
==== Front
BMC Endocr Disord
BMC Endocr Disord
BMC Endocrine Disorders
1472-6823
BioMed Central London

39237970
1698
10.1186/s12902-024-01698-y
Research
Relationship between bone turnover markers and renal disease in elderly patients with type 2 diabetes: a cross-sectional study
Wei Shuwu 12
Pan Xinyu 1
Wei Junping weijunping@126.com

1
1 grid.410318.f 0000 0004 0632 3409 Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
2 https://ror.org/05damtm70 grid.24695.3c 0000 0001 1431 9176 Beijing University of Chinese Medicine, Beijing, China
6 9 2024
6 9 2024
2024
24 1793 2 2024
21 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Objective

The prevalence of type 2 diabetes mellitus (T2DM) and bone metabolism disorders increase with age. Diabetic kidney disease (DKD) is one of the most serious microvascular complications of T2DM, and bone metabolism disorders are closely linked to the occurrence of DKD. The relationship between bone turnover markers(BTMs) and the kidney disease in elderly patients with T2DM remains unclear. Therefore, this study aims to investigate the association between common BTMs and DKD in a large sample of elderly patients. The goal is to provide a basis for early identification of high-risk individuals for DKD among elderly T2DM patients from a bone metabolism perspective.

Methods

In this cross-sectional study, BTMs were collected from a cohort of 2,051 hospitalized Chinese patients. The relationships between 25-hydroxyvitamin D (25-OH-D), β-CrossLaps (β-CTX), osteocalcin (OSTEOC), intact parathyroid hormone (iPTH), and total type I collagen N-terminal propeptide (TP1NP), and DKD, as well as urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were analyzed using regression analysis and restrictive cubic spline (RCS) curves.

Results

Higher 25-OH-D levels were independently linked to a lower incidence of DKD and decreased UACR. The RCS curves showed a linear association of 25-OH-D and DKD, approaching the L-shape. β-CTX was independently and positively correlated with UACR. There is an independent positive correlation between OSTEOC and UACR and a negative correlation with eGFR. iPTH is independently and positively correlated with DKD incidence and UACR, and negatively correlated with eGFR. Additionally, the RCS curves showed a non-linear association of OSTEOC and iPTH and DKD, approaching the J-shape, and the point of inflection is 10.875 ng/L and 34.15 pg/mL respectively. There is an independent positive correlation between TP1NP and UACR incidence, and a negative correlation with eGFR. Risk estimates significantly increase with higher TP1NP levels in the RCS model.

Conclusion

BTMs are closely associated with kidney disease in elderly patients with T2DM. These discoveries potentially assist clinicians in establishing more preventive measures and targeted treatment strategies for elderly patients with T2DM.

Keywords

Diabetic kidney disease
Bone turnover markers
25-hydroxyvitamin D
β-CrossLaps
Osteocalcin
Intact parathyroid hormone
Total type I collagen N-terminal propeptide
Type 2 diabetes mellitus
Elderly
Beijing Municipal Natural Science Foundation7242255 Traditional Chinese Medicine Evidence-Based Capacity Building Project60104 Technology Innovation Project of Major Key Projects at the China Academy of Chinese Medical SciencesC12021A01617 High Level Chinese Medical Hospital Promotion ProjectHLCMHPP2023084 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

As the population ages, the proportion of elderly individuals (aged ≥ 60) in China was approximately 17.3% in 2017. By 2050, this percentage is projected to exceed 30%, with more than 20% of the elderly population expected to suffer from diabetes, of which over 95% will be type 2 diabetes mellitus (T2DM) [1]. Chronic hyperglycemia has been observed to reduce osteoblast numbers, impair bone formation, slow bone mineralization, and enhance osteoclast activity, resulting in an imbalance in bone metabolism, particularly in elderly patients [2, 3]. Diabetic kidney disease (DKD) is a prevalent microvascular complication of diabetes mellitus [4]. The presence of DKD significantly complicates the management of diabetes in elderly patients and poses a serious threat to their health and mortality worldwide. Research indicates that bone metabolism disorders may be a risk factor for the development of kidney complications in T2DM [5]. Identifying potential bone metabolism markers related to incident DKD is essential for screening elderly populations with diabetes mellitus who are at high risk for DKD. It also aids in researching the mechanisms of DKD onset and benefits early intervention and correction of risk factors.

Osteoblasts form new bone, while osteoclasts resorb old bone to maintain bone structure integrity. The metabolites produced during this process are known as bone turnover markers (BTMs). Commonly assessed BTMs include 25-hydroxyvitamin D (25-OH-D), β-CrossLaps (β-CTX), osteocalcin (OSTEOC), intact parathyroid hormone (iPTH), and total type I collagen N-terminal propeptide (TP1NP). Previous studies have suggested that these bone metabolic indicators may be involved in the crosstalk between bone, islet, and adipose tissues [6–9] and may be associated with early renal damage in DKD [10, 11]. However, these findings remain controversial and inconclusive. Only four studies have reported the association between BTMs and the risk of DKD or eGFR and UACR [12–15]. Two studies showed that OSTEOC, TP1NP, and β-CTX levels negatively correlated with eGFR in diabetes patients (one did not differentiate between type 1 and type 2 disease) [13, 14]. Another study found that UACR was positively associated with OSTEOC, TP1NP, β-CTX and 25-OH-D in T2DM patients [15]. In contrast, one study indicated that serum concentrations of BTMs were not associated with the risks of DKD [12]. Notably, most of these studies are limited by small sample sizes and did not clarify the non-linear relationship between BTMs and DKD. Additionally, there are no studies investigating the relationship between BTMs and DKD in the elderly T2DM population currently.

The relationship between BTMs and the occurrence of kidney disease in elderly patients with T2DM remains unclear. Therefore, this study aims to investigate the association between these five common BTMs and kidney disease in a large sample of elderly patients with T2DM. The goal is to provide a basis for early identification of high-risk individuals for DKD among elderly T2DM patients from a bone metabolism perspective. This approach is beneficial for correcting bone metabolism disorders and, concurrently, slowing the progression of DKD, ultimately contributing to an improved quality of life for elderly individuals with diabetes.

Materials and methods

Study design and participants

A total of 2,987 individuals aged ≥ 60 years with T2DM admitted to the Guang’anmen Hospital from February 2017 to February 2022 were enrolled in this study. The flow chart of the study is shown in Fig. 1. T2DM was diagnosed according to the criteria established by the American Diabetes Association [16]. The exclusion criteria were as follows: (1)lacking BTMs results or medical history, (2)experiencing acute complications of diabetes, bone fractures, acute inflammation or infections, autoimmune diseases, or malignancies, (3)receiving steroid or thyroid hormone treatment, and (4)receiving hemodialysis or peritoneal dialysis treatment. Ultimately, 2,051 participants were included in the analysis. This retrospective study obtained approval from the Medical Ethics Committee of Guang’anmen Hospital, China Academy of Chinese Medical Sciences (2023-187-KY), and strictly adhered to the principles outlined in the Declaration of Helsinki.

Fig. 1 Flow chart of the study

Measurements

Information on sex, age, height, weight, duration of diabetes, systolic blood pressure(SBP), diastolic blood pressure(DBP), and medication use was extracted from electronic medical records using standardized questionnaires by the same trained personnel. The medications included anti-osteoporosis drugs (calcium, vitamin D, bisphosphonate, or other drugs), anti-diabetic agents (pioglitazone, SGLT-2 inhibitors, and GLP-1 analogues), and ACEI/ARB. Body mass index (BMI) was calculated as body weight (kg) divided by the square of height (m2). Levels of 25-OH-D, β-CTX, OSTEOC, iPTH, and TP1NP were assayed using electrochemiluminescence assays. Fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), alanine transaminase (ALT), aspartate aminotransferase(AST), alkaline phosphatase (ALP), albumin (ALB), serum calcium, serum phosphorus, serum uric acid, serum creatinine, and hemoglobin were measured using an automated analyzer with standard methods. Urine albumin-to-creatinine ratio (UACR) was calculated from urine albumin and urine creatinine levels. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation designed for individuals of Asian origin. DKD was defined as persistent proteinuria and/or progressive renal insufficiency. In patients without other chronic kidney diseases, those with UACR ≥ 30 mg/g and/or eGFR < 60 mL/min per 1.73 m2 twice after three tests in 3 ~ 6 months were considered to have developed DKD, in accordance with the criteria set by the American Diabetes Association [17].

Statistical analysis

The current analysis was conducted using IBM SPSS Statistics (v 26), R (v 4.4.1), and Zstats (v1.0). Statistical significance was established at a two-sided P-value < 0.05. Continuous variables were presented as means ± standard deviation (SD) or medians ± interquartile range (IQR), while categorical variables were expressed as percentages (%). For the comparison of continuous variables, the nonparametric rank-sum test or Student’s t-test was used, and the Chi-square test was applied for categorical variables. BTMs levels were categorized into quartiles. Regression analysis was performed to identify associations between BTMs and DKD, UACR, and eGFR. The first quartile of BTMs was used as a reference in logistic regression. The associations were evaluated by a crude model 0 with no adjustments, a multivariable model 1 adjusted for age, sex, BMI, and duration of diabetes, and a multivariable model 2 adjusted for age, sex, BMI, duration of diabetes, SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, Hemoglobin, Serum calcium, Serum phosphorus, Serum uric acid and medications.and age and family history of diabetes. Data were summarized as odds ratios or beta coefficients with 95% confidence intervals (CIs). The association of BTMs with the incidence of DKD was further evaluated on a continuous scale with restrictive cubic spline (RCS) curves.

