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分化型甲状腺癌(differentiated thyroid carcinoma, DTC)是最常见的内分泌肿瘤,主要包括乳头状甲状腺癌和滤泡状甲状腺癌。近年来,其发病率呈明显上升趋势[1]。目前该病主要的治疗方法为外科手术、术后131I治疗和TSH抑制治疗。大部分DTC进展较缓慢,预后较好,约90%的患者在治疗后可存活15年以上[2]。常规TSH能够维持术后正常的生理需要,但抑制剂量使患者处于亚临床甲状腺功能亢进(简称甲亢)。研究表明,亚临床甲亢会增加骨折和心血管疾病发生的风险[3-4]。目前,多项研究已报道TSH抑制治疗DTC对骨密度的影响[5-7],但各研究的样本量较小,对骨密度影响的结果各不相同,所得结论的参考价值有限。我们采用Meta分析系统地评价TSH抑制治疗DTC是否对骨密度有负面影响,以期为临床实践提供依据。
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初步筛选出符合纳入标准的文献1475篇,剔除重复文献后剩余829篇,阅读题目和摘要后剩余41 篇,其中有12篇无法提取数据,10篇无法获取全文,4篇非单一治疗,1篇患者血清TSH未达到抑制目标,最终纳入文献14篇[5-18],共计588例DTC患者(表1)。
第一作者 年份 国家 DTC患者数 年龄 (岁) 用药时间 (年) TSH (mU/L) 陈志良[5] 2017 中国 34 59.7±4.1 1.0 <0.30 唐润薇[6] 2016 中国 40 56.5±4.6 1.0 <0.30 Kung[7] 1993 中国 34 62.0±8.0 12.2±6.6 <0.05 Giannini[8] 1994 意大利 25 49.7±2.1 7.6±0.9 <0.10 Reverter[9] 2010 德国 33 56.0±14.0 2.0~3.0 <0.10 Schneider[10](1) 2012 德国 46 39.2±7.7 4.9±5.2 0.05±0.20 Schneider[10](2) 2012 德国 28 40.8±8.0 5.9±5.1 0.04±0.07 Reverter[11] 2005 西班牙 88 51.0±12.0 12.0±5.0 0.03±0.03 Toivonen[12] 1998 芬兰 29 27.0~71.0 9.0~11.0 <0.05 Müller[13] 1995 加拿大 25 47.0±3.0 10.0±1.4 0.08±0.01 Hawkins[14] 1994 西班牙 21 59.6±7.5 5.0 0.30±0.40 Mendonça Monteiro de Barros [15] 2016 巴西 17 27.4±6.4 14.2±7.2 0.16±0.22 Sajjinanont[16] 2005 泰国 22 38.0±7.3 7.0±3.4 <0.10 王勤甫[17] 2016 中国 80 30.0~45.0 1.0 <0.50 Eftekhari[18] 2008 伊朗 66 51.7±7.3 14.9±2.1* <0.30 注:表中,文献[10]有两组患者:[10](1)为绝经前的女性患者;[10](2)为男性患者。*表示单位为月。DTC:分化型甲状腺癌;TSH:促甲状腺激素。 表 1 TSH抑制治疗分化型甲状腺癌对骨密度影响纳入文献的基本信息
Table 1. Basic information of the included literature in the effect of TSH-suppressive therapy on bone mineral density in patients with DTC
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12项研究报道了腰椎骨密度水平,共442例DTC患者[5-16]。各研究间有统计学异质性(P<0.0001,I2=71%),去除Kung等[7]研究,异质性下降至51%,产生异质性的原因可能是其研究中患者均为绝经后女性。亚组分析显示,绝经后女性、绝经前女性、男性DTC患者TSH抑制治疗后腰椎骨密度与对照组比较,差异均无统计学意义[SMD=−0.00,95%CI(−0.26, 0.26),P=0.98](图1)。
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8项研究报道了股骨颈骨密度水平,共328例DTC患者[7, 9, 11-13, 15-17]。各研究间有统计学异质性(P<0.00001,I2=95%)(图2中A),去除王勤甫等[17]的研究,异质性下降至76%(图2中B)。产生异质性的原因可能是其研究中TSH抑制目标有差异。各研究间仍有统计学异质性,经亚组分析异质性明显降低(I2=31%),采用固定效应模型,其结果显示绝经后女性、绝经前女性、男性的股骨颈骨密度与对照组比较差异均无统计学意义[SMD=−0.00,95%CI(−0.15, 0.14),P=0.96](图2中C)。
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4项研究报道了股骨大转子骨密度水平,共137例DTC患者[5-7, 12]。各研究间无统计学异质性(P=0.12,I2=49%),采用固定效应模型分析。Meta分析结果显示,抑制治疗组患者股骨大转子骨密度水平低于对照组,差异有统计学意义[SMD=−0.30,95%CI(−0.53, −0.06),P=0.01](图3)。
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3项研究报道了Ward三角区骨密度水平,共97例DTC患者[5, 7, 12]。各研究间无统计学异质性(P=0.52,I2=0%),采用固定效应模型分析。Meta分析结果显示,抑制治疗组患者Ward三角区骨密度水平低于对照组,差异有统计学意义[SMD=−0.35,95%CI(−0.63, −0.08),P=0.01](图4)。
