骨代谢标志物与原发性醛固酮增多症的相关性研究
A Correlative Study of Bone Metabolism Markers and Primary Aldosteronism
摘要: 目的：本研究通过选取原发性醛固酮增多症(PA)患者与原发性高血压(EH)患者的各项化验指标进行比较，探讨醛固酮过量对骨代谢的影响，分析PA患者各项指标与骨代谢标志物的相关性，为PA继发的骨质疏松精准治疗提供依据，以期改善PA患者的预后及生活质量。方法：回顾性收集2021.01~2025.01就诊于青岛大学附属医院诊断的PA患者255例，EH患者232例，收集患者的年龄、性别、身体质量指数(Body Mass Index, BMI)、最高收缩压、最高舒张压以及骨代谢标志物、性激素指标、肾素–血管紧张素–醛固酮系统(Renin-Angiotensin-Aldosterone System, RAAS)指标、血脂、电解质指标进行统计学对比，为了尽量减少更年期、绝经期的影响，按照年龄分层将PA组与EH组分别分为<60岁组、≥60岁组，进行基线资料对比。选取PA患者RAAS指标与骨代谢标志物、性激素及年龄、性别、BMI进行相关性分析。结果：基线资料对比发现两组患者在年龄、BMI、最高收缩压、性激素相关化验上无显著差异性，PA组患者骨钙素、甲状旁腺激素(parathyroid hormone, PTH)、I型胶原羧基端肽β特殊序列(collagen type I carboxy-terminal telopeptide β-specific sequence, β-CTX)、立位血浆醛固酮(plasma aldosterone concentration, PAC)、ARR显著高于EH组(P < 0.001, P < 0.001, P < 0.001, P < 0.001)，PRA、血钙、血钾、PINP显著低于EH组(P < 0.001, P < 0.001, P < 0.001, P < 0.01)。按照年龄分层后发现<60岁患者中，PA的PAC、ARR、PTH、最高收缩压、骨钙素显著高于EH组(P < 0.001, P < 0.001, P < 0.05, P < 0.01)，血钾、血钙、PRA显著低于EH组(P < 0.01, P < 0.001, P < 0.001)。≥60岁患者中，PA组ARR、PTH、骨钙素显著高于EH组(P < 0.001, P < 0.001, P < 0.01)，血钾、血钙、PRA显著低于EH组(P < 0.001, P < 0.001, P < 0.001)。相关性分析显示PAC与PTH呈显著正相关(r = 0.048, P = 0.035)。结论：PA患者骨代谢标志物显著高于EH患者，且PAC与PTH呈正相关，PA继发的甲状腺功能亢进与其骨丢失相关。PA患者早期诊断治疗、补充维生素D对于预防继发性骨质疏松至关重要。
Abstract: Purpose: This study compared various laboratory parameters between primary aldosteronism (PA) patients and essential hypertension (EH) patients, explored the effects of aldosterone excess on bone metabolism, analyzed the correlations between PA-related indicators and bone metabolism markers, and provided a basis for precision treatment of osteoporosis secondary to PA to improve the prognosis and quality of life of PA patients. Methods: This study retrospectively collected 255 primary aldosteronism (PA) patients and 232 essential hypertension (EH) patients diagnosed at Qingdao University Affiliated Hospital between January 2021 and January 2025. The collected data included age, gender, BMI, maximum systolic blood pressure, maximum diastolic blood pressure, bone metabolism markers, sex hormone indices, RAAS system parameters, blood lipids, and electrolyte parameters for statistical comparison. To minimize menopausal and postmenopausal influences, both PA and EH groups were stratified into <60 years and ≥60 years groups for baseline data comparison. Correlation analysis was performed between PA patients’ RAAS indices and bone metabolism markers, sex hormones, as well as age, gender, and BMI. Results: This study compared baseline data and found no significant differences in age, BMI, maximum systolic blood pressure, or sex hormone-related parameters between the two groups. Osteocalcin, PTH, β-CTX, PAC, and ARR were significantly higher in the PA group compared to the EH group (P < 0.001, P < 0.001, P < 0.001, P < 0.001), while PRA, serum calcium, serum potassium, and PINP were significantly lower (P < 0.001, P < 0.001, P < 0.001, P < 0.01). After age stratification, in the <60 years group, PA patients showed significantly higher PAC, ARR, PTH, maximum systolic blood pressure, and osteocalcin compared to EH patients (P < 0.001, P < 0.001, P < 0.05, P < 0.01), and significantly lower serum potassium, serum calcium, and PRA (P < 0.01, P < 0.001, P < 0.001). In the ≥60 years group, PA patients had significantly higher ARR, PTH, and osteocalcin (P < 0.001, P < 0.001, P < 0.01), and significantly lower serum potassium, serum calcium, and PRA (P < 0.001, P < 0.001, P < 0.001). Correlation analysis revealed a positive correlation between PAC and PTH (r = 0.048, P = 0.035). Conclusion: The study found that bone metabolism markers were significantly higher in PA patients compared to EH patients, and PAC was positively correlated with PTH. Hyperthyroidism secondary to PA is associated with bone loss. Early diagnosis and treatment of patients with PA and vitamin D supplementation are essential for the prevention of secondary osteoporosis.
文章引用：潘晓彤, 刘瑞冬, 张瀚元, 何新姣, 梁韵琦, 曹彩霞. 骨代谢标志物与原发性醛固酮增多症的相关性研究[J]. 临床医学进展, 2025, 15(5): 656-667. https://doi.org/10.12677/acm.2025.1551419