Results

The general and sociodemographic characteristics of the study participants are shown in Table 1. The final analysis included 2,051 diabetic participants. Among them, 1,267 participants (61.7%) were diagnosed without DKD (Non-DKD), while 784 participants (38.2%) were diagnosed with DKD. Compared to Non-DKD participants, those with DKD exhibited significantly higher values for age, the number of men, BMI, duration of diabetes, iPTH, FPG, HbA1c, TG, ALP, serum creatinine, serum uric acid, UACR, HbA1c, number of anti-diabetic agents and the number of ACEI/ARB (all P < 0.05). No differences were observed in DBP, β-CTX, TP1NP, TC, LDL, AST, serum phosphorus, or number of anti-osteoporosis drugs between the two groups. However, SBP, 25-OH-D, OSTEOC, HDL, ALT, ALB, hemoglobin, serum calcium, and eGFR were significantly lower in DKD patients compared to those without DKD (all P < 0.05).

Table 1 General characteristics of the participants by DKD

Characteristics	Non-DKD	DKD	P value	
Age, years	66 ± 6	67 ± 8	<0.001	
Men, %	532(42%)	377(48.1%)	0.007	
BMI, kg/m2	25.31 ± 4.10	26.70 ± 5.41	<0.001	
Duration of diabetes, years	16 ± 12	18 ± 15	<0.001	
SBP, mmHg	138 ± 19	137 ± 20	0.001	
DBP, mmHg	78 ± 15	78 ± 15	0.924	
25-OH-D, nmol/L	17.31 ± 10.46	15.40 ± 9.54	<0.001	
β-CTX, ng/mL	0.35 ± 0.24	0.336 ± 0.25	0.077	
OSTEOC, ng/L	11.26 ± 5.45	10.48 ± 5.40	0.017	
iPTH, pg/ml	34.00 ± 17.20	34.30 ± 22.75	0.013	
TP1NP, µg/L	39.25 ± 21.26	38.64 ± 24.65	0.808	
FPG, mmol/L	11.12 ± 6.99	11.125 ± 7.49	<0.001	
HbA1c, %	8.00 ± 2.20	8.50 ± 2.90	<0.001	
TC, mmol/L	4.33 ± 1.55	4.53 ± 1.81	0.330	
TG, mmol/L	1.39 ± 0.94	1.54 ± 0.87	<0.001	
HDL, mmol/L	1.16 ± 0.34	1.12 ± 0.30	<0.001	
LDL, mmol/L	2.69 ± 1.16	2.93 ± 1.32	0.183	
ALT, U/L	18.10 ± 11.40	17.75 ± 11.32	0.002	
AST, U/L	19.30 ± 8.13	18.85 ± 7.80	0.344	
ALP, U/L	80.0 ± 33.00	83.50 ± 34.75	0.030	
ALB, g/L	43.20 ± 3.72	41.15 ± 4.50	<0.001	
Hemoglobin, g/L	138 ± 19	131 ± 21	<0.001	
Serum calcium, mmol/L	2.395 ± 0.12	2.38 ± 0.14	<0.001	
Serum phosphorus, mmol/L	1.15 ± 0.21	1.18 ± 0.26	0.636	
Serum creatinine, umol/L	62 ± 21	77.95 ± 40.75	<0.001	
Serum uric acid, umol/L	310 ± 114.5	341.5 ± 131.75	<0.001	
UACR, mg/g	9.16 ± 8.74	94.84 ± 303.53	<0.001	
eGFR, mL/min per 1.73 m2	95.64 ± 17.80	80.73 ± 38.38	<0.001	
Medications				
   ACEI/ARB, %	1061(84.2%)	718(91.6%)	<0.001	
   Anti-osteoporosis drugs, %	820(64.7%)	487(62.1%)	0.234	
   Anti-diabetic agents, %	350(27.6%)	321(40.9%)	<0.001	
Diabetic retinopathy	177(14.0%)	520(66.3%)	<0.001	
The data are presented as means ± SD for continuous variables with a normal distribution, medians ± IQR for continuous variables with a skewed distribution, and as numerical proportions for categorical variables. For the comparison of continuous variables, the nonparametric rank-sum test or Student’s t-test was used, and the Chi-square test was applied for categorical variables

DKD Diabetic kidney disease, BMI Body mass index, SBP Systolic blood pressure, DBP Diastolic blood pressure, 25-OH-D 25-hydroxyvitamin D, β-CTX β-CrossLaps, OSTEOC Osteocalcin, iPTH Intact parathyroid hormone, TP1NP Total type I collagen N-terminal propeptide, FPG Fasting plasma glucose, HbA1c Hemoglobin A1C, TC Total Cholesterol, TG Triglyceride, HDL High-density lipoprotein, LDL Low-density lipoprotein, ALT Alanine aminotransferase, AST Aspartate aminotransferase, ALP Alkaline phosphatase, ALB Albumin, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate

We developed several models to evaluate the independent effects of BTMs on DKD, UACR, and eGFR. As presented in Table 2, elevated 25-OH-D levels were associated with a decreased likelihood of DKD, and reduced UACR without any adjustments. After controlling for various confounding variables in model 1 and model 2, the associations between 25-OH-D and the prevalence of DKD, as well as UACR, remained statistically significant. In these three models, β-CTX was positively associated with UACR, elevated OSTEOC levels were associated with increased UACR and reduced eGFR, and iPTH was positively associated with the likelihood of DKD in models 1 and 2, positively associated with UACR in all three models, and negatively associated with eGFR in all three models. TP1NP was positively associated with UACR in all three models and negatively associated with eGFR in models 1 and 2. Multifactor analysis revealed that 25-OH-D is an independent protective factor for DKD, potentially contributing to a decreased UACR, while iPTH is an independent risk factor for DKD, potentially contributing to increased UACR and decreased eGFR. In addition, β-CTX, OSTEOC, iPTH, and TP1NP were independently associated with elevated UACR. OSTEOC and TP1NP were identified as independent risk factors for eGFR.

Table 2 The associations between BTMs and DKD, UACR, and eGFR

	25-OH-D	β-CTX	OSTEOC	iPTH	TP1NP	
OR or β(95%Cl)	P value	OR or β(95%Cl)	P value	OR or β(95%Cl)	P value	OR or β(95%Cl)	P value	OR or β(95%Cl)	P value	
DKD0	0.951(0.929, 0.973)	<0.001	0.711(0.319, 1.587)	0.405	1.007(0.980, 1.036)	0.601	1.014(1.005, 1.024)	0.003	1.005(0.999, 1.012)	0.111	
DKD1	0.953(0.930, 0.976)	<0.001	1.343(0.571, 3.160)	0.499	1.024(0.994, 1.056)	0.118	1.012(1.002, 1.021)	0.016	1.010(1.001, 1.018)	0.023	
DKD2	0.969(0.944, 0.995)	0.02	1.048(0.357, 3.071)	0.932	1.003(0.963, 1.045)	0.880	1.012(0.999, 1.025)	0.064	1.007(0.996, 1.018)	0.200	
UACR0	−8.312(−11.268,−5.356)	<0.001	134.853(18.521, 251.185)	0.023	11.378(7.310,15.447)	<0.001	2.485(1.142,3.828)	<0.001	2.557(1.670, 3.444)	<0.001	
UACR1	−8.445(−11.457,−5.434)	<0.001	170.464(49.078, 291.851)	0.006	12.654(8.455,16.853)	<0.001	2.394(1.040,3.748)	0.001	2.725(1.822, 3.628)	<0.001	
UACR2	−6.294(−9.206,−3.382)	<0.001	128.944(9.116, 248.772)	0.035	9.145(4.801,13.488)	<0.001	1.972(0.588,3.356)	0.005	2.108(1.203, 3.013)	<0.001	
eGFR0	0.096(−0.102,0.293)	0.342	−5.260(−12.894, 2.374)	0.177	−0.532(−0.801,−0.262)	<0.001	−0.308(−0.394,−0.223)	<0.001	−0.060(−0.119,−0.001)	0.048	
eGFR1	−0.033(−0.220, 0.155)	0.734	−9.709(−17.104,−2.315)	0.010	−0.639(−0.897,−0.381)	<0.001	−0.270(−0.350,−0.189)	<0.001	−0.071(−0.127,−0.015)	0.014	
eGFR2	−0.133(−0.309, 0.043)	0.138	−6.720(−13.878, 0.438)	0.066	−0.421(−0.682,−0.161)	0.002	−0.230(−0.311,−0.149)	<0.001	−0.011(−0.066, 0.044)	0.692	
Binary logistic regression analysis was performed to identify the relationships between the prevalence of DKD and BTMs levels, and the findings were summarized as odds ratios and regression coefficients, both with 95% CIs. Linear regression analysis was utilized to examine the associations between UACR and eGFR with BTMs levels, and the results were summarized as beta and regression coefficients, again accompanied by 95% CIs

0 The model was not adjusted

1 The model was adjusted for age, sex, BMI, and duration of diabetes

2 The model was adjusted for model 1and SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, Hemoglobin, Serum calcium, Serum phosphorus, Serum uric acid and medications, and the medications included anti-osteoporosis drugs (calcium, vitamin D, bisphosphonate, or other drugs), anti-diabetic agents (pioglitazone, SGLT−2 inhibitors, and GLP−1 analogues), and ACEI/ARB

DKD Diabetic kidney disease, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate, 25-OH-D 25-hydroxyvitamin D, β-CTX β-CrossLaps, OSTEOC Osteocalcin, iPTH Intact parathyroid hormone, TP1NP Total type I collagen N-terminal propeptide

We evaluated the associations between 25-OH-D quartile levels and DKD, UACR, and eGFR, as shown in Fig. 2. Elevated 25-OH-D quartile levels were significantly associated with a decreased prevalence of DKD and reduced UACR after adjusting for potential confounders. However, no significant associations were observed between 25-OH-D quartile levels and eGFR. Compared to participants in the first quartile of 25-OH-D levels, those in the highest quartile exhibited a significant 68% decrease in the odds of having DKD in model 0. These associations remained significant in both model 1 and model 2. Notably, in modes 1 and 2, the prevalence of DKD among participants in the highest 25-OH-D quartile showed a 66.8% decrease and a 53.1% decrease, respectively, compared to those in the first quartile. Furthermore, our findings revealed that, in these models, as 25-OH-D quartile levels gradually increased, UACR showed a decreasing trend. Compared with the lowest quartile, individuals in the highest quartile exhibited the lowest β for UACR in model 2.

