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The metabolic results of Metformin (Met) and way of life modification in early sort 2 diabetes mellitus (T2DM) administration are nicely established, however their affect on bone transforming stays unsure in under-investigated populations, significantly throughout early remedy when weight reduction and metabolic shifts could transiently have an effect on skeletal turnover. This examine examined the short- and mid-term results of metformin, way of life intervention, and their mixture on bone turnover markers (BTMs) in treatment-naïve Saudi adults with T2DM.
In this 6-month pilot, open-label multicenter randomized managed trial, 114 treatment-naïve Saudi adults with newly identified T2DM (90 males, 24 females; imply age ± SD 53.6 ± 8.4 years; imply BMI 30.3 ± 3.9 kg/m2; imply HbA1c 7.0 ± 0.6) had been assigned to Met (1000 mg/day), way of life modification, or mixed remedy (n = 38/group). Serum markers of bone resorption (C-terminal telopeptide of sort I collagen [CTX], major end result) and bone formation (procollagen sort I N-terminal propeptide [P1NP], osteocalcin), together with sclerostin (SOST), had been measured at baseline, 3 months, and 6 months. Anthropometric, glycemic, lipid, renal, and hepatic parameters had been assessed as secondary outcomes.
After adjustment for baseline P1NP ranges, solely the life-style group demonstrated a major discount in CTX after 6 months (p < 0.05), whereas osteocalcin, SOST and P1NP confirmed no vital modifications throughout all interventions. All interventions had been related to enhancements in anthropometric and glycemic measures; most pronounced within the mixed intervention group.
In treatment-naïve adults with T2DM, way of life intervention alone was related to a major discount in CTX after 6 months, whereas metformin-based interventions confirmed no vital results on bone turnover markers. These exploratory findings could counsel short-term modulation of bone turnover however needs to be interpreted cautiously given the pilot design.
The on-line model accommodates supplementary materials out there at 10.1007/s40520-026-03423-2.
Keywords: Metformin, Lifestyle intervention, Bone turnover markers, Type 2 diabetes mellitus, CTX, P1NP, Randomized managed trial
Metformin is a well-established agent for bettering insulin sensitivity and reducing hepatic glucose output, and the commonest first-line pharmacological method in sort 2 diabetes mellitus (T2DM) and prediabetes administration [1]. A latest umbrella assessment additionally documented that structured way of life interventions, which regularly embrace caloric restriction, elevated bodily exercise, and behavioral counseling, are equally efficient in bettering glycemic indices and lowering cardiometabolic danger, though notable anthropometric advantages seemed to be missing together with metformin [2]. While their metabolic advantages are well-documented, much less is thought about their results on bone turnover and bone-related biomarkers, significantly within the context of weight reduction. A synthesis of proof performed on animal fashions with T2DM however demonstrated that metformin can enhance bone density [3]. In human trials, proof from a meta-analysis of 19 randomized managed trials (n = 4,914) individuals indicated that though anti-T2DM therapies as a bunch had been related to larger bone mineral density (BMD) on the lumbar backbone and femoral neck in contrast with placebo, metformin confirmed a relative benefit over different anti-T2DM brokers, with direct comparisons exhibiting that total remedy results favored metformin [4]. Notably, the absence of clinically significant modifications in bone turnover markers (BTMs) related to metformin, along with the excessive heterogeneity throughout the included research [4], additional reinforces the variability and total inconclusiveness of metformin’s results on BTMs [5].
Bone transforming is influenced by endocrine, metabolic, and mechanical elements [6]. Weight discount, for example, alters mechanical loading and may modify circulating bone markers [7], together with osteocalcin, C-terminal telopeptide of sort I collagen (CTX), Procollagen sort I N-terminal propeptide (P1NP), and sclerostin (SOST) [8]. Osteocalcin and P1NP are markers of bone formation, whereas CTX displays bone resorption. SOST is a Wnt-signalling antagonist that regulates osteoblastic exercise and can also reply to metabolic shifts [9].
Understanding how way of life and pharmacological interventions affect bone metabolism is clinically related, particularly in genetically predisposed populations in danger for each metabolic and skeletal issues. Despite the dearth of convincing proof in people, it has been proposed that metformin influences bone turnover primarily via its canonical AMP-activated protein kinase (AMPK) activation, which reduces oxidative stress, irritation, and mobile senescence throughout the bone marrow area of interest. By suppressing reactive-oxygen species (ROS) manufacturing and pro-inflammatory nuclear issue kappa-light-chain-enhancer of activated B (NF-κB)-dependent cytokines, metformin limits osteoclastogenesis and bone resorption-related markers [10]. Simultaneously, current literature instructed that AMPK-mediated inhibition of mammalian targets of rapamycin (mTOR) enhances autophagy and osteogenic signalling in mesenchymal stem cells, selling bone formation and a beneficial bone turnover profile [10].
In this 6-month, pilot, open-label, randomized managed trial (RCT), we evaluated for the primary time in a treatment-naïve Saudi inhabitants with T2DM, the unbiased and mixed results of metformin and way of life modification on bone turnover markers with CTX as the first end result, alongside secondary assessments of anthropometric parameters, cardiometabolic biomarkers, and renal and hepatic operate. To the most effective of our information, that is the primary RCT within the Arabian Gulf area to evaluate modifications in BTMs amongst remedy naïve adults with T2DM, filling a major hole amongst beneath represented ethnic teams the place each T2DM and osteoporosis are extremely prevalent [11].
