Lu HL, Yu F, Zhou HF, Hu P, Gan SL. Clinical significance of bone metabolic markers in osteoporosis-complicated type 2 diabetes mellitus and risk determinants: A retrospective study. World J Diabetes 2026; 17(8): 123389 [DOI: 10.4239/wjd.123389]
Corresponding Author of This Article
Sheng-Lian Gan, Chief Physician, Department of Endocrinology and Metabolism, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), No. 388 Renmin East Road, Changde 415003, Hunan Province, China. ganshenglian03@126.com
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Lu HL, Yu F, Zhou HF, Hu P, Gan SL. Clinical significance of bone metabolic markers in osteoporosis-complicated type 2 diabetes mellitus and risk determinants: A retrospective study. World J Diabetes 2026; 17(8): 123389 [DOI: 10.4239/wjd.123389]
Hui-Lin Lu, Fang Yu, Hai-Feng Zhou, Ping Hu, Sheng-Lian Gan, Department of Endocrinology and Metabolism, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde 415003, Hunan Province, China
Author contributions: Lu HL participated in the study design, and wrote and revised the manuscript; Lu HL and Gan SL conducted the design of the study and reviewed/edited the drafts, and are guarantors; Lu HL, Yu F, Zhou HF, and Hu P collected and analyzed the data. All authors contributed to the article and approved the submitted article.
AI contribution statement: The authors declare that no AI tools were used in the development or writing of this manuscript and take full responsibility for its integrity, accuracy, and originality.
Institutional review board statement: This study was approved by the Ethic Committee of The First People’s Hospital of Changde City. No. 2026-298-01.
Informed consent statement: Due to the retrospective and de-identified nature of this study, written informed consent was waived.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Corresponding author: Sheng-Lian Gan, Chief Physician, Department of Endocrinology and Metabolism, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), No. 388 Renmin East Road, Changde 415003, Hunan Province, China. ganshenglian03@126.com
Received: May 22, 2026 Revised: July 7, 2026 Accepted: July 31, 2026 Published online: August 15, 2026 Processing time: 74 Days and 16.7 Hours
Abstract
BACKGROUND
The prevalence of osteoporosis (OP) among individuals with type 2 diabetes mellitus (T2DM) has increased significantly, markedly elevating the risk of fragility fractures.
AIM
To investigate the clinical significance of bone metabolic markers (BMMs) in patients with T2DM with comorbid OP and identified associated risk determinants.
METHODS
A total of 215 patients with T2DM, with (OP group) or without (non-OP group) OP, who attended The First People’s Hospital of Changde City between May 2021 and July 2025 were enrolled. The levels of BMMs were compared between the OP and non-OP groups. Using dual-energy X-ray absorptiometry as the gold standard for OP diagnosis, the correlations between BMMs and OP comorbidity in T2DM were evaluated. The risk determinants were subsequently identified.
RESULTS
Significant intergroup differences were observed in age and glycosylated hemoglobin (P < 0.05), whereas alkaline phosphatase, high-density lipoprotein cholesterol, 1,25-dihydroxyvitamin D3, blood phosphorus, blood calcium, total cholesterol, triglyceride, or low-density lipoprotein cholesterol levels did not differ significantly (P > 0.05). Sex and smoking/drinking history were also comparable between groups (P > 0.05). Parathyroid hormone (PTH) and β-C-terminal telopeptide of type I collagen levels were significantly higher in T2DM patients with OP than in those without OP (P < 0.05). The two groups showed no significant differences in DM duration, comorbid diseases, peripheral neuropathy, and fasting blood glucose (P > 0.05). Age and PTH emerged as independent risk determinants for OP comorbidity in T2DM (P < 0.05).
CONCLUSION
Elevated PTH levels in T2DM patients with comorbid OP suggest that PTH provides valuable guidance for OP diagnosis in this population. Age and PTH were independently associated with OP in T2DM.