Fig. 2 The associations between 25-OH-D quartile levels and DKD, UACR, and eGFR. 0 The model was not adjusted. 1 The model was adjusted for age, sex, BMI, and duration of diabetes. 2 The model was adjusted for model 1and SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, Hemoglobin, Serum calcium, Serum phosphorus, Serum uric acid and medications, and the medications included anti-osteoporosis drugs (calcium, vitamin D, bisphosphonate, or other drugs), anti-diabetic agents (pioglitazone, SGLT-2 inhibitors, and GLP-1 analogues), and ACEI/ARB. DKD Diabetic kidney disease, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate

We evaluated the associations between β-CTX quartile levels and DKD, UACR, and eGFR, as shown in Fig. 3. No significant associations were observed between β-CTX quartile levels and the prevalence of DKD or UACR. However, elevated β-CTX quartile levels were found to be significantly associated with decreased eGFR. In these models, as β-CTX quartile levels increased, eGFR showed a decreasing trend after controlling for various confounding variables such as age, sex, BMI, duration of diabetes, SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, hemoglobin, serum calcium, serum phosphorus, serum uric acid and medications. Compared with the lowest quartile, individuals in the highest quartile exhibited the lowest β for eGFR in both model 2 and model 3.

Fig. 3 The associations between β-CTX quartile levels and DKD, UACR, and eGFR. 0 The model was not adjusted. 1 The model was adjusted for age, sex, BMI, and duration of diabetes. 2 The model was adjusted for model 1and SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, Hemoglobin, Serum calcium, Serum phosphorus, Serum uric acid and medications, and the medications included anti-osteoporosis drugs (calcium, vitamin D, bisphosphonate, or other drugs), anti-diabetic agents (pioglitazone, SGLT−2 inhibitors, and GLP−1 analogues), and ACEI/ARB. DKD Diabetic kidney disease, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate

We evaluated the associations between OSTEOC quartile levels and DKD, UACR, and eGFR, as shown in Fig. 4. No significant associations were observed between OSTEOC quartile levels and the prevalence of DKD. However, elevated OSTEOC quartile levels were found to be significantly associated with increased UACR in models 0 and 1, and decreased eGFR in all three models. In these models, as OSTEOC quartile levels increased, UACR showed an increasing trend, while eGFR showed a decreasing trend. Compared to the lowest quartile, individuals in the highest quartile exhibited the highest β for UACR and lowest β for eGFR in all three models.

Fig. 4 The associations between OSTEOC quartile levels and DKD, UACR, and eGFR. 0 The model was not adjusted. 1 The model was adjusted for age, sex, BMI, and duration of diabetes. 2 The model was adjusted for model 1and SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, Hemoglobin, Serum calcium, Serum phosphorus, Serum uric acid and medications, and the medications included anti-osteoporosis drugs (calcium, vitamin D, bisphosphonate, or other drugs), anti-diabetic agents (pioglitazone, SGLT−2 inhibitors, and GLP−1 analogues), and ACEI/ARB. DKD Diabetic kidney disease, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate

We evaluated the associations between iPTH quartile levels and DKD, UACR, and eGFR, as shown in Fig. 5. Compared to participants in the first quartile of iPTH levels, those in the highest quartile exhibited a significant 81.5% increase in the odds of having DKD in model 0. However, after adjusting for various varibles, the association between iPTH and the prevalence of DKD was not significant. Furthermore, elevated iPTH quartile levels were found to be significantly associated with a reduced eGFR after adjusting for potential confounders in all three models. Our findings revealed that, as iPTH quartile levels increased, eGFR showed a decreasing trend in all models. Compared to the lowest quartile, individuals in the highest quartile exhibited the lowest β for eGFR in all three models.

Fig. 5 The associations between iPTH quartile levels and DKD, UACR, and eGFR. 0 The model was not adjusted. 1 The model was adjusted for age, sex, BMI, and duration of diabetes. 2 The model was adjusted for model 1and SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, Hemoglobin, Serum calcium, Serum phosphorus, Serum uric acid and medications, and the medications included anti-osteoporosis drugs (calcium, vitamin D, bisphosphonate, or other drugs), anti-diabetic agents (pioglitazone, SGLT−2 inhibitors, and GLP−1 analogues), and ACEI/ARB. DKD Diabetic kidney disease, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate

We evaluated the associations between TP1NP quartile levels and DKD, UACR, and eGFR, as shown in Fig. 6. No significant associations were observed between TP1NP quartile levels and the prevalence of DKD. However, elevated TP1NP quartile levels were found to be significantly associated with increased UACR and decreased eGFR in all three models. In these models, as TP1NP quartile levels increased, UACR showed an increasing trend, while eGFR showed a decreasing trend. Compared to the lowest quartile, individuals in the highest quartile exhibited the highest β for UACR and the lowest β for eGFR in all models.

Fig. 6 The associations between TP1NP quartile levels and DKD, UACR, and eGFR. 0 The model was not adjusted. 1 The model was adjusted for age, sex, BMI, and duration of diabetes. 2 The model was adjusted for model 1and SBP, DBP, FPG, HbA1c, TC, TG, HDL, LDL, ALT, AST, ALP, Hemoglobin, Serum calcium, Serum phosphorus, Serum uric acid and medications, and the medications included anti-osteoporosis drugs (calcium, vitamin D, bisphosphonate, or other drugs), anti-diabetic agents (pioglitazone, SGLT−2 inhibitors, and GLP−1 analogues), and ACEI/ARB. DKD Diabetic kidney disease, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate

Figure 7 shows that the associations between 25-OH-D and TP1NP levels and the prevalence of DKD were linear in the adjusted RCS model. The risk estimates significantly decreased with increasing 25-OH-D levels, and the association approached the L-shape, while they significantly increased with rising TP1NP levels. β-CTX did not exhibit any independent effects on DKD in the multivariable model. Moreover, the RCS curves showed a non-linear association of OSTEOC and iPTH and DKD, approaching the J-shape, and the point of inflection is 10.875 ng/L and 34.15 pg/mL respectively. The risk estimates markedly increased when OSTEOC levels exceeded 10.875 ng/L and iPTH levels surpassed 34.15 pg/mL.

Fig. 7 Adjusted RCS for BTMs and the prevalence of DKD. Adjusted for age, sex, BMI, and duration of diabetes. DKD Diabetic kidney disease, UACR Urine albumin to creatinine ratio, eGFR Estimated glomerular infiltration rate, 25-OH-D 25-hydroxyvitamin D, β-CTX β-CrossLaps, OSTEOC Osteocalcin, iPTH Intact parathyroid hormone, TP1NP Total type I collagen N-terminal propeptide

Discussion

We observed that 25-OH-D levels were significantly lower in patients with DKD compared to those without DKD. Elevated 25-OH-D levels were independently associated with a reduced incidence of DKD and a decrease in UACR. As 25-OH-D levels increased across quartiles, there was a trend of decreasing DKD incidence and UACR. After adjusting for confounding factors, the highest quartile of 25-OH-D demonstrated a significant 53.1% reduction in the prevalence of DKD compared to the first quartile. In the adjusted RCS model, the relationship between 25-OH-D levels and DKD prevalence was linear, approaching the L-shape, with risk estimates markedly decreasing as 25-OH-D levels increased. This suggests that higher levels of 25-OH-D may act as a protective factor against kidney complications in elderly patients with T2DM. These findings are consistent with previous findings [18–37], although some studies have reported inconsistent conclusions [38–45]. The discrepancies in these findings may be attributed to differences in the populations studied, methodologies used, and the confounding factors controlled for. By dividing patients into pathological subgroups, it was found that up to 91.5% of patients with DKD were affected by vitamin D deficiency and insufficiency [18]. Vitamin D, a fat-soluble vitamin essential for human health, is catalyzed by the liver into 25-OH-D, which is further converted in the kidneys into biologically active 1,25-dihydroxyvitamin D3. This active form binds to receptors in target tissues, participating in the regulation of calcium and phosphorus metabolism [46–50]. Nakai et al. [52] demonstrated that 25-OH-D partially antagonizes nuclear factor κB activation induced by advanced glycation end products in mouse podocytes [53]. Additionally, the vitamin D analog masalone has been shown to reduce oxidative stress through the Nrf2-Keap1 pathway, thereby delaying the progression of diabetic nephropathy in rats. Vitamin D acts as a potent inhibitor of the renin-angiotensin aldosterone system [54], potentially mitigating glomerulosclerosis and fibrosis [55], regulating apoptosis and autophagy, ameliorating podocyte injury, and maintaining the structure of the glomerular filtration barrier [55, 56]. Lower levels of 25-OH-D are particularly detrimental in the context of renin-angiotensin-aldosterone system activation and hyperfiltration in diabetic mice [57]. Moreover, vitamin D may reduce the expression of transforming growth factor-β and inflammation, maintain vascular homeostasis, improve glucose and lipid metabolism, and enhance antioxidant defense and immune function [57–59]. Animal studies have suggested that vitamin D insufficiency may contribute to the pathogenesis of albuminuria [19]. 25-OH-D can decrease proteinuria by suppressing the renin-angiotensin system and TGF-β in mesangial and juxtaglomerular cells, consistent with the findings of this study.

