Abstract
Type 2 diabetes mellitus (T2DM) related bone fracture. The effects of glucagon-like peptide-1 receptor analogs for the treatment of T2DM on bone are controversial in human studies. This study aimed to compare the effects of GLP-1 receptor analogs exenatide and insulin glargine treatment on bone turnover marker levels and bone mineral density (BMD) in postmenopausal female patients with T2DM. Thirty female patients with T2DM who were naive to insulin and incretin-based treatments, with spontaneous postmenopause, were randomized to exenatide or insulin glargine arms and were followed up for 24 weeks. BMD was evaluated using dual-energy X-ray absorptiometry and bone turnover markers by serum enzyme-linked immunosorbent assay. The body mass index significantly decreased in the exenatide group compared to the glargine group (P < .001). Receptor activator of nuclear factor kappa-B (RANK) and RANK ligand (RANKL) levels were significantly decreased with exenatide treatment (P = .009 and P = .015, respectively). Osteoprotegerin (OPG) level significantly increased with exenatide treatment (P = .02). OPG, RANK, RANKL levels did not change with insulin glargine treatment. No statistically significant difference was found between the pre- and posttreatment BMD, alkaline phosphatase, bone-specific alkaline phosphatase, and type 1 crosslinked N-telopeptide levels in both treatment arms. Despite significant weight loss with exenatide treatment, BMD did not decrease, OPG increased, and the resorption markers of RANK and RANKL decreased, which may reflect early antiresorptive effects of exenatide via the OPG/RANK/RANKL pathway.
Keywords: bone dual-energy X-ray absorptiometry, bone turnover markers, exenatide, insulin glargine, RANKL-RANKL/OPG, type 2 diabetes mellitus
1. Introduction
Type 2 diabetes mellitus (T2DM) is associated with increased bone fracture risk.[1] Hyperglycemia is known to decrease bone turnover.[2,3] Accordingly, antihyperglycemic agents can theoretically be considered to resist the harmful effects of T2DM on bone health. However, in studies, T2DM therapy with thiazolidinedione had been associated with increased fracture risk.[4] These data emphasize further investigation of antihyperglycemic agent effects on bone metabolism.
Glucagon-like Peptide-1 (GLP-1) receptor analogs (GLP-1RAs) are recently widely used as antihyperglycemic and anti-obesity agents. Functional GLP-1 receptor expression was identified on osteoblasts in animal models.[5,6] GLP-1RAs reduce bone resorption and enhance bone mineral density (BMD) in obese mice.[7] GLP-1RAs also affect bone turnover due to their weight loss effect.[8] The effects of GLP-1RAs treatment on bone turnover markers used in clinical practice were controversial in human studies.[8–10] Osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL) signaling axis is an essential regulator of bone remodeling.[11] OPG is a soluble glycoprotein produced mainly by osteoblasts that inhibits osteoclastogenesis by preventing the binding of RANKL to its receptor RANK.[12] There are studies showing that OPG, RANK, and RANKL levels increased in diabetic patients compared to non-diabetics, as well as studies showing that those did not change or decrease.[13–15] However, there are not enough studies examining the effect of GLP-1RAs treatment on the OPG/RANK/RANKL signaling axis.
Insulin glargine is a long-acting basal insulin analog used daily for the treatment of T2DM. Insulin receptors are present on osteoblasts, and insulin may promote the number and activity of osteoblasts.[16] However, in human studies, data on the effect of insulin treatment on bone turnover markers and BMD are conflicting.[17,18]
In addition to the known bone effects of diabetes, negative bone remodeling occurs due to hormonal changes caused by menopause, and the risk of osteoporosis and fracture increases rapidly in postmenopausal women.[19] Therefore, the effect of antidiabetic treatment on bone gains importance, especially in this patient group. In this study, we aimed to evaluate the effects of exenatide and glargine treatments on bone turnover markers and BMD in postmenopausal female patients.
To our knowledge, this is the first study to examine the effects of insulin glargine and the first approved agent of GLP1RAs, exenatide, on bone turnover markers and BMD in postmenopausal female patients with T2DM.
2. Material and methods
2.1. Study design and participants
This randomized, controlled, open-label, 2-arm parallel-group study was performed in 2017 to 2019 at Kocaeli University School of Medicine in the endocrinology outpatient unit.