1. 引言

原发性醛固酮增多症(Primary aldosteronism, PA)是最常见的继发性高血压，特征是肾上腺皮质自主分泌过量醛固酮，导致水钠潴留和钾排泄增多，血容量增加，肾素–血管紧张素–醛固酮系统(RAAS)活性受抑制，临床表现为高血压，伴或不伴低血钾[1]。PA最常见的临床分型是醛固酮瘤(Aldosterone producing-adenoma, APA)和双侧肾上腺皮质增生导致的特发性醛固酮增多症(Idiopathic hyperaldosteronism, IHA)，目前的主要治疗是手术切除肾上腺醛固酮瘤或者使用盐皮质激素受体拮抗剂(Mineralocorticoid receptor antagonists, MRA)如螺内酯等药物治疗[2]-[4]。醛固酮分泌过量使得PA患者心脑肾等靶器官的损害风险较原发性高血压(Essential hypertension, EH)更为严重，随着检测水平的提高和检测方法的更新，PA检出率逐年增高，已经不再是以前认为的罕见病[5]-[7]。最近越来越多的研究发现，PA患者过量的醛固酮水平对骨代谢产生不利影响，导致患者骨质疏松风险增加[8] [9]。骨质疏松症(Osteoporosis, OP)是一种常见疾病，其特征是骨量和强度降低，骨微观结构破坏，增加骨折风险。OP可分为原发性OP和继发性OP，继发性OP是可逆的，因此为改善患者后期生活质量，确定其原因及早期干预非常重要[10]-[12]。

PA是导致继发性OP的重要原因，Yokomoto-Umakoshi [13]等人的一项横断面研究发现PA患者椎体骨折(Vertebral fractures, VF)的患病率高于非PA患者，且单侧PA是VF的独立危险因素。Notsu [14]等人的研究也证实PA是VF的危险因素，且独立于血压、糖化血红蛋白(HbA1c)和血脂谱。PA患者尿钙增高导致继发性甲状旁腺功能亢进是发生骨质疏松风险高的原因之一[15] [16]，L Ceccoli [16]等人研究发现与EH相比，PA患者PTH水平和尿钙排泄量显著增加，而血清钙显著降低，维生素D水平未见明显差异，经盐皮质激素受体拮抗剂(MRA)治疗后随访发现PA患者PTH水平显著降低、腰椎、股骨颈和全髋关节部位的Z评分显著改善，APA患者经手术治疗后随访发现PTH水平降低，骨质疏松改善[17] [18]。研究发现骨细胞上存在醛固酮激素受体，过量醛固酮可能直接通过参与骨代谢破坏骨微观结构而减少骨质[19]-[21]，另外PA患者醛固酮增多诱导氧化应激增加是骨质减少的原因之一，但其具体机制尚未明确[22]-[25]。

随着骨质疏松发病机制研究的进展，既往以雌激素为中心的更年期骨质疏松症发病机制研究现已转变为与年龄、氧化应激相关的机制研究，卵巢等其他器官和组织的年龄相关变化加剧了这些机制。衰老是骨量和骨强度损失的关键决定因素，随着年龄增长机体产生氧化应激(Oxidative stress, OS)，氧化过程的产物之一活性氧(Reactive oxygen species, ROS)增多，ROS对多种细胞因子、酶活性、基因通路等产生影响，促进骨髓间充质干细胞、成骨细胞、骨细胞的凋亡和破骨细胞的增生及分化，导致骨量减低甚至OP [24] [26]。目前已有多项研究证实氧化应激与骨质疏松的关系，且发现应用抗氧化剂治疗对小鼠的骨质疏松有所改善[27] [28]。本研究选取PA患者与原发性高血压(EH)患者的各项化验指标进行比较，探讨醛固酮过量对PA患者骨代谢的影响，分析PA患者各项指标与骨代谢的相关性，以期对PA患者骨质疏松的精准治疗提供依据。

2. 研究方法

2.1. 研究对象

本研究回顾性收集2021.01~2025.01就诊于青岛大学附属医院诊断为PA及同期诊断为EH的成年患者，分为PA组255例，EH组232例，入组患者均符合以下纳排标准。

2.1.1. 纳入标准

(1) PA诊断标准：根据2024版中华医学会内分泌学分会《原发性醛固酮增多症诊断治疗的专家共识》进行PA的诊断[2]：筛查前准备1) 尽量将血钾纠正至正常范围。2) 维持正常钠盐摄入。3) 停用对ARR影响较大药物至少4周，包括醛固酮受体拮抗剂、保钾利尿剂、排钾利尿剂及甘草提炼物。4) 需注意血管紧张素转换酶抑制剂(ACEI)、血管紧张素受体拮抗剂(ARB)、钙离子拮抗剂(CCB)等类药物可升高肾素活性，降低醛固酮，导致ARR假阴性，因此，需停用上述药至少2周再次进行检测。如服药时肾素活性 < 1 ng∙ml−1∙h−1或低于正常检测下限同时合并ARR升高，考虑原醛症可能性大，可维持原有药物治疗。5) 如血压控制不佳，建议使用α受体阻滞剂和(或)非二氢吡啶类CCB。当检测的肾素活性和醛固酮浓度单位分别是ng∙ml−1∙h−1和ng/dL时，最常用的ARR切点为30。对于ARR阳性的患者加用≥1种确诊实验即可诊断PA。对于合并自发性低钾血症、血浆肾素水平低于可检测水平，且醛固酮 > 20 ng/dL的患者指南建议直接诊断而无需进行额外的确诊试验。常用确诊实验为卡托普利抑制试验：上午立位口服50 mg卡托普利2 h后测量血浆醛固酮浓度，若被抑制<30%，则可被诊断为PA。

(2) EH诊断标准：根据中国高血压防治指南(2024年修订版) [29]进行EH的诊断，满足以下之一即可确诊：1) 诊室血压标准：在未使用降压药物的情况下，非同日3次规范化测量诊室血压，收缩压 ≥ 140 mmHg和/或舒张压 ≥ 90 mmHg。2) 家庭血压标准：家庭连续规范测量血压5~7天，所有测量血压读数的平均值 ≥ 135/85mmHg。3) 动态血压标准：24小时动态血压平均值 ≥ 130/80mmHg，或白天血压平均值 ≥ 135/85mmHg，或夜间血压平均值 ≥ 120/70mmHg。若患者既往有高血压病史且正在使用降压药物，即使血压低于上述标准，仍应诊断为高血压。