The findings of this study demonstrate that β-CTX is independently and positively correlated with UACR. As quartiles of β-CTX levels increase, there is a trend towards decreasing eGFR. However, β-CTX did not exhibit any independent effects on DKD in the multivariable model using RCS. β-CTX serves as a degradation product of type I collagen, reflecting the biological activity of osteoclasts and indicating the extent of bone resorption [61]. Previous research has highlighted a negative correlation between β-CTX and eGFR in diabetic patients [13, 14], and a positive correlation with UACR [15], which is consistent with the current findings. Nonetheless, the specific mechanism by which β-CTX influences the progression from T2DM to DKD remains unclear and warrants further investigation.

Furthermore, our research reveals an independent positive correlation between OSTEOC and UACR, while it is independently negatively correlated with eGFR. As quartile levels of OSTEOC increase, there is a trend towards increasing UACR and decreasing eGFR. Moreover, the associations between OSTEOC and DKD were non-linear, approaching the J-shape, with risk estimates markedly increasing when OSTEOC levels exceeded 10.875 ng/L. OSTEOC, a specific protein secreted by osteoblasts and composed of 49 amino acids, plays crucial roles in various physiological processes including bone metabolism, energy metabolism, reproduction, and cognition [62]. It reflects the activity status of osteoblasts. OSTEOC has also been implicated in stimulating islet beta cells to release insulin and prompting adipocytes to release adiponectin, thereby enhancing insulin sensitivity [63]. Studies investigating the relationship between OSTEOC and glucose-lipid metabolism have yielded conflicting results, and the underlying mechanisms remain unclear [7, 63–67]. Zhao et al. found a significant positive correlation between UACR and OSTEOC in a cross-sectional study involving 297 T2DM patients [12], consistent with our findings. However, caution is warranted regarding the potential for reverse causality. A prospective cohort study demonstrated that even after adjusting for baseline eGFR and UACR, serum OSTEOC maintains an independent and robust negative correlation with DKD events [69]. In cross-sectional studies, reduced renal function may lead to decreased OSTEOC excretion and consequently higher circulating OSTEOC levels, potentially distorting the exposure-disease relationship.

The findings of this study indicate that iPTH levels are significantly higher in DKD patients compared to those without DKD. iPTH is independently and positively correlated with the incidence of DKD and UACR, while being independently negatively correlated with eGFR. As quartile levels of iPTH increase, there is a downward trend in eGFR. iPTH, a peptide hormone, exerts biological effects by regulating calcium and phosphorus metabolism through actions on target tissues such as bones and kidneys, and it is ultimately cleared by the kidneys. PTH strengthens osteolysis, enhances renal tubular reabsorption of calcium, mobilizes calcium into the bloodstream, and increases blood calcium levels. Previous research has suggested that elevated iPTH levels can act as a uremic toxin, influencing mitochondrial function and contributing to cell death and organ damage [69–71]. Our observations reveal a non-linear association between iPTH and DKD, approaching the J-shape, with risk estimates significantly increasing when iPTH levels exceed 34.15 pg/mL. This reflects the dual nature of iPTH, where within a physiological range it exerts beneficial effects, while beyond this range it may have detrimental effects, consistent with previous findings.

Furthermore, our study reveals an independent positive correlation between TP1NP and the incidence of UACR, while being independently negatively correlated with eGFR. As quartile levels of TP1NP increase, there is a trend of increasing UACR and decreasing eGFR. Additionally, the risk estimates markedly increase with rising TP1NP levels. TP1NP is an extension peptide of type I procollagen [72, 73], synthesized and released into circulation by osteoblasts [74, 75]. It serves as a sensitive marker of bone formation [76]. Previous research supports our findings, indicating a negative correlation between TP1NP levels and eGFR in diabetes patients, and a positive association between TP1NP and UACR in T2DM patients. We propose two potential explanations for this association. First, TP1NP may accumulate in the body as eGFR declines, leading to elevated circulating levels [77]. Second, given that bone remodeling is metabolically demanding, disturbances in energy metabolism and microcirculation in T2DM patients may contribute to observed decreases in bone formation markers [78].

The findings suggest BTMs homeostasis may be related to the etiology and pathogenesis of DKD in elder patients with T2DM. These results highlight the potential utility of BTMs as biomarkers for kidney disease, aiding in the identification of individuals at increased risk for T2DM-related renal complications. This has significant clinical implications for managing bone metabolism disorders and kidney complications in elderly patients with diabetes. Therefore, in clinical practice, attention should be given to the dynamic monitoring of BTMs in elderly T2DM patients. Additionally, maintaining optimal BTM levels from an early age may be associated with a reduced future risk of DKD development.

Our study possesses several strengths. Firstly, we conducted a large-scale population study involving hospitalized elderly T2DM patients, ensuring a substantial sample size and comprehensive data collection, which allowed us to assess common confounders. This is the first study to report the association between BTMs and the prevalence of DKD in an elderly cohort. Secondly, we emphasized the nonlinearity in the study, better illustrating the dose-response relationship. Thirdly, we examined BTMs as both continuous and categorical variables to reduce data analysis contingency and enhance the robustness of our results. Nevertheless, this study has certain limitations. Firstly, selection bias could not be avoided in this single-center, hospital-based study. Secondly, detecting BTMs at a single time point only provides a snapshot and does not allow for an understanding of the dynamic changes in BTMs and their association with DKD. Thirdly, all participants were of Han Chinese ethnicity, which may limit the generalizability of the results to other ethnic groups, as bone metabolism and osteoporosis vary among different races. Fourthly, potential confounding factors affecting BTMs levels, such as sun exposure, outdoor exercise, nutritional status, dietary habits, and seasonal variations, were not included in this analysis.

Conclustions

BTMs are closely associated with kidney disease in elderly patients with T2DM. These discoveries potentially assist clinicians in establishing more preventive measures and targeted treatment strategies for elderly patients with T2DM.

Acknowledgements

The authors thank all the participants in the study and colleagues in the nursing group in their department.

Author contributions

Shuwu Wei conceived the study, participated in its design and coordination, analyzed the data and drafted the manuscript. Xinyu Pan recruited patients and collected data. Junping Wei participated in its design and coordination, and was responsible for project administration, and visualization. All authors read and approved the final manuscript.

Funding

This project was funded by Beijing Municipal Natural Science Foundation (Grant No.7242255), the Traditional Chinese Medicine Evidence-Based Capacity Building Project(Grant No.60104), the Technology Innovation Project of Major Key Projects at the China Academy of Chinese Medical Sciences (Grant No.C12021A01617),and the High Level Chinese Medical Hospital Promotion Project (Grant No. HLCMHPP2023084).