The study included spontaneous postmenopausal female patients with T2DM and hemoglobin A1c (HbA1c) of 7% to 10% despite using only metformin. In addition, patients between the ages of 45 to 65 and body mass index (BMI) > 30 were included in the study. Those who previously used insulin, pioglitazone, and incretin-based treatment and those with acute pancreatitis history were excluded. Other exclusion criteria: Secondary menopause; Known primary or secondary osteoporosis; Drug consumption, such as anti-osteoporosis (bisphosphonates, denosumab, and teriparatide), corticosteroids, immunosuppressive, levothyroxine, antithyroid, oral anticoagulants, and antiepileptic medication, which will affect bone turnover within the last one year or at present; Thyroid, liver, and kidney dysfunctions; and; History of cancer disease.
Thirty-five patients were enrolled in the study and randomized into 1-to-1 exenatide and insulin glargine treatment arms. Exenatide was started at 5 mcg 2 × 1/day, and after 1 month, the daily dose was revised to 10 mcg 2 × 1/day and used for 24 weeks. Exenatide was applied 1 hour before the morning and evening meals. Insulin glargine was started at a dose of 0.2 IU/kg at 10.00 PM, and titration was made according to the average 3-day morning fasting blood glucose value. Routine physical examination, biochemical analyses, and insulin glargine and exenatide dose titrations were performed, and drug side effects were evaluated at patients 0, 4th, 12th, and 24th-week visits.
BMI, 25-hydroxy (25-OH) vitamin D, fasting glucose, HbA1c serum level, bone turnover markers [alkaline phosphatase (ALP), bone-specific ALP, OPG, RANK, RANKL, type 1 crosslinked N-telopeptide (NTX)], and dual-energy X-ray absorptiometry (DXA) scan were evaluated and compared in baseline and 24-week visits in both treatment arms.
The study included 18 patients in the insulin glargine arm and 17 in the exenatide arm. Two patients did not come to follow-up, and 1 did not want the injection treatment; thus, the treatment was completed with 15 patients in the insulin glargine arm. Additionally, 1 patient did not come to follow-up, and 1 stopped the study due to nausea. Thus, the study was completed with 15 patients in the exenatide arm. Diagram of the study design summarized in Figure 1.
Figure 1.
Diagram of study design.
This study was approved by the local ethics committee of our medical school. (KU GOKAEK 2017/159) All participants received written informed consent.
2.2. Biochemical analysis
After an overnight fast, blood samples were taken at the 0 and 24-week visits at 08.00 AM. Routine biochemistry (glucose, HbA1c, 25-hydroxy vitamin D) was analyzed immediately after sampling at the beginning and at the end of the study. Serum was obtained by centrifuging blood samples and stored at − 80 ºC to investigate bone turnover markers. The frozen serums were analyzed at the end of the study in a single batch to decrease analytical alteration. Plasma glucose levels were analyzed with a glucose analyzer using the glucose oxidase method (Glucose Reagent Kit, Bayer). Serum HbA1c level was measured by high-performance liquid chromatography method in an ADAMS A1c HA-8180V (Arkray Factory, Japan) autoanalyzer. The 25-hydroxy vitamin D level was analyzed using the chemiluminescence immunoassay method with the Siemens Centaur XP device (Siemens Healthcare Diagnostics, Forchheim, Germany). An Elabscience enzyme-linked immunosorbent assay (ELISA) kit was used for determining human soluble OPG, RANK, RANKL, and NTX serum values. The measurements were performed using sandwich-ELISA methods. In the OPG ELISA, the detection antibody is a biotinylated polyclonal anti-OPG antibody; in the RANK ELISA, it is a biotinylated polyclonal anti-RANK antibody; in the RANKL ELISA, it is a biotinylated polyclonal anti-RANKL antibody and in the NTx ELISA, it is a biotinylated polyclonal anti-NTx antibody. In all ELISAs, a conjugate is Avidin-Horseradish Peroxidase conjugate. The amount of OPG, RANK, RANKL, and NTx in the sample was directly proportional to the amount of color developed. The optical density is measured spectrophotometrically at a wavelength of 450 nm ± 2 nm. The intra- and inter-assay coefficients of variation were <10% for OPG, RANK, RANKL, and NTx. OPG, RANK, RANKL, and NTx ELİSA kit sensitivity were 0.10 ng/mL, 0.6 ng/mL, 0.093 ng/mL, and 0.18 ng/mL respectively. Serum levels of ALP and bone-specific ALP were measured with MicroVue human ELISA kit. The enzyme activity of the captured ALP and bone-specific ALP were detected with a para-nitrophenyl-phosphate substrate. ALP and bone-specific ALP ELİSA kits of the intra- and inter-assay coefficients of variation were 4.6% and 6.9%, respectively.