2.1.2. 排除标准

(1) 因失眠、焦虑、疼痛等因素引起的暂时性血压升高；(2) 合并甲状腺功能亢进、慢性肝功能不全、成人成骨不全、45岁以内绝经等导致骨质疏松的疾病；(3) 患有恶性肿瘤、血液系统疾病、神经系统疾病、感染性疾病、严重肾功能不全的病例；(4) 近期使用糖皮质激素、双膦酸盐类、雌激素受体调节剂、降钙素类药物的病例；(5) 年龄 < 18岁的患者。

2.2. 资料收集

2.2.1. 一般资料

收集患者的年龄、性别、BMI、最高收缩压(Systolic blood pressure, SBP)、最高舒张压(Diastolic blood pressure, DBP)。

2.2.2. 实验室检查指标

1) 性激素指标：睾酮(Testosterone, T)、雌二醇(Estradiol, E2)、促黄体生成素(Luteinizing Hormone, LH)、促卵泡生成素(Follicle-Stimulating Hormone, FSH)、孕酮(Progesterone, P)、催乳素(Prolactin, PRL)；

2) 血脂、尿酸及电解质指标：甘油三酯(Triglyceride, TG)、总胆固醇(Total cholesterol, TC)、高密度脂蛋白(High-density lipoprotein, HDL)、低密度脂蛋白(Low-density lipoprotein, LDL)、血肌酐(creatinine, Cr)、尿酸(uric acid, UA)、血磷(phosphorus, P)、血钙(calcium, Ca2+)、血钾(potassium, K+)；

3) 骨代谢指标指标：25羟基维生素D3 (25-hydroxyvitamin D, 25(OH)D3)、骨钙素(osteocalcin)、I型前胶原氨基端前肽(procollagen type I amino-terminal propeptide, PINP)、甲状旁腺激素(parathyroid hormone, PTH)、I型胶原羧基端肽β特殊序列(collagen type I carboxy-terminal telopeptide β-specific sequence, β-CTX)；

4) RAAS系统指标：立位血浆醛固酮(plasma aldosterone concentration, PAC)、立位血浆肾素活性(plasma renin activity, PRA)。

2.3. 数据分析

应用IBMSPSS 27.0统计软件进行数据的处理及分析。正态分布的计量资料以均数 ± 标准差表示，两组间比较采用独立样本t检验；非正态分布的计量资料以中位数(P25, P75)表示，两组独立样本间比较采用非参数检验(Mann-Whitney U检验)。计数资料以例数(百分比)表示，组间比较采用卡方检验。在相关性分析中，符合正态分布的数据采用Pearson相关分析，不符合正态分布的数据采用Spearman相关分析。运用多元线性回归分析探讨PA组RAAS与骨代谢指标相关性。对多元线性回归的线性、正态性、同方差性和共线性等假设条件进行检验，结果均符合要求。以双侧检验P < 0.05为差异有统计学意义。

3. 结果

3.1. 一般基线资料

3.1.1. PA组与EH组基线资料对比

根据纳排标准共纳入255例PA患者、232例EH患者，PA组患者平均年龄59.1 ± 10.2岁，男性患者比例45.1%；EH组患者平均年龄59.5 ± 11.7岁，男性患者占比55.2%。如表1所示，两组患者在年龄、BMI、最高收缩压无显著差异性，EH组患者男性占比高于PA组(P < 0.05)。两组患者在睾酮、雌二醇、促黄体生成素、促卵泡生成、孕酮、催乳素上无明显差异。EH组患者的总胆固醇、高密度脂蛋白显著高于PA组(P < 0.05, P < 0.05)，甘油三酯、血磷显著低于PA组(P < 0.05, P < 0.01)。PA组患者骨钙素、PTH、β-CTX、PAC、ARR显著高于EH组(P < 0.001, P < 0.001, P < 0.001, P < 0.001)，PRA、血钙、血钾、PINP显著小于EH组(P < 0.001, P < 0.001, P < 0.001, P < 0.01)。

Table 1. Comparison of baseline data between PA group and EH group

表1. PA组与EH组基线资料对比

分组变量

PA组(n = 255)

EH组(n = 232)

P值

Age (y)

59.1 ± 10.2

59.5 ± 11.7

0.682

Male (n, %)

115 (45.1)

128 (55.2)

0.026*

BMI (kg/m2)

26.51 ± 3.44

26.64 ± 3.29

0.666

SBP (mmHg)

170 (160, 180)

160 (150, 180)

0.072

DBP (mmHg)

100 (99, 110)

100 (91.2, 100)

0.031*

T (nmol/L)

9.17 (0.73, 13.5)

10.45 (0.75, 15.55)

0.05

E2 (pmol/L)

62.3 (39.44, 108.55)

89.3 (132, 62.13)

0.244

LH (mIU/mL)

9.55 (5.76, 22.34)

7.96 (4.73, 16.43)

0.06

FSH (mIU/mL)

12.4 (5.22, 35.8)

8.72 (6.22, 26.78)

0.06

Progesterone (nmol/L)

0.54 (0.28, 0.75)

0.61 (0.38, 1.08)

0.425

PRL (mIU/mL)

324 (270.8, 407.5)

321.5 (277.25, 446.5)

0.181

TG (mmol/L)

1.54 (1.17, 2.30)

1.44 (1.07, 2.34)

0.032*

TC (mmol/L)

5.02 (4.42, 5.65)

5.03 (4.39, 5.49)

0.049*

HDL (mmol/L)

1.27 (1.16, 1.42)

1.36 (1.27, 1.50)

0.018*

LDL (mmol/L)

2.62 ± 0.78

2.74 ± 0.82

0.093

Cr (μmol/L)

86 (76.5, 103)

89 (77.25, 98.5)

0.006**

UA (μmol/L)

336.82 ± 83.88

345.89 ± 92.52

0.261

P (mmol/L)

1.18 (1.02, 1.4)

1.15 (1.03, 1.27)

0.005**

Ca2+ (mmol/L)

2.28 (2.18, 2.32)

2.3 (2.19, 2.38)

