Genetic polymorphisms in the mevalonate pathway affect the therapeutic response to alendronate treatment in postmenopausal Chinese women with low bone mineral density

Abstract

Alendronate is an antiosteoporotic drug that targets the mevalonate pathway. To investigate whether the genetic variations in this pathway affect the clinical efficacy of alendronate in postmenopausal Chinese women with osteopenia or osteoporosis, 23 single-nucleotide polymorphisms (SNPs) in 7 genes were genotyped in 500 patients treated with alendronate for 12 months. Bone mineral density (BMD) was measured at baseline and after 12 months. The rs10161126 SNP in the 3′ flanking region of MVK and the GTCCA haplotype in FDFT1 were significantly associated with therapeutic response. A 6.6% increase in BMD in the lumbar spine was observed in the GG homozygotes of rs10161126; AG heterozygotes and AA homozygotes experienced a 4.4 and 4.5% increase, respectively. The odds ratio (95% confidence interval) of G allele carriers to be responders in lumbar spine BMD was 2.06 (1.08–6.41). GTCCA haplotype in FDFT1 was more frequently detected in the group of responders than in the group of non-responders at the total hip (2.6 vs 0.5%, P=0.009). Therefore, MVK and FDFT1 polymorphisms are genetic determinants for BMD response to alendronate therapy in postmenopausal Chinese women.

Introduction

Osteoporosis, a complex disease associated with aging, leads to a high risk for vertebral and hip fractures. An analysis of National Health and Nutrition Examination Survey 2005–2008 data revealed that 19% of older men and 30% of older women in the United States are at risk for bone fracture and require antiosteoporosis therapy.1 With regard to osteoporosis in China, the rate of hip fracture in individuals over the age of 50 from 2002 to 2006 in Beijing increased 2.76-fold in women and 1.61-fold in men compared with the rates in the same groups reported between 1990 and 1992.2

To date, several anabolic and antiresorptive drugs are available for the treatment of osteoporosis. Among them, alendronate, a potent and specific inhibitor of osteoclast-mediated bone resorption belonging to the bisphosphonate family, is widely used in Europe, America and Asia.3, 4, 5, 6, 7, 8 Several randomized control trials have demonstrated that treatment with 70 mg of alendronate once weekly increases bone mineral density (BMD) and decreases the risk of vertebral fractures by ~50% and the risk of peripheral fractures by ~20–30%.9,10

Although the therapeutic use of alendronate is undoubtedly effective, the response to antiosteoporotic therapy is variable. Recent clinical trials have shown that response rates to bisphosphonate therapy, based on changes in BMD, range from ~70 to 75%.11,12 Several studies have been conducted to identify plausible explanations of this variation based on baseline characteristics,11 early changes in biochemical markers of bone turnover13 and early changes in BMD.14 However, there is currently no effective method to aid clinicians in the decision of whether to initiate treatment with bisphosphonates.

Variability in the therapeutic response may reflect complex genetic factors.15 Indeed, genetic factors including the collagen type I alpha 1 (COL1A1)16 and vitamin D receptor gene (VDR)17, 18, 19 genes have been demonstrated to be associated with response to bisphosphonate therapy. However, pharmacogenetic information for antiosteoporotic drugs remains scarce. A few investigators have explored the association of polymorphisms in genes related to the targeted processes and/or pathways of the drug alendronate. Alendronate inhibits osteoclast function by targeting the mevalonate pathway. When embedded in the bone matrix, alendronate is taken up by osteoclasts. Alendronate prevents the biosynthesis of isoprenoid lipids (farnesyl diphosphate and geranylgeranyl diphosphate (GGPP)), which are essential mediators of the post-translational prenylation of several proteins including various GTPase signaling factors. The loss of prenylated proteins induces cellular dysfunction and ultimately leads to osteoclast apoptosis.20, 21, 22, 23, 24 Recently, two important genetic polymorphisms in the mevalonate pathway have been observed to be associated with therapeutic response to alendronate. The first was reported by Choi et al.25 The authors suggested that the geranylgeranyl diphosphate synthase 1 gene (GGPS1)-8188A ins/del polymorphism was associated with a response in BMD at the femoral neck to bisphosphonate therapy in Korean women with osteoporosis. The second study was conducted in northern Spain. Olmos et al.26 reported a highly significant association between the rs2297480 or rs11264359 alleles of the farnesyl diphosphate synthase gene (FDPS) and BMD changes after amino-bisphosphonate therapy for an average period of 2.5 years. However, the association between the therapeutic response to alendronate and genetic polymorphisms in the entire mevalonate pathway has not been studied to date.