3. Anthropometric measurements
In the first visit, the weight (kg) and height (m) of all participants were measured, and their BMI (kg/m2) was calculated. Body weight and height (without shoes, after an overnight fast) were evaluated using standardized scales calibrated weekly. Weight was measured with the TANITA BC-418 Segmental Body Composition Analyzer in all patients.
3.1. Dual-energy X-ray scan
According to the Lunar standard protocol, BMD was evaluated using DXA using the GE Lunar Prodigy 8743 (GE Healthcare) device. The same blinded technician performed DXA scans. The same blinded investigator analyzed data. DXA measurement was made in the supine position using L1 to L4 vertebrae and left hip posteroanterior projections. Findings were reported as BMD g/cm2, BMD T-score. The baseline and 24-week scans were obtained for each participant on the same device. The coefficient of variation for both spine and hip BMD is approximately 1%.[20]
4. Statistical analysis
Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) for Windows 23.0 (IBM SPSS Inc., Chicago, IL). The conformity of the variables to the normal distribution was examined visually (histogram and probability graphs) and using the Shapiro–Wilk test. Descriptive data were presented as median and maximum-minimum values (median and min-max) for non-normally distributed variables, and additionally as mean and standard deviation for normally distributed data. Mann–Whitney U test was used for independent variables and Wilcoxon Signed Rank test was used for dependent variables to compare the numerical values of the 2 groups that were found to be non-normally distributed. Independent T test was used for independent variables and Paired T test was used for dependent variables to compare the numerical values of the 2 groups that were found to have normal distribution. The results were accepted as 95% confidence interval, statistical significance P < .05.
5. Results
The patient characteristics and pre- and posttreatment biochemical parameters of the exenatide and insulin groups were presented in table 1. Age, age of diabetes, and BMI levels were similar in the insulin glargine and exenatide groups. Two patients in the exenatide group and 3 patients in the glargine group were smokers. None of the patients used alcohol. None of the patients used alcohol. BMI was significantly decreased in the exenatide group (P < .001), whereas there was no significantly decreased (P = .16) in the insulin glargine group (between the groups P < .001) after 24 weeks of treatment. A statistically significant improvement was found in HbA1c levels with exenatide and insulin glargine treatments. However, the improvement was not statistically significant between the groups.
Table 1.
Demographic data, pre, and posttreatment biochemical parameters of the exenatide and insulin glargine groups.
| Variables | Exenatide group (N = 15) | Glargine group (N = 15) | P value |
|---|---|---|---|
| Age (yr) | 52.73 ± 4.68 | 53.00 ± 4.07 | .107 |
| Age of T2DM (yr) | 4.93 ± 4.02 | 6.46 ± 4.27 | .320 |
| Current Smoker (n, %) | 2 (13.33) | 3 (20) | - |
| BMI-pre (kg/m2) | 37.47 ± 4.44 | 34.00 ± 2.91 | .877 |
| BMI -post (kg/m2) | 34.06 ± 3.52 | 33.93 ± 2.83 | .937 |
| P value | <.001 | .167 | |
| Change from baseline (%) | −5.4 (−9.6 to −4.4) | 0.00 (−3.6 to 1.63) | <.001 |
| Glucose-pre (mg/dL) | 147.52 ± 39.44 | 142.81 ± 15.83 | .324 |
| Glucose-post (mg/dL) | 136.73 ± 36.16 | 114.99 ± 18.72 | .044 |
| P value | .004 | .001 | |
| Change from baseline (%) | −13.12 (−24.03 to 5.559) | −20.9 (−35.3 to −6.6) | .005 |
| HBA1C-pre (%) | 8.43 ± 0.99 | 8.10 ± 0.45 | .203 |
| HBA1C-post (%) | 7.32 ± 1.30 | 7.12 ± 0.47 | .595 |
| P value | .003 | <.001 | |
| Change from baseline (%) | −8.5 (−38.5 to 5.9) | −9.6 (−23.4 to 0) | .96 |
| 25-OH vitamin D (ng/mL) | 30.91 ± 14.26 | 30.47 ± 21.43 | .729 |
Data was given as mean ± Standard Deviation or median (min-max) depending on the distribution.
25-OH vitamin D = 25-hydroxy vitamin D, BMI = body mass index, FPG = fasting plasma glucose, HbA1c = hemoglobin A1c, T2DM = Type 2 diabetes mellitus.
