骨转换标志物(bone turnover markers，BTMs)是骨骼重建过程中释放于血液、尿液中，反应骨细胞活动和骨基质代谢的一些活性物质，它分为骨形成标志物和骨吸收标志物，前者代表成骨细胞活动及骨形成状态，包括骨碱性磷酸酶(bone alkaline phosphatase，BALP)、碱性磷酸酶(alkaline phosphatase，ALP)、骨钙素(osteocalcin，OC)、1型原胶原N-端前肽(procollagen 1 N-terminal peptide，P1NP)、骨保护素(osteoprotegerin，OPG)等；后者代表破骨细胞活动及骨吸收状态，包括1型胶原N-末端肽(type 1 collagen protein N-terminal crosslinking peptide，NTX)、1型胶原C-末端肽(type 1 collagen protein C-terminal cross-linking peptide，CTX)、抗酒石酸酸性磷酸酶(tartrate-resistant acid phosphatase，TRACP)等。大多数内分泌代谢性疾病调节骨代谢的机制并不相同，对骨转换的影响也不尽相同，造成了BTMs、骨折风险的差异性。
糖尿病与骨转换标志物 1型糖尿病与骨转换标志物研究认为1型糖尿病(type 1 diabetes mellitus，T1DM)患者骨吸收增强，骨形成减少[1-2]，骨质疏松性骨折风险增加。T1DM患者缺乏促骨形成的重要合成类激素——胰岛素及胰岛素样生长因子1(insulin-like growth factor 1，IGF-1)，骨形成明显减少；T1DM小鼠骨及骨髓中内源性的抗氧化物质如谷胱甘肽过氧化物酶、过氧化物歧化酶应激表达下调，T1DM小鼠骨密度(bone mineral density, BMD)明显下降[3]，此外T1DM患者的自身免疫及炎性反应状态也可以引起骨量丢失以及矿化缺陷[4]，导致骨质疏松性骨折风险增加。
一般认为T1DM患者骨形成指标BALP值不变[5-6]或降低[2]、OC值降低[2, 5-6]。一项包括22篇文章的Meta分析表明，与健康对照组相比，T1DM患者骨形成指标OC值[-1.15 μg/L(-1.78，-0.52)]、骨吸收指标CTX值[-0.14 μg/L(-0.22，-0.05)]均明显降低[6]。但目前对于T1DM患者BTMs的变化仍未有定论，这可能与没有将患者的降糖方案、血糖水平等列入研究有关，因为这些可能会影响骨转换标志物，使我们的研究结果产生偏差。
2型糖尿病与骨转换标志物2型糖尿病(type 2 diabetes mellitus，T2DM)患者代谢性骨病和骨质疏松性骨折风险明显高于普通人群，其骨质疏松的发生率可达20%~60%[7]。一项研究BMD与T2DM的相关性的Meta分析表明T2DM患者骨密度、骨转换是降低的[8]。印度的一项研究表明，与健康对照组相比，T2DM患者的骨形成指标OC[(4.06±1.97)μg/L vs. (9.62±3.29)μg/L，P＜0.001]显著降低[9]。此外一项横断面研究表明，T2DM患者与非糖尿病患者相比，骨形成指标BALP[(14.83±6.5)mg/L vs. (12.96±6.73)mg/L，P=0.110]、OC[(1.48±1.25)μg/L vs. (1.45±1.2)μg/L，P=0.911]差异无统计学意义；骨吸收指标TRAP[(1.39±0.99)UI/L vs. (1.85±0.81)UI/L，P＜0.05]；CTX[(0.20±0.12)μg/L vs. 0.33±0.15)μg/L，P＜0.05]降低[10]。
T2DM患者长期高血糖使体内产生过多的糖基化终末产物(advanced glycation end-products，AGEs)，其对骨骼形成有负面作用[11]；而且AGEs的堆积可以刺激破骨细胞骨吸收因子白介素-6(interleukin-6, IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)形成，这些因子可以促进破骨细胞的成熟，导致骨吸收增加[11-13]。此外T2DM晚期患者的胰岛素分泌不足，影响成骨细胞的分化和形成，并影响骨基质的形成和矿化，从而引起BMD和骨强度的下降，导致骨质疏松。
