Serum Insulin-like Growth Factor-1 and Growth Hormone as Potential Diagnostic Biomarkers for Postmenopausal Osteoporosis Among Chinese Women

Summary

This study aimed to assess serum insulin-like growth factor-1(IGF-1) and growth hormone (GH) as complementary biomarkers for postmenopausal osteoporosis screening in Chinese postmenopausal women. This study identified that IGF-1 effectively identifies low bone mass while GH does not, supporting its use as a viable alternative to dual-energy X-ray absorptiometry (DEXA) scans.

Abstract

Postmenopausal osteoporosis (PMOP) is a significant concern among females. The gold standard for diagnosis involves dual-energy X-ray absorptiometry (DEXA) scans to measure bone mineral density (BMD). However, DEXA becomes impractical when the scanner is unavailable. This study included 345 postmenopausal women aged 45-70 years. All participants underwent DEXA scans and had IGF-1, and GH levels measured. Based on t-scores, subjects were categorized into three groups: control (n = 99), osteopenia (n = 153), and osteoporosis (n = 93). ANOVA assessed IGF-1 and GH across groups. Statistical analyses explored correlations between IGF-1, GH, and other parameters. The diagnostic utility of IGF-1 and GH was evaluated using receiver operating characteristic (ROC) curves. Significant intergroup differences were observed for IGF-1 and GH. IGF-1 exhibited negative correlations with age, menopause duration, procollagen 1 Intact N-Terminal pro peptide (PⅠNP), and parathyroid hormone (PTH), while positively correlating with body mass index (BMI), estradiol (E₂), GH, BMD, and t-scores. GH showed negative correlations with age, menopause duration, BMI, and PTH, and positive correlations with E₂, IGF-1, BMD, and t-scores. ROC analysis indicated high accuracy, specificity, and sensitivity of IGF-1 cutoff values in distinguishing the control group from those with bone mineral deficiency. However, these results were not replicated for GH. Serum IGF-1 measurement holds promise for screening postmenopausal patients. Subsequent DEXA scanning should be considered for severity grading of osteoporosis if indicated. In contrast, GH proved inadequate for diagnosing postmenopausal osteoporosis. In conclusion, serum IGF-1 levels offer a promising screening tool for low bone mass conditions in postmenopausal women, particularly in settings without access to DEXA scanners. Severity grading using DEXA could be facilitated with IGF-1 levels under the cutoff point. In contrast, GH lacks diagnostic potential for PMOP. This study advances the identification of novel serum markers for the diagnosis of clinical postmenopausal osteopenia/osteoporosis.

Introduction

Osteoporosis constitutes a major global health burden characterized by compromised skeletal integrity and elevated fracture risk, with postmenopausal women bearing the greatest disease burden¹. Postmenopausal osteoporosis (PMOP) accounts for over 40% of osteoporotic fractures worldwide, imposing substantial morbidity and socioeconomic costs². The accelerated bone loss following estrogen withdrawal leads to disproportionate trabecular thinning and disrupted microarchitecture - pathological hallmarks distinguishing PMOP from age-related bone loss³. Despite established diagnostic criteria using dual-energy X-ray absorptiometry (DEXA), approximately 60% of fragility fractures occur in individuals not meeting osteoporosis thresholds by bone mineral density (BMD) criteria alone, underscoring the imperative to identify complementary biomarkers reflecting bone quality deterioration⁴.

The estrogen deficiency state fundamentally alters bone remodeling dynamics through multiple pathways. Beyond its direct anti-resorptive effects, estrogen (E₂) modulates osteoanabolic signaling via crosstalk with endocrine networks⁵. Emerging evidence positions the GH/IGF-1 axis as a critical mediator of skeletal actions by E₂. Experimental models demonstrate E₂ stimulates IGF-1 mRNA expression in osteoprogenitor cells, while anti-IGF-1 antibodies abolish E₂-induced calvarial proliferation in dose-dependent fashion^6,7. Clinical observations reveal positive correlations between circulating IGF-1 levels and BMD in postmenopausal cohorts⁸, though current understanding remains fragmented regarding the temporal relationship between GH/IGF-1 alterations and PMOP progression.

While GH and IGF-1 are established regulators of skeletal growth and maturation, their diagnostic utility in PMOP remains underexplored. These pleiotropic hormones influence bone homeostasis through dual mechanisms: IGF-1 directly stimulates osteoblast differentiation and matrix mineralization, while GH enhances bone remodeling via both IGF-1-dependent and independent pathways^9,10. Crucially, the GH/IGF-1 axis exhibits sexual dimorphism and menopause-associated dysregulation - serum IGF-1 concentrations decline by 20-30% during menopausal transition independent of age¹¹. Paradoxically, existing diagnostic frameworks neglect this endocrine dimension, relying predominantly on structural BMD measurements rather than functional metabolic indicators. A critical unresolved question is whether and how this menopause-associated decline in the GH/IGF-1 axis contributes specifically to the deterioration of bone microarchitecture, and whether it holds diagnostic value independent of BMD in Chinese postmenopausal women.