This was an open label, randomized, multicenter, 6-month pilot scientific trial carried out at major healthcare facilities throughout the Hail and Qassim areas, Saudi Arabia. Ethical approvals had been obtained from the Ministry of Health Institutional Review Board in Hail Health Cluster (MOH IRB Log No. 2.24-6, February 6, 2024) and Qassim Health Cluster (MOH IRB Log No. 607/46/3015 September 25, 2024), Kingdom of Saudi Arabia. Ethical approval was additionally obtained from King Saud University (No. E-24-1470, August 05, 2024). This examine was registered at ClinicalTrials.gov (ID: NCT06439758).
Among 208 people screened for T2DM, prognosis was confirmed in 114 individuals by collaborating major care physicians utilizing the American Diabetes Association (ADA) and World Health Organization (WHO) standards. Confirmed treatment-naïve T2DM individuals with written knowledgeable consent had been then randomly allotted to obtain both metformin (1000 mg), way of life intervention solely, or each. Anthropometric measurements and fasting blood samples had been collected by educated personnel at collaborating facilities at baseline, 3 months and 6 months. Participants attended examine visits after in a single day fasting. Written knowledgeable consent was obtained previous to enrollment. Exclusion standards included non-Saudi nationality, age < 25 or > 65 years, pre-existing T2DM on remedy, osteoporosis, main cardiovascular, renal, hepatic or psychiatric illness and morbid weight problems.
Participants had been randomized into three teams for six months: (A) metformin 1000 mg/day; (B) way of life modification (based mostly on structured diabetes prevention program carried out in native primary-care settings and included ≥ 5% weight discount, reasonable bodily exercise (150 min/week), lowered fats consumption, and elevated dietary fiber (15 g/1000 kcal). In temporary, this system was carried out in Arabic and carried out by licensed dietitians and diabetes instructors, lined prediabetes danger, vitamin and weight administration, carbohydrate consciousness, meals label interpretation, bodily exercise (≥ 30 min of reasonable train, 5 days/week), and important self-monitoring practices, with ongoing follow-up assist for way of life modification [12]; (C) metformin plus way of life modification. The variety of schooling periods are offered in supplementary Table 1.
Baseline knowledge had been obtained utilizing a standardized questionnaire capturing demographics, medical historical past, basic well being standing, and osteoporosis danger. Anthropometric measurements included peak (cm), weight (kg), neck (cm), waist (cm) and hip (cm) circumferences, and blood strain (mmHg) (common of two readings).
Fasting blood samples had been collected at baseline and follow-up visits. Routine biochemical parameters [fasting glucose, glycated hemoglobin (HbA1c), liver enzymes (alanine aminotransferase, ALT and aspartate aminotransferase, AST), renal function test (urea and creatinine), and lipid profile (triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol)] had been analyzed at regional major healthcare laboratories utilizing the Dimension EXL 200 analyzer (Siemens Healthineers, Erlangen, Germany). The remaining fasting serum samples had been labeled, saved and transported to the Chair for Biomarkers of Chronic Diseases (CBCD), Biochemistry Department, College of Science, King Saud University (KSU), Riyadh, Saudi Arabia, following standardized biospecimen dealing with and transport procedures set by the Ministry of Health.
The Cobas e 411 analyzer (Roche Diagnostics, Mannheim, Germany) was used for the evaluation of CTX and P1NP, and the corresponding electrochemiluminescence immunoassay (ECLIA) kits provided by the producer. The intra- and inter-assay CV had been 4.7% and 5.7%, respectively, for CTX and three.0% and 4.1%, respectively, for P1NP. The LIAISON XL automated quantitative analyzer (DiaSorin, Saluggia, Italy) was used for chemiluminescent immunoassay (CLIA)-based evaluation of osteocalcin. The intra- and inter-assay CVs had been (8% and 9%, respectively). Serum sclerostin concentrations had been decided utilizing the SpectraMax M5 microplate reader (Molecular Devices, San Jose, CA, USA) along side a commercially out there enzyme-linked immunosorbent assay (ELISA) equipment, following the producer’s protocol. The intra- and inter-assay CVs had been (2.1% and 10.8%, respectively). All assays for BTMs had been carried out at CBCD, KSU, in accordance with producer directions with applicable high quality management.
Sample dimension estimation used outcomes reported by Mori et al. [13] the place they reported the imply change from baseline to three months in CTX values of pioglitazone (15.8 ng/mL) and metformin teams (-13.6 ng/mL), with the very best SD at 36.6, impact dimension > 0.4. The current examine used a conservative impact dimension of 0.3 for the first evaluation of three parallel teams with three repeated measurements. Given the anticipated very excessive correlation amongst repeated measures, repeated-measures ANOVA was used with α = 0.05 (two-tailed), energy = 0.80, the calculated pattern dimension was n = 37 individuals per group. We anticipated 5% attrition and focused 40 individuals per group.
