
==== Front
J Bone Metab
J Bone Metab
Journal of Bone Metabolism
2287-6375
2287-7029
The Korean Society for Bone and Mineral Research

10.11005/jbm.2024.31.3.169
jbm-2024-31-3-169
Review Article
Antidiabetic Agents and Bone Quality: A Focus on Glycation End Products and Incretin Pathway Modulations
https://orcid.org/0009-0007-3941-1228
Zaki Muthanna K. 1
https://orcid.org/0000-0002-2253-4420
Abed Mohammed N. 2
https://orcid.org/0000-0002-2933-9185
Alassaf Fawaz A. 1
1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq
2 Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
Corresponding author: Mohammed N. Abed, Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, University Street, Mosul 41002, Iraq, Tel: +964-7518354126, Fax: +964-7518354126, E-mail: m.n.abed@uomosul.edu.iq
8 2024
31 8 2024
31 3 169181
2 3 2024
1 5 2024
18 5 2024
Copyright © 2024 The Korean Society for Bone and Mineral Research
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diabetes mellitus is associated with inadequate bone health and quality and heightened susceptibility to fractures, even in patients with normal or elevated bone mineral density. Elevated advanced glycation end-products (AGEs) and a suppressed incretin pathway are among the mechanisms through which diabetes affects the bone. Accordingly, the present review aimed to investigate the effects of antidiabetic medications on bone quality, primarily through AGEs and the incretin pathway. Google Scholar, Cochrane Library, and PubMed were used to examine related studies until February 2024. Antidiabetic medications influence AGEs and the incretin pathway directly or indirectly. Certain antidiabetic drugs including metformin, glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl-peptidase-4 (DDP-4) inhibitors, α-glucosidase inhibitors (AGIs), sodium-glucose co-transporter-2 inhibitors, and thiazolidinediones (TZDs), directly affect AGEs through multiple mechanisms. These mechanisms include decreasing the formation of AGEs and the expression of AGEs receptor (RAGE) in tissue and increasing serum soluble RAGE levels, resulting in the reduced action of AGEs. Similarly, metformin, GLP-1RA, DDP-4 inhibitors, AGIs, and TZDs may enhance incretin hormones directly by increasing their production or suppressing their metabolism. Additionally, these medications could influence AGEs and the incretin pathway indirectly by enhancing glycemic control. In contrast, sulfonylureas have not demonstrated any obvious effects on AGEs or the incretin pathway. Considering their favorable effects on AGEs and the incretin pathway, a suitable selection of antidiabetic drugs may facilitate more protective effects on the bone in diabetic patients.

Antidiabetic agents
Bone
Diabetes Mellitus
Glycation
Incretin
==== Body
pmcGRAPHICAL ABSTRACT

INTRODUCTION

Skeletal fragility frequently coexists with type 1 and type 2 diabetes, where it is regarded as a pathological consequence of this condition. While low bone mass in type 1 diabetes mellitus (T1DM) can greatly increase the risk of fractures, individuals with type 2 DM (T2DM) also experience an increased incidence of fractures, even when normal or high bone mineral density (BMD) and a higher body mass index are present (factors that protect against fractures in non-diabetic individuals). Therefore, diabetes may be linked to a reduction in the strength of bone that is not accurately represented by the measurement of BMD. Rendering to the current definition, determining bone strength involves considering both bone density and quality, which include the structural and material characteristics of bone.[1] Historically, the most commonly used measurement for fracture risk prediction was BMD, a quantitative parameter measured by dual energy X-ray absorptiometry, however, this technique could incompletely expresses the fracture risk.[2] On the other hand, image-based noninvasive parameters, such as the trabecular bone score, quantitative computed tomography (QCT), and high-resolution peripheral QCT are newer approaches for assessing the bone quality.[3]

Generally, diabetes decreases the quality of bone instead of BMD. The process of collagen cross-linking is crucial for bone strength. Collagen cross-links can be further classified as enzymatic immature divalent cross-links, mature trivalent cross-links mediated by lysyl hydroxylase and lysyl oxidase, and non-enzymatic cross-links caused by oxidation or glycation (advanced glycation end-products [AGEs]) such as pentosidine (PEN), which is a surrogate marker of AGEs. The formation mechanisms and functionalities of these cross-link types differ from one another.[4] The presence of either reduced enzymatic cross-linking or an increase in non-enzymatic cross-links in bone collagen is believed to be a major contributing factor to the fragility of bones in aging, osteoporosis, and DM.[5]

Furthermore, the incretin hormone which includes glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) was demonstrated to have beneficial effects on bone metabolism, the effect of these hormones is reduced or even absent in diabetic patients.[6] The material qualities of bone tissue are controlled by cellular activity, the rate of bone tissue turnover, and the degrees of oxidative stress and glycation.[7]

Some antidiabetic drugs may decrease the risk of fracture and improve bone quality while others do not. As shown in Table 1, the mechanisms that promote these effects are multiple.[8] However, some antidiabetic medications, including sulfonylureas and insulin, have a greater tendency to cause hypoglycemia, which in turn increases the risk of fall-related fractures regardless of their effects on the bone.[9] This review will summarize the current knowledge about the impacts of antidiabetic medications on bone health, focusing on their effects on AGEs and incretin pathways in diabetic patients. This review article will discuss the effects of AGEs on the bone, the bone effects of incretin hormones including GIP, GLP-1, and GLP-2, the effects of antidiabetic medications on AGEs and incretin pathway, in addition to the clinical impacts of these medications on the bone.

METHODS

This article is a narrative review that mainly discusses the impacts of antidiabetic medications on bone health, focusing on their effects on AGEs and the incretin pathway in T2DM. Using keywords related to the main subject of this study, a literature search was conducted between November 2023 and February 2024 on databases including Google Scholar, Cochrane Library, and PubMed. Antidiabetics, DM, diabetic complications, and bone diseases, were used separately and in combination to reveal articles related to the main topic until the date of drafting this review. Inclusion criteria included articles that discuss bone alterations in diabetic patients, and the effects of antidiabetic drugs on the bone particularly their effects on AGEs and incretin pathway, in addition to articles that discuss the clinical significance and/or non-significance of antidiabetics on the bone. The current narrative review goes into additional detail about these articles.

