, or the odds ratio (OR) of the fracture risk among statin users and controls. Disagreements were resolved by discussions.

Data extraction

Data were extracted independently from the included studies using a standardized data extraction form by two reviewers (SHS and RFL). Discrepancies were solved by consensus. We collected the following information: the characteristics of included trials (study design, intervention type and dose, study country, name of the first author, follow-up duration, publication year), the characteristics of patients (gender, mean age, population), and the outcomes [dichotomous outcomes: the adjusted pooled OR and 95% CI of the fracture, continuous outcomes: the final value and standard deviation (SD) of BMD at three sites and the concentration of three bone turnover markers].

Quality assessment

We assessed the risk of bias for RCTs using the improved Jadad scale. The bias of RCTs was assessed in the following domains: randomization (0–2 points), randomization concealing (0–2 points), double blinding (0–2 points), and quit and withdrawal (0–1 points). The risk of bias of articles was considered as “low” when the total score was 0–3 and “high” when the total score was 4–7. Also, we assessed observational studies using the Newcastle-Ottawa scale (NOS). There were three criteria in the checklist which were divided into eight categories: selection (0–4 stars), comparability (0–2 stars), and outcome (0–3 stars). The risk of bias of studies was defined as “poor” if the number of stars was 0–4, “moderate” if the number of stars was 4–6, and high if the number of stars was 7–9. The quality of each result was assessed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The bias assessment and outcome quality were evaluated independently by two reviewers (MY and GC), and any controversy was resolved by discussion.

Data synthesis and statistical methods

For the dichotomous outcomes (overall fracture risk), the adjustment pooled OR and 95% CI were used as pooled statistics. Also, for the continuous outcomes (BMD and the concentration of bone turnover markers), the standardized mean difference (SMD) was used to standardize differences between groups. Moreover, subgroup analyses were performed based on the characteristics of the treatment duration, gender of participants, and study design.

The meta-analysis was conducted using fixed-effects or random-effects model when heterogeneity was obvious. Heterogeneity between studies was assessed with the chi-squared (χ 2) test and the I 2 test. When the P ≤ 0.10 and I 2 > 50%, the heterogeneity was statistically significant. The magnitude of the publication bias was assessed by the funnel plot and Egger’s and Begg’s tests, and P ≤ 0.05 was considered a significant publication bias in the Egger’s or Begg’s test. The stability of the results was verified by sensitivity analysis.

The meta-analysis was performed using STATA 11.0 software (StataCorp LP, College Station, TX, USA) and Review Manager 5.2 software [(RevMan), The Cochrane Collaboration, Copenhagen].

Results

Search result

Our literature search initially produced 1436 articles and finally identified 33 studies meeting the inclusion criteria. In the final articles, 10 were RCTs [1322], 16 were cohort studies [2338], and 7 were case-control studies [3945]. The detailed selection process is shown in Fig. 1.

Fig. 1
figure1

Flowchart of study selection

The characteristics of the included trials and patients are presented in Table 1. The included studies contained 314,473 patients in the statin group and 1,349,192 patients in the control group. But most of the patients were just assessed using the fracture endpoints that involved 313,745 patients in the intervention group and 1,347,955 patients in the control group. Because some outcomes were combined with different study designs, studies were divided into two or three subgroups according to the study design. Also, the therapeutic effect may be related to the gender of patients and duration of treatment, and so, the data were also separated into different subgroups for our meta-analysis. The detailed bias assessments of the included studies are shown in the electronic Supplementary Tables 1, 2, and 3. The quality assessments of all the outcomes are shown in electronic Supplementary Table 4.

