Evaluation of eNOS gene polymorphisms in relation to BMD in postmenopausal women

Objective

The aim of the present study was to evaluate the relations between T⁻⁷⁸⁶C and Glu298Asp polymorphisms of the endothelial nitric oxide synthase (eNOS) gene and BMD in postmenopausal Turkish women.

Methods

The T⁻⁷⁸⁶C and Glu298Asp polymorphisms were genotyped by PCR-RFLP method in 311 postmenopausal osteoporotic women (OP) and in 305 age-matched postmenopausal females (CG) with normal BMD.

Results

None of the SNPs of the eNOS gene was significantly associated with BMD at the lumbar spine, femoral neck, Ward's triangle and femoral trochanter in the combined group. Mean BMD values were therefore found to be similar across the genotypes in postmenopausal Turkish women. However, there was a significant association between the T⁻⁷⁸⁶C polymorphism and BMD values at the lumbar spine in the normal control group (P = 0.005), and at the femoral trochanter in the osteoporotic patients (P = 0.046). The mean value of the lumbar spine BMD in the normal controls was significantly higher in women with the TC genotype of the T⁻⁷⁸⁶C polymorphism than in women with the TT genotype (P = 0.0012). Women with the CC genotype of the T⁻⁷⁸⁶C polymorphism in the osteoporotic patients had significantly higher BMD value at the femoral trochanter than those with the TC (P = 0.018) and TT genotypes (P = 0.024). Frequencies of the TC heterozygotes for T⁻⁷⁸⁶C polymorphism were significantly higher among osteoporotic subjects than normal controls. Also, the CC and TT genotype frequencies of control group were significantly higher than those of the osteoporotic group at the femoral neck.

Conclusions

We conclude that, although the biological role of the nitric oxide synthases is well established, our study does not suggest that eNOS gene polymorphisms, T⁻⁷⁸⁶C and Glu298Asp, are major contributors to adult bone mineral density in the postmenopausal Turkish women.     

Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral fractures: Results of a randomized controlled ancillary study of HORIZON

Background

In postmenopausal women, yearly intravenous zoledronate (ZOL) compared to placebo (PLB) significantly increased bone mineral density (BMD) at lumbar spine (LS), femoral neck (FN), and total hip (TH) and decreased fracture risk. The effects of ZOL on BMD at the tibial epiphysis (T-EPI) and diaphysis (T-DIA) are unknown.

Methods

A randomized controlled ancillary study of the HORIZON trial was conducted at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. Women with ≥1 follow-up DXA measurement who had received ≥1 dose of either ZOL (n = 55) or PLB (n = 55) were included. BMD was measured at LS, FN, TH, T-EPI, and T-DIA at baseline, 6, 12, 24, and 36 months. Morphometric vertebral fractures were assessed. Incident clinical fractures were recorded as adverse events.

Results

Baseline characteristics were comparable with those in HORIZON and between groups. After 36 months, BMD was significantly higher in women treated with ZOL vs. PLB at LS, FN, TH, and T-EPI (+7.6%, +3.7%, +5.6%, and +5.5%, respectively, p < 0.01 for all) but not T-DIA (+1.1%). The number of patients with ≥1 incident non-vertebral or morphometric fracture did not differ between groups (9 ZOL/11 PLB). Mean changes in BMD did not differ between groups with and without incident fracture, except that women with an incident non-vertebral fracture had significantly higher bone loss at predominantly cortical T-DIA (p = 0.005).

Conclusion

ZOL was significantly superior to PLB at T-EPI but not at T-DIA. Women with an incident non-vertebral fracture experienced bone loss at T-DIA.     

Efficacy of ipriflavone in the prevention and treatment of postmenopausal osteoporosis

The efficacy of ipriflavone was investigated in a 1-year double-blind, placebo-controlled, parallel group clinical trial. Ninety-one postmenopausal women completed the study, 41 received ipriflavone and 50 placebo treatment. After six months the bone mineral density of the L2–L4 vertebral region increased in the ipriflavone-treated group (0.015 g/cm²), whereas it decreased in the placebo-treated group. The differences between the treatment groups were statistically significant. Our results support the efficacy of ipriflavone in the treatment of postmenopausal osteoporosis. Since the positive effect was more pronounced after 6 months, the possibility of an intermittent ipriflavone treatment might be taken into consideration in the future.     

