Diagnostic Value of Plasma Serotonin Precursors and Metabolites in Postmenopausal Osteoporosis

Diagnostic Value of Plasma Serotonin Precursors and Metabolites in Postmenopausal Osteoporosis

September 22, 2025 Author Summary 0

Introduction

Postmenopausal osteoporosis (PMOP) is a metabolic bone disorder marked by reduced bone strength and higher fracture risk. Estrogen deficiency is the primary driver, with aging, genetic susceptibility, and the immune microenvironment contributing. Fragility fractures—especially hip fractures—are common and severe, causing pain and economic burden. As populations age, PMOP is becoming more frequent, and there is a need for new therapeutic targets and better tools to identify risk. Bone mineral density (BMD) is a key indicator for osteopenia and osteoporosis. Biochemical bone turnover markers (BTMs) such as β‑C‑terminal telopeptide of type I collagen (β‑CTX; resorption) and procollagen type I N‑propeptide (PINP; formation) often rise in PMOP and in osteoporotic fractures. In this context, BMD is not directly associated with body mass index, age, or serum calcium and phosphorus. The serotonin (5‑HT) pathway has also attracted attention: peripheral 5‑HT may inhibit osteogenesis and promote bone resorption. Its immediate precursor, 5‑hydroxytryptophan (5‑HTP), and its main metabolite, 5‑hydroxyindoleacetic acid (5‑HIAA), can be measured in blood.

What was done

A retrospective, single‑center cohort of 287 postmenopausal women was classified by DXA‑based BMD into normal (n=79), osteopenia (n=93), and osteoporosis (OP; n=115). Collected data included age, BMI, years since menopause (YSM), serum calcium and phosphorus, and BMD at the lumbar spine and femoral neck. Blood assays measured PINP and β‑CTX (serum) and tryptophan (Trp), 5‑HTP, 5‑HT, and 5‑HIAA (plasma). Analyses covered group comparisons, correlations, multivariable logistic regression, ROC curves, and Kaplan–Meier plots. At baseline, age, BMI, calcium, and phosphorus did not differ among groups; the OP group showed higher YSM, higher BTMs, and lower BMD. (See Table 1, p.3.)

Key findings

1) Serotonin‑pathway markers rise with bone loss
Plasma Trp, 5‑HTP, 5‑HT, and 5‑HIAA were higher in OP than in osteopenia and normal groups, with a stepwise increase across categories (Figure 1, p.4).

2) Links to bone status
All four analytes correlated negatively with lumbar‑spine and femoral‑neck BMD and positively with β‑CTX and PINP. For example, 5‑HT showed r=−0.533 with lumbar‑spine BMD and r=0.766 with PINP (Table 2, p.4).

3) Independent associations
In multivariable logistic regression, YSM, β‑CTX, PINP, 5‑HTP, 5‑HT, and 5‑HIAA were independent risk factors for PMOP; higher lumbar‑spine and femoral‑neck BMD were protective (Table 3, p.4). Trp was not significant.

4) Diagnostic performance
Receiver‑operating characteristic (ROC) analyses (OP vs. non‑OP) showed:

  • 5‑HTP: AUC 0.800 (cut‑off 76.02 ng/mL; sensitivity 89.57%; specificity 55.81%),

  • 5‑HT: AUC 0.864 (cut‑off 73.03 ng/mL; 86.09%; 72.67%),

  • 5‑HIAA: AUC 0.827 (cut‑off 26.68 ng/mL; 90.43%; 63.37%).
    A combined panel of 5‑HTP, 5‑HT, and 5‑HIAA reached AUC 0.903 with 66.96% sensitivity and 94.19% specificity (Table 4; Figure 2, p.5).

5) Relationship with years since menopause
Women with YSM ≥12 years had higher 5‑HTP, 5‑HT, and 5‑HIAA than those with YSM <12 years (Table 5, p.6). Using the ROC cut‑offs above, Kaplan–Meier curves shifted left in the high‑marker groups, with hazard ratios 2.898 (5‑HTP), 3.349 (5‑HT), and 3.195 (5‑HIAA) (Figure 3, p.6).

What’s novel

This work reports significant alterations in 5‑HT precursors and metabolites in PMOP and identifies 5‑HTP, 5‑HT, and 5‑HIAA as independent risk factors that align with bone turnover and BMD. A combined plasma panel improved diagnostic discrimination compared with single markers.

Practical implications

  • Diagnostic support: Plasma 5‑HTP, 5‑HT, and 5‑HIAA can help distinguish osteoporosis from non‑osteoporosis in postmenopausal women. A combined panel provided higher overall accuracy in this cohort.

  • Risk context: Higher levels were observed in women with longer menopause duration and were associated with increased PMOP risk on time‑to‑event plots.

  • Potential applications: Findings suggest clinical potential for these plasma biomarkers in the diagnosis and treatment of PMOP and point to targets related to delaying PMOP onset, especially in relation to YSM.

Limitations and next steps

This was a retrospective, single‑center study with a relatively small sample. The impact of menopause duration could not be fully investigated, and cellular and molecular mechanisms of 5‑HT pathway components were not explored. Future plans include larger, multi‑center cohorts and mechanistic studies.

Where to look in the paper

  • Background on PMOP and serotonin: pp. 1–2.

  • Baseline characteristics: Table 1, p.3.

  • Group differences & correlations: Figure 1 and Table 2, p.4.

  • Multivariable model: Table 3, p.4.

  • Diagnostic metrics: Table 4 and Figure 2, p.5.

  • YSM analyses & risk curves: Table 5 and Figure 3, p.6.

This author summary is based on a study published in Biomolecules & Biomedicine  journal.