EFFECT OF AGES ON THE BONE (Fig. 1)

Type I collagen is a crucial constituent of bone and acts as a structural scaffold that improves the strength of the skeleton through mineralization. Type I collagen is a fibrous protein arranged in a triple-helix pattern, which allows it to form organized fibrils that are made stronger through enzymatic cross-linking. Aside from enzymatic cross-linking, type I collagen can also undergo chemical cross-linking with “free-floating” sugars in the serum through the bonding of exposed amino acid residues. This can lead to post-translational modifications of collagen and ultimately the formation of AGEs. Individuals with DM are more likely to have AGEs accumulation in various organs, including bone.[4]

By interacting with the cell surface receptor for AGEs (RAGE), both non-cross-linking includes Nɛ-carboxymethyllysine and cross-linking forms of AGEs impair osteoblastic function as shown in Figure 1. In the bone AGE-RAGE binding primarily induces apoptosis and altered differentiation of osteoblasts. This is accompanied by an increased expression of the receptor activator of nuclear factor-κB ligand (RANKL), which promotes increased osteoclastogenesis and impedes bone mineralization.[10] Along with an increase in RANKL mRNA expression, these effects are at least in part mediated by osteocalcin mRNA and alkaline phosphatase (ALP) downregulation, as well as an increase in RAGE expression that promotes the AGE-RAGE pathway.[11] Additionally, transforming growth factor-β (TGF-β) is secreted and expressed more when AGE-RAGE binding occurs, which prevents osteoblastic cells from differentiation and mineralization.[12] AGEs also results in the inhibition of signaling pathways, include Wnt/β-catenin (the primary regulator of osteoblast development and activity), that are crucial for maintaining skeletal homeostasis.[13]

On the other hand, the effects of AGEs on bone resorption by osteoclasts are controversial. In response to RANKL stimulation, bone marrow macrophages release a non-histone nuclear protein known as high mobility group box 1 (HMGB1). Via RAGE, the extracellular HMGB1 regulates the remodeling, differentiation, and function of the osteoclastic actin cytoskeleton. Thus, it appears that the regulation of osteoclast activity is also influenced by the interaction between RAGE and other ligands.[14] Additionally, it appears that RANKL encourages the expression of RAGE and, as a result, osteoclast differentiation.[15]

Moreover, RAGE can be generated as a soluble “decoy” receptor that could prevent AGE–RAGE signaling axes by binding AGEs. It has been demonstrated that low serum concentrations of soluble RAGE and elevated serum concentrations of the AGE PEN are independent of BMD risk indicators for fractures in diabetes.[16] Furthermore, AGEs competitively block the production of enzymatic cross-links by binding to lysine residues, which are critical locations for enzymatic cross-linking in collagen molecules. Additionally, AGEs cross-link themselves decrease the strength of bone without causing cellular dysfunction. The overproduction of AGE cross-links in bone results in the brittleness of collagen fibers, leading to the buildup of microdamage. This microdamage then causes a decline in the post-yield properties and toughness of the bone.[17] The regulation of AGEs generation is dependent upon tissue life span, oxidative stress, and glycemic control.[18]

EFFECTS OF INCRETIN PATHWAY ON THE BONE

GLP-1 and GIP are the primary incretins generated by the intestine in response to dietary intake, and they function through signaling-mediated mechanisms by incretin receptors. Enteroendocrine cells in the intestinal mucosa secrete GLP-1, which binds to GLP-1 receptors (GLP-1Rs) found on various cell types, including islet β-cells. This interaction leads to metabolic consequences in multiple organs. Bone-related cells also express GLP-1Rs, which trigger a variety of effects. On the other hand, GIP receptors (GIPRs) are also expressed in human osteoblasts, indicating various stages of differentiation.[19]

Bone turnover is defined as a dynamic process that includes the use of energy from meal consumption. Inadequate availability of essential nutrients, particularly during the night, might stimulate the breakdown of bone tissue to maintain a consistent balance of calcium in the body.[20] Following the intake of meals, bone resorption is subsequently suppressed. The occurrence of this event may be influenced by gastrointestinal hormones that are secreted following the intake of food, such as GLP-1 and GIP.[21] Consistent with this theory, the finding that intravenous feeding is linked to lowered bone density indicates that a deficiency in incretin hormones may contribute to changes in bone remodeling.[22] Notably, many investigations have suggested that the incretin hormones GLP-1 and GIP may have a beneficial effect on bone health related to their ability to reduce bone loss and promote bone growth, as shown in Figure 2. Suggests that antidiabetic medicines such as GLP-1R agonists (GLP-1RA) or dipeptidyl peptidase-4 (DPP-4) inhibitors may have a positive effect on bone metabolism.[23–25]

GIP AND BONE METABOLISM

A functioning GIPR with high affinity that increases intracellular calcium levels via the cyclic adenosine 3′,5′-monophosphate pathway was found by Bollag et al. [19] in their study of GIPR expression in normal rat bone, osteoblasts, osteocytes, and osteoblast-like cell lines. Furthermore, in osteoblastic-like cells, GIP increases ALP activity and collagen type 1 expression, suggesting the anabolic effects of this incretin hormone.[26] These observations have been validated in ovariectomized rats that are associated with bone loss as compared with normal rats, intermittent administration of GIP in these models results in a significant rise in lumbar BMD specifically in ovariectomized rats. In addition, they confirmed that the activity of GIP is dependent on both dose and duration, where within three hours of treatment, high concentrations of GIP decreased GIPR expression in Saos-2 cells, whereas lower concentrations of GIP required a longer exposure period to reduce GIPR. Consequently, intermittent administration of GIP seems to have a beneficial effect on bone health, similar to parathyroid hormone, by promoting bone formation and preventing bone loss.[27] Furthermore, a study on animals with a deletion of the GIPR found a significant reduction in the degree of mineralization of bone matrix, the amount of mature cross-links of the collagen matrix, and lowered intrinsic material characteristics. In this study, the decline in collagen cross-link ratio was higher in trabecular bone (~42%) as compared with cortical bone (~16%). On the other hand, heterogeneity in BMD distribution was not significantly reduced in trabecular bone, while it was significantly increased in cortical bone. In other words, it appears that the alteration of collagen maturity was greater in the trabecular bone, but the alteration of mineral maturity was greater in the cortical bone.[28] The presence of GIPRs was also observed in osteoclastic-like cells of murine, where GIP seems to inhibit bone resorption triggered by RANKL.[29]