Table 1 Characteristics of included studies

Efficacy outcomes

The risk of fracture

A total of 16 studies (313,745 in the statin group, 1,347,955 in the control group) reported data for the risk of fracture [21, 22, 30, 3345]. The risk of overall fracture was reduced by statin therapy compared with the control (OR = 0.81; 95% CI 0.73–0.89; P < 0.0001; I 2 = 87.5%) (Fig. 2). Heterogeneity of the overall fracture endpoint was evident, so we tried to trace the source of the variance. We found that the study country, the drug used, the mean age of patients, the study design, and the gender could not explain the heterogeneity. However, the results were not calculated based on the same adjusted estimates, and the observational studies might show greater variance. No publication bias was detected by the funnel plot, Egger’s test, and Begg’s test (in the Egger’s test, P = 0.080; in the Begg’s test, P = 0.053). This result was consistent with the conclusions of the different study design subgroups, the short and long duration of follow-up subgroups, and the mixed gender subgroups which included both male and female patients but did not accord with the conclusions of the female subgroup and the uncertain duration of the follow-up subgroup. Moreover, the risk of hip fracture was also reduced by statins (OR = 0.75; 95% CI 0.60–0.92; P = 0.007; I 2 = 77.2%). And there was a tendency towards a reduced risk of fracture at the vertebral (OR = 0.81; 95% CI 0.57–1.17; P = 0.263; I 2 = 48.6%) and upper extremity (OR = 0.968; 95% CI 0.896–1.045; P = 0.400; I 2 = 30.2%), but positive effects at these two sites were not obvious. All the results of the fracture outcomes are summarized in Table 2.

Fig. 2
figure2

Forest plot of odds ratio for statins and the fracture risk. Cohort study (1) and case-control study (2)

Table 2 Summary of effect estimates and heterogeneity on the fracture results

The BMD at different sites

The meta-analysis results of BMD at different sites are listed in Table 3.

Table 3 Summary of effect estimates and heterogeneity on the SMD results

At the total hip: A total of seven studies (792 in the statin group, 6955 in the control group) reported data for the BMD at the total hip [14, 17, 2528, 30]. The results of the meta-analysis indicated that statin therapy produced an improvement in BMD at the total hip (SMD = 0.18; 95% CI 0.00–0.36; P < 0.05; I 2 = 62%) (Fig. 3 (a)). The positive effect of statin therapy on the BMD at the total hip did not differ with patient gender, but no positive results were observed in RCTs (SMD = 0.39; 95% CI −0.73–1.50; P = 0.50; I 2 = 90%).

Fig. 3
figure3

Forest plot for the BMD at several sites. Total hip (a), lumbar spine (b), and femoral neck (c)

At the lumbar spine: A total of eight studies (430 in the statins group, 985 in the control group) reported data for the BMD at the lumbar spine [14, 17, 2429]. The results of the meta-analysis indicated that statin therapy produced an improvement in BMD at the lumbar spine (SMD = 0.20; 95% CI 0.07–0.32; P = 0.002; I 2 = 43%) (Fig. 3 (b)). The positive effects of statin therapy on BMD at the lumbar spine were also seen in the male subgroup (SMD = 0.31; 95% CI 0.14–0.48; P = 0.0003; I 2 = 54%) and cohort subgroup (SMD = 0.21; 95% CI 0.08–0.34; P = 0.001; I 2 = 55%) but were not observed in the female subgroup (SMD = 0.07; 95% CI −0.11–0.25; P = 0.43; I 2 = 0%) and RCT subgroup (SMD = 0.08; 95% CI −0.26–0.41; P = 0.65; I 2 = 0%).

At the femoral neck: A total of six studies (358 in the statin group, 944 in the control group) reported data for the BMD at the femoral neck [14, 17, 25, 2729]. The results of the meta-analysis indicated that statin therapy had no effect on the BMD at the femoral neck (SMD = 0.06; 95% CI −0.07–0.19; P = 0.35; I 2 = 48%) (Fig. 3 (c)). The subgroups based on the study design and patient gender also showed no improvement in BMD at this site.