Association study of semaphorin 7a (sema7a) polymorphisms with bone mineral density and fracture risk in postmenopausal Korean women

Bone mineral density (BMD), the major factor determining bone strength, is closely related to osteoporotic fracture risk and is determined largely by multiple genetic factors. Semaphorin 7a (SEMA7A), a recently described member of the semaphorin family, has been shown to play a critical role in the activation of monocyte/macrophages that share progenitors with bone-resorbing osteoclasts and thus might contribute to osteoclast development. In the present study, we directly sequenced the SEMA7A gene in 24 Korean individuals, and identified 15 sequence variants. Five polymorphisms (+15667G>A, +15775C>G, +16285C>T, +19317C>T, +22331A>G) were selected and genotyped in postmenopausal Korean women (n=560) together with measurement of the areal BMD (g/cm²) of the anterior-posterior lumbar spine and the non-dominant proximal femur using dual-energy X-ray absorptiometry. We found that polymorphisms of the SEMA7A gene were associated with the BMD of the lumbar spine and femoral neck. SEMA7A+15775C>G and SEMA7A+22331A>G were associated with low BMD of the femoral neck (P=0.02) and lumbar spine (P=0.04) in a recessive model. SEMA7A-ht4 also showed an association with risk of vertebral fracture (OR=1.87–1.93, P=0.02–0.03). Our results suggest that variations in SEMA7A may play a role in decreased BMD and risk of vertebral fracture.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized usersJung-Min Koh and Bermseok Oh contributed equally to this work     

Prevalence of Osteoporosis in the Korean Population Based on Korea National Health and Nutrition Examination Survey (KNHANES), 2008-2011

Purpose

We analyzed age-related changes of bone mineral density (BMD) and compared with those of U.S and Japanese participants to investigate the prevalence of osteoporosis in Korea.

Materials and Methods

The data were collected in the 2008-2011 in Korea National Health and Nutrition Examination Survey (KNHANES) IV and V to select a representative sample of civilian, noninstitutionalized South Korean population. Bone mineral measurements were obtained from 8332 men and 9766 women aged 10 years and older.

Results

BMD in men continued to decline from 3rd decade, however, in women, BMD remained nearly constant until the 4th decade and declined at rapid rate from the 5th decade. The prevalence of osteoporosis in Korea is 7.3% in males and 38.0% in females aged 50 years and older. The prevalence of osteopenia in Korea is 46.5% in males and 48.7% in females, aged 50 years and older. The lumbar spine and femur BMD in Korean females 20 to 49 years of ages was lower than in U.S. and Japan participants.

Conclusion

There was obvious gender, and age differences in the BMD based on the 2008-2011 KNHANES IV and V, a nationwide, cross-sectional survey conducted in a South Korean population. We expect to be able to estimate reference data through ongoing KNHANES efforts in near future.     

Spanish Menopause Society position statement: Use of denosumab in postmenopausal women

Denosumab is a new drug developed for the treatment of osteoporosis. Moreover, increasing evidences link denosumab with benefits in cancer, an area of interest for those in charge of the postmenopausal health. Denosumab has shown efficacy in the control of bone loss associated with hypogonadic states created by chemotherapy in breast and other cancers. Moreover, some studies reveal efficacy in reducing the progression of metastases. A panel of experts from the Spanish Menopause Society has met to develop usage recommendations based on the best available evidence.     

HLA alleles as predisposal factors for postmenopausal osteoporosis in a Greek population

It is well established that genetic factors play an important role in the pathogenesis of osteoporosis, a common condition characterized by reduced bone mass and increased fracture risk. The major histocompatibility complex in humans, known as human leukocyte antigen (HLA) region, is the most polymorphic human genetic system and it is known as a cluster of genetic markers, associated with several diseases. In order to evaluate the contribution of HLA alleles in bone mass loss, polymorphisms in the HLA class I (-A, -B and -Cw) and class II (-DR and -DQ) antigens were studied in 126 postmenopausal women of Greek origin. It was found that HLA-B7 (P= 0.069), -DR15 (P= 0.019) and -DQ6 (P= 0.026) were associated with a lower bone mineral density measured at the forearm. This study shows a significant association between HLA alleles and bone mass loss in the population studied.     