In addition, the process of bone formation and bone resorption was evaluated using two collagen-based markers, procollagen type N-terminal propeptide of type I collagen (P1NP) and C-terminal telopeptide (CTX). The administration of GIP infusion in this study led to an augmentation of the P1NP response, which is associated with bone formation, and a reduction in the CTX response, which is linked to bone resorption, during the hyperglycemic clamp. Thus, GIP has been shown to have advantageous impacts on bone quality.[30]

GLP-1, GLP-2 AND BONE METABOLISM

Examining the impact of GLP-1 administration on bone in three different glycometabolic condition revealed that participants with glucose metabolism exhibited a beneficial impact of GLP-1 on bone structure after 3 days treatment with either GLP-1 or a placebo.[31]

It was also shown that GLP-1 can interact with human osteoblasts through a receptor that is distinct from the GLP-1R receptor found in the pancreas. GLP-1 selectively attaches to the cell membrane of osteoblastic MC3T3-EI cells to trigger the rapid breakdown of glycosylphosphatidylinositols, resulting in the production of diacylglycerol and inositol phosphoglycans which function as secondary messengers. The interaction between GLP-1 and MC3T3-EI influenced gene expression, specifically increasing the expression of osteocalcin, which is the primary protein released by osteoblasts.[32] In addition, osteocytes release sclerostin (SOST), which is produced by the SOST gene and favors the inhibition of bone development. It has been discovered that GLP-1 decreases SOST mRNA levels, resulting in decreasing the harmful effects of SOST on the bone.[33]

Furthermore, Henriksen et al. [21] demonstrated a reduction in nocturnal bone breakdown following the delivery of GLP-2 at 10 PM. A total of 160 postmenopausal women were randomly grouped into four different groups. Each group received a daily dose of either 0.4, 1.6, or 3.2 mg of GLP-2, or a placebo. Additionally, all participants were given calcium and vitamin D supplements for 120 days. The results indicated that GLP-2 treatment did not have any harmful effects, and, notably, there was a substantial increase in BMD that was depending on the dosage. The 1.6 mg and 3.2 mg doses showed statistically significant improvements in BMD compared to the placebo. The administration of GLP-2 resulted in an instant and continuous reduction in bone resorption markers including CTX. However, the levels of bone production markers, such as osteocalcin, were unaffected.[21]

EFFECTS OF ANTIDIABETIC MEDICATIONS ON AGES AND INCRETIN PATHWAY

Metformin has been demonstrated to reduce AGE-RAGE pathway, beyond glycemic control, it led to inactivation of reactive carbonyl species, thus resulting in lower carbonyl stress and decreased formation of deleterious AGEs. Furthermore, it can effectively decrease the expression of RAGE in endothelial cells subjected to elevated levels of glucose or AGEs.[34] Additionally, metformin inhibited cell death caused by AGE and reduced the production of RAGE protein in cultured osteoblastic cells.[35] Moreover, metformin has been observed to increase plasma active GLP-1 levels with various mechanisms. It promotes the production of pro-glucagon (a precursor of GLP-1) in the large intestine and directly boosts GLP-1 release from entero-endocrine GLP-1-producing cells leading to an elevation in total GLP-1 concentrations.[36] Beyond this stimulating action, metformin has also been linked to the up-regulation of GLP-1R and GIPR expression in pancreatic beta cells through a peroxisome proliferator-activated receptor (PPAR) dependent pathway.[37] Also, it has been observed that metformin inhibits DPP-4 activity in T2DM patients.[38] On the other hand, sulfonylureas reduces AGEs indirectly through the enhancement in glycemic control.[39] Also, it demonstrated no significant effects on the incretin pathway.[40]

GLP-1RA directly activating the GLP-1R that potentiates the incretin pathway.[41] Regarding AGEs, GLP-1 agonists was suggested to suppress oxidative stress generation induced by AGEs-RAGE and reduce tissue expression of RAGE via activation of cyclic adenosine monophosphate pathways.[42]

DPP-4 inhibitors act by inhibiting the degradation of endogenous incretin by DDP-4 enzyme and so improve the action of incretin pathway.[43] It has been discovered that the production of oxidative stress caused by AGE-RAGE interaction leads to the release of DPP-4. This, in turn, enhances the harmful effects of AGEs, DPP-4 inhibitors provide a protection from these effects.[44,45] Additionally, it has been revealed that, vildagliptin, a DPP-4 inhibitor, is associated with decreased AGEs to some extents.[46]

α-glucosidase inhibitors (AGIs) including acarbose demonstrated to reduce the level of AGEs by acting as AGEs-inhibiting in patients with diabetes and decreases AGEs serum levels.[47] Additionally, by blocking α-glucosidase in the upper part of the small intestine, leads to the presence of significant quantities of undigested carbohydrates in the lower part of the small intestine. The ileum, a section of the small intestine, contains a high concentration of entero-endocrine L-cells. When these cells come into contact with foods, particularly carbohydrates they release GLP-1. Therefore, AGIs result in enhancement the secretion of GLP-1 from the intestine and potentiate the incretin pathway.[48]

The impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on AGEs is not well understood however, it was suggested that improvements in glycemic control, as well as the restoration of renal and cardiovascular function, are anticipated mechanism by which SGLT2 inhibitors minimize AGE generation and accumulation.[49] Also, SGLT2 inhibitors have been demonstrated to decrease the formation of reactive oxygen species, therefore decreasing the buildup of AGEs in chronic diseases, including DM. Furthermore, due to enhancements in glomerular filtration resulting from SGLT2 inhibition, AGEs will likely be eliminated more efficiently.[50] These medications have shown to enhance the sensitivity of pancreatic beta cells to GLP-1 and GIP in diabetic patients, which may be related to improved glycemic control.[51] On the other hand, Administering canagliflozin to individuals after gastric bypass surgery did not decrease the 4-hr plasma GLP-1 responses, but it decreased the initial increase in GLP-1 and GIP hormones.[52]