This study investigates the clinical validity of serum IGF-1 and GH as complementary biomarkers for PMOP screening in Chinese postmenopausal women. The study hypothesizes that diminished GH/IGF-1 activity correlates with advanced bone deterioration independent of BMD values, potentially enhancing early risk stratification. By analyzing hormonal profiles in conjunction with DEXA parameters and fracture history, this work addresses critical knowledge gaps regarding: 1) the predictive capacity of GH/IGF-1 for microarchitectural deterioration, and 2) ethnic-specific biomarker thresholds in Asian populations where traditional BMD criteria may underestimate fracture risk. Study findings could inform novel diagnostic algorithms integrating endocrine and densitometric parameters to improve precision in the management of PMOP. The novelty of this translational study lies in its systematic evaluation of the GH/IGF-1 axis as a potential diagnostic adjunct in Chinese postmenopausal women. We aim to elucidate its association with bone microarchitectural deterioration and fracture risk, independent of BMD, and to establish ethnicity-specific thresholds for clinical risk stratification.

Protocol

The research adhered to the ethical guidelines outlined in the World Medical Association's Declaration of Helsinki (Code of Ethics) for human experimentation. Ethical clearance (Approval No. Nan Bu Zhan Qu-LL-2020-047) was secured from the ethics committee of the general hospital of the southern theater command of the Chinese People's Liberation Army, and informed consent was obtained from all participating patients and their families.

Research object
This prospective study spanned four years and was conducted at the inpatient department and physical examination department of the general hospital of the southern theater under the purview of the Chinese People's Liberation Army. It focused on a cohort of postmenopausal women aged 45 to 70 years, using a rigorous cross-sectional design. Exclusion criteria encompassed conditions that potentially impact bone metabolism, including: a) immune system disorders such as ankylosing spondylitis, systemic lupus erythematosus, and rheumatoid arthritis; b) bone tuberculosis; c) disorders affecting adrenal function, severe hepatic or renal insufficiency; d) endocrine disturbances including parathyroid dysfunction, thyroid disorders, and diabetes; e) historical habits of smoking and alcohol consumption; and f) recent use (within the preceding 12 months) of medications with potential effects on bone metabolism, such as glucocorticoids, calcium preparations, vitamin D supplements, bisphosphonates, diuretics, anticonvulsants, and fluoride agents.

Following the diagnostic criteria set forth by the world health organization, the study enrolled a total of 345 subjects, segregated into three distinct cohorts based on bone health status: the control group (characterized by normal BMD, t-score ≥-1.0 SD, n = 99), the osteopenia group (-2.5 SD < t-score < -1.0 SD, n = 153), and the osteoporosis group (t-score ≤-2.5 SD or concurrent fragility fracture, n = 93).

Clinical samples
Patients diagnosed with osteoporosis in the clinical diagnosis of the General Hospital of the Southern Theater Command of the Chinese People's Liberation Army from September 2020 to June 2025, who must meet the following standards: patients with osteopenia and osteoporosis in accordance with the WHO diagnostic criteria; Naturally menopausal, naturally menopausal for ≥1 year, and patients with postmenopausal diseases; Age 45 years ≤ age < 70; Voluntary participation in the investigation. Those meeting all the above conditions can be included in the experimental cases. Normal bone mass group: Naturally menopausal, naturally menopausal for ≥1 year, and those with normal physical examination indicators (including bone density and hematological tests).

For clinical patients who meet the above criteria, patients with the following other diseases must be excluded. The exclusion criteria are as follows: Parathyroid dysfunction, thyroid diseases, diabetes, adrenal diseases, and severe liver and kidney dysfunction, history of malignant tumors, immune system diseases such as ankylosing spondylitis, systemic lupus erythematosus, and rheumatoid arthritis, premature ovarian failure syndrome and oophorectomy, spinal tuberculosis, joint tuberculosis, suppurative arthritis, osteolysis, etc. Patients who have taken drugs that affect bone metabolism (within the past 12 months), such as glucocorticoids, calcium drugs, vitamin D, bisphosphonate preparations, diuretics, anticonvulsants, fluoride, etc., can also be excluded. The presence of any one of the above conditions can lead to exclusion.

Data collection
Participant demographics, including age, years since menopause, height, and weight, were documented. The body mass index (BMI) was calculated using the formula

BMI = Weight (kg) / Height (m²).

Serum sample collection
Following an overnight fast, blood samples were obtained from all participants. Subsequently, serum was promptly separated by centrifugation at approximately 850 × g for 5 min, aliquoted, and stored at -80 °C for subsequent analysis.