Core Tip: Type 2 diabetes (T2DM) is associated with impaired bone quality and an increased risk of fractures. However, assessment based solely on bone density has important limitations. In this retrospective study, patients with T2DM and osteoporosis (OP) exhibited higher serum parathyroid hormone (PTH) and β-C-terminal telopeptide of type I collagen levels than those without OP, suggesting altered bone metabolism. Notably, PTH concentrations in the OP group were more than double those in the non-OP group and were accompanied by evidence of reduced skeletal responsiveness to PTH. Multivariate analysis further identified older age and elevated PTH levels as independent risk factors for OP comorbidity. These findings suggest that routine assessment of PTH and β-C-terminal telopeptide of type I collagen, combined with clinical evaluation, may facilitate the earlier identification of high-risk T2DM patients, thereby enabling early intervention before the occurrence of fragility fractures.
Citation: Lu HL, Yu F, Zhou HF, Hu P, Gan SL. Clinical significance of bone metabolic markers in osteoporosis-complicated type 2 diabetes mellitus and risk determinants: A retrospective study. World J Diabetes 2026; 17(8): 123389
Under the combined influence of global population aging and substantial lifestyle changes, chronic non-communicable diseases have become a major public health challenge worldwide[1,2]. Among these conditions, type 2 diabetes mellitus (T2DM) is being diagnosed with increasing frequency. In China, rapid economic development and improvements in living standards have contributed to a dramatic increase in T2DM prevalence[3,4]. China currently has the highest number of T2DM cases worldwide, placing a considerable burden to the healthcare system[5]. Long-term hyperglycemia can induce several complex pathophysiological changes, leading to chronic complications, including diabetic nephropathy, retinopathy, cardiovascular diseases[6,7].
Accumulating evidence indicates that the skeletal system is also a major target organ affected by T2DM[8]. T2DM-affected individuals are more susceptible to osteoporosis (OP) than the general population[9]. OP is a systemic skeletal disorder characterized by reduced bone mass and deterioration of bone microstructure, resulting in increased bone fragility and fracture risk. This comorbidity further reduces patients’ quality of life, while substantially heightening the risk of fractures, which is a major contributor to disability and mortality among patients with diabetes[10]. Increasing evidence suggests that bone loss in T2DM is characterized by distinct pathophysiological characteristics. Although patients with T2DM often have normal or even increased bone mineral density (BMD), they remain at markedly increased risk of fracture because of impaired bone quality, a phenomenon known as the clinical paradox of diabetic bone disease. This discrepancy is largely attributed to the accumulation of advanced glycation end products within the bone matrix, increased bone marrow adipogenesis, and chronic low-grade inflammation. Collectively, these factors impair the material and structural properties of bone, thereby reducing bone strength and increasing fracture susceptibility. However, the pathogenesis of OP comorbidity in T2DM remains complex and incompletely clarified.
Current clinical strategies regarding early diagnosis and disease monitoring also have certain limitations. Bone metabolic markers (BMMs), which are bioactive substances produced during bone tissue metabolism, can sensitively reflect the dynamic balance between bone formation and bone absorption. Consequently, they provide important information for early diagnosis, disease assessment, and treatment monitoring in patients with T2DM and OP[11]. BMMs are primarily categorized into bone formation markers and bone resorption markers[12]. Bone formation markers include amino-terminal propeptide of type I procollagen (PINP) and osteocalcin, which reflect osteoblast activity, whereas bone resorption markers primarily include β-C-terminal cross-linked peptide of type I collagen (β-CTX), which reflects osteoclast activity[13]. In patients with T2DM, persistent hyperglycemia may suppress osteoblast function, resulting in reduced levels of bone formation markers, whereas changes in bone resorption markers are more complex and generally indicate a state of low bone turnover. Compared with static BMD measurements, BMMs provide dynamic information on bone turnover and therefore offer important supplementary information into diabetes-related abnormalities in bone metabolism. Additionally, identifying the risk determinants for OP in T2DM is of considerable importance for the early prevention and intervention. Accordingly, this study retrospectively analyzed clinical data from patients with T2DM, with and with OP, to evaluate the clinical significance of BMMs and identify associated risk determinants.