<0.001***

K+ (mmol/L)

3.66 (3.29, 3.97)

3.76 (3.57, 4.00)

<0.001***

25(OH)D3 (ng/mL)

16.48 ± 7.94

16.82 ± 5.90

0.6

Osteocalcin (ng/mL)

15.00 (10.70, 20.25)

14.60 (11.05, 16.90)

<0.001***

PINP (ng/mL)

37.30 (29.15, 52.50)

40.5 (31.20, 50.95)

0.01*

PTH (pg/mL)

41.40 (34.55, 53.60)

35.15 (27.13, 42.03)

<0.001***

β-CTX (ng/mL)

0.44 (0.30, 0.74)

0.42 (0.30, 0.55)

0.001**

PAC (ng/dL)

17.15 (11.11, 22.49)

12.74 (9.06, 18.12)

<0.001***

PRA (ng∙ml−1∙h−1)

0.16 (0.1, 0.3)

2.11 (1.13, 3.9)

<0.001***

ARR

73.12 (42.17, 201.73)

6.61 (3.47, 12.17)

<0.001***

注：*：P < 0.05；**：P < 0.01；***：P < 0.001；Age：年龄；Male：男性；BMI：体重指数；SBP：最高收缩压；DBP：最高舒张压；T：睾酮；E2：雌二醇；LH：促黄体生成素；FSH：促卵泡生成；Progesterone：孕酮；PRL：催乳素；TG：甘油三酯；TC：总胆固醇；HDL：高密度脂蛋白；LDL：低密度脂蛋白；Cr：血肌酐；UA：尿酸；P：血磷；K+：血钾；Ca2+：血钙；25(OH)D3：25羟基维生素D3；osteocalcin：骨钙素；PINP：I型前胶原氨基端前肽；PTH：甲状旁腺激素；β-CTX：I型胶原羧基端肽β特殊序列；PAC：血浆立位醛固酮；PRA：血浆立位肾素活性；ARR：立位血浆醛固酮、肾素活性比值。

3.1.2. 按年龄分层的PA、EH基线资料对比

为了尽量减少更年期、绝经期的影响，我们按照年龄将PA组与EH组分别分为<60岁组、≥60岁组，进行基线资料对比，如表2所示。<60岁患者中，PA的PAC、ARR、PTH、最高收缩压、骨钙素显著高于EH组(P < 0.001, P < 0.001, P < 0.05, P < 0.01)，血钾、血钙、PRA显著低于EH组(P < 0.01, P < 0.001, P < 0.001)。≥60岁患者中，EH组113例年龄显著高于EH组(P = 0.04)，PA组ARR、PTH、骨钙素显著高于EH组(P < 0.001, P < 0.001, P < 0.01)，血钾、血钙、PRA显著低于EH组(P < 0.001, P < 0.001, P < 0.001)。

Table 2. Comparison of age group data

表2. 年龄分组资料对比

分组

变量

<60岁

≥60岁

PA组(n = 132)

EH组(n = 119)

P值

PA组(n = 122)

EH组(n = 113)

P值

Age (y)

50 (47, 56.5)

52 (46.7, 56)

0.241

67 (64.3, 69.8)

69 (65, 71.5)

0.04*

Male (n, %)

67 (50.4)

76 (63.9)

0.031*

48 (39.3)

52 (46.0)

0.301

BMI (kg/m2)

28.2 ± 2.8

28.2 ± 3.3

0.419

27.3 (25.7, 27.9)

26.6 (25.1, 28.3)

0.994

SBP (mmHg)

170 (160, 180)

160 (150, 172)

0.008**

170 (160, 200)

172 (150, 180)

0.989

DBP (mmHg)

103 (100, 115)

100 (100, 110)

0.400

94 (82.5, 100)

100 (90, 100)

0.196

PAC (ng/dL)

17.2 (10.3, 24.1)

12.2 (8.1, 18.2)

<0.001***

16.1 ± 5.5

13.5 ± 5.2

0.062

PRA (ng∙ml−1∙h−1)

0.16 (0.1, 0.29)

2.09 (0.7, 3.35)

<0.001***

0.1 (0.1, 0.4)

2.68 (1.2, 4.0)

<0.001***

ARR

70 (39.1, 249.3)

7.0 (3.5, 13.6)

<0.001***

126.4 (46.5, 179.3)

5.5 (2.8, 8.4)

<0.001***

25(OH)D3 (ng/mL)

16 ± 5.4

15.4 ± 4.6

0.027

12.5 ± 4.7

16.0 ± 5.6

0.951

Osteocalcin (ng/mL)

15.7 (10.8, 20.25)

14.7 (10.4, 16.9)

0.07*

15.6 ± 6.3

15 ± 5.0

0.008**

PINP (ng/mL)

16.3 ± 6.4

14.6 ± 4.8

0.245

39.0 (29.5, 54.3)

30.3 (25.3, 37.9)

0.008**

PTH (pg/mL)

39.8 (34, 53.4)

39.2 (27.18, 45.2)

0.030*

30.3 (25.5, 37.9)

49.5 (35, 59.9)

<0.001***

β-CTX (ng/mL)

0.44 (0.3, 0.72)

0.46 (0.36, 0.55)

0.112

0.47 (0.28, 1.15)

0.36 (0.25, 0.55)

0.002**

K+ (mmol/L)

3.63 (3.13, 3.94)

3.70 (3.52, 3.96)

0.007**

3.64 (3.31, 3.96)

3.86 (3.62, 4.10)

<0.001***

P (mmol/L)

1.18 (1.01, 1.4)

1.17 (1.02, 1.27)

0.101

1.19 (1.05, 2.82)

1.13 (1.03, 1.23)

0.017*

Ca2+ (mmol/L)

2.25 (2.16, 2.32)

2.29 (2.12, 2.35)

<0.001***

2.26 (1.39, 2.29)

2.32 (2.24, 2.4)