Thiazolidinediones (TZDs) demonstrated to increase the level of total serum soluble RAGE that may lead to decrease the harmful effects of AGEs.[53] Furthermore, it reduce the tissue RAGE expression resulting in decreases proinflammatory effects of AGEs.[54] Additionally, TZDs was suggested to enhance GIP secretion and action that potentiates the incretin pathway in diabetic patients.[55]

CLINICAL IMPACT OF ANTIDIABETICS ON THE BONE

Many investigations demonstrated that metformin has beneficial effects on the bone.[56,57] A cohort study of 1,964 patients with T2DM has confirmed a decreased incidence of fractures with the use of metformin.[58] Furthermore, in Denmark, a comprehensive case-control study has shown that administering metformin could significantly be linked to a reduced risk of fracture.[59] GLP-1RA and DPP-4 inhibitors have been revealed to induce beneficial or neutral effects on the bone.[60,61] However, a meta-analysis of randomized controlled trials, showed that therapy with GLP-1RA decreased risk of fractures.[62] Additionally, Monami et al. [63] study reported that DPP-4 inhibitors usage may substantially be associated with lower fracture risk rate when compared with non-users. These favorable impacts on the bone by metformin, GLP-1RA, and DPP-4 inhibitors, may be attributed to the ability of these medications to suppress the actions of AGEs and improve the incretin pathway. On the other hand, sulfonylureas and AGIs, have exhibited neutral effects on the bone.[64,65] Concerning SGLT2 inhibitors, despite their beneficial effects on AGEs and incretin pathway, canagliflozin revealed to have detrimental impacts on bone density, bone resorption, and fracture risk. In September 2015, the U.S. Food and Drug Administration revised the drug’s label and added a new warning.[66,67] However, although the CANVAS data (canagliflozin cardiovascular assessment study) has shown that this drug has a harmful impact on the bone, there is still debate over the bone-related adverse effects of canagliflozin, as these effects have not been broadly verified in the subsequent trials.[68] While except for one study involving dapagliflozin,[69] there is no evidence to suggest any impact on BMD, bone markers, or the risk of fractures for empagliflozin and dapagliflozin. Therefore, it appears that both medications have a neutral effect on the metabolism of bones.[70,71] Nevertheless, the issues indicated by research on canagliflozin inevitably influence the entire class. However, SGLT2 inhibitors influence the bone by a mechanism unrelated to AGEs or incretin pathway. SGLT2 inhibitors affect bone by inhibiting the SGLT2 in the cells of the proximal tubule epithelium, where they can disrupt the balance of calcium and phosphate levels in the body. As a result, secondary hyperparathyroidism may be developed causing bone resorption.[72,73] Even though, the promising effects of TZDs in reducing AGEs and enhancing the incretin pathway, there is extensive evidence to support the fact that the clinically approved TZDs, including rosiglitazone and pioglitazone, have been shown to reduce bone density and increase the likelihood of fractures, particularly in women.[74,75] Furthermore, a longitudinal follow-up of patients in the action to control cardiovascular risk in T2DM (ACCORD) study revealed that women were more likely to experience non-spine fractures when taking TZDs, compared to men, and that the risk decreased once the TZDs were discontinued.[76] TZDs modify bone remodeling that results in increasing bone resorption and inhibiting bone formation through their action as full PPAR-γ agonists.[77,78]

According to the above-mentioned evidences, and beyond glycemic control, a proper selection criteria of certain antidiabetics, considering their effects on AGEs and incretin pathway, should be considered to result in a better bone profile and reduced risk of bone abnormality in diabetic individuals.[79] Metformin is recommended in such situation, GLP-1RA and DPP-4 inhibitors also could improve the bone health, while, sulfonylureas and AGIs have a less beneficial effect on the bone. On the other hand, TZDs and canagliflozin should be evaded as their detrimental effects are observed in clinical trials, whereas other SGLT2 inhibitors are less well-validated options. Additionally, when a combination of antidiabetics is the option, an augmentation in the favorable effects of such medications on AGEs and incretin pathway could occur.[80] The use of metformin and sitagliptin together may result in enhanced beneficial effects on bone when compared to metformin alone.[81] Similarly, the combination therapy of metformin and linagliptin has been demonstrated to have a better impact on the bone than metformin only.[82] Furthermore, the administration of a GIP together with GLP-1 resulted in a pronounced suppression of the bone resorption marker CTX than each hormone alone in overweight men without diabetes.[83] In the context of this combination, tirzepatide, which is a dual GIPR/GLP-1RA was recently added, however, more investigations are required about its impact on bone metabolism.[84] Additionally, a combination of GIP and GLP-2 was demonstrated to have a synergistic decrease in bone resorption that was greater than the reduction achieved by each hormone separately supporting a dual GIPR/GLP-2 receptor agonist as future osteoporosis management.[85]

On the other hand, glucagon has been shown to have a beneficial impact on bone metabolism in T2DM. It appears that glucagon may speed up skeletal remodeling, expedite osteogenesis, and enhance the creation of mature bone tissue. Simultaneously, the osteoclastic process was also increased, providing raw materials for osteogenesis and maintaining dynamic balance. Accordingly, the successful use of a drug that acts as a glucagon receptor (GcgR) agonist alone or in combination with other drugs may result in a reduction in osteoporosis in diabetic patients.[86] A novel long-acting GLP-1R/GIPR/GcgR triple agonist (HM15211) that is being developed to treat obesity, has been demonstrated to have bone protective effects despite the significant weight loss that is associated with this compound. Consistent with the bone protective effect in vivo, HM15211 led to significant increases in type 1 collagen-α1, -α2, and carboxylated osteocalcin expression.[87]