MATERIALS AND METHODS
Research participants
This retrospective study included 215 patients with T2DM who were treated at The First People’s Hospital of Changde City between May 2021 and July 2025. According to the presence or absence of OP, participants were assigned to the OP (n = 134) and non-OP (n = 81) groups. Inclusion criteria: (1) T2DM diagnosed according to World Health Organization criteria, including fasting blood glucose (FBG) ≥ 7 mmol/L, 2-hour blood glucose post-oral glucose tolerance testing ≥ 11.1 mmol/L, and/or glycosylated hemoglobin (HbA1c) ≥ 6.5%; in asymptomatic patients, diagnosis was confirmed by at least two abnormal measurements; (2) For the OP group, fulfillment of OP diagnostic criteria, defined as a T-score ≤ -2.5 at one or more lumbar spine or hip sites measured using dual-energy X-ray absorptiometry (DXA); and (3) Complete clinical data. Exclusion criteria: (1) Other DM subtypes (e.g., type 1 DM) or secondary OP (e.g., tumor- or drug-related); (2) Acute metabolic disorders within the previous month, including diabetic ketoacidosis or complicated infection; (3) Use within the previous three months of medications affecting bone metabolism, including bisphosphonates, active vitamin D, calcium supplements, calcitonin, or sex hormones; (4) Thyroid, parathyroid, or adrenal disorders; (5) Acute liver, kidney, heart, or brain diseases, or psychiatric disorders; and (6) Incomplete clinical data.
Patient data collection
(1) General information: Demographic and clinical data, including age, sex, DM course, body mass index, and comorbid chronic diseases (e.g., hypertension and coronary heart disease), were collected form electronic medical records. All participants underwent standardized DXA examinations using a Prodigy densitometer (GE Healthcare, United States) at the lumbar spine (L1-L4) and left hip (femoral neck and total hip); (2) Biochemical indices: The selected BMMs included β-CTX, parathyroid hormone (PTH), alkaline phosphatase (ALP), PINP, blood phosphorus (P), and blood calcium (Ca). On the morning of the second day after admission, 5 mL of fasting venous blood was collected from each participant. After standing at room temperature for 10-20 minutes, samples were centrifuged at 4000 rpm for 10 minutes to obtain serum. Samples were aliquoted into EP tubes, labeled, and stored at -80 °C until analysis. FBG, HbA1c, blood Ca, blood P, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and ALP were measured using an automated biochemical analyzer (Roche C-77). Enzyme-linked immunosorbent assay (ELISA) was used to quantify 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], PTH, β-CTX, and PINP contents. The 1,25(OH)2D3 ELISA kits were purchased from Elabscience (Wuhan, China), whereas the PTH, β-CTX, and PINP ELISA kits were purchased from Roche Diagnostics (Basel, Switzerland).
Statistical analysis
Data were analyzed using SPSS version 25.0. Normality and homogeneity of variance were assessed before statistical testing. Continuous variables are expressed as mean ± SD for normally distributed data or median (interquartile 1, interquartile 3) for non-normally distributed data. Intergroup comparisons were performed using the independent-sample t-test or Wilcoxon rank-sum test, as appropriate. Categorical variables are expressed as n (%) and were analyzed using the χ2 test. Influencing factors were identified using multivariate logistic analysis. A two-sided P < 0.05 was considered statistically significant.
RESULTS
General information
Among the 215 enrolled patients with T2DM, 134 had comorbid OP. The comparison of baseline characteristics showed no significant differences between the two groups in sex, body mass index, DM duration, smoking history, drinking history, hypertension, or peripheral neuropathy (P > 0.05). However, patients with OP were significantly older than those without OP (72.25 ± 9.08 years vs 68.84 ± 8.92 years, P < 0.05; Table 1).
Table 1 General information comparison, mean ± SD.
The two groups were comparable in FBG, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and 1,25(OH)2D3 levels (P > 0.05). However, HbA1c differed significantly, with higher levels observed in the OP group than in the non-OP group (9.67 ± 2.96 vs 5.32 ± 0.85, P < 0.05; Table 2).
Table 2 Intergroup comparison of blood glucose and lipid levels, mean ± SD.