Data had been analyzed utilizing SPSS (model 22.0; Chicago, IL, USA). Continuous variables had been expressed as imply ± customary deviation (SD) for usually distributed knowledge, and as median (twenty fifth–seventy fifth percentiles) for non-normally distributed (non-Gaussian) knowledge. Categorical variables had been offered as frequencies and percentages. Normality of steady variables was assessed utilizing the Kolmogorov–Smirnov take a look at. Non-Gaussian variables had been log-transformed previous to parametric evaluation. Repeated measure evaluation of covariance (ANCOVA) and the Friedman take a look at had been carried out to check imply and median variations, respectively, in Gaussian and non-Gaussian variables among the many way of life, Met, and Met + way of life teams, accounting for group results, time results, and group × time interactions, whereas adjusting for baseline P1NP ranges. Correlations between variables had been assessed utilizing Pearson’s or Spearman’s correlation evaluation, as applicable. Primary evaluation was intention-to-treat precept for inside and between group comparisons as prespecified, utilizing final remark carried ahead (LOCF) to account for lacking knowledge. A p-value of < 0.05 was thought of statistically vital.
Of the 208 individuals recruited and screened, 114 treatment-naïve Saudi adults aged 25–65 years with newly identified T2DM had been randomized into the intervention teams. After 6 months, 63 individuals accomplished the intervention, akin to an attrition fee of 45% (Fig. 1). The imply age of the randomized cohort (n = 114) was 53.6 ± 8.4 years; imply BMI 30.3 ± 3.9 kg/m2; and imply HbA1c 7.0 ± 0.6. All teams had been comparable at baseline by way of age, anthropometrics, glycemic and lipid profiles, renal biomarkers, liver enzymes, and bone markers aside from P1NP ranges which had been considerably decrease in Met+way of life group as in comparison with Met group. (Table 1).
CONSORT circulation diagram of participant recruitment, randomization, follow-up, and evaluation. Primary analyses had been carried out in accordance with the intention-to-treat precept together with all randomized individuals (n = 114)
Baseline Characteristics of Randomized Participants Prior to Intervention Allocation
| Parameters | Lifestyle | Met | Met+ Lifestyle |
|---|---|---|---|
| N | 38 | 38 | 38 |
| M/F | 33/5 | 30/8 | 27/11 |
| Age (years) | 53.3 ± 8.3 | 52.3 ± 7.9 | 55.2 ± 9.2 |
| Weight (kg) | 83.0 ± 12.7 | 85.3 ± 15.3 | 81.3 ± 11.1 |
| BMI (kg/m2) | 29.9 ± 2.8 | 30.9 ± 4.8 | 30.1 ± 4.1 |
| Neck Circumference (cm) | 39.6 ± 3.7 | 40.0 ± 2.4 | 39.0 ± 3.2 |
| Systolic BP (mmHg) | 130.8 ± 15.8 | 126.9 ± 15.2 | 125.6 ± 14.4 |
| Diastolic BP (mmHg) | 77.0 ± 8.1 | 81.0 ± 9.6 | 78.6 ± 7.5 |
| Fasting glucose (mmol/l) | 7.1 ± 2.7 | 7.6 ± 2.9 | 8.8 ± 2.7 |
| HbA1c (%) | 6.8 ± 0.6 | 6.9 ± 0.4 | 7.3 ± 0.8 |
| Creatinine (µmol/l) | 87.7 ± 18.5 | 85.1 ± 19.9 | 76.0 ± 25.1 |
| Triglycerides (mmol/l) | 1.8 (1.1–2.5) | 1.2 (1-1.8) | 1.4 (1.2–2.5) |
| HDL-Cholesterol (mmol/l) | 1.1 ± 0.2 | 1.1 ± 0.1 | 1.2 ± 0.2 |
| Total Cholesterol (mmol/l) | 4.4 ± 1.2 | 4.7 ± 2.1 | 4.2 ± 1.1 |
| AST (U/L) | 16.9 ± 5.6 | 20.2 ± 8.8 | 21.5 ± 12.4 |
| ALT (U/L) | 33.8 ± 11.3 | 36.6 ± 13.3 | 37.2 ± 15.6 |
| Urea (mmol/l) | 5.0 ± 1.7 | 5.4 ± 1.5 | 5.2 ± 1.6 |
| CTX (pg/ml) | 399.6 (252–557) | 284.8 (225–431) | 223.2 (192–372) |
| Osteocalcin (ng/ml) | 18.7 ± 5.6 | 19.3 ± 4.3 | 16.9 ± 8.1 |
| SOST (pg/ml) | 47.8 (34.8–72.0) | 61.9 (42.1–81.8) | 55.2 (38.7–74.0) |
| P1NP (ng/ml) | 54.6 (37.4-116.2) | 73.2 (44.9–95.6) | 38.0 (25.5–53.9) |
In Table 2, within-group comparisons adjusted for baseline P1NP revealed a major lower in median CTX values after 6 months within the way of life group solely (p-value < 0.05). No vital distinction was noticed within the mixed group in addition to within-group comparisons. On the opposite hand, osteocalcin confirmed no vital modifications in all teams after 3 months post-intervention. Modest however non-significant will increase had been famous in osteocalcin ranges in all teams after 6 months. Within and between-group comparisons in SOST ranges confirmed no vital modifications in all teams. Finally, P1NP ranges confirmed a modest however non-significant improve throughout all teams after 6 months. Post-hoc energy evaluation for within-group variations within the metformin group confirmed the achieved statistical energy of CTX, osteocalcin, and P1NP had been 0.1, 0.91, and 0.28, respectively, for baseline and 3-month comparisons.