Moreover, not only antidiabetics could impact the AGEs and incretin pathways, other medications and dietary supplements had an effect.[88–90] Vitamin D3 has been observed to reduce the level of AGEs, and show synergistic protective effects on the bone when using with metformin.[91–95] Additionally, omega-3 fatty acids reported to have favorable effects on AGEs in diabetic patients, and accordingly its combination with metformin could be preferably used in the management of bone health in diabetic patients.[96–98] On the other hand, calcium supplementation has shown to enhance the incretin pathway and its combination with metformin could alleviate the osteoporosis induced by T2DM.[99,100]

CONCLUSIONS

Individuals with T2DM are more likely to experience fragility and fractures due to the damaging effects of diabetes on the bone including the negative effects of AGEs and reduction in the beneficial effects of incretin pathway. Antidiabetic medications could influence AGEs and incretin pathway either directly or indirectly, which could impact the bone. Metformin has been considered to have protective effects on the bone, GLP-1RA and DPP-4 inhibitors could also have beneficial effects on the bone, such effects may be related to the favorable effects of such medications on AGEs and incretin pathway. Sulfonylureas and AGIs reported to have neutral effects on the bone while canagliflozin and TZDs have been shown to have detrimental effects. However, combination therapy of antidiabetic could result in augmentation in the favorable effects of antidiabetics on AGEs and incretin pathway that result in more protective effects on the bone.

Acknowledgments

Our sincere gratitude goes to the University of Mosul and the College of Pharmacy for guidance and assistance.

Fig. 1 Effects of advanced glycation end-products (AGEs) on the bone.[10] AGEs exert direct effects on osteoblast and osteoclast, causing damaging effects on the bone. RAGE, receptor for AGEs; RANKL, receptor activator of nuclear factor-κB ligand; ALP, alkaline phosphatase; TGF-β, transforming growth factor-β.

Fig. 2 The impact of incretin hormones on the metabolic process of bone.[25] Incretin hormones have the dual ability to directly act on osteoblasts and indirectly stimulate osteoblastogenesis through an increase in insulin secretion. In addition, incretin hormones can suppress osteoclastogenesis by enhancing thyroid calcitonin synthesis.

Table 1 Effects of antidiabetic drugs on the bone

Drug	Effect on AGEs	Effects on incretin pathway	Effects on bone	References	
Metformin	Decrease	Increase	Positive	Marx et al. [54], Kim [55]	
Sulfonylureas	Decrease	Neutral	Neutral	Driessen et al. [60], Kanemoto et al. [91]	
GLP-1 agonists	Decrease	Increase	Positive/neutral	Melton et al. [58], Alassaf et al. [92]	
DPP-4 inhibitors	Decrease	Increase	Positive/neutral	Loh et al. [57], Vestergaard et al. [59]	
AGIs	Decrease	Increase	Neutral	Bunck et al. [61]	
SGLT2 inhibitorsa)	Decrease	Increase	Negative/neutral	Cheng et al. [62], Dabhi et al. [65], Bilezikian et al. [66]	
TZDsb)	Decrease	Increase	Negative	Ljunggren et al. [71], Owusu et al. [93]	
a) Their effects on bone by mechanism not related to AGEs or incretin pathway, they cause alteration in calcium and phosphate homeostasis that can lead to bone loss.[67]

b) Their effects on bone is not related to AGEs or incretin pathway, but by stimulating PPAR-γ.[72]

AGEs, advanced glycation end-products; GLP-1, glucagon-like peptide-1; DPP-4, dipeptidyl peptidase 4; AGIs, α-glucosidase inhibitors; SGLT2, sodium glucose cotransporter 2; TZDs, thiazolidinediones; PPAR-γ, peroxisome proliferator-activated receptor-γ.

Ethics approval and consent to participate

Not applicable.

Conflict of interest

No potential conflict of interest relevant to this article was reported.
==== Refs
REFERENCES