Accordingly, we hypothesized that genetic polymorphisms in seven genes that encode key enzymes of the mevalonate pathway are good candidates to explain the variable responses in BMD to alendronate treatment. Therefore, we undertook this study to examine whether 23 single-nucleotide polymorphisms (SNPs) in FDPS, GGPS1, isopentenyl-diphosphate delta isomerase 2 (IDI2), mevalonate kinase (MVK), farnesyl-diphosphate farnesyltransferase 1 (FDFT1), mevalonate (diphospho) decarboxylase (MVD) and phosphomevalonate kinase (PMVK) were associated with the therapeutic response to alendronate treatment in postmenopausal Chinese women with osteopenia or osteoporosis.

Materials and methods

Study subjects

Five hundred genetically unrelated postmenopausal Han Chinese women with osteopenia or osteoporosis, who were treated with 70 mg of alendronate (Forsamax, Merck, Hangzhou, China) once weekly, 600 mg of calcium and 125 IU of vitamin D daily for 1 year, were recruited by the Department of Osteoporosis and Bone Diseases Outpatient Clinic from 2009 to 2012 (Figure 1). The patients were instructed to take alendronate orally with a copious amount of water (200 ml) in the morning following an overnight fast and at least 30 min before breakfast and then to remain upright for at least 30 min after ingestion.

Figure 1
figure1

A flow chart of study participants. BMD, Bone mineral density; 25OHD, 25-hydroxyvitamin D; SNP, single-nucleotide polymorphism.

PowerPoint slide

The inclusion criteria were as follows: natural menopause after 40 years of age and a BMD at least 1.0 s.d. below the peak mean bone density of healthy young women (–1.0 T-score) at the posterior-anterior L1-4, the femoral neck or the total hip. The exclusion criteria were as follows: a history of (1) chronic renal disease manifested by a endogenous creatinine clearance of <35 ml per minute; (2) acute inflammation of the gastrointestinal tract (for example, gastritis and ulcerations); (3) esophagitis or certain malformations and malfunctions of the esophagus (strictures and achalasia); (4) taking proton pump inhibitor along with alendronate treatment; (5) an inability to stand, walk or sit for 30 min after oral administration of alendronate; (6) hypersensitivity to alendronate or another ingredient in the therapeutic compound; (7) hypocalcemia (serum Ca <2.08 mmol l−1) or hypophosphatemia (serum P<0.80 mmol l−1); (8) increased serum parathyroid hormone levels (normal values: 15–65 ng l−1); (9) serious residual effects of cerebral vascular disease; (10) diabetes mellitus, except for adult asymptomatic hyperglycemia controlled by diet; (11) chronic liver disease or alcoholism; (12) 12 weeks of corticosteroid therapy at pharmacologic levels; (13) 6 months of treatment with anticonvulsant therapy; (14) evidence of other metabolic or inherited bone diseases (for example, hyperparathyroidism or hypoparathyroidism, Paget’s disease of the bone, osteomalacia or osteogenesis imperfecta); (15) rheumatoid arthritis or collagen disease; (16) significant disease of any endocrine organ that would affect bone mass (for example, Cushing’s syndrome or hyperthyroidism); (17) any neurologic or musculoskeletal condition that would be a non-genetic cause of low bone mass; (18) a body mass index (BMI) of <18 kg m−2 or >30 kg m−2; and (19) any previous treatment with bisphosphonate, sodium fluoride, calcitonin, a selective estrogen receptor modulator, strontium ranelate, the recombinant form of parathyroid hormone or current use of hormone replacement therapy.

The procedures used during the study were in accordance with the guidelines of the Helsinki Declaration on human experimentation. This study was approved by the Ethics Committee of the Shanghai Jiao Tong University affiliated Sixth People’s Hospital.