Changes in Anthropometrics and Biochemical parameters over time
| Parameters | Lifestyle | Met | Met+ Lifestyle | Time Effect P-Value | Group Effect P-Value | Group & Time Effect |
|---|---|---|---|---|---|---|
| N | 38 | 38 | 38 | |||
| Weight (kg) | < 0.001 | 0.16 | < 0.001 | |||
| 3 months | 77.8 ± 12.1 | 83.6 ± 14.5 | 76.9 ± 11.0 | |||
| 6 months | 75.3 ± 12.0 | 83.2 ± 14.6 | 72.7 ± 10.3 | |||
| Change at 3 months | -5.2 (-6.1 to -4.4)* | -1.7 (-2.3 to -1.0)* | -4.4 (-6.2 to -2.6)* | |||
| Change at 6 months | -7.7 (-9.0 to -6.5)* | -2.1 (-3.0 to -1.1)* | -8.6 (-10.5 to -6.8)* | |||
| BMI (kg/m 2 ) | < 0.001 | 0.095 | < 0.001 | |||
| 3 months | 28.0 ± 2.6 | 30.3 ± 4.5 | 28.4 ± 4.0 | |||
| 6 months | 27.1 ± 2.6 | 30.2 ± 4.5 | 27.0 ± 3.8 | |||
| Change at 3 months | -1.9 (-2.2 to -1.6)* | -0.6 (-0.8 to -0.4)* | -1.6 (-2.4 to -0.9)* | |||
| Change at 6 months | -2.8 (-3.2 to -2.3)* | -0.7 (-1.1 to -0.4)* | -3.0 (-3.8 to -2.3)* | |||
| Neck Circumference (cm) | < 0.001 | 0.045 | < 0.001 | |||
| 3 months | 36.8 ± 3.6 | 38.4 ± 2.6 | 35.8 ± 3.2 | |||
| 6 months | 35.5 ± 3.5 | 37.8 ± 2.7 | 34.0 ± 3.1 | |||
| Change at 3 months | -2.8 (-3.4 to -2.2)* | -1.6 (-1.9 to -1.2)* | -3.2 (-4.2 to -2.3)* | |||
| Change at 6 months | -4.1 (-4.8 to -3.4)* | -2.2 (-2.6 to -1.8)* | -5.0 (-6.0 to -4.0)* | |||
| Systolic BP (mmHg) | 0.13 | 0.86 | 0.62 | |||
| 3 months | 127.3 ± 21.7 | 134.1 ± 20.0 | 132.7 ± 17.8 | |||
| 6 months | 131.3 ± 20.3 | 133.9 ± 19.4 | 132.8 ± 22.4 | |||
| Change at 3 months | -3.5 (-13.5 to six.5) | 7.2 (-5.0 to 19.3) | 7.1 (-4.1 to 18.3) | |||
| Change at 6 months | 0.5 (-11.3 to 12.4) | 7.0 (-1.2 to fifteen.2) | 7.1 (-4.7 to 19.0) | |||
| Diastolic BP (mmHg) | 0.24 | 0.53 | 0.97 | |||
| 3 months | 79.7 ± 12.7 | 75.9 ± 7.3 | 81.6 ± 11.1 | |||
| 6 months | 74.5 ± 7.9 | 79.2 ± 9.9 | 76.5 ± 9.9 | |||
| Change at 3 months | 2.7 (-2.4 to 7.8) | -5.0 (-9.2 to -0.9) | 3.0 (-4.3 to 10.2) | |||
| Change at 6 months | -2.5 (-8.6 to three.5) | -1.8 (-8.6 to five.1) | -2.1 (-7.9 to three.7) | |||
| Fasting glucose (mmol/l) | < 0.001 | 0.86 | 0.004 | |||
| 3 months | 7.0 ± 3.0 | 6.8 ± 1.8 | 6.7 ± 1.4 | |||
| 6 months | 6.6 ± 2.4 | 6.8 ± 2.1 | 6.1 ± 1.4 | |||
| Change at 3 months | -0.1 (-1.2 to 1.0) | -0.8 (-1.9 to 0.4) | -2.1 (-3.1 to -1.0)* | |||
| Change at 6 months | -0.5 (-1.7 to 0.7) | -0.8 (-2.2 to 0.5) | -2.7 (-3.9 to -1.6)* | |||
| HbA1c | < 0.001 | 0.60 | < 0.001 | |||
| 3 months | 6.5 ± 0.7 | 6.3 ± 0.5 | 6.5 ± 0.8 | |||
| 6 months | 6.3 ± 0.7 | 6.2 ± 0.4 | 6.1 ± 0.6 | |||
| Change at 3 months | -0.3 (-0.4 to -0.2)* | -0.6 (-0.7 to -0.4)* | -0.8 (-0.9 to -0.7)* | |||
| Change at 6 months | -0.5 (-0.7 to -0.3)* | -0.7 (-0.9 to -0.6)* | -1.2 (-1.4 to -1.0)* | |||
| Creatinine (µmol/l) | 0.04 | 0.58 | 0.04 | |||
| 3 months | 89.0 ± 22.3 | 73.8 ± 18.1 | 83.6 ± 18.0 | |||
| 6 months | 86.5 ± 13.8 | 87.9 ± 18.1 | 92.9 ± 24.0 | |||
| Change at 3 months | 1.3 (-11.3 to 13.8) | -11.3 (-19.7 to -2.9)* | 7.6 (-7.2 to 22.4) | |||
| Change at 6 months | -1.1 (-8.5 to six.2) | 2.8 (-4.7 to 10.2) | 17.0 (6.2 to 27.7)* | |||