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Declarations

Ethical approval and consent to participate

The ethics committee has waived the requirement of informed consent for this study. The full name of the Institutional Review Board that waived the informed consent procedure is “Ethical Committee in Guan’anmen Hospital, China Academy of Chinese Medical Sciences” (registration code:2023−187-KY). We confirm that methods were performed in accordance with declaration of Helsinki’s guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Chinese Elderly Type 2 Diabetes Prevention and Treatment of Clinical Guidelines Writing Group. [Clinical guidelines for prevention and treatment of type 2 diabetes mellitus in the elderly in China (2022 edition)]. Zhonghua nei ke za zhi. 2022;61(1):12–50. Chinese. Geriatric Endocrinology and Metabolism Branch of Chinese Geriatric Society; Geriatric Endocrinology and Metabolism Branch of Chinese Geriatric Health Care Society.
2. Cosman F de Beur SJ LeBoff MS Lewiecki EM Tanner B Randall S Clinician’s guide to Prevention and treatment of osteoporosis Osteoporos Int 2014 25 10 2359 81 10.1007/s00198-014-2794-2 25182228
Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. Clinician’s guide to Prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359–81.25182228 10.1007/s00198-014-2794-2
3. Rathinavelu S Guidry-Elizondo C Banu J Molecular modulation of osteoblasts and osteoclasts in type 2 diabetes J Diabetes Res 2018 2018 6354787 10.1155/2018/6354787 30525054
Rathinavelu S, Guidry-Elizondo C, Banu J. Molecular modulation of osteoblasts and osteoclasts in type 2 diabetes. J Diabetes Res. 2018;2018:6354787.30525054 10.1155/2018/6354787
4. Zou Y Zhao L Zhang J Wang Y Wu Y Ren H Development and internal validation of machine learning algorithms for end-stage renal disease risk prediction model of people with type 2 diabetes mellitus and diabetic kidney disease Ren Fail 2022 44 1 562 70 10.1080/0886022X.2022.2056053 35373711
Zou Y, Zhao L, Zhang J, Wang Y, Wu Y, Ren H, et al. Development and internal validation of machine learning algorithms for end-stage renal disease risk prediction model of people with type 2 diabetes mellitus and diabetic kidney disease. Ren Fail. 2022;44(1):562–70.35373711 10.1080/0886022X.2022.2056053
5. Winiarska A Filipska I Knysak M Stompór T Dietary phosphorus as a marker of Mineral Metabolism and Progression of Diabetic kidney disease Nutrients 2021 13 3 789 10.3390/nu13030789 33673618
Winiarska A, Filipska I, Knysak M, Stompór T. Dietary phosphorus as a marker of Mineral Metabolism and Progression of Diabetic kidney disease. Nutrients. 2021;13(3):789.33673618 10.3390/nu13030789
6. Tan A Gao Y Yang X Zhang H Qin X Mo L Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey Metabolism 2011 60 8 1186 92 10.1016/j.metabol.2011.01.002 21353261
Tan A, Gao Y, Yang X, Zhang H, Qin X, Mo L, et al. Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey. Metabolism. 2011;60(8):1186–92.21353261 10.1016/j.metabol.2011.01.002
7. Rui X Xu B Su J Pan C Zhan C Su B Differential pattern for regulating insulin secretion, insulin resistance, and lipid metabolism by osteocalcin in male and female T2DM patients Med Sci Monit 2014 20 711 9 10.12659/MSM.890130 24785155
Rui X, Xu B, Su J, Pan C, Zhan C, Su B, et al. Differential pattern for regulating insulin secretion, insulin resistance, and lipid metabolism by osteocalcin in male and female T2DM patients. Med Sci Monit. 2014;20:711–9.24785155 10.12659/MSM.890130
8. Bador KM, Wee LD, Halim SA, Fadi MF, Santhiran P, Rosli NF, et al. Serum osteocalcin in subjects with metabolic syndrome and central obesity. Diabetes Metab Syndr. 2016 Jan-Mar;10(1 Suppl 1):S42–5.
9. Chen Y Zhao Q Du G Xu Y Association between serum osteocalcin and glucose/lipid metabolism in Chinese Han and Uygur populations with type 2 diabetes mellitus in Xinjiang: two cross-sectional studies Lipids Health Dis 2017 16 1 139 10.1186/s12944-017-0512-8 28732499
Chen Y, Zhao Q, Du G, Xu Y. Association between serum osteocalcin and glucose/lipid metabolism in Chinese Han and Uygur populations with type 2 diabetes mellitus in Xinjiang: two cross-sectional studies. Lipids Health Dis. 2017;16(1):139.28732499 10.1186/s12944-017-0512-8
10. Tejwani V Qian Q Calcium regulation and bone mineral metabolism in elderly patients with chronic kidney disease Nutrients 2013 5 6 1913 36 10.3390/nu5061913 23760058
Tejwani V, Qian Q. Calcium regulation and bone mineral metabolism in elderly patients with chronic kidney disease. Nutrients. 2013;5(6):1913–36.23760058 10.3390/nu5061913
11. Kochanek M Said A Lerma EV Mineral metabolism in chronic kidney disease Dis Mon 2015 61 10 425 33 10.1016/j.disamonth.2015.08.003 26518114
Kochanek M, Said A, Lerma EV. Mineral metabolism in chronic kidney disease. Dis Mon. 2015;61(10):425–33.26518114 10.1016/j.disamonth.2015.08.003
12. Zhao X Zhang XM Yuan N Yu XF Ji LN Associations of Bone Mineral density and bone metabolism indices with urine albumin to creatinine ratio in Chinese patients with type 2 diabetes Exp Clin Endocrinol Diabetes 2019 127 1 50 5 30396213
Zhao X, Zhang XM, Yuan N, Yu XF, Ji LN. Associations of Bone Mineral density and bone metabolism indices with urine albumin to creatinine ratio in Chinese patients with type 2 diabetes. Exp Clin Endocrinol Diabetes. 2019;127(1):50–5.30396213
13. Zhu X Zhou Y Hong S Xue Y Cui Y Correlation between serum bone turnover markers and estimated glomerular filtration rate in Chinese patients with diabetes Dis Markers 2021 2021 6731218 10.1155/2021/6731218 33505536
Zhu X, Zhou Y, Hong S, Xue Y, Cui Y. Correlation between serum bone turnover markers and estimated glomerular filtration rate in Chinese patients with diabetes. Dis Markers. 2021;2021:6731218.33505536 10.1155/2021/6731218
14. Maghbooli Z Shabani P Gorgani-Firuzjaee S Hossein-Nezhad A The association between bone turnover markers and microvascular complications of type 2 diabetes J Diabetes Metab Disord 2016 15 51 10.1186/s40200-016-0274-2 27826545
Maghbooli Z, Shabani P, Gorgani-Firuzjaee S, Hossein-Nezhad A. The association between bone turnover markers and microvascular complications of type 2 diabetes. J Diabetes Metab Disord. 2016;15:51.27826545 10.1186/s40200-016-0274-2
15. Hou Y Hou X Nie Q Xia Q Hu R Yang X Association of bone turnover markers with type 2 diabetes Mellitus and Microvascular complications: a matched case-control study Diabetes Metab Syndr Obes 2023 16 1177 92 10.2147/DMSO.S400285 37139349
Hou Y, Hou X, Nie Q, Xia Q, Hu R, Yang X, et al. Association of bone turnover markers with type 2 diabetes Mellitus and Microvascular complications: a matched case-control study. Diabetes Metab Syndr Obes. 2023;16:1177–92.37139349 10.2147/DMSO.S400285
16. American Diabetes Association Standards of Medical Care in Diabetes-2017 abridged for primary care providers Clin Diabetes 2017 35 1 5 26 10.2337/cd16-0067 28144042
American Diabetes Association. Standards of Medical Care in Diabetes-2017 abridged for primary care providers. Clin Diabetes. 2017;35(1):5–26.28144042 10.2337/cd16-0067
17. American Diabetes Association. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S124-S138.
18. Duan S Lu F Wu B Zhang C Nie G Sun L Association of Serum 25 (OH) vitamin D with chronic kidney Disease Progression in Type 2 diabetes Front Endocrinol (Lausanne) 2022 13 929598 10.3389/fendo.2022.929598 35846303
Duan S, Lu F, Wu B, Zhang C, Nie G, Sun L, et al. Association of Serum 25 (OH) vitamin D with chronic kidney Disease Progression in Type 2 diabetes. Front Endocrinol (Lausanne). 2022;13:929598.35846303 10.3389/fendo.2022.929598
19. de Boer IH Ioannou GN Kestenbaum B Brunzell JD Weiss NS 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III) Am J Kidney Dis 2007 50 1 69 77 10.1053/j.ajkd.2007.04.015 17591526
de Boer IH, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis. 2007;50(1):69–77.17591526 10.1053/j.ajkd.2007.04.015
20. Chen X Wan Z Geng T Zhu K Li R Lu Q Vitamin D status, Vitamin D Receptor Polymorphisms, and risk of Microvascular complications among individuals with type 2 diabetes: a prospective study Diabetes Care 2023 46 2 270 7 10.2337/dc22-0513 36169213
Chen X, Wan Z, Geng T, Zhu K, Li R, Lu Q, et al. Vitamin D status, Vitamin D Receptor Polymorphisms, and risk of Microvascular complications among individuals with type 2 diabetes: a prospective study. Diabetes Care. 2023;46(2):270–7.36169213 10.2337/dc22-0513