BMD measurements

The BMD of the anteroposterior lumbar spine 1–4 (L1–4); the left proximal femur, including the femoral neck; and the total hip were measured using a lunar prodigy dual energy X-ray absorptiometry densitometer (GE Healthcare, Madison, WI, USA). The BMD of the right hip was measured only in patients with a history of left hip fracture or surgery. The data were analyzed using the Prodigy enCORE software (ver. 6.70, standard-array mode; GE Healthcare). The machine was calibrated daily, and the coefficient of variability values of the dual energy X-ray absorptiometry measurements (obtained from triplicate measurements of the same 15 individuals) at L1–4, the total hip and the femoral neck were 1.39, 0.70 and 2.22%, respectively.27 Therefore, the least significant change in BMD at L1–4, total hip and femoral neck were 3.85, 1.94 and 6.15%, respectively. The long-term reproducibility of our dual energy X-ray absorptiometry data during the trial, based on weekly repeated phantom measurements, was 99.55%.28 Height and body weight were measured using standardized equipment. BMI was defined as weight/height2 in kg m−2. BMD was measured at baseline and after 1 year of treatment.

Biochemical parameters

To assess the basic clinical characteristics of all participants and to rule out secondary osteoporosis, the levels of serum albumin, alanine aminotransferase, aspartate transaminase, alkaline phosphatase, total bilirubin, urea nitrogen, creatinine, calcium (Ca), phosphorus (P), parathyroid hormone (Roche Diagnostic, Mannheim, Germany) and total serum 25-hydroxyvitamin D (25(OH)D; DiaSorin, Saluggia (VC), Italy) were measured at baseline. Among these testings, the levels of parathyroid hormone and 25(OH)D were measured using an electrochemiluminescent method. Serum samples were collected between 08:00 and 1000 h, following an overnight fast of at least 12 h.

SNP selection and genotyping

Seven candidate genes that encode key enzymes in the mevalonate pathway (PMVK, FDPS, GGPS1, FDFT1, IDI2, MVK and MVD) were selected for the investigation. Twenty-three SNPs were chosen based on the following criteria: (1) tag SNPs in the seven candidate genes based on the HapMap Data Rel 24/phase II Nov08 with minor allele frequency (MAF) >0.05 and pairwise r2>0.8 and (2) potentially functional SNPs in candidate genes (Table 1).

Table 1 General information of the 23 SNPs in the 7 candidate genes investigated in the present study

Blood samples were collected from the study subjects, and genomic DNA was isolated from peripheral blood leukocytes using a conventional phenol-chloroform extraction method. Genotyping was performed using the high-throughput SNaPshot technique (Applied Biosystems, Foster City, CA, USA). Genotype frequencies were tested against Hardy–Weinberg equilibrium (HWE) using the χ2 test to detect genotyping errors.

Statistical analyses

SNPs with a P-value of <0.01 for the HWE test and a call rate of <75% were excluded from further analysis.

Clinical data and biochemical parameters were expressed as the mean value±s.d. for continuous variables with symmetrical distributions and as the median (25th and 75th percentiles) for asymmetrical distributions. The response of BMD to alendronate treatment was estimated by the % change in BMD at L1–4, the femoral neck and the total hip. The associations of alleles with baseline BMD and 1-year follow-up absolute value of % change in BMD were analyzed using a univariate general linear model after adjustment for covariates (age, BMI and baseline BMD). All statistical analyses were performed using the SPSS 17.0 (SPSS, Chicago, IL, USA).

In the present study, we used least significant change at L1–4, femoral neck or total hip as a cutoff level suggested by the ISCD (International Society For Clinical Densitometry) 2007 adult and pediatric official positions to divide our participants into two groups, responder(s) and non-responder(s). The association between the examined SNPs and the opportunity of being a responder to 1 year of alendronate treatment at L1–4, the total hip or the femoral neck were analyzed using PLINK (http://pngu.mgh.harvard.edu/purcell/plink/).29 The default additive effects of allele dosage were selected in the logistic model.

Haplotypes were constructed from the population genotypic data by the Stephens algorithm using the Phase program version 2.0.2 (http://www.stat.washington.edu/stephens/phase/download.2.0.2.html). The significance level for LD between tested gene markers was assessed according to the observed haplotype and allelic frequencies using Haploview version 3.2 (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview). The Lewontin’s D′ and LD coefficient r2 between all pairs of biallelic loci were examined. In the present study, five haplotype blocks have been constructed from 23 studied genes. PLINK was utilized in quality control filtering and haplotype association tests.29

Our primary outcome was the change in BMD in the lumbar spine or hips. Using Quanto (http://hydra.usc.edu/gxe/), the sample size required was calculated to be 468 participants to achieve 80% power with a P-value of 0.05 (two-sided).