<0.001***

注：*：P < 0.05；**：P < 0.01；***：P < 0.001；Age：年龄；Male：男性；BMI：体重指数；SBP：最高收缩压；DBP：最高舒张压；PAC：血浆立位醛固酮；PRA：血浆立位肾素活性；ARR：立位血浆醛固酮、肾素活性比值；25(OH)D3：25羟基维生素D3；osteocalcin：骨钙素；PINP：I型前胶原氨基端前肽；PTH：甲状旁腺激素；β-CTX：I型胶原羧基端肽β特殊序列；P：血磷；K+：血钾；Ca2+：血钙。

3.2. 相关性分析

将PA患者RAAS指标与骨代谢标志物、性激素及年龄、性别、BMI进行相关性分析，如图1所示：可见PAC与PTH呈正相关(P < 0.05)，BMI与PTH呈正相关(P < 0.01)；PTH与25(OH)D3呈负相关(P < 0.001)，与骨钙素呈正相关(P < 0.001)。如表3、图2所示，PAC与PTH呈显著正相关(r = 0.048, P = 0.035)，提示PTH增高可能是PA患者骨代谢异常的主要原因。

注：*：P < 0.05；**：P < 0.01；***：P < 0.001；PAC：血浆立位醛固酮；PRA：血浆立位肾素活性；ARR：立位血浆醛固酮、肾素活性比值；Sex：性别；Age：年龄；BMI：体重指数；T：睾酮；E2：雌二醇；LH：促黄体生成素；FSH：促卵泡生成；Progesterone：孕酮；PRL：催乳素；25(OH)D：25羟基维生素D3；osteocalcin：骨钙素；PINP：I型前胶原氨基端前肽；PTH：甲状旁腺激素；β-CTX：I型胶原羧基端肽β特殊序列；P：血磷；Ca2+：血钙。

Figure 1. Correlation analysis between RAAS indexes and bone metabolism markers, sex hormones, age, gender, and BMI in PA patients

图1. PA患者RAAS指标与骨代谢标志物、性激素、年龄、性别、BMI的相关性分析

Table 3. Correlation Analysis of Bone Metabolism Markers with RAAS

表3. 骨代谢标志物与RAAS的相关性分析

PTH (pg/mL)

osteocalcin (ng/mL)

PINP (ng/mL)

25OHD (ng/mL)

β-CTX (ng/mL)

PAC (ng/dL)

P值

0.035*

0.737

0.446

0.723

0.825

r值

0.048

−0.003

−0.011

−0.001

−6.487

PRA (ng∙ml−1∙h−1)

P值

0.171

0.502

0.906

0.844

0.471

r值

19.972

3.303

−0.741

−0.450

−0.092

ARR

P值

0.611

0.956

0.482

0.692

0.100

r值

0.011

3.159

−0.001

−0.001

−2.874

注：*：P < 0.05差异有统计学意义；PTH：甲状旁腺素；osteocalcin：骨钙素；25OHD：25-羟基维生素D3；PINP：总I型胶原氨基端延长肽；β-CTX为I型胶原羧基端肽交联；PAC为血浆立位醛固酮；PRA为血浆立位肾素；ARR为立位血浆醛固酮、肾素活性比值。

Figure 2. Correlation analysis between RAAS indexes and bone metabolism markers in PA patients

图2. PA患者RAAS指标与骨代谢标志物相关性分析

4. 讨论

骨质疏松症是一个全球公共卫生问题，原发性骨质疏松症最为常见，发生在与更年期和随年龄增长而发生的性激素变化相关的正常衰老过程中。然而高达30%的绝经后妇女、超过50%的绝经前女性以及50%至80%的男性患有继发性骨质疏松症[30]，中国50岁以上人群中骨质减少的患病率超过60% [31]，随着我国老龄化的进展，骨质疏松患病率也将增长。对于继发性OP，为了改善患者的预后及生活质量，排除继发性病因至关重要，因为此类患者的治疗通常需从控制原发病入手[32]。PA是最常见的内分泌性高血压，其过量分泌的醛固酮导致骨代谢异常、骨量减少，进而发展成为继发性OP。因此本研究选取PA患者与EH患者进行分析，我们的研究发现PAC与PTH呈显著正相关(r = 0.048, P = 0.035)。

1985年Resnick等人[33]的研究第一次提出PA患者PTH水平升高，越来越多的研究证明了这一点，过量分泌的醛固酮可能通过减少近端肾小管对钠和钙的再吸收、增加尿钙排泄和长期钙化引起继发性甲状旁腺功能亢进[15] [34]。PTH是由甲状旁腺分泌的84个氨基酸组成的肽类激素，和醛固酮之间存在相互作用，PTH通过与PTH/PTH-rP受体结合增加肾上腺球状带细胞中的钙离子浓度刺激醛固酮分泌，也可通过间接增强血管紧张素II的诱导效应刺激醛固酮分泌[35] [36]。我们的研究发现PA患者PTH显著高于EH组，且PTH与PAC呈正相关。PTH通过与I型甲状旁腺激素受体(PTH1R)结合调控骨代谢：一方面直接作用于间充质干细胞、成骨细胞谱系细胞、骨细胞和T细胞发挥成骨作用；另一方面通过间接作用于破骨前体细胞和破骨细胞，并直接作用于T细胞参与破骨过程，在这些细胞中，PTH可激活Wnt信号通路、环磷酸腺苷–蛋白激酶A (cAMP-PKA)、环磷酸腺苷–蛋白激酶C (cAMP-PKC)以及核因子κB受体活化因子配体–核因子κB受体活化因子–骨保护素(RANKL-RANK-OPG)通路等多种信号转导途径[37]。与我们的研究结果一致，PA患者高水平PTH导致骨代谢异常，血钙水平显著低于EH组。其次，Beavan等人[38]研究发现人类骨细胞中存在醛固酮激素受体(MR)，醛固酮因此可以直接作用于骨细胞。其次盐皮质激素途径的几个基因(NR3C2、PIK3R1、PRKCH和SCNN1B)可能会影响骨强度[20]。醛固酮过量引起机体氧化应激、慢性炎症也可能增加成骨细胞和骨细胞凋亡[39]。因此PA患者早期诊断治疗尤为重要，应用MRA可降低醛固酮水平，进而降低患者继发性OP风险。