No significant intergroup differences were observed in ALP, PINP, blood P, and blood Ca levels (P > 0.05). However, PTH and β-CTX levels differed significantly, with higher PTH [72.89 (45.17, 103.54)] and β-CTX [0.45 (0.23, 0.96)] levels in the OP group than in the non-OP group [PTH: 42.36 (26.25, 54.62); β-CTX: 0.37 (0.22, 0.54)] (P < 0.05; Table 3).
Table 3 Intergroup comparison of bone metabolic markers, mean ± SD/median (interquartile 1, interquartile 3).
Using the mean PTH and β-CTX values of the two groups as the exposure thresholds, the correlations between these BMMs and T2DM-OP comorbidity were analyzed. As presented in Table 4, both PTH [odds ratio (OR) = 12.60, 95% confidence interval (CI): 4.489-33.58] and β-CTX (OR = 8.595, 95%CI: 1.326-92.76) exposure levels were significantly associated with comorbid OP in patients with DM (P < 0.05). These findings indicate that elevated PTH and β-CTX levels are associated with an increased risk of OP in diabetic patients.
Table 4 Correlation between bone metabolic markers and type 2 diabetes mellitus complicated with osteoporosis.
Multivariate logistic regression analysis of OP in T2DM
With OP occurrence (yes = 1, no = 0) as the dependent variable, factors identified as significant in univariate analysis were entered into the multivariate model. Additionally, disease duration and drinking history were included as clinically relevant covariates. The analysis identified age (OR = 1.040, 95%CI: 1.005-1.077) and PTH (OR = 1.017, 95%CI: 1.007-1.027) as independent contributors to comorbid OP in T2DM (P < 0.05; Table 5).
Table 5 Multivariate regression analysis of risk determinants for osteoporosis in type 2 diabetes mellitus.
Comorbid OP in DM is largely attributed to long-term glucose metabolism disorders that decrease bone mass, alter bone microarchitecture, and impair bone strength[13]. Therefore, OP is frequently observed in diabetic patients. Given that early OP is often asymptomatic, many cases remain undetected until fractures occur after minor trauma, thereby increasing disability risk. Previous studies have also reported substantial alterations in BMM levels in patients with OP alone[14]. However, whether DM affects BMMs in patients with OP remains incompletely understood.
In this study, PTH and β-CTX levels were significantly elevated in patients with T2DM and OP compared with those without OP, whereas other BMMs, including ALP and 1,25(OH)2D3, differed insignificantly between groups. These findings suggest that PTH and β-CTX may serve as relevant OP-specific markers in patients with T2DM. PTH is a key regulator of Ca-P metabolism, and elevated levels promote osteoclast activity and bone resorption. In T2DM, chronic hyperglycemia may impair renal function and reduce 1,25(OH)2D3 synthesis, thereby stimulating PTH secretion[15]. The comparable 1,25(OH)2D3 levels but significantly higher PTH levels observed in the OP group may therefore reflect impaired renal vitamin D activation in diabetic patients[16]. Insulin resistance may also contribute, as insulin suppresses PTH release by inhibiting parathyroid cell proliferation; consequently, insulin resistance may promote increased PTH secretion[17]. Notably, PTH levels were significantly elevated despite unchanged serum calcium, phosphorus, and magnesium levels, a finding that appears inconsistent with classical Ca-P homeostasis. Traditionally, elevated PTH level is expected to increase serum Ca level and decrease P level. However, this study’s results may be explained by the diabetic bone microenvironment. Chronic hyperglycemia can induce skeletal resistance to PTH. Extensive accumulation of advanced glycation end products and chronic low-grade inflammation may impair PTH receptor function or downstream signaling in osteocytes, thereby reducing PTH-mediated calcium mobilization from bone[18]. Additionally, subclinical renal dysfunction, common in long-standing diabetes, may attenuate renal tubular responsiveness to PTH and reduce phosphate excretion[19]. Impaired renal hydroxylase activity may further inhibit the expected upregulation response. Therefore, the elevated PTH may reflect secondary hyperparathyroidism, which maintains serum calcium homeostasis at the expense of sustained bone demineralization[20]. β-CTX is a specific marker of bone resorption, and elevated levels indicate increased osteoclast activity and accelerated bone loss. The significantly higher β-CTX levels observed in OP-complicated T2DM patients suggest enhanced bone resorption in this population. This finding may be attributable to hyperglycemia-induced oxidative stress, which activates osteoclasts and promotes bone resorption[21]. Moreover, the chronic inflammatory state characteristic of diabetes may further stimulate osteoclast differentiation and activity, thus increasing bone resorption[22].