The markers of bone metabolism

In order to explore the mechanisms of action of statins on the bone, we added three bone turnover markers. The results of the meta-analysis indicated that statin therapy produced an improvement in the osteocalcin (OC) concentration (SMD = 0.21; 95% CI 0.00–0.42; P = 0.04; I 2 = 0%) (Fig. 4 (a)) but had no significant influence on the bone-specific alkaline phosphatase (BALP) concentration (SMD = 0.10; 95% CI −0.09–0.28; P = 0.31; I 2 = 2%) (Fig. 4 (b)) and serum C-terminal peptide of type I collagen (S-CTX) concentration (SMD = −0.33; 95% CI −0.89–0.24; P = 0.26; I 2 = 88%) (Fig. 4 (c)).

Fig. 4
figure4

Forest plot for the markers of bone anabolism. OC (a), BALP (b), and S-CTX (c)

Sensitivity analysis and publication bias

The results of the sensitivity analysis at all endpoints suggested that no individual study had a significant effect on the pooled effect size. Also, no publication bias was discovered by the funnel plot and Egger’s and Begg’s test for all outcomes.

Discussion

The mechanisms of bone anabolism regulated by statins have not been fully elucidated. Some pathways have been identified in which statins may influence bone anabolism. (1) Statins increase bone morphogenetic protein-2 (BMP-2) through the Ras-PI3K-Akt/MAPK signaling pathway [46], and BMP-2 induces osteoblast differentiation through the Runt-related transcription factor 2 (Runx2) [47, 48]. (2) Statins inhibit the mevalonate pathway stopping the synthesis of downstream products. Consequently, the FPP and GGPP synthesis are blocked [49], and these negatively regulate osteoblastic differentiation [50]. (3) Statins inhibit osteoblast apoptosis via the TGFβ/Smad3 pathway [51, 52]. (4) Statins suppress osteoclastogenesis by the OPG/RANKL/RANK pathway [53]. Therefore, statins are considered to be associated with bone anabolism. However, from the three biochemical markers of bone metabolism included in our study, we proved that statins affected OC. Both OC and BALP are markers of bone formation, but there was no evident influence on BALP. And there was only one marker of bone resorption (S-CTX), but the results did not reach significant statistical differences, and there was evident heterogeneity. So, whether statins affect bone resorption remains uncertain.

From this meta-analysis of statins on bone anabolism which included 33 clinical trials, we obtained the following results. Statins significantly reduced the risk of overall fracture, but statins did not have such an effect on female patients. And based on the subgroup analysis of different skeleton sites, statin users had a lower risk of hip fracture compared with nonusers, but there were no clearly positive effects on vertebral fracture and upper extremity fracture in statin users. In addition, compared with the baseline level, statin users had a higher BMD at the lumbar spine and total hip, but not at the femoral neck. Up to now, no convincing evidence can explain the discrepancy in the effect of statins on fracture and the BMD at different skeleton sites. Rejnmark indicated that the BMD at different skeleton sites may be associated with different reactions to a variety of pathological conditions [17]. For instance, the cortical BMD was more reduced than the trabecular BMD in hyperparathyroid patients [54]. So, the risk of fracture and the BMD at different skeleton sites may vary. However, no positive effect on the BMD at the lumbar spine was seen in female patients. The major mechanism of bone loss is decreased osteoblastic function in males; however, increased bone resorption related to reduced estrogen level in females [55]. We speculate that statins cannot entirely make up for the bone loss related to estrogen loss. And the results on BMD in studies with different designs were paradoxical in that the observational studies showed a greater effect than RCTs. So, these benefits should be interpreted cautiously. Furthermore, we also conducted an analysis of bone turnover markers. The results obtained indicated that statins improve the OC concentration but not that of BALP and S-CTX. This result demonstrated that statins may affect one bone formation marker, but they had no marked effect on bone resorption markers and other markers of bone formation. The results of the bone turnover markers were paradoxical possibly because of the different sensitivity of the bone turnover markers. Also, the probable explanation for no significant effect at some endpoints could be the variable and low uptake of statins into bone and the low bioavailability of statins in bone, because statins reach bone tissue after undergoing first-pass metabolism [56]. In addition, the doses of statins were too low, because statin doses used were tenfold higher than those used for cholesterol lowering in animal studies [57]. Therefore, if statins can bypass the liver, they may have a greater effect on the bone.