生信分析肾阳虚型绝经后骨质疏松症分子机制及淫羊藿的靶向治疗机制

目的 基于生物信息学方法探究肾阳虚型绝经后骨质疏松症的分子机制及淫羊藿的治疗靶点。方法 通过GEO挖掘阳虚型绝经后骨质疏松症患者与健康人群的差异基因,运用GeneCards及OMIM预测绝经后骨质疏松症靶点,通过匹配筛选出肾阳虚型绝经后骨质疏松症靶点;通过String构建蛋白互作网络,采用DAVID进行富集分析,利用分子对接预测淫羊藿治疗肾阳虚型骨质疏松症的靶点。结果 共得到差异基因509个,其中下调基因313个,上调基因196个;绝经后骨质疏松症靶点1187个,筛选得到阳虚型绝经后骨质疏松症靶点48个;GO富集分析这些靶点主要涉及细胞增殖、细胞迁移等生物过程,KEGG信号通路中差异基因主要富集于PI3K-Akt信号通路、Th17细胞分化等信号通路调节;分子对接显示淫羊藿3种有效成分槲皮素、木犀草素、山柰酚能够作用于EGF、CRP、FOS等核心蛋白。结论 肾阳虚型绝经后骨质疏松症可能主要由PI3K-Akt信号通路、Th17细胞分化等信号通路调控,淫羊藿可能靶向EGF、CRP等蛋白,通过PI3K-Akt、Th17细胞分化信号通路调节骨代谢,从而实现防治阳虚型绝经后骨质疏松症。     

Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

Our specific aims were to evaluate the power of bivariate analysis and to compare its performance with traditional univariate analysis in samples of unrelated subjects under varying sampling selection designs. Bivariate association analysis was based on the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We conducted extensive simulations for the case of two correlated quantitative phenotypes, with the quantitative trait locus making equal or unequal contributions to each phenotype. Our simulation results confirmed that the power of bivariate analysis is affected by the size, direction and source of the phenotypic correlations between traits. They also showed that the optimal sampling scheme depends on the size and direction of the induced genetic correlation. In addition, we demonstrated the efficacy of SUR-based bivariate test by applying it to a real Genome-Wide Association Study (GWAS) of Bone Mineral Density (BMD) values measured at the lumbar spine (LS) and at the femoral neck (FN) in a sample of unrelated males with low BMD (LS Z-scores ≤ -2) and with high BMD (LS and FN Z-scores >0.5). A substantial amount of top hits in bivariate analysis did not reach nominal significance in any of the two single-trait analyses. Altogether, our studies suggest that bivariate analysis is of practical significance for GWAS of correlated phenotypes.     

Genetic Polymorphism of Geranylgeranyl Diphosphate Synthase (GGSP1) Predicts Bone Density Response to Bisphosphonate Therapy in Korean Women

Purpose

Genetic factor is an important predisposing element influencing the susceptibility to osteoporosis and related complications. The purpose of the present study is to investigate whether genetic polymorphisms of farnesyl diphosphate synthase (FDPS) or geranylgeranyl diphosphate synthase (GGPS) genes were associated with the response to bisphosphonate therapy.

Materials and Methods

In the present study, 144 Korean women with osteoporosis were included. Among 13 genetic polymorphisms found within the FDPS and GGPS1 gene, 4 genetic polymorphisms with frequencies > 5% were selected for further study. Bone mineral density (BMD) response after 1 year treatment of bisphosphonate therapy was analyzed according to the genotypes.

Results

Women with 2 deletion allele of GGPS1 -8188A ins/del (rs3840452) had significantly higher femoral neck BMD at baseline compared with those with one or no deletion allele (0.768 ± 0.127 vs. 0.695 ± 0.090 respectively; p = 0.041). The response rate of women with 2 deletion allele of GGPS1 -8188A ins/del (28.6%) was significantly lower than the rate of women with one (81.4%) or no deletion allele (75.0%) (p = 0.011). Women with 2 deletion allele of GGPS1 -8188A ins/del had 7-fold higher risk of non-response to bisphosphonate therapy compared with women with other genotypes in GGPS1 -8188 after adjusting for baseline BMD (OR = 7.48; 95% CI = 1.32-42.30; p = 0.023). Other polymorphisms in FDPS or GGPS1 were not associated with lumbar spine BMD or femoral neck BMD.