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剔除样本量<50的研究,对腰椎、股骨颈骨密度灵敏度进行分析。腰椎为[SMD=−0.02, 95%CI (−0.27, 0.22),P=0.8] vs. [SMD=−0.12, 95%CI (−0.37, 0.13),P=0.33];股骨颈为[SMD=−0.48, 95%CI (−1.22, 0.26),P=0.2] vs. [SMD=−0.61, 95%CI (−1.42, 0.20),P=0.14]。剔除前后腰椎、股骨颈骨密度的统计学结果均未发生改变,这说明本研究结果总体较稳定。
TSH抑制治疗分化型甲状腺癌对骨密度影响的Meta分析
Impact of TSH-suppressive therapy on bone mineral density in patients with differentiated thyroid carcinoma: a Meta-analysis
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摘要:
目的 通过Meta分析的方法评价促甲状腺激素(TSH)抑制治疗分化型甲状腺癌(DTC)对骨密度的影响。 方法 检索PubMed、Medline、万方数据库、中文科技期刊数据库(VIP)、中国学术期刊全文数据库、中国生物医学文献数据库,收集2017年10月前所有TSH抑制治疗DTC的横断面研究、队列研究、前瞻性对照研究、病例对照研究,分析TSH抑制治疗对腰椎骨密度、股骨颈骨密度、股骨大转子骨密度、Ward三角区骨密度的影响。由2位研究者独立提取资料后,采用RevMan 5.3软件进行系统评价。计数资料以比值比(OR)表示,计量资料以加权均数差或标准化均数差(SMD)表示。根据研究的异质性,利用固定效应模型和随机效应模型进行综合分析。 结果 共纳入14项研究,合计588例DTC患者。Meta分析结果显示,TSH抑制治疗组与对照组相比,腰椎骨密度[SMD=−0.00,95%CI(−0.26, 0.26),P=0.98]、股骨颈骨密度[SMD=−0.00,95%CI(−0.15, 0.14),P=0.96]的差异均无统计学意义,股骨大转子骨密度[SMD=−0.30,95%CI(−0.53, −0.06),P=0.01]、Ward三角区骨密度[SMD=−0.35,95%CI(−0.63, −0.08),P=0.01]的差异均有统计学意义。 结论 TSH抑制治疗主要降低DTC患者股骨近端骨密度,在长期随访中应注意定期检测骨密度。 Abstract:Objective To evaluate the effect of TSH-suppressive therapy on bone mineral density(BMD) in patients with differentiated thyroid carcinoma(DTC). Methods The cross-sectional, cohort, prospective controlled, and case-control studies on the BMD change in patients with DTC after TSH-suppressive therapy from databases were searched, including PubMed, Medline, Wanfang Database, VIP, China National Knowledge Infrastructure, and CBM. The effect of TSH-suppressive therapy on the BMD of lumbar, femoral neck, femoral greater trochanter, and Ward triangle were analyzed. Data from the date of database establishment to October 2017 were all reviewed. Meta-analysis was performed with RevMan 5.3 software after two reviewers independently screened the date. The categorical variables were expressed as odds ratios, and numerical variables were expressed as weighted mean or standardized mean differences. Based on the heterogeneity of the study, a comprehensive analysis was performed by using fixed or random effect models. Results A total of 14 studies involving 588 patients with differentiated thyroid cancer were included. No significant difference in the BMD of lumbar indications between the experimental and control groups was observed: SMD=−0.00, 95%CI [−0.26, 0.26],P=0.98. The BMD of femoral neck indications: SMD=−0.00, 95%CI [−0.15, 0.14],P=0.96. A significant difference between the experimental and control groups in the BMD of femoral trochanter indications was observed: SMD=−0.30, 95%CI [−0.53, −0.06],P=0.01. The BMD of Ward's triangle indications: SMD=−0.35, 95%CI [−0.63, −0.08],P=0.01. Conclusions TSH-suppressive therapy in patients with DTC mainly reduces proximal femur BMD, and BMD must be followed-up regularly. -