| Triglycerides (mmol/l) | 0.02 | 0.77 | 0.76 | |||
| 3 months | 1.6 ± 0.8 | 1.3 ± 0.7 | 2.0 ± 1.3 | |||
| 6 months | 1.8 ± 0.8 | 2.0 ± 1.1 | 2.2 ± 1.0 | |||
| Change at 3 months | -0.3 (-0.8 to 0.2) | -0.1 (-0.4 to 0.2) | 0.1 (-0.7 to 0.9) | |||
| Change at 6 months | -0.2 (-0.7 to 0.4) | 0.6 (0.0 to 1.1)* | 0.3 (-0.3 to 0.9) | |||
| HDL-Cholesterol (mmol/l) | 0.02 | 0.76 | 0.37 | |||
| 3 months | 1.2 ± 0.3 | 1.4 ± 0.4 | 1.3 ± 0.2 | |||
| 6 months | 1.3 ± 0.2 | 1.2 ± 0.2 | 1.3 ± 0.2 | |||
| Change at 3 months | 0.1 (-0.0 to 0.2) | 0.3 (0.1 to 0.4)* | 0.0 (-0.1 to 0.2) | |||
| Change at 6 months | 0.2 (0.0 to 0.3)* | 0.1 (-0.0 to 0.2) | 0.0 (-0.1 to 0.2) | |||
| Total Cholesterol (mmol/l) | 0.81 | 0.08 | 0.49 | |||
| 3 months | 4.2 ± 1.5 | 5.0 ± 1.4 | 4.2 ± 1.7 | |||
| 6 months | 4.2 ± 1.3 | 5.1 ± 1.1 | 4.3 ± 1.3 | |||
| Change at 3 months | -0.2 (-0.6 to 0.2) | 0.3 (-0.3 to 0.8) | -0.0 (-0.7 to 0.6) | |||
| Change at 6 months | -0.2 (-0.7 to 0.2) | 0.3 (-0.7 to 1.4) | 0.1 (-0.4 to 0.6) | |||
| AST (U/L) | 0.16 | 0.17 | 0.21 | |||
| 3 months | 16.0 ± 7.9 | 21.4 ± 8.1 | 19.3 ± 6.7 | |||
| 6 months | 21.1 ± 6.6 | 21.6 ± 7.2 | 20.5 ± 5.8 | |||
| Change at 3 months | -0.8 (-4.5 to 2.8) | 1.2 (-2.5 to 4.8) | -2.2 (-7.9 to three.5) | |||
| Change at 6 months | 4.2 (2.1 to six.2)* | 2.2 (-1.8 to six.2) | -1.0 (-7.0 to five.0) | |||
| ALT (U/L) | 0.90 | 0.70 | 0.55 | |||
| 3 months | 38.3 ± 12.1 | 37.4 ± 12.9 | 35.3 ± 10.7 | |||
| 6 months | 34.6 ± 8.4 | 38.0 ± 14.6 | 34.6 ± 9.4 | |||
| Change at 3 months | 4.5 (-2.3 to 11.3) | 0.8 (-6.0 to 7.7) | -1.9 (-10.7 to six.9) | |||
| Change at 6 months | 0.8 (-5.6 to 7.2) | 1.4 (-6.0 to eight.8) | -2.5 (-8.8 to three.7) | |||
| Urea (mmol/l) | 0.08 | 0.81 | 0.94 | |||
| 3 months | 4.8 ± 1.2 | 4.9 ± 1.3 | 4.9 ± 1.7 | |||
| 6 months | 4.7 ± 1.5 | 4.8 ± 1.0 | 4.7 ± 1.5 | |||
| Change at 3 months | -0.2 (-1.0 to 0.6) | -0.5 (-1.2 to 0.1) | -0.3 (-1.2 to 0.5) | |||
| Change at 6 months | -0.3 (-1.0 to 0.5) | -0.7 (-1.2 to -0.1) | -0.5 (-1.3 to 0.3) | |||
| CTX (pg/ml) | 0.11 | 0.29 | 0.59 | |||
| 3 months | 220.8 (165.7-502.1) | 251.2 (169.5-371.6) | 238.5 (191.8-280.3) | |||
| 6 months | 241.6 (171.4-312.3) | 273.8 (174.2-348.4) | 313.7 (205.2-427.4) | |||
| Change at 3 months | -26.4 (-233.6 to 44.8) | -37.8 (-216.5 to 44.8) | 0.0 (-73.3 to 56.4) | |||
| Change at 6 months | -147.1 (-293.1 to -6.0)* | 2.8 (-157.6 to 79.9) | 42.4 (-37.3 to 111.0) | |||
| Osteocalcin (ng/ml) | 0.44 | 0.48 | 0.35 | |||
| 3 months | 15.7 ± 5.3 | 15.2 ± 5.5 | 13.0 ± 5.2 | |||
| 6 months | 17.9 ± 9.4 | 16.1 ± 7.7 | 17.8 ± 9.3 | |||
| Change at 3 months | -3.0 (-6.2 to 0.2) | -3.8 (-7.4 to -0.2) | -4.0 (-8.8 to 0.8) | |||
| Change at 6 months | -0.9 (-5.6 to three.9) | -3.3 (-7.6 to 1.0) | 1.1 (-3.7 to five.9) | |||
| SOST (pg/ml) | 0.25 | 0.30 | 0.54 | |||
| 3 months | 51.3 (43.1–72.9) | 45.9 (37.1-110.9) | 47.5 (29.7–63.1) | |||
| 6 months | 41.8 (32.3–62.2) | 52.4 (34.4–72.0) | 55.6 (32.5–74.1) | |||
| Change at 3 months | 3.2 (-11.9 to 25.3) | -2.2 (-24.6 to 10.3) | -7.3 (-27.0 to 19.9) | |||