Conclusion

Our study suggested that GGPS1 - 8188A ins/del polymorphism may confer susceptibility to femoral neck BMD response to bisphosphonate therapy in Korean women. However, further study should be done to confirm the results in a larger population.     

Mitochondria-wide association study of common variants in osteoporosis

Mitochondrial DNA (mtDNA) variants are involved in the pathogenesis of human complex diseases, especially for age-related disorders, including osteoporosis. However, the role of mtDNA variants in osteoporosis is largely unknown. In this study, we performed a mitochondria-wide association study for osteoporosis in a large sample of 2286 unrelated Caucasian subjects. A total of 445 mtSNPs were genotyped and 72 mtSNPs survived the quality control. We first examined association between mtSNPs and bone mineral density (BMD), and identified that an mtSNP, mt4823 within the ND2 gene, was strongly associated with hip BMD (P= 2.05 × 10(-4)), even after Bonferroni correction. The C allele of mt4823 was associated with reduced hip BMD and the effect size (β) was ～0.044. Another SNP mt15885 within the MT-CYB gene was associated both with spine (P= 1.66 × 10(-3)) and hip BMD (P= 0.023). The T allele of mt15885 had a protective effect on spine (β= 0.064) and hip BMD (β= 0.038). Next, we classified subjects into the nine common European haplogroups and conducted association analyses. Subjects classified as haplogroup X had significantly lower hip BMD values than others (P= 0.040). Our results highlighted the importance of mtDNA variants in osteoporosis.     

Effect of Vibration on Cortical Bone in Tail-suspended Rats

Humans in Space suffer from microgravity-induced muscle atrophy and attenuated bone strength. High-frequency, low-amplitude vibration has been proposed as a treatment to prevent bone loss and the decrease in strength of bone. In this study, the effect of vibration on countering microgravity-induced bone loss was investigated. 15 SD rats were divided into three groups （n=5, each）： tail-suspension （TS）, TS plus 45 Hz （0.3 g） vibration exercise （TSV）, and control （CON）. Tail-suspension was to unload rat hindlimbs and a device was developed by our group, with which the rats were trained by vibration twice per day on hindlimbs during tail-suspension. After 21 d, bone mineral density （BMD） was measured by micro-CT and porosity by combining EXAKT and Olympus BX51 in tibia. The results showed that trabecular BMD was significantly decreased and cortical porosity increased in TS compared with CON, while there was no significantly difference between TSV and CON. These suggest that vibration exercise could prevent bone attenuation induced by simulated weightlessness and it is possible to be as a countermeasure of microgravity-induced osteoporosis.     

2013 Up-date of the consensus statement of the Spanish Menopause Society on postmenopausal osteoporosis

Postmenopausal osteoporosis is a major female health problem that increases morbidity, mortality and healthcare system costs. Considering that gynecologists are the primary health practitioners involved in the treatment of women with osteoporosis in our country, a panel of experts from the Spanish Menopause Society met to establish a set of criteria and procedures for the diagnosis and treatment of this disease based on the best available evidence and according to the model proposed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system to elaborate clinical practice guidelines and to classify the quality of the evidence and the strength of the recommendations. These recommendations should be a reference to gynecologist and other health professionals involved in the treatment of postmenopausal women.     

绝经后骨质疏松症相关长链非编码RNA的研究进展

绝经后骨质疏松症（PMOP）是绝经后妇女常见的全身性、代谢性骨病,以骨量降低和骨组织微结构破坏、退化为特征,增加了绝经后妇女骨折的风险。现有研究显示长链非编码RNA（lncRNA）在调节成骨细胞分化、破骨细胞分化等方面有重要作用。本文就lncRNA在PMOP中调控骨代谢的作用、与微小RNA（miRNA）及雌激素的相互作用等方面展开综述,以期为临床PMOP的诊治提供一定参考。     

A susceptible haplotype within APOE gene influences BMD and intensifies the osteoporosis risk in postmenopausal women of Northwest India

Background

The association of apolipoprotein E (APOE) genotypes with bone mineral density (BMD) and risk of osteoporosis have remained unclear. The influence of APOE gene polymorphisms on BMD as genetic mediators of osteoporosis risk needs to be explored in Indian postmenopausal females where this disease is rising rampantly.