1 Schwartz AV Diabetes, bone and glucose-lowering agents: clinical outcomes Diabetologia 2017 60 1170 9 10.1007/s00125-017-4283-6 28451714
2 Broy SB Cauley JA Lewiecki ME Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD official positions part 1: Hip geometry J Clin Densitom 2015 18 287 308 10.1016/j.jocd.2015.06.005 26277848
3 Hunt HB Donnelly E Bone quality assessment techniques: geometric, compositional, and mechanical characterization from macroscale to nanoscale Clin Rev Bone Miner Metab 2016 14 133 49 10.1007/s12018-016-9222-4 28936129
4 Saito M Marumo K Bone quality in diabetes Front Endocrinol (Lausanne) 2013 4 72 10.3389/fendo.2013.00072 23785354
5 Vestergaard P Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis Osteoporos Int 2007 18 427 44 10.1007/s00198-006-0253-4 17068657
6 Boer GA Holst JJ Incretin hormones and type 2 diabetes-mechanistic insights and therapeutic approaches Biology (Basel) 2020 9 473 10.3390/biology9120473 33339298
7 Saito M Marumo K Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus Osteoporos Int 2010 21 195 214 10.1007/s00198-009-1066-z 19760059
8 Deeba F Younis S Qureshi N Effect of diabetes mellitus and anti-diabetic drugs on bone health: a review J Bioresour Manag 2021 8 131 48 10.35691/JBM.1202.0187
9 Johnston SS Conner C Aagren M Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes Diabetes Obes Metab 2012 14 634 43 10.1111/j.1463-1326.2012.01583.x 22335246
10 Cavati G Pirrotta F Merlotti D Role of advanced glycation end-products and oxidative stress in type-2-diabetes-induced bone fragility and implications on fracture risk stratification Antioxidants (Basel) 2023 12 928 10.3390/antiox12040928 37107303
11 Taguchi K Fukami K RAGE signaling regulates the progression of diabetic complications Front Pharmacol 2023 14 1128872 10.3389/fphar.2023.1128872 37007029
12 Kay AM Simpson CL Stewart JA Jr The role of AGE/RAGE signaling in diabetes-mediated vascular calcification J Diabetes Res 2016 2016 6809703 10.1155/2016/6809703 27547766
13 Li G Xu J Li Z Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling Biochem Biophys Res Commun 2012 423 684 9 10.1016/j.bbrc.2012.06.015 22699121
14 Zhou Z Han JY Xi CX HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE J Bone Miner Res 2008 23 1084 96 10.1359/jbmr.080234 18302500
15 Zhou Z Immel D Xi CX Regulation of osteoclast function and bone mass by RAGE J Exp Med 2006 203 1067 80 10.1084/jem.20051947 16606672
16 Schwartz AV Garnero P Hillier TA Pentosidine and increased fracture risk in older adults with type 2 diabetes J Clin Endocrinol Metab 2009 94 2380 6 10.1210/jc.2008-2498 19383780
17 Saito M Mori S Mashiba T Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs Osteoporos Int 2008 19 1343 54 10.1007/s00198-008-0585-3 18373056
18 Saito M Fujii K Mori Y Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats Osteoporos Int 2006 17 1514 23 10.1007/s00198-006-0155-5 16770520
19 Bollag RJ Zhong Q Phillips P Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors Endocrinology 2000 141 1228 35 10.1210/endo.141.3.7366 10698200
20 Abed MN Alassaf F Qazzaz ME Insights into the perspective correlation between vitamin D and regulation of hormones: thyroid and parathyroid hormones Clin Rev Bone Miner Metab 2020 18 87 93 10.1007/s12018-021-09279-6
21 Henriksen DB Alexandersen P Hartmann B Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD Bone 2009 45 833 42 10.1016/j.bone.2009.07.008 19631303
22 Henriksen DB Alexandersen P Bjarnason NH Role of gastrointestinal hormones in postprandial reduction of bone resorption J Bone Miner Res 2003 18 2180 9 10.1359/jbmr.2003.18.12.2180 14672353
23 Kitaura H Ogawa S Ohori F Effects of incretin-related diabetes drugs on bone formation and bone resorption Int J Mol Sci 2021 22 6578 10.3390/ijms22126578 34205264
24 Hansen MSS Tencerova M Frølich J Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on Bone Cell Metabolism Basic Clin Pharmacol Toxicol 2018 122 25 37 10.1111/bcpt.12850 28722834
25 Ceccarelli E Guarino EG Merlotti D Beyond glycemic control in diabetes mellitus: effects of incretin-based therapies on bone metabolism Front Endocrinol (Lausanne) 2013 4 73 10.3389/fendo.2013.00073 23785355
26 Zhong Q Ding KH Mulloy AL Glucose-dependent insulinotropic peptide stimulates proliferation and TGF-beta release from MG-63 cells Peptides 2003 24 611 6 10.1016/s0196-9781(03)00103-7 12860206
27 Bollag RJ Zhong Q Ding KH Glucose-dependent insulinotropic peptide is an integrative hormone with osteotropic effects Mol Cell Endocrinol 2001 177 35 41 10.1016/s0303-7207(01)00405-1 11377818
28 Mieczkowska A Irwin N Flatt PR Glucose-dependent insulinotropic polypeptide (GIP) receptor deletion leads to reduced bone strength and quality Bone 2013 56 337 42 10.1016/j.bone.2013.07.003 23851294
29 Zhong Q Itokawa T Sridhar S Effects of glucose-dependent insulinotropic peptide on osteoclast function Am J Physiol Endocrinol Metab 2007 292 E543 E8 10.1152/ajpendo.00364.2006 17003233
30 Gasbjerg LS Hartmann B Christensen MB GIP’s effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH(2) Bone 2020 130 115079 10.1016/j.bone.2019.115079 31622777
31 Nuche-Berenguer B Moreno P Portal-Nuñez S Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states Regul Pept 2010 159 61 6 10.1016/j.regpep.2009.06.010 19586609
32 Nuche-Berenguer B Portal-Núñez S Moreno P Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor J Cell Physiol 2010 225 585 92 10.1002/jcp.22243 20506394
33 Daniilopoulou I Vlachou E Lambrou GI The impact of GLP1 agonists on bone metabolism: a systematic review Medicina (Kaunas) 2022 58 224 10.3390/medicina58020224 35208548
34 Merhi Z Advanced glycation end products and their relevance in female reproduction Hum Reprod 2014 29 135 45 10.1093/humrep/det383 24173721
35 Schurman L McCarthy AD Sedlinsky C Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells Exp Clin Endocrinol Diabetes 2008 116 333 40 10.1055/s-2007-992786 18273753
36 Migoya EM Bergeron R Miller JL Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1 Clin Pharmacol Ther 2010 88 801 8 10.1038/clpt.2010.184 21048706