| Change at 6 months | -10.2 (-18.5 to 2.7) | -17.7 (-28.9 to -3.6) | -7.4 (-28.6 to 12.6) | |||
| P1NP (ng/ml) | 0.85 | 0.007 | 0.50 | |||
| 3 months | 44.1 (32.4–49.5) | 34.4 (22.1–51.3) | 36.2 (26.9–41.8) | |||
| 6 months | 58.5 (34.2–85.1) | 44.6 (30.5–83.3) | 41.9 (32.2–73.8) | |||
| Change at 3 months | -12.5 (-28.3 to three.0) | -21.1 (-53.0 to -4.3) | -0.9 (-14.3 to eight.7) | |||
| Change at 6 months | -12.8 (-33.0 to 19.2) | -26.1 (-50.5 to eight.7) | -1.3 (-33.1 to 37.5) |
Within and between-group comparisons adjusted for baseline P1NP confirmed a major lower in weight, BMI, and neck circumference in all teams after 6 months, with the Met+way of life group having probably the most reductions and vital interplay results (p-values < 0.001). No vital variations had been noticed in each imply systolic and diastolic blood pressures over time (Table 2).
Both fasting glucose and HbA1c declined considerably over time in all teams (p-values 0.004 and < 0.001, respectively), with the Met+way of life group exhibiting the best fasting glucose (-2.7) and HbA1c reductions (–1.2) after 6 months post-intervention, each of which had been vital (p-values < 0.01) (Table 2).
HDL elevated considerably within the Met group after 3 months in addition to within the way of life group after 6 months (p-values < 0.05). Triglycerides within the Met group considerably elevated after 6 months (p = 0.02) whereas complete ldl cholesterol confirmed no vital modifications extra time in all teams. Creatinine confirmed a major interplay impact (p = 0.04), with the Met+way of life group exhibiting a major improve 6 months post-intervention. Lastly, urea, AST and ALT confirmed no vital modifications over time in all teams (Table 2).
At 3 months, reasonable optimistic correlations had been noticed amongst BTMs throughout all individuals. Changes in CTX had been considerably correlated with Δ osteocalcin (r = 0.44, p < 0.01) and ΔP1NP (r = 0.51, p < 0.01). Additionally, Δ osteocalcin was correlated with Δ creatinine (r = 0.44, p < 0.05). In the life-style group, ΔWHR confirmed vital optimistic correlations with ΔCTX and Δ osteocalcin (r = 0.62 and 0.57, p < 0.01). Δ P1NP was positively correlated with Δ weight, Δ BMI and Δ ALT (r = 0.44, 0.45, 0.49; p-values < 0.05), however inversely correlated with ΔSBP (r = − 0.46; p < 0.05). Within the Met group, ΔCTX was positively correlated with Δ osteocalcin and Δ weight (r = 0.51 and 0.44, p-values < 0.05) with vital and robust inverse correlations with Δ HDL and Δ complete ldl cholesterol (r= -0.75, -0.58, p-values < 0.01). In the identical group Δ osteocalcin was positively correlated with each Δ P1NP and Δ creatinine (r = 0.52, 0.54 p-values < 0.05) and inversely with Δ HDL (r = − 0.53; p < 0.05). Lastly within the Met+way of life group, ΔCTX was positively related to Δ osteocalcin, Δ P1NP and Δ urea (r = 0.49, 0.71 and 0.46; p-values < 0.05, < 0.01 and < 0.05, respectively), whereas Δ osteocalcin was positively correlated with Δ P1NP (r = 0.49; p < 0.05) (Table 3).