甲状腺疾病与骨转换标志物 甲状腺功能亢进与骨转换标志物甲状腺功能亢进系由多种病因导致甲状腺素分泌过多，引起以神经、循环、消化等系统兴奋性增高和代谢亢进为主要表现的一种临床综合征。甲状腺素对骨代谢有调节作用，能加速骨的形成和吸收，其中对骨吸收过程影响更大[14-15]。研究发现甲状腺功能亢进患者的骨形成指标OC(37.690 μg/L)显著高于健康人群(21.8 μg/L)，骨吸收指标CTX(0.766 μg/L)水平也显著高于健康人群(0.309 μg/L)[16]。
甲状腺功能亢进患者促甲状腺素(thyroid stimulating hormone，TSH)降低，TSH可抑制骨吸收[17-18]，Karga等[18]发现在稳定甲状腺素水平下，予重组人促甲状腺素(thyroid stimulating hormone, TSH)替代治疗后，骨吸收指标(NTX、CTX)显著下降，骨形成指标(BALP、OC)没有变化。有体外研究证实TSH可抑制破骨细胞活性，促进其凋亡；还可以通过结合前成骨细胞和破骨细胞上的TSH受体，抑制破骨细胞的形成和存活，抑制成骨细胞的分化和I型胶原的产生，对骨重建过程发挥负性调节作用[17]。但是也有一些动物实验和流行病学研究认为极低的TSH水平对骨代谢无明显不良影响[19-20]。
Bauer等[21]曾观察了686名65岁以上的女性，病例组TSH水平降低，在校正相关因素(如年龄、既往甲状腺功能亢进史、有无雌激素使用和有无甲状腺素替代治疗)后，发现当受抑制的TSH≤0.1 mIU/L时，髋部骨折的发生率是正常对照组的3倍，椎骨骨折的发生率为正常对照组的4倍。成年人中明显的甲状腺功能亢进会导致骨重建周期缩短50%，而且能造成骨形成、骨吸收过程的紊乱[22]，增加骨折风险[22-24]。
甲状腺功能减退与骨转换标志物甲状腺功能减退是因多种因素导致甲状腺素合成、分泌或生物效应不足引起的一种临床综合征。甲状腺功能减退可导致骨转换过程减慢，骨折风险增加[25]，甲状腺功能减退导致低钙血症，甲状旁腺素(parathyroid hormone，PTH)水平升高，降钙素(caltonin，CT)水平降低，CT能抑制破骨细胞活性，使得溶骨过程减弱，同时还能使成骨过程增强，骨组织中钙、磷沉积增加，当其缺乏时将会引起骨量流失，导致骨质疏松性骨折。
一项横断面研究表明甲状腺功能减退患者与健康人群之间骨形成标志物OC和骨吸收标志物CTX间差异无统计学意义，甲状腺功能减退患者激素治疗1年后的OC、CTX水平与治疗前相比差异无统计学意义[16]。但也有研究认为甲状腺素替代治疗后，OC水平会降低，因为其排出增加[26]。
甲状旁腺疾病与骨转换标志物 甲状旁腺功能亢进与骨转换标志物原发性甲状旁腺功能亢进症(primary hyperparathyroidism，PHPT)是由于甲状旁腺本身病变引起的PTH合成、分泌过多，致使钙、磷和骨代谢紊乱的一种全身性疾病，PHPT患者中骨形成及骨吸收的标志物都是显著增加的[27-29]，PTH能直接抑制成骨细胞凋亡，延长其成骨作用时间[30]，促进成骨细胞祖细胞或未成熟的成骨样细胞增生分化[31]；还能直接作用于破骨细胞，促进骨吸收[32]。但也有研究表明PTH不能促进成骨细胞分化[33-34]，其对破骨细胞的直接作用也不确定[35]。在一项横断面研究中也表明，56%的PHPT患者血ALP值增加，11%患者尿NTX值增加[29]。
大多数轻症PHPT患者经外科治疗骨转换标志物都能下降[36-38]。一项包括了674位PHPT患者的大样本研究也表明，外科治疗后，PHPT患者骨折的相关风险性从治疗前的1.8下降至1.0，这种下降在前臂骨更明显[1.9(95% CI：1.1~3.3) vs. 0.7(0.4~1.4)]，脊柱骨折的风险性也是下降的[1.9(95% CI：1.1~3.3) vs. 0.7(0.4~1.4)]，然而在髋部骨折方面，其风险性相较于手术前后差异无统计学意义[1.4(0.8~2.7) vs. 1.2(0.7~2.0)，P=0.650][39]。在外科手术10年后，PHPT患者骨折的风险性从1~9年的0.8升至1.7，这主要是由于前臂骨骨折的风险性明显上升。另一项大样本研究显示保守治疗平均6年以上的PHPT患者骨折率较手术患者会升高(14% vs. 9%)[30]。