The pre-and posttreatment bone turnover marker levels in exenatide and insulin glargine groups were summarized in table 2. pretreatment ALP, bone-specific ALP, NTx, RANK, RANKL, and OPG levels were similar between the groups. No statistically significant difference was found between the pre- and posttreatment ALP, bone-specific ALP, and NTX levels in both groups. RANK and RANKL levels were significantly decreased with exenatide treatment (P = .009 and P = .015, respectively). On the other hand, pre- and posttreatment RANK and RANKL levels were similar in the insulin glargine group. OPG level significantly increased with exenatide treatment (P = .02). Pre- and posttreatment OPG levels were similar with insulin glargine treatment. Comparing OPG changes in 2 groups revealed a significantly increased OPG in the exenatide arm (between the groups P = .007).
Table 2.
Impact of exenatide versus insulin glargine treatment on bone turnover markers.
| Variables | Exenatide group (N = 15) | Glargine group (N = 15) | P value |
|---|---|---|---|
| ALP-pre IU/L | 72.94 ± 18.19 | 74.31 ± 20.19 | .464 |
| ALP-post IU/L | 73.40 ± 21.86 | 70.93 ± 14.57 | .719 |
| P value | .608 | .084 | |
| Change from baseline (%) | 3.4 (−20 to 31.5) | −7.6 (−25.5 to 17) | |
| Bone-specific ALP -pre (μg/L) | 18.78 ± 9.79 | 19.10 ± 7.06 | .268 |
| Bone-specific ALP -post(μg/L) | 17.75 ± 5.71 | 18.04 ± 6.90 | .907 |
| P value | .386 | .102 | |
| Change from baseline (%) | 7.42 (−29.6–42.8) | −8.48 (−38–29.5) | .06 |
| NTX-pre (ng/dL) | 0.18 ± 0.12 | 0.34 ± 0.18 | .069 |
| NTX-post (ng/dL) | 0.21 ± 0.14 | 0.30 ± 0.15 | .151 |
| P value | 1.00 | .67 | .674 |
| Change from baseline (%) | 0.0 (−84.2–82.6) | 0.0 (−75.3–266.6) | .702 |
| RANK-pre (ng/mL) | 3.90 ± 3.26 | 2.61 ± 2.67 | .172 |
| RANK-post (ng/mL) | 2.18 ± 1.98 | 1.75 ± 2.42 | .604 |
| P value | .009 | .140 | |
| Change from baseline (%) | −40.1 (−91.9 to 220.2) | −31.4 (−87.7 to 2966.6) | .389 |
| RANKL-pre (ng/mL) | 0.24 ± 0.29 | 0.41 ± 0.35 | .164 |
| RANKL-post (ng/mL) | 0.02 ± 0.02 | 0.38 ± 0.36 | .01 |
| P value | .015 | .279 | |
| Change from baseline (%) | 45.07 (−53.3 to 930.9) | −9.1 (−91.2 to 1738) | .046 |
| Osteoprotegerin-pre (ng/mL) | 0.64 ± 0.31 | 0.73 ± 0.88 | .596 |
| Osteoprotegerin-post (ng/mL) | 2.54 ± 2.67 | 0.51 ± 0.53 | .01 |
| P value | .020 | .836 | |
| Change from baseline (%) | −31.9 (−81.6 to 62.7) | 28.7 (−58.8 to 4445) | .007 |
Data was given as mean ± Standard Deviation or median (min-max) depending on the distribution.
ALP = alkaline phosphatase, BMP-7 = bone morphogenetic protein, NTX = type 1 crosslinked N-telopeptide, OPG = Osteoprotegerin, RANK = receptor activator of nuclear factor kappa-B, RANKL = RANK ligand.
Group’s pre- and posttreatment DXA parameters were presented in Table 3. No statistically significant difference was found between the pre- and posttreatment lumbar L1 to L4 T-score, lumbar L1 to L4 BMD, femur neck BMD, femur total T-score, and femur total BMD values in both treatment arms.
Table 3.
Impact of exenatide versus insulin glargine treatment on DXA parameters.
