The effect of statins on bone turnover biomarkers: a systematic review and meta-analysis of randomized controlled trials

Abstract

Few studies have considered the effect of statins on bone turnover biomarker levels and the results of these studies are inconsistent. Here we performed a meta-analysis of the effect of statins on bone turnover biomarker levels. We used keywords, free words, and related words that included the terms “hydroxymethylglutaryl-CoA reductase inhibitors,” “statin,” and “bone turnover biomarkers” to search PubMed, Cochrane Library, and Embase. The Cochrane Risk Bias Evaluation Tool was used to evaluate the risk of bias, and Review Manager 5.3 and Stata 13.0 were used for statistical analyses. Six randomized controlled trials involving a total of 382 subjects were included in the meta-analysis. The results showed that statins increased the osteocalcin (OC) [mean difference (MD) = 0.73 ng/mL, 95% CI: 0.12, 1.35, I² = 23% and p = 0.26], and decreased cross-linked N-telopeptide (NTX) (MD = –1.14 nM BCE, 95% CI: –2.21, –0.07, I² = 0%, p = 0.53) and C-terminal peptide of type I collagen (CTX) (MD = –0.03 ng/mL, 95% CI: –0.05, –0.01, I² = 0% and p = 0.56). There was no effect on bone-specific alkaline phosphatase (MD = –1.37 U/L, 95% CI: –3.09, 0.34, I² = 0% and p = 0.94) and intact parathyroid hormone (MD = –1.73 pg/mL, 95% CI: –4.35, 0.89, I² = 0% and p = 0.77). Statins increase bone formation biomarker OC and decrease bone resorption biomarker NTX and CTX levels.

HYDROXYMETHYLGLUTARYL-CoA reductase inhibitors (statins) used for treating hyperlipidemia are also being used as primary and secondary preventive treatment options for cardiovascular diseases (CVDs) [1-3]. The use of statins can significantly reduce recurrent hospitalizations due to CVD as well as mortality associated with it [4, 5]. Futhermore, the effect of statins on bone metabolism and osteoporosis, has attracted widespread attention. The effects of statins on bone growth and development may involve multiple mechanisms including proliferation, differentiation, osteoblast protection, and osteoclast formation reduction [6].

A study including 5,254 patients with newly diagnosed stroke reported that statins significantly reduced the incidence of osteoporosis, and hip and vertebral fractures [7]. A meta-analysis [8] of 33 studies involving 1,663,665 subjects (including men and women) showed that the statin-treatment group (314,473 subjects) was characterized by low risk of overall fractures, including hip fractures, and statin treatment is also related to increased bone density of the overall hip and lumbar spine.

Bone turnover biomarkers (BTMs) reflect whole body rates of bone resorption and bone formation, and provide a dynamic assessment of the skeleton which may complement the static information given by bone mass evaluation [9]. Therefore, BTMs may be more sensitive indicators of bone metabolism. Therefore, these biomarkers are sensitive indicators as they can be used for dynamically assessing bone metabolism.

However, only a few studies have been performed that have reported the effect of statins on BTMs levels and inter-study results are inconsistent. For example, a cross-sectional study from Spain indicated that simvastatin administration (10–40 mg/day) was associated with increased levels of serum osteocalcin (OC) but not of C-terminal peptide of type I collagen (CTX) and aminoterminal propeptide of type I collagen (PINP) in patients with hyperlipidemia [10]. Another cross-sectional study from the Camargo Cohort Study included 2,331 subjects older than 50 years (1,401 women and 930 men) reported that statin users had lower CTX and PINP levels than non-users [9]. A randomized controlled trial (RCT) reported that in subjects with hyperlipidemia, CTX level was significantly lower in the statin-administered group (moderate to high simvastatin dosage [40 mg/d to 80 mg/d]) than in the non-statin group (gemfibrozil or fibrate) [11].

In our study, we performed a meta-analysis to determine the effects of statins on bone formation and resorption biomarkers’ levels, and to explore the relationship between lipid lowering drugs (statins) and bone metabolism.

Materials and Methods

Literature search and screening

We searched PubMed, Embase, and Cochrane using key words, free words, and related words that included the terms “hydroxymethylglutaryl-CoA reductase inhibitors,” “statin,” and “bone turnover biomarkers.” Related references in the articles were also searched. EndNote was used to import data from all the literature articles and this software was used for reference management accordingly.

First, duplicate literature searches were removed from the software. Second, we excluded literature articles such as reviews, case reports, and animal and cell-based studies. Thereafter, we read the abstracts to exclude unrelated literature articles. Lastly, literature articles were screened according to the following inclusion and exclusion criteria.