37 Pan QR Li WH Wang H Glucose, metformin, and AICAR regulate the expression of G protein-coupled receptor members in INS-1 beta cell Horm Metab Res 2009 41 799 804 10.1055/s-0029-1234043 19672815
38 Cuthbertson J Patterson S O’Harte FP Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus Metabolism 2011 60 52 6 10.1016/j.metabol.2010.01.001 20152998
39 Md Isa SH Najihah I Nazaimoon WM Improvement in C-reactive protein and advanced glycosylation end-products in poorly controlled diabetics is independent of glucose control Diabetes Res Clin Pract 2006 72 48 52 10.1016/j.diabres.2005.09.011 16253380
40 Cordiner RLM Mari A Tura A The impact of low-dose gliclazide on the incretin effect and indices of beta-cell function J Clin Endocrinol Metab 2021 106 2036 46 10.1210/clinem/dgab151 33693776
41 Drucker DJ Mechanisms of action and therapeutic application of glucagon-like peptide-1 Cell Metab 2018 27 740 56 10.1016/j.cmet.2018.03.001 29617641
42 Yamagishi S Nakamura N Suematsu M Advanced glycation end products: a molecular target for vascular complications in diabetes Mol Med 2015 21 Suppl 1 S32 40 10.2119/molmed.2015.00067 26605646
43 Vella A Mechanism of action of DPP-4 inhibitors-new insights J Clin Endocrinol Metab 2012 97 2626 8 10.1210/jc.2012-2396 22869847
44 Nakashima S Matsui T Takeuchi M Linagliptin blocks renal damage in type 1 diabetic rats by suppressing advanced glycation end products-receptor axis Horm Metab Res 2014 46 717 21 10.1055/s-0034-1371892 24710699
45 Ishibashi Y Matsui T Maeda S Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor Cardiovasc Diabetol 2013 12 125 10.1186/1475-2840-12-125 23984879
46 Zhang L Li P Tang Z Effects of GLP-1 receptor analogue liraglutide and DPP-4 inhibitor vildagliptin on the bone metabolism in ApoE(−/−) mice Ann Transl Med 2019 7 369 10.21037/atm.2019.06.74 31555683
47 Tsunosue M Mashiko N Ohta Y An alpha-glucosidase inhibitor, acarbose treatment decreases serum levels of glyceraldehyde-derived advanced glycation end products (AGEs) in patients with type 2 diabetes Clin Exp Med 2010 10 139 41 10.1007/s10238-009-0074-9 19834782
48 Kalra S Incretin enhancement without hyperinsulinemia: α-glucosidase inhibitors Expert Rev Endocrinol Metab 2014 9 423 5 10.1586/17446651.2014.931807 30736205
49 Ahmed GM Abed MN Alassaf FA An overview of the effects of sodium-glucose co-transporter-2 inhibitors on hematological parameters in diabetic patients Iraqi J Pharm 2023 20 65 71
50 Tang L Wu Y Tian M Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes Am J Physiol Endocrinol Metab 2017 313 E563 E76 10.1152/ajpendo.00086.2017 28811292
51 Ahn CH Oh TJ Min SH Incretin and pancreatic β-cell function in patients with type 2 diabetes Endocrinol Metab (Seoul) 2023 38 1 9 10.3803/EnM.2023.103 36781163
52 Martinussen C Veedfald S Dirksen C The effect of acute dual SGLT1/SGLT2 inhibition on incretin release and glucose metabolism after gastric bypass surgery Am J Physiol Endocrinol Metab 2020 318 E956 E64 10.1152/ajpendo.00023.2020 32182123
53 Tan KCB Chow WS Tso AWK Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes Diabetologia 2007 50 1819 25 10.1007/s00125-007-0759-0 17639302
54 Marx N Walcher D Ivanova N Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products Diabetes 2004 53 2662 8 10.2337/diabetes.53.10.2662 15448098
55 Kim SW Triple combination therapy using metformin, thiazolidinedione, and a GLP-1 analog or DPP-IV inhibitor in patients with type 2 diabetes mellitus Korean Diabetes J 2010 34 331 7 10.4093/kdj.2010.34.6.331 21246005
56 Wang LX Wang GY Su N Effects of different doses of metformin on bone mineral density and bone metabolism in elderly male patients with type 2 diabetes mellitus World J Clin Cases 2020 8 4010 6 10.12998/wjcc.v8.i18.4010 33024757
57 Loh DKW Kadirvelu A Pamidi N Effects of metformin on bone mineral density and adiposity-associated pathways in animal models with type 2 diabetes mellitus: a systematic review J Clin Med 2022 11 4193 10.3390/jcm11144193 35887957
58 Melton LJ 3rd Leibson CL Achenbach SJ Fracture risk in type 2 diabetes: update of a population-based study J Bone Miner Res 2008 23 1334 42 10.1359/jbmr.080323 18348689
59 Vestergaard P Rejnmark L Mosekilde L Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk Diabetologia 2005 48 1292 9 10.1007/s00125-005-1786-3 15909154
60 Driessen JH Henry RM van Onzenoort HA Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis Calcif Tissue Int 2015 97 104 12 10.1007/s00223-015-9993-5 25894068
61 Bunck MC Poelma M Eekhoff EM Effects of vildagliptin on postprandial markers of bone resorption and calcium homeostasis in recently diagnosed, well-controlled type 2 diabetes patients J Diabetes 2012 4 181 5 10.1111/j.1753-0407.2011.00168.x 22051153
62 Cheng L Hu Y Li YY Glucagon-like peptide-1 receptor agonists and risk of bone fracture in patients with type 2 diabetes: a meta-analysis of randomized controlled trials Diabetes Metab Res Rev 2019 35 e3168 10.1002/dmrr.3168 30974033
63 Monami M Dicembrini I Antenore A Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials Diabetes Care 2011 34 2474 6 10.2337/dc11-1099 22025784
64 Colhoun HM Livingstone SJ Looker HC Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs Diabetologia 2012 55 2929 37 10.1007/s00125-012-2668-0 22945303
65 Dabhi AS Bhatt NR Shah MJ Voglibose: an alpha glucosidase inhibitor J Clin Diagn Res 2013 7 3023 7 10.7860/jcdr/2013/6373.3838 24551718
66 Bilezikian JP Watts NB Usiskin K Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin J Clin Endocrinol Metab 2016 101 44 51 10.1210/jc.2015-1860 26580234
67 Watts NB Bilezikian JP Usiskin K Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus J Clin Endocrinol Metab 2016 101 157 66 10.1210/jc.2015-3167 26580237
68 Wikarek A Grabarczyk M Klimek K Effect of drugs used in pharmacotherapy of type 2 diabetes on bone density and risk of bone fractures Medicina (Kaunas) 2024 60 393 10.3390/medicina60030393 38541119