Difference change correlation (at 0–3 month)
| All | Lifestyle | Met | Met + Lifestyle | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Δ CTX | Δ Osteo | Δ CTX | Δ Osteo | Δ P1NP | Δ CTX | Δ Osteo | Δ CTX | Δ Osteo | |
| Δ Osteo | 0.44** | 0.51* | 0.49* | ||||||
| Δ P1NP | 0.51** | 0.42** | 0.48* | 0.52* | 0.71** | 0.49* | |||
| Δ Weight | 0.44* | 0.44* | |||||||
| Δ BMI | 0.45* | ||||||||
| Δ WHR | 0.62** | 0.57** | |||||||
| Δ SBP | -0.46* | ||||||||
| Δ CREA | 0.26* | 0.54* | |||||||
| Δ HDL | -0.75** | -0.53* | |||||||
| Δ Total Chol | -0.58** | ||||||||
| Δ ALT | -0.49* | ||||||||
| Δ Urea | 0.46* | ||||||||
At 6 months, a number of correlations remained vital in contrast with the 3-month findings (Table 4). Overall, ΔCTX confirmed a optimistic correlation with ΔWHR and ΔAST (r = 0.46 and 0.39, p < 0.01,0.05, respectively), Δ osteocalcin was inversely correlated Δ fasting glucose (r = − 0.26, p < 0.05). Furthermore, ΔSOST correlated inversely with ΔP1NP and complete ldl cholesterol and positively with Δ creatinine (r = − 0.38, -0.33 and 0.26 p-values < 0.05). In subgroup analyses, the life-style group confirmed vital inverse correlations between ΔCTX with Δ weight, and Δ BMI (r = − 0.75 and − 0.66, p-values < 0.01 and 0.05, respectively) and positively correlated with ΔWHR (r = 0.61, p < 0.05). Δ Osteocalcin confirmed vital inverse correlations with ΔHbA1c and Δ urea (r=-0.55, -0.53, p-values < 0.05). ΔSOST was positively related to Δ fasting glucose and Δ creatinine (r = 0.59, 0.65, p-values < 0.01), and ΔP1NP was positively correlated with Δ WHR (r = 0.49; p < 0.05) and inversely correlated with Δ fasting glucose and ΔHbA1c (r=-0.49, -0.57: p < 0.05). In the Met group, ΔCTX was noticed to be positively correlated with ΔHbA1c, Δ AST and Δ ALT (r = 0.62,0.63 and 0.64; p-values < 0.05) and ΔSOST was inversely correlated with Δ neck circumference (r = − 0.49; p < 0.05). Lastly, within the Met+way of life group, ΔCTX was positively correlated with Δ complete ldl cholesterol (r = 0.79; p < 0.01) and inversely with ΔHDL (r= -0.79; p < 0.05). ΔAST was positively correlated with Δ osteocalcin (r = 0.48; p < 0.05) and inversely with ΔP1NP (r=-0.74; p < 0.01) (Table 4).
Difference change correlation (at 0–6 months)
| All | Lifestyle | Met | Met + Lifestyle | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Δ CTX | Δ Osteo | Δ SOST | Δ P1NP | Δ CTX | Δ Osteo | Δ SOST | Δ P1NP | Δ CTX_ | Δ SOST | Δ CTX_ | Δ Osteo | Δ P1NP | |
| Δ P1NP | -0.38* | ||||||||||||
| Δ Weight | -0.75** | ||||||||||||
| Δ BMI | -0.66* | ||||||||||||
| Δ WHR | 0.46** | 0.61* | 0.49* | ||||||||||
| Δ Neck | -0.49* | ||||||||||||
| Δ FBS | -0.26* | 0.59** | -0.49* | ||||||||||
| Δ HbA1c | -0.33* | -0.55** | -0.57* | 0.62* | |||||||||
| Δ Crea | 0.26* | 0.65** | |||||||||||
| Δ HDL | -0.79* | ||||||||||||
| Δ Total Chol | -0.37** | 0.79* | |||||||||||
| Δ AST | 0.39* | 0.63* | 0.48* | -0.74** | |||||||||
| Δ ALT | 0.64* | ||||||||||||
| Δ Urea | -0.33* | -0.53* | |||||||||||
The current pilot, open-label trial is the primary to guage the short- and mid-term results of metformin monotherapy, way of life modification, and their mixture on BTMs in treatment-naïve Saudi adults with T2DM, with secondary evaluation of anthropometric and metabolic outcomes. At baseline, all teams had been nicely matched by way of demographic and cardiometabolic parameters, minimizing confounding elements and permitting significant comparisons in modifications to the interventions. The major discovering was a temporal however non-significant discount in CTX after 6 months noticed in all teams, probably indicating suppressed bone resorption over time. The discount sample in CTX is according to latest research from different ethnic teams investigating the results of metformin monotherapy in T2DM topics [14, 15]. This discovering is according to improved metabolic management and lowered inflammatory signaling, each of that are recognized to downregulate osteoclast exercise in T2DM [16, 17]. The absence of an analogous discount within the mixed metformin+way of life group could mirror inter-individual variability or a extra balanced transforming state ensuing from concurrent anabolic and anti-resorptive influences. Importantly, CTX modifications had been positively correlated with osteocalcin and P1NP at each time factors, reinforcing the coupled nature of bone transforming on this cohort.
In the current examine, most bone formation markers demonstrated a definite temporal sample. More notably, P1NP, the reference marker of collagen synthesis, elevated modestly however non-significantly throughout all teams by 6 months. This reversible sample helps the interpretation of transient transforming adaptation somewhat than persistent impairment of osteoblast operate, as a number of the nicely proposed mechanisms of metformin in bone transforming is the activation of AMPK and Wnt signaling pathways that promote osteoblast differentiation [18]. It is worthy to notice that the low post-hoc energy for P1NP and CTX at early time factors additional means that bigger samples or longer follow-up could also be required to completely characterize these early skeletal responses. Lastly, SOST ranges remained unchanged all through the examine, probably indicating that the noticed alterations in bone turnover had been both unlikely mediated via the canonical Wnt–β-catenin inhibition pathway [19], or beneath powered pattern dimension. Nonetheless, the noticed inverse correlations at 6 months between sclerostin and P1NP, in addition to lipid and choose anthropometric parameters, counsel a attainable oblique position of metabolic standing in modulating osteocyte signaling over time [20]. Cumulatively, the acute results of all of the interventions in contrast within the current examine almost about BTMs reinforce earlier findings from different populations, and whereas quick time period modifications seem promising, longer follow-ups are nonetheless required to seize the complete transforming cycle [21, 22].