Key words:
- Thyrotropin /
- Thyroid neoplasms /
- Bone density /
- Meta-analysis /
- Suppressive therapy
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表 1 TSH抑制治疗分化型甲状腺癌对骨密度影响纳入文献的基本信息
Table 1. Basic information of the included literature in the effect of TSH-suppressive therapy on bone mineral density in patients with DTC
第一作者 年份 国家 DTC患者数 年龄 (岁) 用药时间 (年) TSH (mU/L) 陈志良[5] 2017 中国 34 59.7±4.1 1.0 <0.30 唐润薇[6] 2016 中国 40 56.5±4.6 1.0 <0.30 Kung[7] 1993 中国 34 62.0±8.0 12.2±6.6 <0.05 Giannini[8] 1994 意大利 25 49.7±2.1 7.6±0.9 <0.10 Reverter[9] 2010 德国 33 56.0±14.0 2.0~3.0 <0.10 Schneider[10](1) 2012 德国 46 39.2±7.7 4.9±5.2 0.05±0.20 Schneider[10](2) 2012 德国 28 40.8±8.0 5.9±5.1 0.04±0.07 Reverter[11] 2005 西班牙 88 51.0±12.0 12.0±5.0 0.03±0.03 Toivonen[12] 1998 芬兰 29 27.0~71.0 9.0~11.0 <0.05 Müller[13] 1995 加拿大 25 47.0±3.0 10.0±1.4 0.08±0.01 Hawkins[14] 1994 西班牙 21 59.6±7.5 5.0 0.30±0.40 Mendonça Monteiro de Barros [15] 2016 巴西 17 27.4±6.4 14.2±7.2 0.16±0.22 Sajjinanont[16] 2005 泰国 22 38.0±7.3 7.0±3.4 <0.10 王勤甫[17] 2016 中国 80 30.0~45.0 1.0 <0.50 Eftekhari[18] 2008 伊朗 66 51.7±7.3 14.9±2.1* <0.30 注:表中,文献[10]有两组患者:[10](1)为绝经前的女性患者;[10](2)为男性患者。*表示单位为月。DTC:分化型甲状腺癌;TSH:促甲状腺激素。 -
[1] Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer[J]. Thyroid, 2010, 20(2): 135−146. DOI: 10.1089/thy.2009.0311 [2] Murphy E, Williams GR. The thyroid and the skeleton[J]. Clin Endocrinol(Oxf), 2004, 61(3): 285−298. DOI: 10.1111/j.1365−2265.2004.02053.x [3] Flynn RW, Bonellie SR, Jung RT, et al. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy[J]. J Clin Endocrinol Metab, 2010, 95(1): 186−193. DOI: 10.1210/jc.2009−1625 [4] Sun J, Yao L, Fang Y, et al. Relationship between Subclinical Thyroid Risk of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Cohort Studies[J]. Int J Endocrinol, 2017, 2017: 8130796. DOI: 10.1155/2017/8130796 [5] 陈志良, 李瑞平, 陈国豪, 等. TSH抑制治疗对老年甲状腺癌术后骨代谢相关指标的影响[J]. 现代医院, 2017, 17(2): 241−244. DOI: 10.3969/j.issn.1671−332X.2017.02.029
Chen ZL, Li RP, Chen GH, et al. Effect on Bone Metabolism Related Indexes in Elderly Patients with Thyroid Cancer after TSH Suppressive Therapy[J]. Morden Hosp, 2017, 17(2): 241−244. DOI: 10.3969/j.issn.1671−332X.2017.02.029[6] 唐润薇. 抑制剂量的甲状腺激素对40例分化型甲状腺癌患者骨生化和骨密度的影响[J]. 药物评价研究, 2016, 39(5): 814−817. DOI: 10.7501/j.issn.1674−6376.2016.05.021
