Gut-Derived Peptide Hormone Analogues and Potential Treatment of Bone Disorders in Obesity and Diabetes Mellitus

Abstract

Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these metabolic disorders and compromised bone health. Interestingly, both obesity and diabetes lead to elevated risk of bone fracture which is independent of effects on bone mineral density (BMD). In this regard, gastrointestinal (GIT)-derived peptide hormones and their related long-acting analogues, some of which are already clinically approved for diabetes and/or obesity, also seem to possess positive effects on bone remodelling and microarchitecture to reduce bone fracture risk. Specifically, the incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2), exert key direct and/or indirect benefits on bone metabolism. This review aims to provide an initial appraisal of the relationship between obesity, diabetes and bone, with a focus on the positive impact of these GIT-derived peptide hormones for bone health in obesity/diabetes. Brief discussion of related peptides such as parathyroid hormone, leptin, calcitonin and growth hormone is also included. Taken together, drugs engineered to promote GIP, GLP-1 and GLP-2 receptor signalling may have potential to offer therapeutic promise for improving bone health in obesity and diabetes.

Plain Language Summary

Impact of peptides from the gut on bone health in obesity and diabetes mellitus

Obesity and related type 2 diabetes (T2D) are prevalent diseases. Unfortunately, there is now a clear link between obesity and related T2D and poor bone health, leading to increased bone fracture risk. However, we know that peptides derived from the gut following a meal can possess positive effects on bone health and reduce bone fracture risk. These peptides are called glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). Moreover, some of these peptides, GLP-1 and GIP, are already being used to treat obesity and T2D, whilst GLP-2 is used to treat people with short bowel syndrome. In other words, drugs that mimic the action of GLP-1, GLP-2 and GIP are available for human use. This current review article aims to provide an initial appraisal of the relationship between obesity, diabetes and bone health, with a focus on the positive impact of peptide hormones like GLP-1, GLP-2 and GIP for bone health in obesity/diabetes. The take home message is that drugs engineered to promote GIP, GLP-1 and GLP-2 action may have potential to offer therapeutic promise for improving bone health in obesity and diabetes.

Keywords

Diabetes obesity bone incretin peptide analogue

Introduction

Obesity and type 2 diabetes mellitus (T2DM) are related diseases that have adverse effects on various physiological systems within the body.¹ On a global scale, the prevalence of T2DM has increased dramatically in recent years, with over 1 in 10 adults now currently living with the condition.² Since release of the International Diabetes Federation (IDF) data in 2000, the estimated occurrence of diabetes in individuals aged 20 to 79 has more than doubled, rising steadily from approximately 151 million in 2000 (4.6% of the world’s population) to 537 million (10.5% of the world’s population) in 2021. If appropriate measures are not taken to address this issue, projections indicate that this number will surge to an alarming 783 million individuals by 2045.³ In accord with this, the prevalence of obesity has more than tripled globally since 2016,² and it is anticipated that by 2030 one billion people will be clinically obese.⁴

The increase in obesity and T2DM is partly related to a progressively ageing population, adoption of a more sedentary lifestyle and consumption of high energy processed foods.⁵ In keeping with this, the prevalence of osteoporosis and fragility bone fractures is also rising.⁶ More notably, obesity and diabetes independently increase bone fracture risk, linked to impairments in bone turnover and a detrimental alteration of bone microarchitecture.^7,8 Consequently, there is a need to better understand how obesity and T2DM specifically impact bone health, with a view towards developing tailored treatments to address this unique challenge.