69 Kohan DE Fioretto P Tang W Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control Kidney Int 2014 85 962 71 10.1038/ki.2013.356 24067431
70 Ptaszynska A Johnsson KM Parikh SJ Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events Drug Saf 2014 37 815 29 10.1007/s40264-014-0213-4 25096959
71 Ljunggren Ö Bolinder J Johansson L Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin Diabetes Obes Metab 2012 14 990 9 10.1111/j.1463-1326.2012.01630.x 22651373
72 Meier C Schwartz AV Egger A Effects of diabetes drugs on the skeleton Bone 2016 82 93 100 10.1016/j.bone.2015.04.026 25913633
73 Taylor SI Blau JE Rother KI Possible adverse effects of SGLT2 inhibitors on bone Lancet Diabetes Endocrinol 2015 3 8 10 10.1016/s2213-8587(14)70227-x 25523498
74 Kaku K Hashiramoto M Thiazolidinediones and bone fractures J Diabetes Investig 2011 2 354 5 10.1111/j.2040-1124.2011.00142.x
75 Aubert RE Herrera V Chen W Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes Diabetes Obes Metab 2010 12 716 21 10.1111/j.1463-1326.2010.01225.x 20590749
76 Paschou SA Dede AD Anagnostis PG Type 2 diabetes and osteoporosis: a guide to optimal management J Clin Endocrinol Metab 2017 102 3621 34 10.1210/jc.2017-00042 28938433
77 Lazarenko OP Rzonca SO Hogue WR Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone Endocrinology 2007 148 2669 80 10.1210/en.2006-1587 17332064
78 Kanda J Izumo N Kobayashi Y Effect of the antidiabetic agent pioglitazone on bone metabolism in rats J Pharmacol Sci 2017 135 22 8 10.1016/j.jphs.2017.08.004 28928054
79 Ahmed GM Abed MN Alassaf FA Impact of calcium channel blockers and angiotensin receptor blockers on hematological parameters in type 2 diabetic patients Naunyn Schmiedebergs Arch Pharmacol 2024 397 1817 28 10.1007/s00210-023-02731-y 37750935
80 Ahmed GM Abed MN Alassaf FA The diabetic-anemia nexus: implications for clinical practice Mil Med Sci Lett 2023 92 1 11 10.31482/mmsl.2023.042
81 Liu K Ahemaiti A Tuernisaguli K Effect of metformin combined with DPP-4 inhibitor on alveolar bone density in patients with type 2 diabetes mellitus and chronic periodontitis Shanghai Kou Qiang Yi Xue 2023 32 410 6 38044737
82 Nirwan N Vohora D Linagliptin in combination with metformin ameliorates diabetic osteoporosis through modulating BMP-2 and sclerostin in the high-fat diet fed C57BL/6 mice Front Endocrinol (Lausanne) 2022 13 944323 10.3389/fendo.2022.944323 35928902
83 Bergmann NC Lund A Gasbjerg LS Separate and combined effects of GIP and GLP-1 infusions on bone metabolism in overweight men without diabetes J Clin Endocrinol Metab 2019 104 2953 60 10.1210/jc.2019-00008 30848791
84 Nauck MA D’Alessio DA Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction Cardiovasc Diabetol 2022 21 169 10.1186/s12933-022-01604-7 36050763
85 Gabe MBN Skov-Jeppesen K Gasbjerg LS GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment Pharmacol Res 2022 176 106058 10.1016/j.phrs.2022.106058 34995796
86 Guo H Sui C Ge S Positive association of glucagon with bone turnover markers in type 2 diabetes: a cross-sectional study Diabetes Metab Res Rev 2022 38 e3550 10.1002/dmrr.3550 35621313
87 Lee S Kim YY Lee JS Bone protective effect of a novel long-acting GLP-1/GIP/Glucagon triple agonist (HM15211) in an animal model Diabetes 2018 67 Suppl 1 1105-P 10.2337/db18-1105-P 29545266
88 Kim B Kim YJ Kim JH Melatonin protects bone microarchitecture against deterioration due to high-fat diet-induced obesity J Bone Metab 2023 30 69 75 10.11005/jbm.2023.30.1.69 36950842
89 Alassaf FA Jasim MHM Alfahad M Effects of bee propolis on FBG, HbA1c, and insulin resistance in healthy volunteers Turk J Pharm Sci 2021 18 405 9 10.4274/tjps.galenos.2020.50024 34496480
90 Al-Dabbagh BMA Abed MN Mahmood NM Anti-inflammatory, antioxidant and hepatoprotective potential of milk thistle in albino rats Lat Am J Pharm 2022 41 1832 41
91 Kanemoto Y Iwaki M Sawada T Advances in the administration of vitamin D analogues to support bone health and treat chronic diseases J Bone Metab 2023 30 219 29 10.11005/jbm.2023.30.3.219 37718900
92 Alassaf FA Alfahad M Jasim MHM Insights into the perspective correlation between vitamin D and regulation of hormones: adrenal hormones and vasopressin Lat Am J Pharm 2022 41 2242 7
93 Owusu J Huffman F Liuzzi J Effect of 4000 IU vitamin D3 supplements on advanced glycation end products (AGEs) among adults with type 2 diabetes and hypovitaminosis D Curr Dev Nutr 2020 4 Suppl 2 nzaa067_56 10.1093/cdn/nzaa067_05
94 Ha NN Huynh TKT Phan NUP Synergistic effect of metformin and vitamin D(3) on osteogenic differentiation of human adipose tissue-derived mesenchymal stem cells under high d-glucose conditions Regen Ther 2024 25 147 56 10.1016/j.reth.2023.12.003 38486821
95 Qazzaz ME Abed MN Alassaf FA Insights into the perspective correlation between vitamin D and regulation of hormones: sex hormones and prolactin Curr Issues Pharm Med Sci 2021 34 192 200
96 Mirhashemi SM Rahimi F Soleimani A Effects of omega-3 fatty acid supplementation on inflammatory cytokines and advanced glycation end products in patients with diabetic nephropathy: a randomized controlled trial Iran J Kidney Dis 2016 10 197 204 27514766
97 Adeyemi WJ Olayaki LA Abdussalam TA Co-administration of omega-3 fatty acids and metformin showed more desirable effects than the single therapy on indices of bone mineralisation but not gluco-regulatory and antioxidant markers in diabetic rats Biomed Pharmacother 2020 121 109631 10.1016/j.biopha.2019.109631 31715372
98 Thanoon IAJ Jasim MHM Abed MN Effects of omega-3 on renal function tests and uric acid level in healthy volunteers Lat Am J Pharm 2021 40 2319 23
99 Gonzalez JT Stevenson EJ Calcium co-ingestion augments postprandial glucose-dependent insulinotropic peptide(1–42), glucagon-like peptide-1 and insulin concentrations in humans Eur J Nutr 2014 53 375 85 10.1007/s00394-013-0532-8 23689561
100 Li XY He R Jiang YZ Effect of metformin combined with calcium on the metabolism of bone in elderly type 2 diabetes patients Shiyong Pharm Clin Remedies 2014 17 1638 41