Tang RW. Effect of thyroid stimulating hormone with inhibiting dose on bone biochemical and bone mineral density in 40 cases of postoperative patients with differentiated thyroid carcinoma[J]. Drug Evaluation Research, 2016, 39(5): 814−817. DOI: 10.7501/j.issn.1674−6376.2016.05.021[7] Kung AW, Lorentz T, Tam SC. Thyroxine suppressive therapy decreases bone mineral density in post-menopausal women[J]. Clin Endocrinol(Oxf), 1993, 39(5): 535−540. DOI: 10.1111/j.1365−2265.1993.tb02405.x [8] Giannini S, Nobile M, Sartori L, et al. Bone density and mineral metabolism in thyroidectomized patients treated with long-term L-thyroxine[J]. Clin Sci(Lond), 1994, 87(5): 593−597. DOI: 10.1042/cs0870593 [9] Reverter JL, Colomé E, Holgado S, et al. Bone mineral density and bone fracture in male patients receiving long-term suppressive levothyroxine treatment for differentiated thyroid carcinoma[J]. Endocrine, 2010, 37(3): 467−472. DOI: 10.1007/s12020−010−9339−z [10] Schneider R, Schneider M, Reiners C, et al. Effects of levothyroxine on bone mineral density, muscle force, and bone turnover markers: a cohort study[J]. J Clin Endocrinol Metab, 2012, 97(11): 3926−3934. DOI: 10.1210/jc.2012−2570 [11] Reverter JL, Holgado S, Alonso N, et al. Lack of deleterious effect on bone mineral density of long-term thyroxine suppressive therapy for differentiated thyroid carcinoma[J]. Endocr Relat Cancer, 2005, 12(4): 973−981. DOI: 10.1677/erc.1.01072 [12] Toivonen J, Tähtelä R, Laitinen K, et al. Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy[J]. Eur J Endocrinol, 1998, 138(6): 667−673. DOI: 10.1530/eje.0.1380667 [13] Müller CG, Bayley TA, Harrison JE, et al. Possible limited bone loss with suppressive thyroxine therapy is unlikely to have clinical relevance[J]. Thyroid, 1995, 5(2): 81−87. DOI: 10.1089/thy.1995.5.81 [14] Hawkins F, Rigopoulou D, Papapietro K, et al. Spinal bone mass after long-term treatment with L-thyroxine in postmenopausal women with thyroid cancer and chronic lymphocytic thyroiditis[J]. Calcif Tissue Int, 1994, 54(1): 16−19. DOI: 10.1007/BF00316283 [15] Mendonça Monteiro de Barros G, Madeira M, Vieira NL, et al. Bone mineral density and bone microarchitecture after long-term suppressive levothyroxine treatment of differentiated thyroid carcinoma in young adult patients[J]. J Bone Miner Metab, 2016, 34(4): 417−421. DOI: 10.1007/s00774−015−0680−4 [16] Sajjinanont T, Rajchadara S, Sriassawaamorn N, et al. The comparative study of bone mineral density between premenopausal women receiving long term suppressive doses of levothyroxine for well-differentiated thyroid cancer with healthy premenopausal women[J]. J Med Assoc Thai, 2005, 88(Suppl 3): S71−76. [17] 王勤甫, 赵顺林, 相开放, 等. 采用TSH抑制疗法对分化型甲状腺癌患者术后骨密度及骨代谢标志物的影响[J/OL]. 临床检验杂志(电子版), 2016, 5(4): 199−201[2018−06−03]. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=lcjyzz-d201604005.