Inclusion criteria: (i) RCT; (ii) adult subjects (≥18 years old); (iii) the article described the use of at least one type of statin and determined BTMs levels; (iv) the literature provided original data or relevant data that could be obtained based on data conversion.

Exclusion criteria: (i) case-control, cohort, or cross-sectional studies; (ii) studies that included patients with severe cardiovascular and cerebrovascular diseases, other metabolic bone diseases (hyperparathyroidism, hypoparathyroidism, Paget’s disease, Cushing’s syndrome); a history of parathyroidectomy; and untreated hyperthyroidism; (iii) original data were unclear or could not be obtained.

Information and data extraction

From the included studies, we extracted the following information: author names; publication year; patient age and sex; subjects included; sample size; lost to follow-up rate; intervention time; statin type and dosage; BTMs levels before and after statin intervention; and post-pre intervention difference.

Quality assessment

The quality of the literature articles was assessed by using Cochrane Risk Bias Evaluation Tool and meta-analysis was performed using RevMan 5.3. The tool has 7 items including selection, performance, detection, attrition, reporting, and other bias. Each item has three grades: low, unclear, and high risk. We selected the appropriate grade (high, unclear or low) for each article depending on the 7 items.

Statistical analyses

Statistical analyses were performed using RevMan 5.3 and Stata 13.0 software. In the studies by Hsia and Rosenson, the types or doses of statins involved were different, so we divided these two studies into several small studies and analyzed them separately. BTMs levels in the form of continuous data were expressed as mean difference (MD) and 95% confidence interval (95% CI). Inverse variance was used as the statistical model. Fixed effect was used as the analysis model. Heterogeneity analysis was performed by Q and I² tests. A p-value of >0.1 in the Q test or an I² value <50% in the I² test was considered homogeneous. If the p-value was <0.1 or I² value was >50%, it was regarded heterogeneous. Random effect was employed if large heterogeneity was noticed, and the source of heterogeneity was identified according to sensitivity and subgroup analysis [12]. Egger’s test was performed using Stata software to quantitatively evaluate publication bias. A p-value of >0.05 indicated no publication bias [13].

Results

While we routinely pay attention to the effects of statins on blood lipids, their effects on bone metabolism also attract our interest and the results of previous studies are inconsistent. In this study, we searched three databases and selected articles according to inclusion and exclusion criteria, and then explored the effects of statins on bone turnover biomarkers. The results showed statins increased bone formation biomarker OC and decreased bone resorption biomarker NTX and CTX levels.

Literature article retrieval and inclusion

We retrieved 846 literature articles from the three databases. After systematically screening them, 6 were included (Fig. S1). Our meta-analysis involved 382 subjects and statin intervention duration ranged from 2 to 12 months. Statins administered to these patients included atrorvastatin, fluvastatin, simvastatin, pitavastatin, and pravastatin. The fundamental information of the included studies [14-19] has been summarized in Table 1.

Table 1 Characteristics of included studies

Author	Country	Age	Sex	Sample size	Lost to follow-up rate	Statin type (and dosage)	Intervention time (months)	Subjects	Osteopenia/osteoporosis	Medication affects bone metabolism
Berthold 2004 [14]	Germany	61.4 ± 5.1	F	49	2.0%	atrorvastatin 20 mg/day	2	Women >55 years with a minimum postmenopause period of 2 years.	No	Calcium intake of >1,000 mg per day.
Chen 2014 [15]	China	80.1 ± 6.6	M	60	6.3%	atrorvastatin 10 mg/day	12	Mild dyslipidemia (LDL-C level, 3.4–4.1 mmol/L and TG, 1.7–2.3 mmol/L).	Osteopenia	No
Hsia (I) 2002 [16] Hsia (II) 2002 [16]	USA	56.1 ± 9.7	F	22	8.3%	(I) simvastatin 20 mg/day (II) simvastatin 40 mg/day	3	Women	Osteopenia	Some took calcium and vitamin D.
Jiang 2014 [17]	USA	43.5 ± 3.1	M, F	37	9.8%	simvastatin 40 mg/day	3	Subjects were overweight/obese 25–59 years, sedentary, possessed at least 2 of 5 the metabolic syndrome characteristics.	Some had	No
Majima 2007 [18]	Japan	58.6 ± 12.0	M, F	95	5.9%	pitavastatin 1 mg/day	3	Hypercholesterolemia (TC >220 mg/dL and LDL-C >140 mg/dL).	No	No
Rosenson (I) 2005 [19] Rosenson (II) 2005 [19] Rosenson (III) 2005 [19]	USA	50.5 ± 7.9	M, F	55	21.4%	(I) pravastatin 40 mg/day (II) simvastatin 20 mg/day (III) simvastatin 80 mg/day	2	Nonsmoking men and postmenopausal women, aged 35–65 years, with LDL-C between 3.38–4.90 mmol/L and TG <4.52 mmol/L.	No	No

Note: F: female, M: male, BMD: bone mineral density, BMI: body mass index, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, TC: total cholesterol, TG: triglyceride, LDL-C: low-density lipoprotein cholesterol.