In the analysis of 23 SNPs and 5 haplotype blocks, uncorrected P-values of less than <0.05 were defined as nominally significant, while the Bonferroni-corrected P-value thresholds for statistical significance were 0.002 for allelic association and 0.01 for haplotypic associations.

Results

Basic characteristics of all participants and general information of 23 SNPs

Of the 500 participants, 16 subjects (3.3%) were excluded because they had missing genotype data for >20% of all SNPs. Therefore, 484 postmenopausal participants were included in the statistical analyses. The basic characteristics of the participants are summarized in Supplementary Table S1.

The average baseline age, height, weight and BMI were 66.98±8.50 years, 153.77±6.42 cm, 54.74±8.23 kg and 23.26±2.99 kg m−2, respectively. After 1 year of treatment, the average height, weight and BMI were 153.51±6.61 cm, 54.25±8.23 kg and 24.02±3.08 kg m−2, respectively. No significant difference was found between baseline and follow-up weight, height or BMI.

As expected with an antiresorptive agent, BMD at L1–4 and hip increased significantly (all P<0.001). The median (25th and 75th percentiles) of the % change in BMD at L1–4, the femoral neck and the total hip were 4.77% (1.71%, 7.74%), 1.82% (−3.50%, 3.91%) and 2.26% (2.47%, 4.03%), respectively.

The general information of all examined SNPs including closest gene, minor allele, the HapMap reference MAF, the MAF in the present study and the P-value of HWE are summarized in Table 1. Because no SNP was inconsistent with HWE or had a call rate of <75%, all 23 SNPs were included in the following association analyses. No SNP was found to be associated with baseline BMD at L1–4, the femoral neck or the total hip.

Association between genetic polymorphisms and the therapeutic response to alendronate treatment

The associations between the 23 examined SNPs and the absolute value of % change in BMD at L1–4, the femoral neck or the total hip were analyzed as the first step. We detected that two SNPs in MVK (rs10161126 and rs11067376), one SNP in MVD (rs4782395) and one SNP in PMVK (rs4578216) were nominally significantly associated with the % change in BMD at L1–4, while one SNP in GGPS1 (rs3806393) was nominally significantly associated with the % change in BMD of the total hip (Table 2). After Bonferroni correction, however, only the association between rs10161126 and the % change in BMD at L1-4 was significant (P=0.002). Compared with homozygous AA and heterozygous AG, individuals homozygous for GG at rs10161126 achieved the highest increase (6.6%) in BMD at L1–4.

Table 2 Six single-nucleotide polymorphisms significantly associated with the % change in BMD at the lumbar spine 1–4, the femoral neck or the total hip after 1 year of alendronate therapy

In response to 70 mg weekly of alendronate, 53.9% (261 cases) experienced a least significant change in spine BMD, 10.7% (52 cases) in femoral neck BMD and 55.4% (268 cases) in total hip BMD after 12 months. The associations between each SNP and being a responder to alendronate treatment at L1–4, the femoral neck or the total hip were analyzed in the second step. Two SNPs (rs10161126 and rs11067376) in MVK, one (rs2803851) in GGPS1 and one (rs12357207) in IDI2 showed a nominally significant association with the therapeutic response to alendronate treatment at L1–4 or the femoral neck (Table 3). Of these, only rs10161126 in MVK remained significantly associated with BMD response at L1–4 after Bonferroni correction (P=0.002). The odd ratio (OR) and 95% confidence interval (CI) of a G allele carrier to be a responder were 2.06 and 1.08–6.41. Therefore, the G allele of rs10161126 was determined to be a genetic factor positively associated with being a responder to alendronate at the lumbar spine.

Table 3 The 23 genotyped SNPs and the likelihood of being a responder to alendronate treatment at L1–4, the femoral neck and the total hip

Five haplotype blocks were constructed from 23 studied genes: one in IDI2, one in MVD, one in MVK and two in FDFT1. Only GA haplotype of rs4766613 and rs11067376 in MVK showed a nominally association with % change in BMD at L1–4 (P=0.04). Although one haplotype of rs4766613 and rs11067376 in MVK and two haplotypes of five SNPs in FDFT1 (rs12676995, rs1293320, rs1293322, rs3735810 and rs3735809) showed nominally significant association with BMD response to alendronate therapy, only GTCCA in FDFT1 was significantly associated with therapeutic response at the total hip after Bonferroni correction. The GTCCA was more frequently detected in the group of responders than in the group of non-responders at the total hip (2.6 vs 0.5%, P=0.009; Supplementary Tables S2 and S3).