Multivariate analysis identified age and PTH as independent determinants of OP in T2DM. Age-related declines in bone mass and BMD are well-established contributors to OP risk. In T2DM, these effects may be related to factors such as reduced insulin secretion, increased insulin resistance, and vitamin D deficiency[23]. Compared with previous studies[24,25], this study’s findings further highlight the complex skeletal phenotype of T2DM, characterized by both accelerated bone resorption and systemic skeletal resistance to PTH. Elderly diabetic patients frequently suffering from multiple chronic diseases, including hypertension and coronary heart disease, and both the diseases and the corresponding therapeutic drugs may adversely affect bone metabolism, further increasing OP risk[26]. As a potent promoter of bone resorption, elevated PTH levels can directly lead to bone loss and OP development[27]. Importantly, PTH emerged as an independent predictor of OP in T2DM, suggesting that elevated PTH levels may be an important early warning signal for OP in diabetic patients. Therefore, regular BMD monitoring should be considered, particularly in elderly patients and those with elevated PTH levels, to facilitate early detection and timely intervention. In contrast, DM duration, comorbid diseases, peripheral neuropathy, and FBG were not identified as main correlates of OP in this cohort, possibly because of limited sample size and selection bias. Collectively, these findings support a novel, practical risk-stratification approach in which advanced age and elevated PTH levels may help identify high-risk patients before clinically evident fractures occur.
Several limitations should be acknowledged. First, the retrospective, single-center design may have introduced selection bias. Additionally, the cohort exhibited a sex imbalance, with a significantly higher proportion of female participants. Because of limitations in retrospective data collection, information regarding menopausal status, duration of postmenopause, and baseline serum estrogen levels was unavailable. Given the ample evidence that estrogen deficiency accelerates bone loss by upregulating pro-inflammatory cytokines and prolonging osteoclast survival, the inability to adjust for estrogen-related factors may have confounded some observed associations. Second, only selected BMMs were assessed, and other potentially relevant markers may have been overlooked. Third, lifestyle and nutritional factors that may influence bone metabolism and OP were not evaluated. Fourth, although patients receiving conventional anti-osteoporotic medications were excluded, the potential effects of other medications could not be fully eliminated. Many elderly patients with T2DM had cardiovascular comorbidities, and long-term use of thiazide diuretics, loop diuretics, or statins may have influenced bone metabolism. Although hypertension prevalence did not differ significantly between groups, medication-specific effects were not incorporated into the regression models. Fifth, the use of mean PTH and β-CTX values as cutoff points may limit the direct clinical relevance of these findings compared with established laboratory reference ranges. However, stratification using reference limits would have resulted in highly unbalanced sample sizes across groups, thereby weakening the statistical power of subgroup comparisons. Future larger-scale studies should evaluate clinically standardized cutoff values. Therefore, multi-center prospective studies with larger sample sizes are needed to elucidate the pathogenesis and risk factors of OP comorbidity in patients with T2DM.
CONCLUSION
In summary, age and PTH are independent determinants of OP in patients with T2DM. The novelty of our study is the identification of advanced age and elevated PTH as powerful, independent risk determinants, providing a dynamic, biochemically driven early warning cluster for OP risk assessment. Clinicians should attach adequate importance to the bone health assessment in patients with T2DM by promoting regular assessment of BMMs and BMD. Furthermore, monitoring bone turnover using these specific biochemical markers provides an opportunity for proactive intervention that complements the static information provided by DXA. This approach may be particularly valuable for older patients and those with elevated PTH levels, enabling prognostic amelioration through prompt implementation of intervention measures.
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