Methods and results

The present study investigated the role and relevance of four pertinent APOE single nucleotide polymorphisms: 5′UTR G/C (rs440446), Int2 G/A (rs769450), Exon4 T/C (rs429358), Exon4 C/T (rs7412) in DEXA verified 133 osteoporotic, 57 osteopenic and 83 normal postmenopausal females of India, who were not taking hormone replacement therapy. Minor allele frequencies of rs440446 and rs429358 were higher in osteoporotic females (0.31, 0.18) than osteopenic (0.29, 0.15) and females having normal bone mass (0.16, 0.07). Disease association analysis revealed a susceptibility haplotype CGTC (in order of rs440446, rs769450, rs429358, rs7412) and the carriers of this haplotype has higher risk of osteopenia (OR 3.53, 95% CI 1.21–11.0, P = 0.017) and osteoporosis (OR 3.61, 95% CI 1.53–9.48, P = 0.002) after adjusting the confounding effect of age, BMI and years since menopause. Females who possess either one copy or two copies of the haplotype have lesser BMD values of lumbar spine (0.88 and 0.85 g/cm²) and femoral neck (0.84 and 0.82 g/cm²) than those females who possess zero copy (0.9 and 0.87 g/cm², respectively).

Conclusions

The present study exposed a susceptibility haplotype CGTC, within APOE gene, which was found to be associated with BMD and risk of osteopenia and osteoporosis in postmenopausal females of India.     

绝经后妇女骨质疏松患者血清IGF-1、IGFBP-3与骨密度及骨代谢指标的关系

目的：探讨胰岛素样生长因子-1（IGF-1）和胰岛素样生长因子结合蛋白-3（IGFBP-3）与绝经后妇女骨密度及骨代谢指标之间的关系。方法：通过检测90例绝经后妇女骨质疏松患者及70例绝经后骨量正常的健康对照组血清IGF-1、IGFBP-3、骨钙素（BGP）、I型胶原异构C端肽（β-CTX）、雌激素（E2）、降钙素（CT）、甲状旁腺激素（PTH）、钙（Ca）、磷（P）等指标,然后同用双能X线骨密度仪检测的两组研究对象的腰椎（L2-L4）侧位、左股骨颈骨密度进行比较。结果：绝经后骨质疏松组妇女腰椎、股骨颈骨密度显著低于对照组（均P0.05）。骨质疏松组和对照组腰椎侧位、左股骨颈BMD均与IGF-1、IGFBP-3、E2、BGP、CT水平呈正相关,与β-CTX、PTH水平呈负相关,而与血钙、血磷无明显关系。结论：IGF-1、IGFBP-3、E2、BGP、CT、β-CTX、PTH血清水平与腰椎、左股骨质具有明显的相关性,通过检测上述指标可考虑作为筛查绝经后妇女是否容易患有骨质疏松症的一项有价值的生化参考指标。     

骨代谢生化指标在评价绝经后女性骨质疏松治疗中的应用

目的:探讨骨代谢生化指标在绝经后妇女并发骨质疏松的早期诊断和治疗后监测中的应用.方法:临床收集绝经后的女性糖尿病患者56例,合并有骨质疏松,随机分为药物干预组和未治疗组各28例,药物干预组服用二磷酸盐类药物(阿仑膦酸钠)10mg,1片/d;对照组;给予安慰剂,连续观察6个月,分别测定药物干预前后的腰椎、股骨颈骨密度(B...     

Relationship between postmenopausal osteoporosis and the components of clinical sarcopenia

Purpose

The aim of the study was to determine the relationship between the components of clinical sarcopenia and osteoporosis in postmenopausal women.

Methods

A population-based cohort of 590 Finnish postmenopausal women (mean age 67.9; range 65–72) was selected from the Osteoporosis Fracture Prevention (OSTPRE-FPS) study in 2002. Bone mineral density (BMD) and lean tissue mass were assessed by dual X-ray absorptiometry (DXA). The study sample was divided into three categories according to the WHO BMD classification: normal, osteopenia and osteoporosis. The study sample was divided into non-sarcopenic, presarcopenic, sarcopenic and non-classified groups according to quartiles of RSMI i.e. relative skeletal muscle index (appendicular muscle mass (kg)/square of height (m)), hand grip strength (kPa) and walking speed.