甲状旁腺功能减退与骨转换标志物甲状旁腺功能减退症被定义为低血钙状态，同时具有不适当的低PTH水平，其通常导致骨转换减低。甲状旁腺功能减退通常认为不需要替换治疗补充缺失激素[40-41]。但有研究发现激素替代治疗后甲状旁腺功能减退患者的骨形成标志物P1NP、OC及骨吸收标志物CTX、NTX迅速增加[42-47]。有研究调查了甲状旁腺功能减退1年以上的5名青少年在予hPTH 1-34替代治疗后，其骨转换标志物的变化情况，发现经过18个月的hPTH 1-34替代治疗后，其骨转换增强：OC[(53±61)μg/L vs. (356±82)μg/L，P＜0.001]、NTX[(76±104)nmol vs. (54.2±156.0)nmol]值均升高，其中OC水平在hPTH 1-34治疗期间持续上升[48]，NTX似乎在前12个月内达到峰值，然后稳定或下降，hPTH 1-34替代疗法的长期骨骼影响还需进一步研究。
男性性腺功能减退与骨转换标志物男性性腺功能减退被认为是男性骨质疏松的主要原因之一[49-50]，这主要是由原发性性腺功能减退[51]、年龄相关的雄激素水平下降[52]、前列腺癌的雄激素去除疗法引起的[53-55]。某些流行病学研究表明，30%的男性发生髋部骨折[56]。最近的研究分析证明骨折的危险性，比起BMD值，可能跟骨转换程度关系更为密切[57]。在男性性腺功能减退患者中，骨转换是亢进的[58-59]，这与睾酮缺乏有关，睾酮作为男性体内最重要的雄激素，其可以刺激骨膜成骨，抑制骨小梁重吸收；而且睾酮可转化为雌二醇，对骨骼产生影响。有研究表明，除了睾酮，睾丸与骨代谢另有联系，睾丸间质细胞产生胰岛素样物质3，参与成骨细胞调节[60]；睾丸间质细胞表达细胞色素P450 2R1(cytochrome P450 2R1，CYP2R1)基因，该基因编码维生素D 25羟化所需的25羟化酶[61]。
有动物研究发现睾丸切除后，小鼠血清OC水平[(397.11±49.72)μg/L vs. (307.01±39.56)μg/L，P＜0.001]和CTX水平[(102.55±6.71)μg/L vs. (90.17±16.07)μg/L，P＜0.05]较健康对照组升高，骨转换亢进[58]。睾丸切除12周后小鼠血清OC值(313.96±47.62 μg/L)较前下降，但相比同年龄段的对照组(221.64±99.38 μg/L)增加了41%，血清CTX值[(75.95±24.38)μg/L vs.(81.78±21.11)μg/L]较对照组下降。睾丸切除18周后小鼠血清OC值[(191.84±86.46)μg/L vs. (123.73±63.68)μg/L]、血清CTX值[(68.01±33.55)μg/L vs. (82.54±26.62)μg/L]与对照组比较，差异均没有统计学意义(P＞0.05)。这些发现与之前Vanderschueren等[59]的观点一致，他发现在睾丸切除后1个月内小鼠骨转换有暂时的亢进，在4个月后会重新回归到正常水平。因此睾丸切除后引起的骨代谢增强，可能与女性中雌激素耗竭造成的骨转换亢进相似，包括绝经后骨质疏松[58]。
高泌乳素血症与骨转换标志物泌乳素分泌性腺瘤是最常见的分泌性垂体肿瘤的类型，约占所有垂体腺瘤的40%~60%[62-64]。骨密度降低、骨吸收的增加已被证明经常发生在性腺功能减退的、高泌乳素血症的男性和女性中[65]。Mazziotti等[66]曾发现骨量减少在高泌乳素血症患者中发生率高，并且在患有泌乳素瘤的妇女中椎骨骨折有高发病率(32.6%，P＜0.001)，未经治疗的高泌乳素血症妇女椎体骨折的发生率(P=0.010)显著高于使用卡麦角林治疗的妇女。在绝经后的泌乳素瘤妇女中，其椎体骨折的发生率(P＜0.001)显著高于绝经前患者及绝经后对照组女性。在绝经前的泌乳素瘤妇女中，椎体骨折的发生率(P=0.070)与绝经前对照组女性无明显差异。此外，绝经前患者椎体骨折的发生率与是否闭经无相关性(P=0.370)，这与高泌乳素血症可能对骨重塑的影响独立于性激素之外的假说相符[67-72]。