本研究结果显示PA和EH患者的血清25OHD水平没有显著差异，相关性分析显示PTH与25OHD呈负相关(P < 0.001)，与我们的研究类似的是Forman等人[40]研究显示血清维生素D水平降低会刺激PTH分泌并上调RAAS系统，低维生素D水平可能与高醛固酮水平一起影响PA患者的PTH分泌和骨代谢，增加OP风险[41]。Noor Ashikin Ismail等人[42]在一项评估维生素D治疗对PA患者临床和生化结果的影响研究中发现对缺乏维生素D的PA患者进行维生素D补充治疗后可观察到血钙水平升高、PTH降低。因此PA患者治疗过程中应监测维生素D水平，必要时给予口服或静脉药物补充维生素D，可减低后期OP风险，但其具体机制还需进一步研究。

血脂方面我们研究结果显示PA患者的TC、HDL显著低于EH组(P < 0.05, P < 0.05)，TG显著高于EH组(P < 0.05, P < 0.01)，两组LDL无明显差异。一项横断面研究发现TC和TG的增加与骨质疏松症风险增加有关，LDL和HDL水平与骨质疏松症无关，年龄、性别和体重指数(BMI)与TC和TG与骨质疏松症的关系没有相互作用[28]。也有研究显示LDL的升高与骨密度的降低有关[43]，血脂与骨代谢之间的关系可能受到多种因素的影响，包括年龄、性别、遗传特征、生活方式以及是否合并高血压、糖尿病等，因此本研究并不能准确说明血脂与骨代谢之间的关系，较高的血脂水平影响骨代谢可能与增加机体氧化应激有关，其具体机制还需进一步研究。结合本研究结果，血脂对骨代谢影响可能在PA之下。

越来越多的证据表明氧化应激在骨的重塑中起着至关重要的作用，氧化应激的增加会通过调节激酶和转录因子活性，包括激活c-Jun N末端激酶、Wnt/b-catenin、核因子κb信号通路等，增加RANKL表达，降低成骨细胞的分化和活性，从而诱导骨丢失[44] [45]，也有研究发现某些抗氧化剂的应用在小鼠可以抑制破骨细胞分化和骨吸收[46]。年龄增长是机体氧化应激的重要原因之一，氧化应激随着年龄的增长而增加[47] [48]，本研究按年龄分层≥60岁组中，EH组年龄显著大于PA组，但其血钙显著低于PA组，提示PA对骨代谢的影响大于年龄因素，然而抗氧化剂治疗是否可以改善PA引起的骨流失还需要进一步研究。

综上所述，继发性甲旁亢、年龄增长和醛固酮诱导的氧化应激可能在PA导致的骨丢失中发挥作用，PA患者PAC与PTH呈正相关，提示PA继发的甲状腺功能亢进可能是其骨丢失的原因。我们的研究是一项回顾性研究，存在不足性，PA患者临床指标多为确诊初期指标，未能完整收集患者腰椎骨密度、炎症指标等，后期还需继续收集相关指标，随访PA治疗后指标变化，对PA导致的骨质疏松进一步研究。年龄、性别、BMI、药物使用等因素都是骨代谢的影响因素，后期需要通过多因素分析来进一步分析这些混杂因素的影响。未对两组患者的生活方式、饮食习惯、进行充分的控制，可能导致结果的偏差。

5. 结论

PA患者骨代谢标志物显著高于EH患者，且PAC与PTH呈正相关，PA继发的甲状腺功能亢进可能是其骨丢失的原因。PA患者早期诊断治疗、补充维生素D对于预防继发性骨质疏松至关重要。