Impact of Diabetes on Bone Health

Osteoclasts and osteoblasts are key cells involved in the well-described bone remodelling process, which mediate bone resorption and subsequent bone formation, respectively.⁹ However, the equilibrium between bone development and bone resorption is disrupted in obesity and T2DM¹⁰ (Figure 1). As such, all forms of diabetes are associated with prolonged hyperglycaemia, that is known to negatively impact bone.¹¹ In keeping with this, receptor activator of nuclear factor-κB ligand (RANKL), that simulates mature osteoclasts to resorb bone,¹² also directly affects pancreatic beta-cell function and overall glucose metabolism but has impaired function in obesity/diabetes.¹³ Additionally, the RANKL monoclonal antibody used to treat osteoporosis, namely denosumab (Dmab), promotes pancreatic beta-cell proliferation¹⁴ and has recently been suggested to positively regulate glucose homoeostasis in patients with T2DM.¹⁵ However, benefits of Dmab on fasting glucose in T2DM were not superior to ibandronate therapy.¹⁵ In accordance with this, other studies indicate that RANKL increases hepatic and muscular insulin resistance and upregulates negative glycaemic regulators such as the adipokine resistin and the incretin-degrading enzyme dipeptidyl peptidase-4 (DPP-4).¹³ Hyperglycaemia can also trigger a rise in TNF-α and IL-6 expression, with these cytokines being linked to osteoclast development and activation,^16,17 that ultimately promotes bone loss. Furthermore, a prolonged hyperglycaemic environment exerts a negative impact on osteoblast metabolism and maturation.¹⁸ Increased generation of advanced glycation end-products (AGEs) may also be involved in the bone defects of diabetes (Figure 1), with AGE-induced upregulation of sclerostin, an inhibitor of osteoblast function,¹⁹ disrupting the delicate balance between bone formation and resorption.²⁰

Figure 1.

The complex interplay between diabetes, obesity, and bone health. T2DM is associated with a pro-inflammatory state induced by hyperglycaemia and obesity, resulting in insulin resistance. Several factors contribute to the deleterious effects of diabetes on bone health, including increased levels of AGEs and ROS. These factors play increase osteoclast activation and promote osteoblast dysfunction, ultimately culminating in bone disorders and increased fracture risk.

Importantly, diabetes also negatively impacts bone micro-architecture at a structural level, and people living with diabetes have been found to have decreased trabecular bone connectivity and cortical bone thickness.²¹ Such structural changes render the bone more susceptible to fragility fracture and also impair the healing process.²² In agreement with this, osteocyte morphology and osteocyte network topology have been shown to be impaired in insulin-resistant mice fed a high-fat diet,²³ whilst bone strength and cortical microstructure are impaired in insulin-deficient mice administered the specific pancreatic beta-cell toxin, streptozotocin (STZ).²⁴ A brief overview of the influence of the 2 major forms of diabetes, namely type 1 diabetes mellitus (T1DM) and T2DM, on bone health is provided below. However, it should be noted that there is still an incomplete understanding of the complex mechanisms related to the negative impact of diabetes on bone microarchitecture (Figure 1).

T1DM and bone health

T1DM is characterised by the autoimmune destruction of insulin-secreting pancreatic beta-cells, leading to insulin deficiency with obvious negative effects on bone health.^25
-27 Consequently, low BMD, increased risk of fractures and inadequate fracture healing are all observed in T1DM,^25,26 with the disease being linked to early-onset osteopenia or osteoporosis.²⁷ Indeed, a long-term observational study, known as the Epidemiology of Diabetes Interventions and Complications study (EDIC), following 1058 participants originally enrolled in the Diabetes Control and Complications Trial (DCCT), reveals that poor glycaemic control and AGE accumulation represent independent risk factors for lower hip BMD in older adults with T1DM.²⁸ Furthermore, osteoblasts express the insulin receptor, where physiological insulin levels have been shown to enhance production of bone anabolic markers and collagen synthesis.^29
-31 Moreover, insulin triggers bone cells to synthesise and activate osteocalcin, an endocrine hormone that not only helps to coordinate appropriate bone formation, but also positively regulates glucose metabolism.³¹ Consequently, mice lacking the insulin receptor in osteoblasts have low levels of circulating osteocalcin and limited bone growth.³² Underlying mechanisms for disrupted bone physiology in T1DM include elevated levels of pro-inflammatory cytokines such as TNF-α, IFN-α, IL-6, IL-17 and IL-21, also thought to be involved in the onset and progression of T1DM,³³ that ultimately contribute to bone loss by encouraging osteoclast differentiation and/or suppressing osteoblast development and function.³⁴