Quality assessment results

The results of the risk of bias evaluation were shown in Fig. S2. In general, the quality of included studies was acceptable. Selection bias, attrition bias, reporting bias and other bias were low, performance bias and detection bias were unclear.

Changes in bone turnover biomarkers (BTMs) levels

Bone formation biomarker levels

Bone-specific alkaline phosphatase (BAP) levels

Four literature articles involving a total of 221 participants determined BAP levels after statin treatment. In the fixed effect model, the MD of the total effect amount was –1.37 U/L (95% CI: –3.09, 0.34, I² = 0% and p = 0.94), indicating no heterogeneity and that statins did not have effect on BAP (Fig. 1). There was no publication bias because p = 0.675 (Fig. S3).

Fig. 1

Forest plot of bone-specific alkaline phosphatase levels.

Osteocalcin (OC) levels

Four studies involving a total of 265 participants determined OC level. In the fixed effect model, the MD of the total effect amount for OC was 0.73 ng/mL (95% CI: 0.12, 1.35, I² = 23% and p = 0.26), indicating that statins increased OC level (Fig. 2). P-value was 0.474 in the Egger’s test, indicating that there was no publication bias (Fig. S4).

Fig. 2

Forest plot of osteocalcin levels.

Bone resorption biomarker levels

Cross-linked N-telopeptide (NTX) levels

Three studies involving a total of 172 participants reported NTX levels. Statins decreased NTX levels in the participants, as indicated by an MD value of –1.14 nM BCE (95% CI: –2.21, –0.07) and I² = 0% with p = 0.53 in the fixed effect model (Fig. 3). P-value was 0.052 in the Egger’s test, indicating that there was no publication bias (Fig. S5).

Fig. 3

Forest plot of cross-linked N-telopeptide levels.

C-terminal peptide of type I collagen (CTX) levels

Two studies involving a total of 105 participants reported CTX levels. In the fixed effect model, the combined effect was determined by an MD value of –0.03 ng/mL (95% CI: –0.05, –0.01), indicating no heterogeneity (I² = 0% and p = 0.56) and that statins decreased CTX levels in these participants (Fig. 4). Egger’s test could not be performed because only two studies were included.

Fig. 4

Forest plot of C-terminal peptide of type I collagen levels.

Intact parathyroid hormone (iPTH) levels

Two articles involving a total of 114 subjects reported iPTH levels. The total effect amount was determined by an MD value of –1.73 pg/mL (95% CI: –4.35, 0.89; I² = 0%; p = 0.77) in the fixed effect model, indicating no heterogeneity (Fig. 5). Only two studies were included so Egger’s test could not be conducted.

Fig. 5

Forest plot of intact parathyroid hormone levels.

Discussion

The skeletal system undergoes homeostasis and this process is called bone remodeling, whereby old bones are resorbed and replaced with new ones. An imbalance between bone formation and resorption leads to abnormal bone metabolism [20]. The mechanisms involved in the beneficial effects of statins on bone metabolism may be roughly summarized into two aspects. The one is to promote bone formation. For example, statins may increase the expression of bone morphogenetic protein-2 (BMP-2) through the rat sarcoma/protein kinase B/mitogen-activated protein kinase pathway [21] and suppress osteoblast apoptosis through the transforming growth factor/drosophila mothers against decapentaplegic protein-3 pathway [22]. The other one is to inhibit bone resorption. For example, statins suppress osteoclast formation through the osteoprotegerin/receptor activator of nuclear factor kappa-B ligand/receptor activator of nuclear factor kappa-B system [23, 24]. In addition, statins are lipid-lowering drugs that include two types: lipophilic statins, such as simvastatin and lovastatin, and hydrophilic statins, such as pravastatin, atorvastatin and fluvastatin. Owing to their polarity, bone availability, and complex actions on angiogenesis, different types of statins have varying effects on bone metabolism [11, 22]. Most studies suggest that lipophilic lipid-lowering drugs can promote bone formation. For example, simvastatin can increase the production of BMP-2 via enhanced osteoblast activity and inhibition of farnesyl diphosphate synthase by reducing osteoclast activity [25, 26]. However, a double-blind, placebo-controlled, dose-ranging trial reported no significant changes in BTMs between each atorvastatin (10, 20, 40, or 80 mg) and placebo group in postmenopausal women with dyslipidemia [27]. Some other studies showed similar results [28, 29]. It may be related to many confounding factors such as type of statin, dose, intervention time and characteristics of subjects, so more rigorous studies are needed to generate evidence.