| Variables | Exenatide group (N = 15) | Glargine group (N = 15) | P value |
|---|---|---|---|
| Lumbar L1–L4 T-score-pre | 0.06 ± 1.25 | −0.32 ± 1.10 | .303 |
| Lumbar L1–L4 T-score-post | −0.05 ± 1.32 | −0.16 ± 1.06 | .803 |
| P value | .614 | .235 | |
| Lumbar L1–L4 BMD-pre (g/cm2) | 0.19 ± 0.14 | 1.11 ± 0.15 | .188 |
| Lumbar L1-L4 BMD-post (g/cm2) | 1.17 ± 0.14 | 1.13 ± 0.15 | .521 |
| P value | .482 | .255 | |
| Change from baseline (%) | −0.24 (−5.4 to 7.1) | 0.0 (−5.3 to 7.3) | .14 |
| Femur neck T-score-pre | −0.13 ± 1.27 | −0.03 ± 1.21 | .865 |
| Femur neck T- score-post | −0.01 ± 1.11 | 0.47 ± 1.57 | .397 |
| P value | .340 | .389 | |
| Femur neck BMD-pre (g/cm2) | 1.02 ± 0.17 | 0.99 ± 0.18 | .721 |
| Femur neck BMD-post (g/cm2) | 1.04 ± 0.14 | 1.11 ± 0.21 | .357 |
| P value | .348 | .406 | |
| Change from baseline (%) | 0.8 (−4.4 to 14.2) | −0.06 (−5.6 to 72) | .61 |
| Femur Total T- score-pre | 0.51 ± 1.26 | 0.28 ± 1.19 | .698 |
| Femur Total T- score-post | 0.62 ± 1.34 | 0.89 ± 1.46 | .549 |
| P value | .598 | .452 | |
| Femur total BMD-pre (g/cm2) | 1.08 ± 0.15 | 1.05 ± 0.16 | .801 |
| Femur total BMD-post(g/cm2) | 1.09 ± 0.16 | 1.15 ± 0.18 | .393 |
| P value | .582 | .472 | |
| Change from baseline (%) | 0.000 (−3.1 to 5.33) | 0.004 (−6.2 to 49.5) | .68 |
Data was given as mean ± Standard Deviation or median (min-max) depending on the distribution.
BMD = bone mineral density, DXA = dual-energy X-ray absorptiometry.
6. Discussion
This study revealed a significant weight loss with exenatide compared to glargine treatment; also, RANK and RANKL levels significantly decreased, and the OPG level increased with the exenatide treatment. However, bone formation markers did not change with these treatments, and hip and spine BMD were preserved.
In the literature, it was previously showed that GLP-1RAs decreased RANKL expression and increased OPG expression in diabetic and osteoporotic rats.[21] Consistently, another study showed that OPG expression was increased by both GLP-1 and exendin-4 administration; however, RANKL expression was increased with GLP-1 but unchanged with exendin-4 administration in hyperlipidemic rats.[7] In a recent study, the impact of gastric inhibitory polypeptide and GLP-1 on osteoblast-like MC3T3-E1 cells was examined, and it was found that GLP-1 significantly increased the prostaglandin F2 alpha -induced synthesis of OPG.[22] To our knowledge, there was no human study on this issue yet. Our clinical study, consistently revealed that OPG significantly increased after exenatide treatment and was also unchanged with the glargine treatment. On the other hand, RANK and RANKL levels were significantly decreased with exenatide treatment but did not change with glargine treatment in this study.
Weight loss results in bone loss and a decrease in BMD. Weight loss-induced bone loss is due to increased bone turnover, with greater stimulation of bone resorption than bone formation.[23] Although there are studies showing a decrease in BMD in hip and spine, a large meta-analysis showed that diet-induced weight loss affected the BMD at the hip but not at the spine, increasing or not changing bone formation and resorption markers.[24,25] GLP-1RAs can cause significant weight loss. Thus, after especially among patients in advanced age, rapid weight loss increases the risk of fractures, and negatively affect bone formations.[26,27] In the present study, despite significant weight loss compared to glargine, we observed no changes in the spine and lumbar BMD, however OPG level increased, RANK and RANKL levels decreased with exenatide treatment. Similar to our study, Bunck et al[9] found that 44 weeks of treatment with the exenatide did not change total body BMD despite weight loss in patients with T2DM. Hygum et al[28] showed that both spine and femoral neck total BMD remained stable during weight loss and weight maintenance with liraglutide treatment in patients with T2DM by DXA and quantitative computed tomography. Consistent with this study, Cai et al[29] showed that 52-week exenatide treatment increased total hip BMD. There are conflicting data on this subject, and long-term studies with large groups are needed.[30,31] There was no significant change in BMI and BMD with treatment in the glargine group. Similar to our study, there are studies in the literature showing that BMD does not change with glargine treatment[9] and there are studies showing that it increases differently with our study.[29]
The lack of bone resorption despite weight loss with exenatide treatment can be considered due to its effects on OPG/RANK/RANKL signaling system. RANKL binds to RANK receptor in osteoclast progenitor cells and leads to differentiation and activation of osteoclasts. Moreover, RANKL is bound by OPG, which inhibits osteoclast differentiation.[32,33] Bone resorption decreases when OPG increases and RANKL decreases. OPG can protect bones by neutralizing RANKL’s osteoclastic features it was also showed in postmenopauseal patient grup[34–36] One of the important causes of increased bone resorption in menopause is the sharp decrease in estrogen level. The decline in serum estrogen leads to increased expression of RANKL and an in vivo metabolite of phytoestrogens, which significantly increases the mRNA and protein expression of OPG and OPG/RANKL ratio.[37,38] Although previously mentioned animal studies found evidence of these associations between GLP-1RAs and OPG/RANK/RANKL systems, the impacts of GLP-1RAs on the OPG/RANK/RANKL system appear contradictory in the literature.