Obesity, T2DM and bone health

Insulin resistance, a prominent characteristic of obesity and T2DM, exerts a significant negative effect on skeletal integrity through the impairment of osteoblast activity and augmentation of bone resorption, mediated in part by relative insulin deficiency.²² In addition, obesity per se exerts a substantial influence on bone health, primarily by elevated mechanical stress with weight-bearing joints such as the knees and hips being particularly affected.³⁵ Although sarcopenia, an age-related progressive loss of muscle mass and strength, can be difficult to define,³⁶ it has been shown compromise bone health in obesity. In that regard, interventions to improve muscle mass may help lower fracture risk in sarcopenic obesity.³⁷ Moreover, since adipocytes and osteoblasts are derived from the same multipotent mesenchymal stem cell, obesity may favour adipocyte over osteoblast differentiation.³⁸ Obesity is also linked to a persistent state of low-grade inflammation and increased concentrations of specific cytokines such as IL-6 and TNFα, that can exert detrimental effects on bone health such as increasing bone resorption and impeding bone formation.^34,39 Furthermore, individuals with obesity are more prone to reduced circulating levels of vitamin D, due to sequestration of the fat-soluble vitamin within adipose tissue.⁴⁰ Accordingly, vitamin D deficiency contributes to a decline in BMD and augments susceptibility to bone fractures.⁴¹ Mechanistically, vitamin D insufficiency causes impaired calcium absorption, which eventually results in the release of calcium from bones in a bid to maintain normal circulating concentrations of the ion, compromising integrity of the bone.⁴² Furthermore, the bone remodelling process is modulated by adipokines including leptin, adiponectin and resistin,^43,44 and circulating levels of these adipose-derived hormones are disrupted in obesity.⁴⁵ Interestingly, leptin receptors are present on bone cells and contribute to the growth and mineralisation of osteoblasts,⁴⁶ as well as inhibiting osteoclast activity,⁴⁷ which may partly explain the unfavourable bone phenotype observed in obese-diabetic db/db mice.⁴⁸ Finally, development of AGEs in obesity and diabetes leads to permanent crosslinking of collagen fibres and impairment of organic bone matrix quality, making the bone more brittle and prone to fracture^49,50 (Figure 1). Moreover, osteoblast apoptosis is triggered by extracellular AGEs,⁵¹ linked to the downregulation of expression of genes necessary for osteoblast development, such as osterix and Runx2.^52,53 In addition to this, microvascular disease is a well-defined complication of T2DM and has been shown to impair skeletal integrity and lead to increased bone fragility, primarily by detrimentally affecting osteocyte function.⁵⁴

The Gastrointestinal Tract and Bone

As discussed above, several endocrine factors are known to regulate the bone remodelling process.⁵⁵ Of particular interest in this regard, and with key relevance to obesity and diabetes, are hormones secreted from the gastrointestinal tract (GIT). As such, a role for GIT derived peptide hormones in the maintenance of bone integrity and strength has now largely been confirmed.⁵⁶ In this respect, the incretin hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have received much attention to date. GLP-1 mimetics are approved for the treatment of both obesity and T2DM,^57
-59 whilst a dual-acting GLP-1/GIP receptor co-agonist, namely tirzepatide, has also recently gained clinical approved for T2DM⁶⁰ and obesity.⁶¹ Both GIP and GLP-1 are considered to either directly or indirectly affect the skeleton,⁶² with their activity and/or secretion detrimentally altered in obesity-diabetes, that might contribute to alterations of bone quality in this setting. Beyond this, the sister hormone of GLP-1, namely glucagon-like peptide-2 (GLP-2), now utilised in a form resistant to DPP-4 degradation for the treatment of short bowel syndrome,⁶³ also exerts well established effects on bone metabolism.⁶⁴ The following sections will highlight the role of GIP, GLP-1 and GLP-2 in bone biology (Figure 2), with specific reference to potential application for the treatment of bone disorders observed in obesity and diabetes. Given the wealth of information covered within these areas, summary tables that present the main findings from rodent and human studies have been generated (Tables 1 and 2). Although data derived from the clinic is encouraging (Table 2) there are limitations in terms of overall interpretation, since bone composition and material properties are unable to be fully investigated. Thus, positive observations with GIP, GLP-1 and GLP-2 receptor agonists on bone in rodents still need to be fully translated to the human setting.