21. Zhou T Shen L Li Z Jia J Xing H Wang N Severe 25-Hydroxyvitamin D Deficiency May Predict Poor renal outcomes in patients with Biopsy-Proven Diabetic Nephropathy Front Endocrinol (Lausanne) 2022 13 871571 10.3389/fendo.2022.871571 35600603
Zhou T, Shen L, Li Z, Jia J, Xing H, Wang N, et al. Severe 25-Hydroxyvitamin D Deficiency May Predict Poor renal outcomes in patients with Biopsy-Proven Diabetic Nephropathy. Front Endocrinol (Lausanne). 2022;13:871571.35600603 10.3389/fendo.2022.871571
22. Wang X Liu X Zhao J Chen M Wang L Construction of a Nomogram-based prediction model for the risk of Diabetic kidney disease in T2DM Diabetes Metab Syndr Obes 2024 17 215 25 10.2147/DMSO.S442925 38229907
Wang X, Liu X, Zhao J, Chen M, Wang L. Construction of a Nomogram-based prediction model for the risk of Diabetic kidney disease in T2DM. Diabetes Metab Syndr Obes. 2024;17:215–25.38229907 10.2147/DMSO.S442925
23. Kim MJ Frankel AH Donaldson M Darch SJ Pusey CD Hill PD Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition Kidney Int 2011 80 8 851 60 10.1038/ki.2011.224 21832985
Kim MJ, Frankel AH, Donaldson M, Darch SJ, Pusey CD, Hill PD, et al. Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int. 2011;80(8):851–60.21832985 10.1038/ki.2011.224
24. Wan H Wang Y Zhang K Chen Y Fang S Zhang W Associations between vitamin D and microvascular complications in middle-aged and elderly diabetic patients Endocr Pract 2019 25 8 809 16 10.4158/EP-2019-0015 31013151
Wan H, Wang Y, Zhang K, Chen Y, Fang S, Zhang W, et al. Associations between vitamin D and microvascular complications in middle-aged and elderly diabetic patients. Endocr Pract. 2019;25(8):809–16.31013151 10.4158/EP-2019-0015
25. Liang Q Hu H Wu H Chen X Wang W Le Y A nonlinear relationship between serum 25-Hydroxyvitamin D and urine albumin to creatinine ratio in type 2 diabetes: a cross-sectional study in China Diabetes Metab Syndr Obes 2021 14 2581 93 10.2147/DMSO.S308390 34135610
Liang Q, Hu H, Wu H, Chen X, Wang W, Le Y, et al. A nonlinear relationship between serum 25-Hydroxyvitamin D and urine albumin to creatinine ratio in type 2 diabetes: a cross-sectional study in China. Diabetes Metab Syndr Obes. 2021;14:2581–93.34135610 10.2147/DMSO.S308390
26. Hong SH Kim YB Choi HS Jeong TD Kim JT Sung YA Association of Vitamin D Deficiency with Diabetic Nephropathy Endocrinol Metab (Seoul) 2021 36 1 106 13 10.3803/EnM.2020.826 33677932
Hong SH, Kim YB, Choi HS, Jeong TD, Kim JT, Sung YA. Association of Vitamin D Deficiency with Diabetic Nephropathy. Endocrinol Metab (Seoul). 2021;36(1):106–13.33677932 10.3803/EnM.2020.826
27. Grammatiki M Karras S Kotsa K The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: a narrative review Horm (Athens) 2019 18 1 37 48 10.1007/s42000-018-0063-z
Grammatiki M, Karras S, Kotsa K. The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: a narrative review. Horm (Athens). 2019;18(1):37–48.10.1007/s42000-018-0063-z
28. Xie S Huang L Cao W Hu Y Sun H Cao L Association between serum 25-hydroxyvitamin D and diabetic kidney disease in Chinese patients with type 2 diabetes PLoS ONE 2019 14 4 e0214728 10.1371/journal.pone.0214728 31017918
Xie S, Huang L, Cao W, Hu Y, Sun H, Cao L, et al. Association between serum 25-hydroxyvitamin D and diabetic kidney disease in Chinese patients with type 2 diabetes. PLoS ONE. 2019;14(4):e0214728.31017918 10.1371/journal.pone.0214728
29. Peng Y Li LJ Serum 25-hydroxyvitamin D level and diabetic nephropathy in patients with type 2 diabetes mellitus Int Urol Nephrol 2015 47 6 983 9 10.1007/s11255-015-0983-3 25902763
Peng Y, Li LJ. Serum 25-hydroxyvitamin D level and diabetic nephropathy in patients with type 2 diabetes mellitus. Int Urol Nephrol. 2015;47(6):983–9.25902763 10.1007/s11255-015-0983-3
30. Zhao WJ Xia XY Yin J Relationship of serum vitamin D levels with diabetic microvascular complications in patients with type 2 diabetes mellitus Chin Med J (Engl) 2021 134 7 814 20 10.1097/CM9.0000000000001364 33538508
Zhao WJ, Xia XY, Yin J. Relationship of serum vitamin D levels with diabetic microvascular complications in patients with type 2 diabetes mellitus. Chin Med J (Engl). 2021;134(7):814–20.33538508 10.1097/CM9.0000000000001364
31. Ravani P Malberti F Tripepi G Pecchini P Cutrupi S Pizzini P Vitamin D levels and patient outcome in chronic kidney disease Kidney Int 2009 75 1 88 95 10.1038/ki.2008.501 18843258
Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P, et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int. 2009;75(1):88–95.18843258 10.1038/ki.2008.501
32. Agarwal R Vitamin D Proteinuria, diabetic nephropathy, and progression of CKD Clin J Am Soc Nephrol 2009 4 9 1523 8 10.2215/CJN.02010309 19478099
Agarwal R, Vitamin D. Proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol. 2009;4(9):1523–8.19478099 10.2215/CJN.02010309
33. Xiao X Wang Y Hou Y Han F Ren J Hu Z Vitamin D deficiency and related risk factors in patients with diabetic nephropathy J Int Med Res 2016 44 3 673 84 10.1177/0300060515593765 26944386
Xiao X, Wang Y, Hou Y, Han F, Ren J, Hu Z. Vitamin D deficiency and related risk factors in patients with diabetic nephropathy. J Int Med Res. 2016;44(3):673–84.26944386 10.1177/0300060515593765
34. Liyanage P, Lekamwasam S, Weerarathna TP, Liyanage C. Effect of vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: a randomized, double-blind clinical trial. J Postgrad Med. 2018 Jan-Mar;64(1):10–5.
35. Senyigit A. The association between 25-hydroxy vitamin D deficiency and diabetic complications in patients with type 2 diabetes mellitus. Diabetes Metab Syndr. 2019 Mar-Apr;13(2):1381–6.
36. Ucak S Sevim E Ersoy D Sivritepe R Basat O Atay S Evaluation of the relationship between microalbuminuria and 25-(OH) vitamin D levels in patients with type 2 diabetes mellitus Aging Male 2019 22 2 116 20 10.1080/13685538.2018.1479385 29944055
Ucak S, Sevim E, Ersoy D, Sivritepe R, Basat O, Atay S. Evaluation of the relationship between microalbuminuria and 25-(OH) vitamin D levels in patients with type 2 diabetes mellitus. Aging Male. 2019;22(2):116–20.29944055 10.1080/13685538.2018.1479385
37. Derakhshanian H Shab-Bidar S Speakman JR Nadimi H Djafarian K Vitamin D and diabetic nephropathy: a systematic review and meta-analysis Nutrition 2015 31 10 1189 94 10.1016/j.nut.2015.04.009 26238534
Derakhshanian H, Shab-Bidar S, Speakman JR, Nadimi H, Djafarian K. Vitamin D and diabetic nephropathy: a systematic review and meta-analysis. Nutrition. 2015;31(10):1189–94.26238534 10.1016/j.nut.2015.04.009
38. Herrmann M Sullivan DR Veillard AS McCorquodale T Straub IR Scott R FIELD study investigators. Serum 25-hydroxyvitamin D: a predictor of macrovascular and microvascular complications in patients with type 2 diabetes Diabetes Care 2015 38 3 521 8 10.2337/dc14-0180 25524951
Herrmann M, Sullivan DR, Veillard AS, McCorquodale T, Straub IR, Scott R, et al. FIELD study investigators. Serum 25-hydroxyvitamin D: a predictor of macrovascular and microvascular complications in patients with type 2 diabetes. Diabetes Care. 2015;38(3):521–8.25524951 10.2337/dc14-0180
39. Felício JS de Rider Britto HA Cortez PC de Souza Resende F de Lemos MN de Moraes LV Association between 25(OH)vitamin D, HbA1c and Albuminuria in Diabetes Mellitus: Data from a Population-based study (VIDAMAZON) Front Endocrinol (Lausanne) 2021 12 723502 10.3389/fendo.2021.723502 34690928
Felício JS, de Rider Britto HA, Cortez PC, de Souza Resende F, de Lemos MN, de Moraes LV, et al. Association between 25(OH)vitamin D, HbA1c and Albuminuria in Diabetes Mellitus: Data from a Population-based study (VIDAMAZON). Front Endocrinol (Lausanne). 2021;12:723502.34690928 10.3389/fendo.2021.723502
40. Abasheva D Dolcet-Negre MM Fernández-Seara MA Mora-Gutiérrez JM Orbe J Escalada FJ Association between circulating levels of 25-Hydroxyvitamin D3 and Matrix Metalloproteinase-10 (MMP-10) in patients with type 2 diabetes Nutrients 2022 14 17 3484 10.3390/nu14173484 36079742
Abasheva D, Dolcet-Negre MM, Fernández-Seara MA, Mora-Gutiérrez JM, Orbe J, Escalada FJ, et al. Association between circulating levels of 25-Hydroxyvitamin D3 and Matrix Metalloproteinase-10 (MMP-10) in patients with type 2 diabetes. Nutrients. 2022;14(17):3484.36079742 10.3390/nu14173484
41. Joergensen C Gall MA Schmedes A Tarnow L Parving HH Rossing P Vitamin D levels and mortality in type 2 diabetes Diabetes Care 2010 33 10 2238 43 10.2337/dc10-0582 20606205