Considering the studies examining other bone markers in the literature, Li et al[10] revealed that bone formation and resorption markers remained unaffected after the 24-week exenatide treatments. Also, Hygum et al[28] revealed that bone formation and resorbtion markers were affected by GLP-1 RAs, neither during weight loss nor during weight maintenance. In a recent study, exenatide treatment added to insulin in patients with type 1 diabetes mellitus showed no significant change in BMD, C-terminal cross-linking telopeptide (CTX) one of the resorption markers, and procollagen type 1 N- terminal propeptide (P1NP) one of the formation markers, despite significant weight loss in the exenatide arm.[39] Consistent with these studies, the present study revealed that the NTx, ALP, and bone-specific ALP were unchanged with exenatide and insulin glargine treatment. In contrast, Iepsen et al[8] showed that GLP-RAs increased P1NP and osteocalcin in nondiabetic obese patients; however, their effect on CTX has not been demonstrated. Similar to the present study, Bunck et al showed ALP did not change with 44 weeks of glargine treatment. Also, Stage et al[18] showed that short or long-acting human insulin did not affect CTX and P1NP levels.
Limitations of our study include a lack of bone quality assessment, such as quantitative computed tomography or bone biopsy evaluation, and the short follow-up period of 6 months, which could be insufficient to observe bone quality improvements. The number of patients was small and included a small specific group. Another limitation of our study was that we did not evaluate bone fractures or fracture risk.
7. Conclusion
This study showed that despite significant weight loss with exenatide treatment, BMD did not decrease; In addition, there was no significant BMI and BMD change after glargine treatment. While there was no increase in bone formation markers, OPG increased, and the resorption markers of RANK and RANKL decreased, which may reflect early antiresorptive effects of exenatide via the OPG/RANK/RANKL pathway in postmenopausal diabetic women. Further evaluation is required with patients with a larger number of patients and longer follow-ups.
Acknowledgments
Preparation for publication of this article is supported by the Society of Endocrinology and Metabolism.
Author contributions
Conceptualization: Ozlem Zeynep Akyay, Zeynep Canturk, Alev Selek, Berrin Cetinarslan, İlhan Tarkun, Yagmur Cakmak, Canan Baydemir.
Data curation: Ozlem Zeynep Akyay, Zeynep Canturk, Alev Selek, Yagmur Cakmak.
Formal analysis: Ozlem Zeynep Akyay, Zeynep Canturk, Alev Selek, Berrin Cetinarslan, İlhan Tarkun, Yagmur Cakmak, Canan Baydemir.
Funding acquisition: Ozlem Zeynep Akyay.
Investigation: Ozlem Zeynep Akyay, Zeynep Canturk, Alev Selek.
Methodology: Ozlem Zeynep Akyay, Zeynep Canturk, Alev Selek, Berrin Cetinarslan, İlhan Tarkun.
Project administration: Ozlem Zeynep Akyay, Zeynep Canturk.
Resources: Ozlem Zeynep Akyay.
Software: Ozlem Zeynep Akyay, Alev Selek, Yagmur Cakmak.
Supervision: Zeynep Canturk, Alev Selek, Berrin Cetinarslan, İlhan Tarkun.
Validation: Zeynep Canturk, Alev Selek, İlhan Tarkun, Yagmur Cakmak.
Visualization: Ozlem Zeynep Akyay, Alev Selek, Berrin Cetinarslan, İlhan Tarkun, Yagmur Cakmak.
Writing – review & editing: Zeynep Canturk, Alev Selek, Berrin Cetinarslan, İlhan Tarkun, Canan Baydemir.
Abbreviation:
- ALP
- alkaline phosphatase
- BMD
- bone mineral density
- BMI
- body mass index
- CTX
- C-terminal cross-linking telopeptide
- DXA
- dual-energy X-ray absorptiometry
- ELISA
- enzyme-linked immunosorbent assay
- GLP-1
- glucagon-like peptide-1
- GLP-1Ras
- GLP-1 receptor analogs
- HbA1c
- hemoglobin A1c
- NTX
- type 1 crosslinked N-telopeptide
- OPG
- osteoprotegerin
- P1NP
- procollagen type 1 N- terminal propeptide
- RANK
- receptor activator of nuclear factor kappa-B
- RANKL
- RANKL ligand
- T2DM
- type 2 diabetes mellitus
This study was supported by Kocaeli University Scientific Research Projects Unit. (KOU BAP 2017/193).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Akyay OZ, Canturk Z, Selek A, Cetinarslan B, Tarkun İ, Cakmak Y, Baydemir C. The effects of exenatide and insulin glargine treatments on bone turnover markers and bone mineral density in postmenopausal patients with type 2 diabetes mellitus. Medicine 2023;102:39(e35394).