Beyond the skeletal outcomes, the secondary endpoint outcomes revealed all interventions led to favorable anthropometric modifications, with the mixed Met+way of life group demonstrating the best and clinically significant reductions in weight, BMI, and neck circumference, highlighting the additive advantages of pharmacologic and behavioral interventions on this inhabitants even in major care settings [23–27]. Glycemic management improved considerably in all teams, with the mixed intervention yielding the biggest reductions in fasting glucose and HbA1c, once more aligning with present proof supporting multimodal methods in early T2DM administration [2, 28].
Metabolic enhancements had been additional mirrored in lipid and renal biomarkers. HDL elevated modestly within the Met+way of life teams, whereas different lipid fractions remained steady, suggesting a selective cardioprotective impact somewhat than broad lipid transforming. Renal and hepatic parameters remained largely steady, supporting the short-term security of all interventions. Correlation analyses revealed constant associations between modifications in BTMs and anthropometric, glycemic, lipid, and hepatic markers, underscoring the shut interaction between skeletal transforming and metabolic well being in T2DM [29]. Notably, inverse associations between osteocalcin or P1NP and glycemic indices at 6 months reinforce the rising idea of bone as an energetic metabolic organ [30, 31]. It can be attention-grabbing to notice that a rise in creatinine was noticed within the mixture group, and whereas the magnitude of change remained throughout the clinically regular vary, even refined variations in renal operate could affect circulating sclerostin concentrations [32]. Notably, adjustment for creatinine didn’t alter the noticed traits, suggesting that the findings are unlikely to be pushed solely by renal clearance.
The strengths of this examine embrace its randomized design, inclusion of treatment-naïve T2DM individuals, simultaneous evaluation of resorption, formation, and regulatory bone markers, and repeated measurements enable for temporal interpretation in major care settings. The concentrate on a heterogeneous Arab inhabitants additionally addresses a important regional information hole. However, limitations needs to be acknowledged. First is the small pattern dimension primarily because of excessive attrition fee. The achieved pattern dimension was decrease than initially deliberate, lowering the statistical energy and rising the chance of a sort II error. However, whereas the absence of statistically vital between-group variations could partially mirror underpowering, the findings shouldn’t be interpreted solely by way of statistical significance. The course and magnitude of the noticed results, along with the consistency of traits throughout outcomes, present preliminary insights into potential organic responses on this inhabitants. Therefore, whereas some findings reached statistical significance, their scientific relevance needs to be interpreted contemplating impact dimension and established thresholds for significant change. Conversely, sure non-significant traits should still maintain scientific significance, significantly given the pilot nature of the examine. Accordingly, the outcomes are greatest interpreted as exploratory and hypothesis-generating, according to a pilot examine design, and warrant affirmation in bigger adequately powered trials. Other limitations embrace male predominance, absence of BMD or microarchitectural evaluation, and exclusion of people over 65 years in addition to sufferers with osteoporosis, which limits the applicability of the exploratory findings to populations at highest danger for each T2DM and fragility fractures. Additionally, longer follow-up is required to find out whether or not the noticed acute biochemical variations translate into structural or fracture-related outcomes.
In abstract, though no vital between-group variations had been noticed for CTX or different BTMs following the intervention, exploratory within-group analyses within the metformin arm revealed modest reductions in P1NP and osteocalcin at 3 months, in addition to SOST at 6 months, suggesting temporal and short-term modulation of bone turnover, doubtlessly reflecting early adaptive responses to improved metabolic standing somewhat than sustained alterations in skeletal transforming. However, these findings needs to be interpreted with warning given the pilot nature of the examine, the restricted statistical energy, and the absence of constant between-group results. Larger, adequately powered trials with longer follow-up and incorporation of structural skeletal endpoints are required to substantiate these observations and make clear their scientific significance.
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The authors thank Dr Muhaned M. Al Shammari and Dr Mervat Babiker for help in knowledge and pattern assortment.
Conceptualization, MA, SS, NMA; Methodology, MA, SS, and NMA; Sample evaluation, MA, SS and KW; Data curation, MNKK; Writing—authentic draft preparation, MA and SS; Writing—assessment and enhancing, NMA, ISA, SS, and NV; Supervision, SS and NMA; Project administration, SS; Funding acquisition, NMA. All authors have learn and agreed to the revealed model of the manuscript.
The authors are grateful to the Ongoing Research Funding Program-Research Chairs (ORF-RC-2026-14-00), King Saud University, Riyadh, Saudi Arabia, for funding this analysis.
Data are included within the article; additional inquiries will be directed to the corresponding writer.
The authors declare no competing pursuits.
Ethical approval for this examine was granted by the Ministry of Health Institutional Review Board of the Hail Health Cluster (MOH IRB Log No. 2.24-6; February 6, 2024) and the Qassim Health Cluster (MOH IRB Log No. 607/46/3015; September 25, 2024), Kingdom of Saudi Arabia, in addition to by the Institutional Review Board of King Saud University (Approval No. E-24-1470; August 5, 2024). The trial was registered with ClinicalTrials.gov (Identifier: NCT06439758).
Written knowledgeable consent was obtained from all individuals concerned within the examine.
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