Results

In logistic regression analysis sarcopenic women had 12.9 times higher odds of having osteoporosis (p ≤ 0.001, OR = 12.9; 95% CI = 3.1–53.5) in comparison to non-sarcopenic women. In comparison to women in the highest grip strength quartile, women within the lowest quartile had 11.7 times higher odds of having osteoporosis (p = 0.001, OR = 11.7; 2.6–53.4). Sarcopenic women had 2.7 times higher odds of having fractures than their non-sarcopenic counterparts (p = 0.005, OR = 2.732; 1.4–5.5). Sarcopenic women had also 2.1 times higher risk of falls during the preceding 12 months compared to non-sarcopenic women (p = 0.021, OR = 2.1; 1.1–3.9). Adjustment for age, body mass index (BMI), physical activity and hormone therapy (HT) did not significantly alter these results.

Conclusions

The components of clinical sarcopenia are strongly associated with osteoporosis. Grip strength is the most significant measurement to reveal the association between sarcopenia and osteoporosis, falls and fractures.     

唑来膦酸注射液联合金天格胶囊治疗 绝经后骨质疏松症疗效分析

目的 分析唑来膦酸注射液与金天格胶囊联合治疗绝经后骨质疏松症的效果及VAS评分。方法 选取2016年6月~2018年6月本院68例绝经后骨质疏松患者的临床资料,按照数字随机法分为对照组和研究组,各34例。对照组给予唑来膦酸注射液治疗,研究组给予唑来膦酸注射液与金天格胶囊联合治疗,比较两组的实验室相关指标、骨密度及VAS评分。结果 研究组骨密度腰椎（0.92±0.15）g/cm2、股骨颈（0.85±0.17）g/cm2、股骨大转子（0.91±0.13）g/cm2、Ward's三角区（0.81±0.12）g/cm2,高于对照组（0.72±0.11）g/cm2、（0.62±0.08）g/cm2、（0.68±0.11）g/cm2、（0.61±0.08）g/cm2,差异有统计学意义（P＜0.05）;骨钙素（10.28±1.27）ng/ml、骨特异性碱性磷酸酶（20.12±3.06）U/L,异有统计学意义（P＜0.05）;VAS评分（1.66±0.12）分,低于对照组（3.88±1.06）分,差异有统计学意义（P＜0.05）。结论 唑来膦酸注射液联合金天格胶囊治疗绝经后骨质疏松症的临床效果显著,有利于改善患者的骨密度和骨代谢指标,减轻疼痛。     

肠道微生态影响绝经后骨质疏松症发生发展的研究进展

肠道微生物的数量是人类细胞数的数十倍,可以被看成人体的一种器官,以多种方式与宿主相互作用并影响宿主;它包含的基因数远远超过人类的基因数,被称为人体的“第二基因组”;它可以影响宿主组织(如骨组织)的发育和稳态。绝经后骨质疏松症是一种在绝经后妇女中高发的疾病,是指绝经后妇女由于卵巢衰退,雌激素水平下降导致骨吸收大于骨形成,出现以骨量降低和骨组织的显微结构退行性变为特征、骨脆性和骨折易感性增加的一种全身代谢疾病。女性雌激素衰退是绝经后骨质疏松症发生的重要诱因,而肠道微生物在性激素缺乏引起骨质流失的发生中处于中心地位。肠道微生物通过宿主的免疫系统调控骨代谢;雌激素缺乏导致的肠壁通透性增加会引起细菌移位和增强机体的炎症反应,而肠道益生菌可以通过抑制炎症反应和增强肠道上皮的屏障功能来防止骨质流失。肠道微生物亦可通过机体的代谢来调节骨代谢,短链脂肪酸是益生元发酵的主要产物,它能诱导IGF-1的产生,增加骨量。肠道微生物还可以通过增强营养物质摄取、合成人体必需营养物质从而改善机体的营养状况的方式来影响骨代谢。