Joergensen C, Gall MA, Schmedes A, Tarnow L, Parving HH, Rossing P. Vitamin D levels and mortality in type 2 diabetes. Diabetes Care. 2010;33(10):2238–43.20606205 10.2337/dc10-0582
42. Joergensen C Hovind P Schmedes A Parving HH Rossing P Vitamin D levels, microvascular complications, and mortality in type 1 diabetes Diabetes Care 2011 34 5 1081 5 10.2337/dc10-2459 21525501
Joergensen C, Hovind P, Schmedes A, Parving HH, Rossing P. Vitamin D levels, microvascular complications, and mortality in type 1 diabetes. Diabetes Care. 2011;34(5):1081–5.21525501 10.2337/dc10-2459
43. Dall’Agnol A Brondani LA Cancelier VDA Camargo EG Silveiro SP Lower serum 25-hydroxyvitamin D levels are associated with impaired glomerular filtration rate in type 2 diabetes patients Ther Adv Endocrinol Metab 2020 11 2042018820930904 10.1177/2042018820930904 32782774
Dall’Agnol A, Brondani LA, Cancelier VDA, Camargo EG, Silveiro SP. Lower serum 25-hydroxyvitamin D levels are associated with impaired glomerular filtration rate in type 2 diabetes patients. Ther Adv Endocrinol Metab. 2020;11:2042018820930904.32782774 10.1177/2042018820930904
44. Xiao Y Wei L Xiong X Yang M Sun L Association between Vitamin D Status and Diabetic complications in patients with type 2 diabetes Mellitus: a cross-sectional study in Hunan China Front Endocrinol (Lausanne) 2020 11 564738 10.3389/fendo.2020.564738 33042022
Xiao Y, Wei L, Xiong X, Yang M, Sun L. Association between Vitamin D Status and Diabetic complications in patients with type 2 diabetes Mellitus: a cross-sectional study in Hunan China. Front Endocrinol (Lausanne). 2020;11:564738.33042022 10.3389/fendo.2020.564738
45. Xiong R Yuan Y Zhu Z Wu Y Ha J Han X Micronutrients and Diabetic Retinopathy: evidence from the National Health and Nutrition Examination Survey and a Meta-analysis Am J Ophthalmol 2022 238 141 56 10.1016/j.ajo.2022.01.005 35033539
Xiong R, Yuan Y, Zhu Z, Wu Y, Ha J, Han X, et al. Micronutrients and Diabetic Retinopathy: evidence from the National Health and Nutrition Examination Survey and a Meta-analysis. Am J Ophthalmol. 2022;238:141–56.35033539 10.1016/j.ajo.2022.01.005
46. Mohammed A Marie MA Abdulazim DO Hassan M Shaker O Ayeldeen G Serum urate lowering therapy using Allopurinol improves serum 25 Hydroxy vitamin D in Stage 3–5 CKD patients: a pilot study Nephron 2021 145 2 133 6 10.1159/000512340 33378761
Mohammed A, Marie MA, Abdulazim DO, Hassan M, Shaker O, Ayeldeen G, et al. Serum urate lowering therapy using Allopurinol improves serum 25 Hydroxy vitamin D in Stage 3–5 CKD patients: a pilot study. Nephron. 2021;145(2):133–6.33378761 10.1159/000512340
47. Schön A Leifheit-Nestler M Deppe J Fischer DC Bayazit AK Obrycki L Active vitamin D is cardioprotective in experimental uraemia but not in children with CKD stages 3–5 Nephrol Dial Transpl 2021 36 3 442 51 10.1093/ndt/gfaa227
Schön A, Leifheit-Nestler M, Deppe J, Fischer DC, Bayazit AK, Obrycki L, et al. Active vitamin D is cardioprotective in experimental uraemia but not in children with CKD stages 3–5. Nephrol Dial Transpl. 2021;36(3):442–51.10.1093/ndt/gfaa227
48. Caccamo D Cannata A Ricca S Catalano LM Montalto AF Alibrandi A Role of Vitamin-D receptor (VDR) single nucleotide polymorphisms in gestational hypertension development: a case-control study PLoS ONE 2020 15 11 e0239407 10.1371/journal.pone.0239407 33186385
Caccamo D, Cannata A, Ricca S, Catalano LM, Montalto AF, Alibrandi A, et al. Role of Vitamin-D receptor (VDR) single nucleotide polymorphisms in gestational hypertension development: a case-control study. PLoS ONE. 2020;15(11):e0239407.33186385 10.1371/journal.pone.0239407
49. Vernia F Valvano M Longo S Cesaro N Viscido A Latella G Vitamin D in Inflammatory Bowel diseases Mech Action Therapeutic Implications Nutrients 2022 14 2 269
Vernia F, Valvano M, Longo S, Cesaro N, Viscido A, Latella G. Vitamin D in Inflammatory Bowel diseases. Mech Action Therapeutic Implications Nutrients. 2022;14(2):269.
50. de Souza Freitas R Fratelli CF de Souza Silva CM de Lima LR Stival MM da Silva ICR Association of Vitamin D with the TaqI polymorphism of the VDR Gene in Older Women attending the Basic Health Unit of the Federal District, DF (Brazil) J Aging Res 2020 2020 7145193 10.1155/2020/7145193 33029399
de Souza Freitas R, Fratelli CF, de Souza Silva CM, de Lima LR, Stival MM, da Silva ICR, et al. Association of Vitamin D with the TaqI polymorphism of the VDR Gene in Older Women attending the Basic Health Unit of the Federal District, DF (Brazil). J Aging Res. 2020;2020:7145193.33029399 10.1155/2020/7145193
51. Nakai K Fujii H Kono K Goto S Kitazawa R Kitazawa S Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats Am J Hypertens 2014 27 4 586 95 10.1093/ajh/hpt160 24025724
Nakai K, Fujii H, Kono K, Goto S, Kitazawa R, Kitazawa S, et al. Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats. Am J Hypertens. 2014;27(4):586–95.24025724 10.1093/ajh/hpt160
52. Rüster C Franke S Reuter S Mrowka R Bondeva T Wolf G Vitamin D3 partly antagonizes Advanced-Glycation endproducts-Induced NFκB activation in Mouse Podocytes Nephron 2016 134 2 105 16 10.1159/000448106 27505422
Rüster C, Franke S, Reuter S, Mrowka R, Bondeva T, Wolf G. Vitamin D3 partly antagonizes Advanced-Glycation endproducts-Induced NFκB activation in Mouse Podocytes. Nephron. 2016;134(2):105–16.27505422 10.1159/000448106
53. Alam U Arul-Devah V Javed S Malik RA Vitamin D and Diabetic complications: true or false prophet? Diabetes Ther 2016 7 1 11 26 10.1007/s13300-016-0159-x 26971351
Alam U, Arul-Devah V, Javed S, Malik RA. Vitamin D and Diabetic complications: true or false prophet? Diabetes Ther. 2016;7(1):11–26.26971351 10.1007/s13300-016-0159-x
54. Lei M Liu Z Guo J The emerging role of vitamin D and Vitamin D Receptor in Diabetic Nephropathy Biomed Res Int 2020 2020 4137268 10.1155/2020/4137268 32766307
Lei M, Liu Z, Guo J. The emerging role of vitamin D and Vitamin D Receptor in Diabetic Nephropathy. Biomed Res Int. 2020;2020:4137268.32766307 10.1155/2020/4137268
55. Hamzawy M Gouda SAA Rashid L Attia Morcos M Shoukry H Sharawy N The cellular selection between apoptosis and autophagy: roles of vitamin D, glucose and immune response in diabetic nephropathy Endocrine 2017 58 1 66 80 10.1007/s12020-017-1402-6 28889337
Hamzawy M, Gouda SAA, Rashid L, Attia Morcos M, Shoukry H, Sharawy N. The cellular selection between apoptosis and autophagy: roles of vitamin D, glucose and immune response in diabetic nephropathy. Endocrine. 2017;58(1):66–80.28889337 10.1007/s12020-017-1402-6
56. Li YC Kong J Wei M Chen ZF Liu SQ Cao LP 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system J Clin Invest 2002 110 2 229 38 10.1172/JCI0215219 12122115
Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2):229–38.12122115 10.1172/JCI0215219
57. Tecilazich F Formenti AM Giustina A Role of vitamin D in diabetic retinopathy: pathophysiological and clinical aspects Rev Endocr Metab Disord 2021 22 4 715 27 10.1007/s11154-020-09575-4 33026598
Tecilazich F, Formenti AM, Giustina A. Role of vitamin D in diabetic retinopathy: pathophysiological and clinical aspects. Rev Endocr Metab Disord. 2021;22(4):715–27.33026598 10.1007/s11154-020-09575-4
58. Grammatiki M Rapti E Karras S Ajjan RA Kotsa K Vitamin D and diabetes mellitus: causal or casual association? Rev Endocr Metab Disord 2017 18 2 227 41 10.1007/s11154-016-9403-y 28062940
Grammatiki M, Rapti E, Karras S, Ajjan RA, Kotsa K. Vitamin D and diabetes mellitus: causal or casual association? Rev Endocr Metab Disord. 2017;18(2):227–41.28062940 10.1007/s11154-016-9403-y
59. Lee H Lee H Lim Y Vitamin D3 improves lipophagy-associated renal lipid metabolism and tissue damage in diabetic mice Nutr Res 2020 80 55 65 10.1016/j.nutres.2020.06.007 32693268
Lee H, Lee H, Lim Y. Vitamin D3 improves lipophagy-associated renal lipid metabolism and tissue damage in diabetic mice. Nutr Res. 2020;80:55–65.32693268 10.1016/j.nutres.2020.06.007
60. Iglesias P Arrieta F Piñera M Botella-Carretero JI Balsa JA Zamarrón I Serum concentrations of osteocalcin, procollagen type 1 N-terminal propeptide and beta-CrossLaps in obese subjects with varying degrees of glucose tolerance Clin Endocrinol (Oxf) 2011 75 2 184 8 10.1111/j.1365-2265.2011.04035.x 21521304