在男性中，持续高泌乳素血症导致性欲降低、勃起功能障碍、不孕症和男子乳腺发育症[64]，这些临床特征来自泌乳素过量对性腺功能的负面影响。泌乳素诱导的性腺功能减退被认为是高泌乳素血症患者引起骨量减少的主要机制[73-74]。Mazziotti等[75]研究发现在男性泌乳素瘤患者中，高泌乳素血症和放射性椎骨骨折的高患病率相关，泌乳素过量可能独立于性腺功能减退，对骨骼产生负面效应。Mazziotti等[75]选取了32位泌乳素瘤的男性患者(10个微腺瘤和22个大腺瘤)和64位泌乳素值正常、年龄相当的对照组男性，通过测量腰椎的BMD来评估椎骨骨折。结果发现：13位泌乳素瘤患者(40.6%)具有正常的BMD T评分，而骨质减少的有15例(46.9%)和骨质疏松4例(12.5%)。BMD T值≤-1.0的发生率在泌乳素瘤患者中显著高于对照组(P＜0.001)。椎体骨折发生在12例泌乳素瘤患者(37.5%)和5位对照组男性中(7.8%，P＜0.001)，骨折患者有更低的BMD T值(P=0.007)和更长的患病时间(P＜0.001)。骨折发生率，与用卡麦角林治疗的患者相比，在未治疗的高泌乳素血症患者中更高(P=0.030)，但前者的椎体骨折率仍然高于对照组。泌乳素瘤患者的性腺功能减退发生率更高，但是椎体骨折的发生率在性腺功能良好和性腺功能低下的患者中差异无统计学意义(33.3% vs. 38.5%，P=0.800)。此外，在骨折和非骨折男性中血清睾酮值差异无统计学意义(P=0.400)。多因素回归分析显示泌乳素腺瘤和椎体骨折之间的相关性，独立于性腺机能减退的影响(优势比：8.8，95% CI:1.50~51.10，P=0.010)。
库欣病与骨转换标志物库欣病(Cushing's disease，CD)是一种罕见的垂体功能障碍，最常见于垂体微腺瘤，多发于成人[76-78]。CD患者成骨细胞活性降低、破骨细胞活性增强[79-80]。Carolina等[81]调查了10例儿童发病、18例成人发病的CD患者和28名年龄、性别、体质量指数(body mass index, BMI)相匹配的健康对照组在血清OC、尿NTX值方面的差异，发现CD患者的骨形成指标：血清OC值，不管是儿童患者[(1.7±0.2)μg/L vs. (8.9±1.7)μg/L，P＜0.001]还是成人患者[(1.5±0.1)μg/L vs. (9.4±3.1)μg/L，P＜0.05]均显著低于对照组；骨吸收指标：尿NTX水平，不管是儿童[(161.3±6.9)μg/L vs. (82.4±3.5)μg/L，P＜0.001]还是成人[(125.9±3.3)μg/L vs. (80.3±2.8)μg/L，P＜0.001]均显著高于对照组。经过有效治疗后，儿童患者的OC水平[(5.37±0.5)μg/L vs. (1.73±0.2)μg/L，P＜0.001]、成人患者的OC水平[(5.14±0.3)μg/L vs. (1.58±0.2)μg/L，P＜0.001]均较诊断初期显著增加；不管是儿童[(83.7±5.7)μg/L vs. (159.7±7.9)μg/L，P＜0.001]还是成人[(77.0±3.2)μg/L vs. (125.9±3.3)μg/L，P＜0.001]，其尿NTX水平均比基础值降低[82]。
长期高皮质醇血症通常会引起骨质疏松症及骨质疏松性骨折[83-84]。有研究发现长期糖皮质激素(glucocorticoid)暴露导致椎体和非脊椎骨折风险的显著增加，其被认为是继发性骨质疏松的最常见原因[85-86]。库欣综合征(Cushing's syndrome，CS)患者中骨折率高达76%[87-88]。Belaya等[89]研究发现，CS患者的OPG水平和健康个体差异无统计学意义(P=0.140)，在40位CS患者中19名有低创伤性骨折(14例患者有多处椎体骨折；3例患者有1例椎骨骨折，1例有髋关节骨折，并且在3种情况下检测到肋骨骨折)，这些骨折患者具有较低的OC，但是BMD没有差异，这与认为OC可诊断测试内源性CS的假说一致[90-91]。
综上所述，BTMs已在内分泌代谢性疾病中被广泛研究，BTMs水平升高从理论上可预测骨折风险，联合检测BMD，可以更全面、合理的评估骨转换，及时发现骨质疏松性骨折高危人群，有利于骨质疏松症的早期诊断及治疗。但是在有关BTMs与骨折关系的研究中，由于所涉及的BTMs指标种类繁多、统计方法各异、不同的混杂因素等原因，研究结论不一致，限制了BTMs在骨折风险预测方面的应用。
BTMs的影响因素很多，有很多变异性如生理节律、年龄、性别和绝经状态等，目前BTMs与这些内分泌代谢性疾病的关系有些仍无定论，还有待进一步深入研究。
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| (收稿日期：2017-04-18) |