Wang QF, Zhao SL, Xiang KF, et al. Effects of TSH inhibition on bone mineral density and bone metabolic markers in patients with differentiated thyroid cancer[J/OL]. Clin Lab J (Electr Edit), 2016, 5(4): 199−201 [2018−06−03]. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=lcjyzz-d201604005.[18] Eftekhari M, Asadollahi A, Beiki D, et al. The long term effect of levothyroxine on bone mineral density in patients with well differentiated thyroid carcinoma after treatment[J]. Hell J Nucl Med, 2008, 11(3): 160−163. [19] 中华医学会核医学分会. 131I治疗分化型甲状腺癌指南(2014版)[J]. 中华核医学与分子影像杂志, 2014, 34(4): 264−278. DOI: 10.3760/cma.j.issn.2095−2848.2014.04.002
Chinese Society of Nuclear Medicine. Clinical guidelines for 131I therapy of differentiated thyroid cancer[J]. Chin J Nucl Med Mol Imaging, 2014, 34(4): 264−278. DOI: 10.3760/cma.j.issn.2095−2848.2014.04.002[20] Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer[J]. Thyroid, 2006, 16(2): 109−142. DOI: 10.1089/thy.2006.16.109 [21] 杜娜, 王忠超, 盛琦, 等. 分化型甲状腺癌患者停用甲状腺激素后血脂与甲状腺功能的相关性分析[J]. 中华内分泌代谢杂志, 2016, 32(2): 112−116. DOI: 10.3760/cma.j.issn.1000−6699.2016.02.006
Du N, Wang ZC, Sheng Q, et al. Relationship between serum lipid profile and thyroid function after thyroid hormone withdrawal in patients with differentiated thyroid carcinoma[J]. Chin J Endocrinol Metab, 2016, 32(2): 112−116. DOI: 10.3760/cma.j.issn.1000−6699.2016.02.006[22] Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer[J]. Thyroid, 2016, 26(1): 1−133. DOI: 10.1089/thy.2015.0020 [23] Pacini F, Schlumberger M, Dralle H, et al. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium[J]. Eur J Endocrinol, 2006, 154(6): 787−803. DOI: 10.1530/eje.1.02158 [24] 中华医学会核医学分会. 甲状腺结节和分化型甲状腺癌诊治指南[J]. 中华核医学与分子影像杂志, 2013, 33(2): 96−115. DOI: 10.3760/cma.j.issn.2095−2848.2013.02.003
Chinese Society of Nuclear Medicine. Clinical guidelines for the diagnosis and management of thyroid nodules and differentiated thyroid cancer[J]. Chin J Nucl Med Mol Imaging, 2013, 33(2): 96−115. DOI: 10.3760/cma.j.issn.2095−2848.2013.02.003[25] 赵咏桔. 分化型甲状腺癌的个体化TSH抑制治疗: 双风险评估治疗目标[J]. 外科理论与实践, 2014, 19(3): 208−213. DOI: 10.3969/j.issn.1007−9610.2014.03.007
Zhao YJ. Individualized TSH suppression therapy for differentiated thyroid carcinoma: A dual risk assessment of treatment objectives[J]. J Surg Concepts Pract, 2014, 19(3): 208−213. DOI: 10.3969/j.issn.1007−9610.2014.03.007[26] Tournis S, Antoniou JD, Liakou CG, et al. Volumetric bone mineral density and bone geometry assessed by peripheral quantitative computed tomography in women with differentiated thyroid cancer under TSH suppression[J]. Clin Endocrinol (Oxf), 2015, 82(2): 197−204. DOI: 10.1111/cen.12560 [27] Cardoso LF, Maciel LM, Paula FJ. The multiple effects of thyroid disorders on bone and mineral