RCTs were included in this study because they have higher evidence level compared with case-control, cohort, or cross-sectional studies. The results showed that the level of bone formation marker OC increased while that of the bone resorption marker NTX and CTX decreased in the statin group compared with the control group. Previous systematic reviews and meta-analyses also explored the effects of statins on bone turnover markers. An et al.’s meta-analysis included 698 subjects (8 RCTs and 3 cohorts) found that statin treatment increased OC levels, but not the BAP and CTX levels [8]. In the study of six RCTs by Yue et al. [30], statin treatment from 8 to 52 weeks did not change the levels of bone formation (OC and BAP) or bone destruction indicators (CTX and NTX) in postmenopausal women (mean age, >62.7 years old). Bauer et al. [31] conducted a review but not a quantitative meta-analysis, but we can also observe that different studies reported different results. For example, Chan et al. [32] reported that serum OC rose 85% over 4 weeks treated with simvastatin (20 mg/day) while NTX fell 5.3%. Another clinical trial showed OC and BAP fell 24% after 6 months in fluvastatin group (20 mg/day), and fell 44% and 25% in pravastatin (10 mg/day) group [33].

As for whether statin treatment is recommended for hyperlipemia, osteopenia, and osteoporosis, thorough clinical trials must be conducted to evaluate the independent and combined effects of statins and traditional treatments for osteopenia/osteoporosis to include their effects of BTMs and bone morphology.

Vitamin D status or the use of vitamin D supplements could potentially influence the results of this meta-analysis. Vitamin D is crucial for skeletal health and bone metabolism. It can help to maintain a balance between bone turnover and bone growth via its direct action on osteoblasts and osteoclasts and interaction with non-skeletal tissues such as extraosseous tissues, PTH, and the intestine [34, 35]. Among the studies included in this meta-analysis, only Chen’s study provided each patient’s 25-hydroxyvitamin D (25-OHD) level, which is an indicator of vitamin D status. Thus, we did not compare 25-OHD levels between the statin and control groups. We also did not conduct subgroup analysis focusing on vitamin D as a potential factor. In addition, vitamin D and statins may impact one another. For example, Catalano et al. [36] showed that vitamin D may even boost the effects of statins. The effect of statin on bone metabolism indicators may also be related to different disease states, such as diabetes. Because there are fewer eligible RCTs included and the information provided is not particularly complete, no further subgroup analysis was performed.

Our meta-analysis still has some limitations. First, because only a few BTMs were included in the single study, all the biomarkers were not included in the meta-analysis, for example PINP, a key indicator of bone formation. Thus, we could not determine the changes in the levels of all biomarkers. Second, different types of statins were administered, which may affect the final results because lipophilic statins (simvastatin) and hydrophilic statins (pravastatin) seem to have different effects on bone metabolism: lipophilic statins, not hydrophilic statins exert beneficial effects on bone metabolism. A better method is to investigate the effect of different types of statins (lipophilic and hydrophilic statins) or one statin on BTMs levels. Third, the number of RCTs was small. In our meta-analysis, only six RCTs were included. The inclusion of more RCTs will make the results more reliable. Fourth, the duration of statin intervention in the included studies ranged 2–12 months. Two months represent a relatively short period, and an obvious effect on some bone turnover markers may not be observed in this period, which would affect the final result.

In conclusion, statins can increase OC levels and decrease NTX levels, which can lead to improved bone formation and suppressed bone resorption. Statins reduce blood lipids, which benefit cardiovascular and cerebrovascular diseases. At the same time, they can promote bone formation and suppress bone resorption, which is expected to reduce the risk of OP. How different kinds of lipid-lowering drugs affect bone metabolism requires further exploration. In addition, the effects of statins on bone metabolism in subjects of different ages are also worthy of further study.

Abbreviations

CVD, cardiovascular diseases; BTMs, bone turnover biomarkers; OC, osteocalcin; CTX, C-terminal peptide of type I collagen; PINP, aminoterminal propeptide of type I collagen; RCT, randomized controlled trial; MD, mean difference (MD); 95% CI, 95% interval confidence; BAP, bone-specific alkaline phosphatase; BMP-2, bone morphogenetic protein-2

Acknowledgments

We thank Elsevier Language Editing Services, for editing the English text of a draft of this manuscript.

Declarations

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disclosure of interest

None of the authors have any potential conflicts of interest associated with this research.

Code availability

Not applicable.

Ethics approval

All analyses were based on previous published studies, thus no ethical approval and patient consent are required.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Availability of data and material

The original data can be obtained by email request.

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