NOTES

*通讯作者。

参考文献

[1] Choy, K.W., Fuller, P.J., Russell, G., Li, Q., Leenaerts, M. and Yang, J. (2022) Primary Aldosteronism. BMJ, 377, e065250.
https://doi.org/10.1136/bmj-2021-065250
[2] 中华医学会内分泌学分会. 原发性醛固酮增多症诊断治疗的专家共识(2024版) [J]. 中华内分泌代谢杂志, 2025, 41(1): 12-24.
[3] Reincke, M., Bancos, I., Mulatero, P., Scholl, U.I., Stowasser, M. and Williams, T.A. (2021) Diagnosis and Treatment of Primary Aldosteronism. The Lancet Diabetes & Endocrinology, 9, 876-892.
https://doi.org/10.1016/s2213-8587(21)00210-2
[4] Pilz, S., Kocjan, T., Theiler-Schwetz, V. and Trummer, C. (2023) Primary Aldosteronism 2.0: An Update for Clinicians on Diagnosis and Treatment. Polish Archives of Internal Medicine, 133, Article 16585.
https://doi.org/10.20452/pamw.16585
[5] Calhoun, D.A. (2007) Is There an Unrecognized Epidemic of Primary Aldosteronism? (Pro). Hypertension, 50, 447-453.
https://doi.org/10.1161/hypertensionaha.106.086116
[6] Mulatero, P., Monticone, S., Bertello, C., Viola, A., Tizzani, D., Iannaccone, A., et al. (2013) Long-Term Cardio-and Cerebrovascular Events in Patients with Primary Aldosteronism. The Journal of Clinical Endocrinology & Metabolism, 98, 4826-4833.
https://doi.org/10.1210/jc.2013-2805
[7] Turcu, A.F., Yang, J. and Vaidya, A. (2022) Primary Aldosteronism—A Multidimensional Syndrome. Nature Reviews Endocrinology, 18, 665-682.
https://doi.org/10.1038/s41574-022-00730-2
[8] Kim, B., Lee, S.H. and Koh, J. (2018) Bone Health in Adrenal Disorders. Endocrinology and Metabolism, 33, 1-8.
https://doi.org/10.3803/enm.2018.33.1.1
[9] Shi, S., Lu, C., Tian, H., Ren, Y. and Chen, T. (2020) Primary Aldosteronism and Bone Metabolism: A Systematic Review and Meta-Analysis. Frontiers in Endocrinology, 11, Article 574151.
https://doi.org/10.3389/fendo.2020.574151
[10] Vidal, M., Thibodaux, R.J., Neira, L.F.V. and Messina, O.D. (2019) Osteoporosis: A Clinical and Pharmacological Update. Clinical Rheumatology, 38, 385-395.
https://doi.org/10.1007/s10067-018-4370-1
[11] LeBoff, M.S., Greenspan, S.L., Insogna, K.L., Lewiecki, E.M., Saag, K.G., Singer, A.J., et al. (2022) The Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International, 33, 2049-2102.
https://doi.org/10.1007/s00198-021-05900-y
[12] Gregson, C.L., Armstrong, D.J., Bowden, J., Cooper, C., Edwards, J., Gittoes, N.J.L., et al. (2022) UK Clinical Guideline for the Prevention and Treatment of Osteoporosis. Archives of Osteoporosis, 17, Article No. 58.
https://doi.org/10.1007/s11657-022-01061-5
[13] Yokomoto‐Umakoshi, M., Sakamoto, R., Umakoshi, H., Matsuda, Y., Nagata, H., Fukumoto, T., et al. (2020) Unilateral Primary Aldosteronism as an Independent Risk Factor for Vertebral Fracture. Clinical Endocrinology, 92, 206-213.
https://doi.org/10.1111/cen.14145
[14] Notsu, M., Yamauchi, M., Yamamoto, M., Nawata, K. and Sugimoto, T. (2017) Primary Aldosteronism as a Risk Factor for Vertebral Fracture. The Journal of Clinical Endocrinology & Metabolism, 102, 1237-1243.
https://doi.org/10.1210/jc.2016-3206
[15] Petramala, L., Zinnamosca, L., Settevendemmie, A., Marinelli, C., Nardi, M., Concistrè, A., et al. (2014) Bone and Mineral Metabolism in Patients with Primary Aldosteronism. International Journal of Endocrinology, 2014, Article 836529.
https://doi.org/10.1155/2014/836529
[16] Ceccoli, L., Ronconi, V., Giovannini, L., Marcheggiani, M., Turchi, F., Boscaro, M., et al. (2013) Bone Health and Aldosterone Excess. Osteoporosis International, 24, 2801-2807.
https://doi.org/10.1007/s00198-013-2399-1
[17] Maniero, C., Fassina, A., Seccia, T.M., Toniato, A., Iacobone, M., Plebani, M., et al. (2012) Mild Hyperparathyroidism: A Novel Surgically Correctable Feature of Primary Aldosteronism. Journal of Hypertension, 30, 390-395.
https://doi.org/10.1097/hjh.0b013e32834f0451
[18] Salcuni, A.S., Palmieri, S., Carnevale, V., Morelli, V., Battista, C., Guarnieri, V., et al. (2012) Bone Involvement in Aldosteronism. Journal of Bone and Mineral Research, 27, 2217-2222.
https://doi.org/10.1002/jbmr.1660
[19] Law, P.H., Sun, Y., Bhattacharya, S.K., Chhokar, V.S. and Weber, K.T. (2005) Diuretics and Bone Loss in Rats with Aldosteronism. Journal of the American College of Cardiology, 46, 142-146.
https://doi.org/10.1016/j.jacc.2005.03.055
[20] Gupta, M., Cheung, C., Hsu, Y., Demissie, S., Cupples, L.A., Kiel, D.P., et al. (2011) Identification of Homogeneous Genetic Architecture of Multiple Genetically Correlated Traits by Block Clustering of Genome-Wide Associations. Journal of Bone and Mineral Research, 26, 1261-1271.
https://doi.org/10.1002/jbmr.333
[21] Styrkarsdottir, U., Halldorsson, B.V., Gretarsdottir, S., Gudbjartsson, D.F., Walters, G.B., Ingvarsson, T., et al. (2008) Multiple Genetic Loci for Bone Mineral Density and Fractures. New England Journal of Medicine, 358, 2355-2365.
https://doi.org/10.1056/nejmoa0801197
[22] Petramala, L., Pignatelli, P., Carnevale, R., Zinnamosca, L., Marinelli, C., Settevendemmie, A., et al. (2014) Oxidative Stress in Patients Affected by Primary Aldosteronism. Journal of Hypertension, 32, 2022-2029.
https://doi.org/10.1097/hjh.0000000000000284
[23] Sun, Y., Ahokas, R., Bhattacharya, S., Gerling, I., Carbone, L. and Weber, K. (2006) Oxidative Stress in Aldosteronism. Cardiovascular Research, 71, 300-309.
https://doi.org/10.1016/j.cardiores.2006.03.007