 

The translation of the preceding English text in Chinese:

 

引言

绝经后骨质疏松（postmenopausal osteoporosis，PMOP）是一种代谢性骨病，其特征为骨强度下降和骨折风险增加。雌激素缺乏是主要驱动因素，同时衰老、遗传易感性以及免疫微环境也有重要作用。脆性骨折——尤其是髋部骨折——常见且严重，导致疼痛和经济负担。随着人口老龄化，PMOP 发病率逐渐升高，亟需新的治疗靶点和更好的风险识别工具。骨密度（bone mineral density，BMD）是骨量减少和骨质疏松的重要指标。骨转换生化标志物（bone turnover markers，BTMs），如 I 型胶原 β-C 末端肽（β-CTX；骨吸收指标）和 I 型前胶原氨基端前肽（PINP；骨形成指标），在 PMOP 和骨质疏松性骨折中常升高。在这种情况下，BMD 与体质指数（BMI）、年龄以及血清钙磷并无直接相关。血清素（5-HT）通路也受到关注：外周 5-HT 可能抑制成骨并促进骨吸收。其直接前体 5-羟色氨酸（5-HTP）及主要代谢产物 5-羟吲哚乙酸（5-HIAA）均可在血液中检测。

研究方法

一项回顾性单中心队列研究纳入了 287 名绝经后女性，根据 DXA 测得的 BMD 分为正常组（n=79）、骨量减少组（n=93）和骨质疏松组（OP，n=115）。收集的数据包括年龄、BMI、绝经年限（YSM）、血清钙磷、腰椎和股骨颈 BMD。血液检测包括 PINP 和 β-CTX（血清）以及色氨酸（Trp）、5-HTP、5-HT 和 5-HIAA（血浆）。分析方法包括组间比较、相关性分析、多变量逻辑回归、ROC 曲线和 Kaplan–Meier 曲线。基线时，年龄、BMI、血清钙磷在组间无差异；OP 组 YSM 较长、BTMs 较高、BMD 较低（见表 1，第 3 页）。

主要发现

1）血清素通路标志物随骨量丢失而升高
OP 组血浆 Trp、5-HTP、5-HT 和 5-HIAA 均高于骨量减少组和正常组，并随组别呈阶梯式升高（图 1，第 4 页）。

2）与骨状态的关系
四种分析物均与腰椎和股骨颈 BMD 呈负相关，与 β-CTX 和 PINP 呈正相关。例如，5-HT 与腰椎 BMD 的相关系数 r=−0.533，与 PINP 的相关系数 r=0.766（表 2，第 4 页）。

3）独立关联因素
在多变量逻辑回归中，YSM、β-CTX、PINP、5-HTP、5-HT 和 5-HIAA 为 PMOP 的独立危险因素；腰椎和股骨颈 BMD 较高则为保护因素（表 3，第 4 页）。Trp 无显著意义。

4）诊断效能
ROC 分析（OP vs 非 OP）显示：

  • 5-HTP：AUC 0.800（截断值 76.02 ng/mL；敏感性 89.57%；特异性 55.81%），

  • 5-HT：AUC 0.864（截断值 73.03 ng/mL；敏感性 86.09%；特异性 72.67%），

  • 5-HIAA：AUC 0.827（截断值 26.68 ng/mL；敏感性 90.43%；特异性 63.37%）。

三者联合检测的 AUC 为 0.903，敏感性 66.96%，特异性 94.19%（表 4，图 2，第 5 页）。

5）与绝经年限的关系
YSM ≥12 年女性的 5-HTP、5-HT 和 5-HIAA 水平高于 YSM <12 年者（表 5，第 6 页）。根据上述 ROC 截断值，Kaplan–Meier 曲线在高标志物组明显左移，风险比分别为：5-HTP 2.898，5-HT 3.349，5-HIAA 3.195（图 3，第 6 页）。

创新点

本研究首次报道 PMOP 中 5-HT 前体和代谢产物的显著变化，明确了 5-HTP、5-HT 和 5-HIAA 是与骨转换和 BMD 一致的独立危险因素。血浆联合检测面板在诊断区分上优于单一指标。

实际意义

  • 诊断支持：血浆 5-HTP、5-HT 和 5-HIAA 可辅助区分绝经后女性的骨质疏松与非骨质疏松。三者联合检测在本队列中表现出更高的总体准确性。

  • 风险背景：水平较高者多见于绝经年限较长的女性，并在随访中与 PMOP 风险增加相关。

  • 潜在应用：提示这些血浆生物标志物在 PMOP 诊断与治疗中具有临床潜力，并为延缓 PMOP 的发生提供靶点，尤其与绝经年限相关。

局限性与后续研究

本研究为单中心回顾性研究，样本量相对较小。绝经年限的影响未能充分探讨，5-HT 通路成分的细胞和分子机制尚未研究。后续计划包括更大规模的多中心队列研究及机制研究。

论文查阅指引

  • PMOP 与血清素背景：第 1–2 页。

  • 基线特征：表 1，第 3 页。

  • 组间差异与相关性：图 1 和表 2，第 4 页。

  • 多变量模型：表 3，第 4 页。

  • 诊断指标：表 4 和图 2，第 5 页。

  • YSM 分析与风险曲线：表 5 和图 3，第 6 页。

本作者摘要基于 Biomolecules & Biomedicine 期刊发表的研究。

Reference:

Peiying Li, Shuyi Wu, Wenshan Chen, Minjuan Liu

Plasma serotonin precursors and metabolites as diagnostic and therapeutic biomarkers for osteoporosis in postmenopausal women.

Biomol Biomed [Internet]. 2025 Jun. 11 [cited 2025 Sep. 22];25(11):2519–2527.

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11513

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