Contributor Information
Zeynep Canturk, Email: zeynepcanturk@hotmail.com.
Alev Selek, Email: alevselek@gmail.com.
Berrin Cetinarslan, Email: barslan@kocaeli.edu.tr.
İlhan Tarkun, Email: ilhantarkun@superonline.com.
Yagmur Cakmak, Email: dr.ygmr@gmail.com.
Canan Baydemir, Email: canandoruk@hotmail.com.
References
- [1].Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377:1276–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Brown JP, Don-Wauchope A, Douville P, et al. Current use of bone turnover markers in the management of osteoporosis. Clin Biochem. 2022;109-110:1–10. [DOI] [PubMed] [Google Scholar]
- [3].Purnamasari D, Puspitasari MD, Setiyohadi B, et al. Low bone turnover in premenopausal women with type 2 diabetes mellitus as an early process of diabetes-associated bone alterations: a crosssectional study. BMC Endocr Disord. 2017;17:72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Wei W, Wan Y. Thiazolidinediones on PPARgamma: the roles in bone remodeling. PPAR Res. 2011;2011:867180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Pereira M, Jeyabalan J, Jørgensen CS, et al. Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice. Bone. 2015;81:459–67. [DOI] [PubMed] [Google Scholar]
- [6].Sun HX, Lu N, Liu DM, et al. The bone- preserving effects of exendin-4 in ovariectomized rats. Endocrine. 2016;51:323–32. [DOI] [PubMed] [Google Scholar]
- [7].Nuche-Berenguer B, Lozano D, Gutiérrez-Rojas I, et al. GLP-1 and exendin-4 can reverse hyperlipidic-related osteopenia. J Endocrinol. 2011;209:203–10. [DOI] [PubMed] [Google Scholar]
- [8].Iepsen EW, Lundgren JR, Hartmann B, et al. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J Clin Endocrinol Metab. 2015;100:2909–17. [DOI] [PubMed] [Google Scholar]
- [9].Bunck MC, Eliasson B, Cornér A, et al. Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:374–7. [DOI] [PubMed] [Google Scholar]
- [10].Li R, Xu W, Luo S, et al. Effect of exenatide, insulin and pioglitazone on bone metabolism in patients with newly diagnosed type 2 diabetes. Acta Diabetol. 2015;52:1083–91. [DOI] [PubMed] [Google Scholar]
- [11].Martin TJ, Sims NA. RANKL/OPG; critical role in bone physiology. Rev Endocr Metab Disord. 2015;16:131–9. [DOI] [PubMed] [Google Scholar]
- [12].Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol United States. 2002;22:549–53. [DOI] [PubMed] [Google Scholar]
- [13].Movahed A, Larijani B, Nabipour I, et al. Reduced serum osteocalcin concentrations are associated with type 2 diabetes mellitus and the metabolic syndrome components in postmenopausal women: the crosstalk between bone and energy metabolism. J Bone Miner Metab. 2012;30:683–91. [DOI] [PubMed] [Google Scholar]
- [14].Rozas Moreno P, Reyes García R, García-Martín A, et al. Serum osteoprotegerin: bone or cardiovascular marker in type 2 diabetes males? J Endocrinol Invest. 2013;36:16–20. [DOI] [PubMed] [Google Scholar]
- [15].Sassi F, Buondonno I, Luppi C, et al. Type 2 diabetes affects bone cells precursors and bone turnover. BMC Endocr Disord. 2018;18:55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Fulzele K, Riddle RC, DiGirolamo DJ, et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142:309–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Liu D, Bai JJ, Yao JJ, et al. Association of insulin glargine treatment with bone mineral density in patients with type 2 diabetes mellitus. Diabetes Metab Synd Obes. 2021;14:1909–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Stage TB, Christensen M-MH, Jørgensen NR, et al. Effects of metformin, rosiglitazone and insulin on bone metabolism in patients with type 2 diabetes. Bone. 2018;112:35–41. [DOI] [PubMed] [Google Scholar]
- [19].Kanis JA, Cooper C, Rizzoli R, et al. Reginster JY on behalf of the Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the committees of scientific advisors and national societies of the international osteoporosis foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2019;30:3–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Orwoll ES, Oviatt SK. Longitudinal precision of dual-energy x-ray absorptiometry in a multicenter study. The Nafarelin/bone study group. J Bone Miner Res. 1991;6:191–7. [DOI] [PubMed] [Google Scholar]