[24] Manolagas, S.C. (2010) From Estrogen-Centric to Aging and Oxidative Stress: A Revised Perspective of the Pathogenesis of Osteoporosis. Endocrine Reviews, 31, 266-300.
https://doi.org/10.1210/er.2009-0024
[25] 樊长萍, 侯建明. 原发性醛固酮增多症与骨质疏松症的相关性[J]. 中华骨质疏松和骨矿盐疾病杂志, 2016, 9(2): 199-204.
[26] Giorgio, M., Trinei, M., Migliaccio, E. and Pelicci, P.G. (2007) Hydrogen Peroxide: A Metabolic By-Product or a Common Mediator of Ageing Signals? Nature Reviews Molecular Cell Biology, 8, 722-728.
https://doi.org/10.1038/nrm2240
[27] Jagger, C.J., Lean, J.M., Davies, J.T. and Chambers, T.J. (2005) Tumor Necrosis Factor-Α Mediates Osteopenia Caused by Depletion of Antioxidants. Endocrinology, 146, 113-118.
https://doi.org/10.1210/en.2004-1058
[28] Basu, S., Michaëlsson, K., Olofsson, H., Johansson, S. and Melhus, H. (2001) Association between Oxidative Stress and Bone Mineral Density. Biochemical and Biophysical Research Communications, 288, 275-279.
https://doi.org/10.1006/bbrc.2001.5747
[29] 中国高血压防治指南修订委员会. 中国高血压防治指南(2024年修订版) [J]. 中华高血压杂志, 2024, 32(7): 603-700.
[30] DeLange Hudec, S.M. and Camacho, P.M. (2013) Secondary Causes of Osteoporosis. Endocrine Practice, 19, 120-128.
https://doi.org/10.4158/ep12059.ra
[31] Zeng, Q., Li, N., Wang, Q., Feng, J., Sun, D., Zhang, Q., et al. (2019) The Prevalence of Osteoporosis in China, a Nationwide, Multicenter DXA Survey. Journal of Bone and Mineral Research, 34, 1789-1797.
https://doi.org/10.1002/jbmr.3757
[32] Ebeling, P.R., Nguyen, H.H., Aleksova, J., Vincent, A.J., Wong, P. and Milat, F. (2021) Secondary Osteoporosis. Endocrine Reviews, 43, 240-313.
https://doi.org/10.1210/endrev/bnab028
[33] Resnick, L.M. and Laragh, J.H. (1985) Calcium Metabolism and Parathyroid Function in Primary Aldosteronism. The American Journal of Medicine, 78, 385-390.
https://doi.org/10.1016/0002-9343(85)90328-6
[34] Pilz, S., Kienreich, K., Drechsler, C., Ritz, E., Fahrleitner-Pammer, A., Gaksch, M., et al. (2012) Hyperparathyroidism in Patients with Primary Aldosteronism: Cross-Sectional and Interventional Data from the GECOH Study. The Journal of Clinical Endocrinology & Metabolism, 97, E75-E79.
https://doi.org/10.1210/jc.2011-2183
[35] Tomaschitz, A., Ritz, E., Pieske, B., Rus-Machan, J., Kienreich, K., Verheyen, N., et al. (2014) Aldosterone and Parathyroid Hormone Interactions as Mediators of Metabolic and Cardiovascular Disease. Metabolism, 63, 20-31.
https://doi.org/10.1016/j.metabol.2013.08.016
[36] Olgaard, K., Lewin, E., Bro, S., et al. (1994) Enhancement of the Stimulatory Effect of Calcium on Aldosterone Secretion by Parathyroid Hormone. Mineral and Electrolyte Metabolism, 20, 309-314.
[37] Chen, T., Wang, Y., Hao, Z., Hu, Y. and Li, J. (2021) Parathyroid Hormone and Its Related Peptides in Bone Metabolism. Biochemical Pharmacology, 192, Article 114669.
https://doi.org/10.1016/j.bcp.2021.114669
[38] Beavan, S., Horner, A., Bord, S., Ireland, D. and Compston, J. (2001) Colocalization of Glucocorticoid and Mineralocorticoid Receptors in Human Bone. Journal of Bone and Mineral Research, 16, 1496-1504.
https://doi.org/10.1359/jbmr.2001.16.8.1496
[39] Li, Q., Gao, Z., Chen, Y. and Guan, M. (2017) The Role of Mitochondria in Osteogenic, Adipogenic and Chondrogenic Differentiation of Mesenchymal Stem Cells. Protein & Cell, 8, 439-445.
https://doi.org/10.1007/s13238-017-0385-7
[40] Renke, G., Starling-Soares, B., Baesso, T., Petronio, R., Aguiar, D. and Paes, R. (2023) Effects of Vitamin D on Cardiovascular Risk and Oxidative Stress. Nutrients, 15, Article 769.
https://doi.org/10.3390/nu15030769
[41] Tomaschitz, A., Pilz, S., Ritz, E., Grammer, T., Drechsler, C., Boehm, B.O., et al. (2010) Independent Association between 1,25-Dihydroxyvitamin D, 25-Hydroxyvitamin D and the Renin-Angiotensin System. Clinica Chimica Acta, 411, 1354-1360.
https://doi.org/10.1016/j.cca.2010.05.037
[42] Ismail, N.A., Kamaruddin, N.A., Azhar Shah, S. and Sukor, N. (2020) The Effect of Vitamin D Treatment on Clinical and Biochemical Outcomes of Primary Aldosteronism. Clinical Endocrinology, 92, 509-517.
https://doi.org/10.1111/cen.14177
[43] Tan, A., Shu, J., Huang, H., Shao, H. and Yang, J. (2023) The Correlation between the Serum LDL-C/Apo B Ratio and Lumbar Bone Mineral Density in Young Adults. BMC Musculoskeletal Disorders, 24, Article No. 213.
https://doi.org/10.1186/s12891-023-06325-w
[44] Wauquier, F., Leotoing, L., Coxam, V., Guicheux, J. and Wittrant, Y. (2009) Oxidative Stress in Bone Remodelling and Disease. Trends in Molecular Medicine, 15, 468-477.
https://doi.org/10.1016/j.molmed.2009.08.004
[45] Bai, X., Lu, D., Liu, A., Zhang, Z., Li, X., Zou, Z., et al. (2005) Reactive Oxygen Species Stimulates Receptor Activator of NF-κB Ligand Expression in Osteoblast. Journal of Biological Chemistry, 280, 17497-17506.
https://doi.org/10.1074/jbc.m409332200
[46] Sun, X., Xie, Z., Hu, B., Zhang, B., Ma, Y., Pan, X., et al. (2020) The Nrf2 Activator RTA-408 Attenuates Osteoclastogenesis by Inhibiting STING Dependent NF-κB Signaling. Redox Biology, 28, Article 101309.
https://doi.org/10.1016/j.redox.2019.101309
[47] Almeida, M. (2012) Aging Mechanisms in Bone. Bonekey Reports, 1, Article 102.
[48] Salhotra, A., Shah, H.N., Levi, B. and Longaker, M.T. (2020) Mechanisms of Bone Development and Repair. Nature Reviews Molecular Cell Biology, 21, 696-711.
https://doi.org/10.1038/s41580-020-00279-w

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