Discussion

Alendronate is the most commonly used bisphosphonate worldwide. In the Fracture Intervention Trial study, alendronate administration was shown to achieve significant increases in BMD at both the spine and the hip and reduce the incidence of vertebral, wrist and hip fractures in women with or without prevalent vertebral fractures.9,10,30,31

It is well known that the treatment response to antiosteoporotic therapy (such as bisphosphonates and selective estrogen receptor modulators) is highly variable. Although genetic differences may be responsible for the differences in therapeutic response, there is little evidence regarding the specific genetic determinants involved in the response to once-weekly alendronate therapy in postmenopausal Chinese women with osteopenia or osteoporosis.

In the present study, the association between candidate polymorphisms and baseline BMD, % change in BMD and the status of being a responder at L1–4, the femoral neck and the total hip were analyzed in postmenopausal Chinese women with low BMD. Initially, no SNP was associated with baseline BMD at L–4, the femoral neck or the total hip. Next, four SNPs in three candidate genes (MVD, MVK and PMVK) and one SNP in GGPS1 were nominally significantly associated with the % change in BMD in the L1–4 or the total hip, respectively. Among them, however, only one SNP in MVK (rs10161126) was significantly associated with the % change in BMD at the L1–4 after a Bonferroni correction. Third, according to the ISCD 2007 adult and pediatric official positions, the participants who experienced a least significant change in BMD at L1–4, the femoral neck or the total hip after alendronate treatment were defined as responder(s).32 The G allele of rs10161126 was significantly associated with an increased likelihood of being a responder at L1–4 after Bonferroni correction. The OR (95% CI) of the G allele carrier to be a responder was 2.06 (1.08–6.41; P=0.002). Finally, GTCCA haplotype in FDFT1 showed a significant association with treatment response at the total hip after Bonferroni correction.

Because rs10161126 in MVK and the GTCCA haplotype in FDFT1 were significantly associated with treatment response in BMD at L1–4 or total hip after Bonferroni correction, we suggest that polymorphisms in MVK and FDFT1 may be important genetic determinants for the therapeutic response to alendronate treatment in postmenopausal Chinese women with low BMD. The MVK gene encodes the key early peroxisomal enzyme mevalonate kinase in isoprenoid and sterol synthesis. rs10161126 is in the 3′ flanking region of MVK, which often contains sequences that affect the formation of the 3′ end of the transcript. Substantial evidence indicates that this region may also contain enhancers or other protein binding sites.33,34 FDFT1 encodes a membrane-associated enzyme located at a branch point in the mevalonate pathway. The encoded FDFT1 catalyzes the conversion of trans-farnesyldiphosphate into squalene. This is the first specific step in the cholesterol biosynthetic pathway.35 In 2009, Do et al.36 investigated squalene synthase and FDFT1 and concluded that they have a role in the regulation of cellular and plasma cholesterol levels. They suggested that squalene synthase may be involved in the etiology of hypercholesterolemia. Currently, however, few studies have focused on the association between genetic polymorphisms in MVK and FDFT1 and the response to alendronate therapy. On the basis of our findings, we suggest that the G allele of rs10161126 in MVK and GTCCA haplotype of rs12676995, rs1293320, rs1293322, rs3735810 and rs3735809 in FDFT1 enhance the response rate at the lumbar spine or total hip. The mechanisms involved in the genotype-related differences remain to be elucidated.