Many meta-analyses evaluated the association between statin use and osteoporosis. The most recently published systematic review and meta-analysis on statins involving the risk of fracture was published in 2015 and concluded that statin use was associated with a reduced risk of fracture [12]. Although our findings are similar to earlier conclusions, it is worth noticing that there were a number of differences between our study and previous ones. Firstly, earlier meta-analysis just used the risk of fracture as the only outcome with an evident heterogeneity; however, in our meta-analysis, we combined this with six other outcomes which also reflected the efficacy of statins for treating osteoporosis. And the added outcomes may explain the mechanism of action and a judgment of the result from several viewpoints. Secondly, we excluded two trials [58, 59] and added one new trial [21] involving the fracture outcome. The two excluded studies were not original studies. One [58] was a meta-analysis of four studies, but the original text did not involve the effects of statins on the bone and provide meaningful data. In addition, because of the rigid inclusion criteria, we also excluded one article [58] on BMD outcomes that was included in former meta-analyses of BMD. This article contained four trials with a very large number of patients. We referred to original articles which did not present available data and originally study of statins on osteoporosis. And patients used other drugs that could influence bone metabolism in the original trials. So, we excluded the article which may have a high weight on the overall results. As a consequence, we firstly discovered that statins had no significant effect on BMD at the femoral neck. The other one [59] was a correspondence, and the original study was a cross-sectional study which was different from our included types of clinical trials. And the quality of the included trials was also assessed and had never been done in former meta-analyses of this topic. Due to the quality assessment, our results were more convincing. Thirdly, our conclusions indicated that statins had no significant effect in female patients, and this was different from earlier findings. And the BMD outcomes also confirmed this point which was not detected previously.

Nevertheless, our meta-analysis had several limitations. Firstly, the included studies were mostly observational studies that tended to have a publication bias, even though this was not shown by Egger’s and Begg’s tests. Moreover, the pooled effected sizes did not consistently match the results of the different study designs. And because of the observational studies, the quality assessments of the evidence were mostly low. Secondly, there was no complete collection of confounding factors, such as an individual and family history of fracture, a habit of exercise, dietary habits, and so on. And many confounding factors can affect the results. The fracture outcomes were not calculated according to the same adjusted estimates, and insufficient information may influence the effect of statins on the bone. Also, the risk of fracture is related to the body mass index, and the association differs across skeletal sites [60]. And some comorbidities may affect the results. For example, hyperglycemia and proteinuria can cause calciuria and a loss of new bone formation [61, 62]. Thirdly, in some of estimates, the heterogeneity was large, and we found that the study design, age, country, polarity, duration, gender, or funding source could not explain the heterogeneity. So, we were unable to identify the cause for the heterogeneity of some outcomes. The sources of heterogeneity may include variations in the pharmacodynamics of statins or patient clinical conditions. Therefore, the large heterogeneity of some results should be interpreted cautiously. In addition, the evidence of the benefit was limited to the small numbers of RCTs. The RCTs with a long duration, well designed, and large sizes are on demand to investigate the efficacy of statins for treating osteoporosis.

In conclusion, statins are effective in reducing the risk of fracture, improving the BMD at the lumbar spine and total hip and increasing the OC concentration. Furthermore, regarding the efficacy of statins on osteoporosis, they have a more significant effect in male patients than in female patients.

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Acknowledgements

This project was supported by grants from the “Faculty of Medical Devices-Jingxin” Cooperation Fund of Shenyang Pharmaceutical University.

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An, T., Hao, J., Sun, S. et al. Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos Int 28, 47–57 (2017). https://doi.org/10.1007/s00198-016-3844-8

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Keywords

  • Bone maker
  • Bone mineral density
  • Fracture
  • HMG-CoA reductase inhibitors
  • Osteoporosis
  • Statins