- [21].Wen B, Zhao L, Zhao H, et al. Liraglutide exerts a bone-protective effect in ovariectomized rats with streptozotocin-induced diabetes by inhibiting osteoclastogenesis. Exp Ther Med. 2018;15:5077–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Hioki T, Kuroyanagi G, Fujita K, et al. Incretins Enhance PGF2α-Induced Synthesis of IL-6 and osteoprotegerin in osteoblasts. Horm Metab Res. 2022;54:42–9. [DOI] [PubMed] [Google Scholar]
- [23].Villareal DT, Shah K, Banks MR, et al. Effect of weight loss and exercise theraphy on bone metabolism and mass in obese older adults: a one year randomized controlled trial. J Clin Endocrinol Metab. 2008;93:2181–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Zibellini J, Seimon RV, Lee CM, et al. Does diet-induced weight loss Lead to bone loss in overweight or obese adults? A systematic review and meta-analysis of clinical trials. J Bone Miner Res. 2015;30:2168–78. [DOI] [PubMed] [Google Scholar]
- [25].Villalon KL, Gozansky WS, Van Pelt RE, et al. A losing battle: weight regain does not restore weight loss-induced bone loss in postmenopausal women. Obesity (Silver Spring). 2011;19:2345–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Jensen LB, Quaade F, Sørensen OH. Bone loss accompanying voluntary weight loss in obese humans. J Bone Miner Res. 1994;9:459–63. [DOI] [PubMed] [Google Scholar]
- [27].Langlois JA, Mussolino ME, Visser M, et al. Weight loss from maximum body weight among middle-aged and older white women and the risk of hip fracture: the NHANES I epidemiologic follow-up study. Osteoporos Int. 2001;12:763–8. [DOI] [PubMed] [Google Scholar]
- [28].Hygum K, Harsløf T, Jørgensen NR, et al. Bone resorption is unchanged by liraglutide in type 2 diabetes patients: a randomised controlled trial. Bone. 2020;132:115197. [DOI] [PubMed] [Google Scholar]
- [29].Cai TT, Li HQ, Jiang LL, et al. Effects of GLP-1 receptor agonists on bone mineral density in patients with type 2 diabetes mellitus: a 52-week clinical study. Biomed Res Int. 2021;2021:3361309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [30].Su B, Sheng H, Zhang M, et al. Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists treatment: a meta-analysis of randomized controlled trials. Endocrine. 2015;48:107–15. [DOI] [PubMed] [Google Scholar]
- [31].Huang CF, Mao TY, Hwang SJ. The effects of switching from dipeptidyl peptidase-4 inhibitors to glucagon-like peptide-1 receptor agonists on bone mineral density in diabetic patients. Diabetes Metab Syndr Obes. 2023;16:31–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [32].Luo G, Liu H, Lu H. Glucagon-like peptide-1(GLP-1) receptor agonists: Potential to reduce fracture risk in diabetic patients? Br J Clin Pharmacol. 2016;81:78–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [33].Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci. 2006;1092:385–96. [DOI] [PubMed] [Google Scholar]
- [34].Tyrovola JB, Spyropoulos MN, Makou M, et al. Root resorption and the OPG/RANKL/RANK system: a mini review. J Oral Sci. 2008;50:367–76. [DOI] [PubMed] [Google Scholar]
- [35].Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med. 2005;11:76–81. [DOI] [PubMed] [Google Scholar]
- [36].Weitzmann MN. The role of inflammatory cytokines, the RANKL/OPG axis, and the immunoskeletal interface in physiological bone turnover and osteoporosis. Scientific. 2013;2013:125705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [37].Ni X, Wu B, Li S, et al. Equol exerts a protective effect on postmenopausal osteoporosis by upregulating OPG/RANKL pathway. Phytomedicine. 2023;108:154509. [DOI] [PubMed] [Google Scholar]
- [38].Tella SH, Gallagher JC. Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol. 2014;142:155–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [39].Johansen NJ, Dejgaard TF, Lund A, et al. Effect of short – acting exenatide added three times daily to insulin theraphy on bone metabolism in type 1 diabetes. Diabetes Obes Metab. 2022;24:221–7. [DOI] [PubMed] [Google Scholar]