In addition to polymorphisms in MVK and FDFT1, polymorphisms in GGPS1 are also worthy of attention. GGPS1 is a member of the prenyltransferase gene family and encodes a protein with GGPP synthase activity. The enzyme catalyzes the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. GGPP is an important molecule responsible for the C20-prenylation of proteins and for the regulation of a nuclear hormone receptor. In postmenopausal Korean women, those with two deletions in the allele of GGPS1 -8188A ins/del (rs3840452) had significantly higher baseline femoral neck BMD and a sevenfold higher risk of non-response to bisphosphonate therapy compared with women with other genotypes in GGPS1 -8188, after adjusting for baseline BMD. Therefore, Choi et al25 suggested that the GGPS1 -8188A ins/del polymorphism is associated with the BMD response to bisphosphonate therapy at the femoral neck in Korean women. Because no HapMap data for rs3840452 in a Chinese population could be found, two tagging SNPs (s3806393 and rs2803851) were chosen for the present study. rs3806393 comes from the same AT-rich interactive domain 4B (RBP1-like) as the rs3840452 location. We found that TG genotype carriers of rs3806393 had a lower % change in BMD in the total hip compared with the wild TT genotype and C allele of rs2803851 was a genetic factor positively associated with being a responder to alendronate at the lumbar spine. Although the association between these two SNPs and the % change in BMD or the therapeutic response were no longer significant after a Bonferroni correction (P=0.01 and 0.05), GGPS1 polymorphisms should be further investigated in the future with longer-term follow-up because the follow-up period in the current study was relatively short.

In humans, IDI2 is expressed at high levels only in skeletal muscle, where it may be involved in the specialized production of isoprenyl diphosphates for the posttranslational modification of proteins.37 In the present study, we found that the G allele of rs12357207 in IDI2 was nominally associated with the therapeutic response to alendronate at the femoral neck. The function of IDI2 is to transform unreactive IPP into its reactive isomer DMAPP.38 In 2010, Kato et al.39 reported that a segmental copy-number gain in the IDI1/IDI2 gene region may have a significant role in the pathogenesis of sporadic amyotrophic lateral sclerosis. However, the role of IDI2 in the bone metabolism is still unclear. The functional study should be performed in the future.

In several previous studies, the relationship between genetic polymorphisms of FDPS and clinical efficacy to amino-bisphosphonate therapy has been investigated with controversial conclusions. For example, rs2297480 and rs11264359 of FDPS were reported to be associated with amino-bisphosphonate therapy in 2012.26 rs2297480 and rs11264361 of FDPS, however, were not associated with spinal and femoral BMD responses to bisphosphonate treatments in Korean25 or Danish postmenopausal women.33 Because rs2297480 and rs11264359 are in strong linkage disequilibrium, only rs11264359 was analyzed in the present study, although, unfortunately, no significant association was found.

Because no SNP was associated with a simultaneous % change in BMD at L1–4 and the hip in the current study, we suggest that genetic factors may have site-specific effects on the response alendronate treatment. Our conclusion is in accordance with previous studies that suggested that cortical bone and trabecular bone have different drug responses as well as different regulating genes.25,34

We acknowledge that our study has limitations. First, bone turnover markers were not evaluated. In addition to the change in BMD, bone turnover markers are another important parameter to evaluate the effects of alendronate treatment. Second, the follow-up period in the current study was relatively short, at only 12 months. Further studies are required to determine the association between bone turnover markers, genetic variations and changes in BMD over a longer-term follow-up period.

In conclusion, this study demonstrated that polymorphisms in MVK and FDFT1 influenced the therapeutic response of the lumbar spine or the total hip to alendronate. We suggest that the genetic background is important for individualized antiresorptive therapy. These results may help to formulate better strategies to optimize the current approaches in the prognosis, treatment and prevention of bone fractures.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (NSFC) (81070692, 81170803 and 81370978 to ZL Zhang, 81270964 to C Wang and 81200646 to JM Gu), the National Basic Research Program of China (Grant No. 2014CB942903 to ZL Zhang), Academic Leaders in Health Sciences in Shanghai (XBR2011014) and Shanghai Leading Talents Award (051 to ZL Zhang), the Science and Technology Commission of Shanghai municipality (11ZR1427300 to C Wang), the Frontier Technology Joint Research Program of the Shanghai municipal hospitals (SHDC12013115 to ZL Zhang) and the Science and Technology Commission of Chongqing municipality (CSTC2013jcyjC00009 to ZL Zhang). We thank all participants for their cooperation as well as the Drug Innovation Program of the National Science and Technology Project (2011zx09307-001-02).

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Wang, C., Zheng, H., He, J. et al. Genetic polymorphisms in the mevalonate pathway affect the therapeutic response to alendronate treatment in postmenopausal Chinese women with low bone mineral density. Pharmacogenomics J 15, 158–164 (2015). https://doi.org/10.1038/tpj.2014.52

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