Sample size calculation
A priori power analysis was performed using G*Power. Based on preliminary data showing mean serum IGF-1 levels of 89.46 ± 18.89, 72.52 ± 16.32, and 60.23 ± 15.63 ng/mL for the normal bone mass, osteopenia, and osteoporosis groups, respectively, the calculated effect size (Cohen's f) was 0.86. With α = 0.05 and power = 0.80 for a one-way ANOVA, a minimum of 9 participants per group (27 total) was required. To ensure robustness for our cross-sectional design-accounting for multivariable adjustment, subgroup analyses, and potential data issues-we targeted a larger sample. The final cohort included 345 postmenopausal women (99 with normal bone mass, 153 with osteopenia, 93 with osteoporosis), well exceeding the calculated requirement.

Clinical data assessment
Bone mineral density measurement
Bone mineral density (BMD) was assessed using a DEXA scan at the lumbar spine (L_1-4), left femoral neck, and upper end of the femoral neck. Scans of the femoral neck and upper end were conducted with flexed knees, while the supine position was maintained during lumbar spine (L_1-4) scans. Trained professionals from the nuclear medicine department of the general hospital of the Southern Theater Command of the Chinese People's Liberation Army administered all tests. Prior to each measurement, a quality control prosthesis scan was performed, ensuring rigorous standards were met before proceeding with participant scans. The coefficient of variation was recorded at 0.40%. BMD values were expressed in g/cm².

Serum indicator measurement
Serum indicator measurements were conducted at the laboratory department of the general hospital of the Southern Theater Command of the Chinese People's Liberation Army. The panel of assessed indicators primarily comprised GH, IGF-1, 25-hydroxyvitamin D [25(OH)D], β-collagen degradation products (β-CTX), total collagen type I amino-terminal propeptide (PⅠNP), parathyroid hormone (PTH), N-terminal osteocalcin (BGP), calcium (Ca), and estradiol (E₂). The operations are carried out strictly in accordance with the kit instructions, and the process uses automated equipment from the laboratory department (GE). Timely recording of the assay outcomes following their analysis was ensured.

The experimental methodologies employed for the respective indicators were as follows: GH quantification was performed through luminol electrochemiluminescence immunoassay; IGF-1 levels were determined using enzyme-linked immunosorbent assay and chemiluminescence techniques. E₂ levels were measured using a commercial immunoassay kit. Serum calcium measurements were performed using a colorimetric method on an automated biochemistry analyzer. The analysis of 25(OH)D, β-CTX, PⅠNP, PTH, and BGP was measured using electrochemiluminescence immunoassay (ECLIA) with commercial assay kits.

Instruments and reagents
The key commercial instruments, assay kits, and reagents used in this study are listed comprehensively in the Table of Materials.

Statistical analysis
Data analysis employed the SPSS 20.0 statistical software package and GraphPad Prism7. Results were presented as mean ± SE. Univariate analysis of variance (ANOVA), Pearson's correlation analysis, partial correlation analysis, and ROC analysis were appropriately applied. A significance level of P < 0.05 was adopted.

Results

Baseline characteristics and serum GH/IGF-I levels comparison
Statistical analysis revealed that bone mass changes in patients with osteoporosis were significantly positively correlated with years since menopause, BMI, and serum E2 levels (P < 0.05), and significantly negatively correlated with serum 25(OH)D, PTH, β-CTX, and PINP levels (P < 0.05). Notably, the serum GH and IGF-1 levels in the osteoporosis group were significantly lower than those in the control group and the osteopenia group (...

Discussion

Bone mineral density (BMD) serves as a pivotal determinant of bone strength, complemented by clinical features in osteoporosis diagnosis¹². However, BMD's applicability as an epidemiological screening tool is impeded by cost and accessibility concerns⁴. While bone turnover markers guide therapeutic response assessment, their diagnostic limitations persist¹³. Addressing the role of IGF-1 and GH in postmenopausal osteoporosis, this study explored their...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
25(OH)D3 Kit	Roche Diagnostics	3017970190	For 25-hydroxyvitamin D [25(OH)D] detection
β-CTX Kit	Roche Diagnostics	3017938190	For β-collagen degradation products (β-CTX) detection
BGP Kit	Roche Diagnostics	3017912190	For N-terminal osteocalcin (BGP) detection
Centrifuge	Labortechnik (Hermle)	Z 216 MK	Experimental conditions: 4 °C, 18620 g, centrifugation for 20 min
Dual-energy X-ray absorptiometry (DEXA) scans	GE Healthcar	Lunar Prodigy	For bone mineral density (BMD) and body composition measurement.
E2 Kit	Roche Diagnostics	3017888190	For estradiol (E2) detection
GH Kit	Roche Diagnostics	3017954190	For growth hormone (GH) detection
IGF-1 Kit	Roche Diagnostics	3017962190	For insulin-like growth factor-1 (IGF-1) detection
PINP Kit	Roche Diagnostics	3017946190	For total collagen type I amino-terminal propeptide (PINP) detection
PTH Kit	Roche Diagnostics	3017920190	For parathyroid hormone (PTH) detection
Roche Cobas c Series Biochemical Analyzer	Roche Diagnostics	cobas c 702	Instrument for calcium biochemical detection
Roche Cobas e Series Electrochemiluminescence Analyzer	Roche Diagnostics	cobas e 602	Instrument for immunoassay detection