metabolism[J]. Arq Bras Endocrinol Metabol, 2014, 58(5): 452−463. DOI: 10.1590/0004−2730000003311 [28] Lee MY, Park JH, Bae KS, et al. Bone mineral density and bone turnover markers in patients on long-term suppressive levothyroxine therapy for differentiated thyroid cancer[J]. Ann Surg Treat Res, 2014, 86(2): 55−60. DOI: 10.4174/astr.2014.86.2.55 [29] de Melo TG, da Assumpção LV, Santos Ade O, et al. Low BMI and low TSH value as risk factors related to lower bone mineral density in postmenospausal women under levothyroxine therapy for differentiated thyroid carcinoma[J]. Thyroid Res, 2015, 8: 7. DOI: 10.1186/s13044−015−0019−1 [30] 霍艳雷, 王丹阳, 吴书其, 等. TSH抑制治疗对绝经后分化型甲状腺癌患者骨密度的影响[J]. 中华核医学与分子影像杂志, 2017, 37(4): 212−215. DOI: 10.3760/cma.j.issn.2095−2848.2017.04.005
Huo YL, Wang DY, Wu SQ, et al. Effect of postoperative thyrotropin suppression on bone mineral density in postmenopausal women with differentiated thyroid carcinoma[J]. Chin J Nucl Med Mol Imaging, 2017, 37(4): 212−215. DOI: 10.3760/cma.j.issn.2095-2848.2017.04.005[31] 王玉, 贺亮, 蒋森, 等. 分化型甲状腺癌患者术后TSH抑制治疗对骨密度影响的前瞻性研究[J]. 中国骨质疏松杂志, 2016, 22(1): 76−82. DOI: 10.3969/j.issn.1006−7108.2016.01.016
Wang Y, He L, Jiang S, et al. The effect of TSH suppressive therapy for differentiated thyroid carcinoma on bone mineral density: a prospective study[J]. Chin J Osteoporosis, 2016, 22(1): 76−82. DOI: 10.3969/j.issn.1006−7108.2016.01.016[32] 张译徽, 郭辉, 朱新生. 腰椎松质骨CT值与年龄、双能X线骨密度值相关性研究[J]. 中国骨质疏松杂志, 2016, 22(6): 695−699. DOI: 10.3969/j.issn.1006−7108.2016.06.008
Zhang YH, Guo H, Zhu XS. Correlation among CT attenuation value of cancellous bone in the lumbar vertebrae, age, and bone mineral density measured by dual-energy X-ray absorptiometry[J]. Chin J Osteoporo, 2016, 22(6): 695−699. DOI: 10.3969/j.issn.1006−7108.2016.06.008[33] 申才良, 刘斌, 唐天驷, 等. 冷冻、冻干、辐照对用于脊柱融合的胫骨皮质骨力学性能的影响[J]. 医用生物力学, 2016, 31(1): 61−66. DOI: 10.3871/j.1004−7220.2016.01.061
Shen CL, Liu B, Tang TS, et al. Effects from deep-freezing, freeze-drying or radiation on mechanical properties of cortical bone for spinal fusion[J]. J Med Biomechanics, 2016, 31(1): 61−66. DOI: 10.3871/j.1004−7220.2016.01.061[34] Ma R, Latif R, Davies TF. Thyrotropin-independent induction of thyroid endoderm from embryonic stem cells by activin A[J]. Endocrinology, 2009, 150(4): 1970−1975. DOI: 10.1210/en.2008−1374 [35] Abe E, Marians RC, Wang QY, et al. TSH is a negative regulator of skeletal remodeling[J]. Cell, 2003, 115(2): 151−162. DOI: 10.1016/s0092−8674(03)00771−2 [36] 孙蕴, 贺丽英, 马兆坤, 等. Ward三角区再研究[J]. 中国骨质疏松杂志, 2016, 22(6): 706−710, 717. DOI: 10.3969/j.issn.1006−7108.2016.06.010
Sun Y, He LY, Ma ZK, et al. Further study on the Ward's triangle region[J]. Chin J Osteoporosis, 2016, 22(6): 706−710, 717. DOI: 10.3969/j.issn.1006−7108.2016.06.010