Iglesias P, Arrieta F, Piñera M, Botella-Carretero JI, Balsa JA, Zamarrón I, et al. Serum concentrations of osteocalcin, procollagen type 1 N-terminal propeptide and beta-CrossLaps in obese subjects with varying degrees of glucose tolerance. Clin Endocrinol (Oxf). 2011;75(2):184–8.21521304 10.1111/j.1365-2265.2011.04035.x
61. Zhou H Seibel MJ Bone Osteoblasts and global energy metabolism - beyond osteocalcin Nat Rev Rheumatol 2017 13 5 261 2 10.1038/nrrheum.2017.35 28275261
Zhou H, Seibel MJ, Bone. Osteoblasts and global energy metabolism - beyond osteocalcin. Nat Rev Rheumatol. 2017;13(5):261–2.28275261 10.1038/nrrheum.2017.35
62. Lee NK Sowa H Hinoi E Ferron M Ahn JD Confavreux C Endocrine regulation of energy metabolism by the skeleton Cell 2007 130 3 456 69 10.1016/j.cell.2007.05.047 17693256
Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130(3):456–69.17693256 10.1016/j.cell.2007.05.047
63. Choudhury AB Sarkar PD Sakalley DK Petkar SB Role of adiponectin in mediating the association of osteocalcin with insulin resistance and type 2 diabetes: a cross sectional study in pre- and post-menopausal women Arch Physiol Biochem 2014 120 2 73 9 10.3109/13813455.2013.877488 24405382
Choudhury AB, Sarkar PD, Sakalley DK, Petkar SB. Role of adiponectin in mediating the association of osteocalcin with insulin resistance and type 2 diabetes: a cross sectional study in pre- and post-menopausal women. Arch Physiol Biochem. 2014;120(2):73–9.24405382 10.3109/13813455.2013.877488
64. Chen L Li Q Yang Z Ye Z Huang Y He M Osteocalcin, glucose metabolism, lipid profile and chronic low-grade inflammation in middle-aged and elderly Chinese Diabet Med 2013 30 3 309 17 10.1111/j.1464-5491.2012.03769.x 22913521
Chen L, Li Q, Yang Z, Ye Z, Huang Y, He M, et al. Osteocalcin, glucose metabolism, lipid profile and chronic low-grade inflammation in middle-aged and elderly Chinese. Diabet Med. 2013;30(3):309–17.22913521 10.1111/j.1464-5491.2012.03769.x
65. Liu DM Guo XZ Tong HJ Tao B Sun LH Zhao HY Erratum to: Association between osteocalcin and glucose metabolism: a meta-analysis Osteoporos Int 2015 26 12 2835 6 10.1007/s00198-015-3286-8 26370824
Liu DM, Guo XZ, Tong HJ, Tao B, Sun LH, Zhao HY, et al. Erratum to: Association between osteocalcin and glucose metabolism: a meta-analysis. Osteoporos Int. 2015;26(12):2835–6.26370824 10.1007/s00198-015-3286-8
66. Shu H Pei Y Chen K Lu J Significant inverse association between serum osteocalcin and incident type 2 diabetes in a middle-aged cohort Diabetes Metab Res Rev 2016 32 8 867 74 10.1002/dmrr.2808 27061949
Shu H, Pei Y, Chen K, Lu J. Significant inverse association between serum osteocalcin and incident type 2 diabetes in a middle-aged cohort. Diabetes Metab Res Rev. 2016;32(8):867–74.27061949 10.1002/dmrr.2808
67. Wang Q Zhang B Xu Y Xu H Zhang N The relationship between serum osteocalcin concentration and glucose metabolism in patients with type 2 diabetes Mellitus Int J Endocrinol 2013 2013 842598 10.1155/2013/842598 23533407
Wang Q, Zhang B, Xu Y, Xu H, Zhang N. The relationship between serum osteocalcin concentration and glucose metabolism in patients with type 2 diabetes Mellitus. Int J Endocrinol. 2013;2013:842598.23533407 10.1155/2013/842598
68. Ye X Yu R Jiang F Hou X Wei L Bao Y Osteocalcin and risks of Incident Diabetes and Diabetic kidney disease: a 4.6-Year prospective cohort study Diabetes Care 2022 45 4 830 6 10.2337/dc21-2113 35090006
Ye X, Yu R, Jiang F, Hou X, Wei L, Bao Y, et al. Osteocalcin and risks of Incident Diabetes and Diabetic kidney disease: a 4.6-Year prospective cohort study. Diabetes Care. 2022;45(4):830–6.35090006 10.2337/dc21-2113
69. Kuriwaka-Kido R Kido S Miyatani Y Ito Y Kondo T Omatsu T Parathyroid hormone (1–34) counteracts the suppression of interleukin-11 expression by glucocorticoid in murine osteoblasts: a possible mechanism for stimulating osteoblast differentiation against glucocorticoid excess Endocrinology 2013 154 3 1156 67 10.1210/en.2013-1915 23397032
Kuriwaka-Kido R, Kido S, Miyatani Y, Ito Y, Kondo T, Omatsu T, et al. Parathyroid hormone (1–34) counteracts the suppression of interleukin-11 expression by glucocorticoid in murine osteoblasts: a possible mechanism for stimulating osteoblast differentiation against glucocorticoid excess. Endocrinology. 2013;154(3):1156–67.23397032 10.1210/en.2013-1915
70. Krikorian A, Shah S, Wasman J. Parathyroid hormone-related protein: an unusual mechanism for hypercalcemia in sarcoidosis. Endocr Pract 2011 Jul-Aug;17(4):e84–6.
71. Chen T Wang Y Hao Z Hu Y Li J Parathyroid hormone and its related peptides in bone metabolism Biochem Pharmacol 2021 192 114669 10.1016/j.bcp.2021.114669 34224692
Chen T, Wang Y, Hao Z, Hu Y, Li J. Parathyroid hormone and its related peptides in bone metabolism. Biochem Pharmacol. 2021;192:114669.34224692 10.1016/j.bcp.2021.114669
72. Nordklint AK Almdal TP Vestergaard P Lundby-Christensen L Jørgensen NR Boesgaard TW Effect of Metformin vs. Placebo in combination with insulin analogues on bone markers P1NP and CTX in patients with type 2 diabetes Mellitus Calcif Tissue Int 2020 107 2 160 9 10.1007/s00223-020-00711-5 32468187
Nordklint AK, Almdal TP, Vestergaard P, Lundby-Christensen L, Jørgensen NR, Boesgaard TW, et al. Effect of Metformin vs. Placebo in combination with insulin analogues on bone markers P1NP and CTX in patients with type 2 diabetes Mellitus. Calcif Tissue Int. 2020;107(2):160–9.32468187 10.1007/s00223-020-00711-5
73. Takada J Dinavahi R Miyauchi A Hamaya E Hirama T Libanati C Correction to: relationship between P1NP, a biochemical marker of bone turnover, and bone mineral density in patients transitioned from alendronate to romosozumab or teriparatide: a post hoc analysis of the STRUCTURE trial J Bone Min Metab 2020 38 4 605 10.1007/s00774-020-01099-w
Takada J, Dinavahi R, Miyauchi A, Hamaya E, Hirama T, Libanati C, et al. Correction to: relationship between P1NP, a biochemical marker of bone turnover, and bone mineral density in patients transitioned from alendronate to romosozumab or teriparatide: a post hoc analysis of the STRUCTURE trial. J Bone Min Metab. 2020;38(4):605.10.1007/s00774-020-01099-w
74. Zuo CT Yin DC Fan HX Lin M Meng Z Xin GW Study on diagnostic value of P1NP and β-CTX in bone metastasis of patients with breast cancer and the correlation between them Eur Rev Med Pharmacol Sci 2019 23 12 5277 84 31298379
Zuo CT, Yin DC, Fan HX, Lin M, Meng Z, Xin GW, et al. Study on diagnostic value of P1NP and β-CTX in bone metastasis of patients with breast cancer and the correlation between them. Eur Rev Med Pharmacol Sci. 2019;23(12):5277–84.31298379
75. Hansen S Shanbhogue VV Jørgensen NR Beck-Nielsen SS Elevated bone remodeling markers of CTX and P1NP in addition to Sclerostin in patients with X-linked hypophosphatemia: a cross-sectional controlled study Calcif Tissue Int 2019 104 6 591 8 10.1007/s00223-019-00526-z 30710161
Hansen S, Shanbhogue VV, Jørgensen NR, Beck-Nielsen SS. Elevated bone remodeling markers of CTX and P1NP in addition to Sclerostin in patients with X-linked hypophosphatemia: a cross-sectional controlled study. Calcif Tissue Int. 2019;104(6):591–8.30710161 10.1007/s00223-019-00526-z
76. Glendenning P Chubb SAP Vasikaran S Clinical utility of bone turnover markers in the management of common metabolic bone diseases in adults Clin Chim Acta 2018 481 161 70 10.1016/j.cca.2018.03.009 29544749
Glendenning P, Chubb SAP, Vasikaran S. Clinical utility of bone turnover markers in the management of common metabolic bone diseases in adults. Clin Chim Acta. 2018;481:161–70.29544749 10.1016/j.cca.2018.03.009
77. Hayer MK Radhakrishnan A Price AM Liu B Baig S Weston CJ Defining myocardial abnormalities across the stages of chronic kidney disease: a Cardiac magnetic resonance imaging study JACC Cardiovasc Imaging 2020 13 11 2357 67 10.1016/j.jcmg.2020.04.021 32682713
Hayer MK, Radhakrishnan A, Price AM, Liu B, Baig S, Weston CJ, et al. Defining myocardial abnormalities across the stages of chronic kidney disease: a Cardiac magnetic resonance imaging study. JACC Cardiovasc Imaging. 2020;13(11):2357–67.32682713 10.1016/j.jcmg.2020.04.021
78. Wang H Zheng X Zhang Y Huang J Zhou W Li X The endocrine role of bone: novel functions of bone-derived cytokines Biochem Pharmacol 2021 183 114308 10.1016/j.bcp.2020.114308 33137323
Wang H, Zheng X, Zhang Y, Huang J, Zhou W, Li X, et al. The endocrine role of bone: novel functions of bone-derived cytokines. Biochem Pharmacol. 2021;183:114308.33137323 10.1016/j.bcp.2020.114308