Figure 2.

Positive impact of GIP, GLP-1 and GLP-2 on bone metabolism. GIP exerts direct benefits through activation of receptors present on bone. The positive bone effects of GLP-1 and GLP-2 may be mediated indirectly through promotion of insulin and PTH secretion, respectively. Together these GIT-derived peptides increase osteoblast survival and decrease bone resorption leading to improvements of bone formation as well as overall bone mass and strength.

Table 1.

Overview of effects of gut-derived peptide analogues on bone health in animal models of diabetes and/or obesity and rodent cell lines.

Peptide name	Model	Key findings	Reference
Exenatide	OVX rats	Promotes osteoblast activation, enhances bone strength, inhibits bone resorption, and prevents deterioration of trabecular microarchitecture	Ma et al, 2013¹⁰⁵
Liraglutide	STZ-induced diabetes and/or OVX-rats/mice	Reduces osteoclast numbers and protects against femoral bone mineral loss and deterioration of bone microarchitecture. Increased serum osteocalcin and decreased bone resorption markers.	Wen et al, 2018¹⁰⁶ & Mansur et al, 2015²⁴
(D-Ala²)GIP	STZ-diabetic mice, Bone marrow cells, Raw 264.7 cells	Increased bone quality and effectively halted degradation of bone matrix to improve bone fracture resistance. Reduced osteoclast formation and decline in bone resorption.	Mansur et al, 2019¹¹² & Mabilleau et al, 2016²³
N-AcGIP	Bone marrow cell, MC3T3 cells	Reduction in osteoclast count and CTX levels. Improved tissue material properties of bone. Increased alkaline phosphatase activity.	Mabilleau et al, 2016²³
GL-0001 and GL-007 (GIP/GLP-2 co-agonists)	OVX mice, Raw 264.7 cells	Reduced osteoclast resorption. Preservation of trabecular bone mass. Enhanced collagen cross-linking. Improved fracture resistance	Gobron et al, 2023¹²⁶
Lipidated long-acting GLP-2R agonists	COS-7 cell line, transgenic mice and rats	Trophic effects on bones. Lowered bone resorption CTX levels.	Gadgaard et al, 2023⁸⁵
(D-Ala²)GIP-Oxm (GIP/GLP-1/glucagon triple agonist)	db/db mice	Improved bone strength following 3 weeks treatment	Mansur et al, 2016¹¹
HM15211 (GIP/GLP-1/glucagon triple agonist)	OVX rats, SaOS2 cell	Protects against bone loss. Type 1 collagen-α1, -α2, and carboxylated osteocalcin expression significantly increased.	Kim et al, 2017¹²⁷

Table 2.

Overview of effects of gut-derived peptide analogues on bone health in humans with diabetes and/or obesity and human cell lines.

Peptide name	Model	Key findings	Reference
Exenatide	T2DM	Increase BMD and reduce fracture risk. Improved trabecular bone mass and architecture by increasing bone formation rate.	Cai et al, 2021¹¹⁰
Liraglutide	Obesity/T2DM	Reduction in the number of osteoclasts. Augmentation of bone formation, safeguarding against reduction of mineral content and bone structural integrity.	Xie et al, 2021⁹⁰
Dulaglutide	T2DM, SW1353 chondrocytes	Increase BMD and reduce fracture risk. Diminishing ROS levels and expression levels of multiple pro-inflammatory cytokines and chemokines associated with osteoarthritis.	Cai et al, 2021¹¹⁰ & Li et al, 2020¹⁵⁴
Lixisenatide	Primary human chondrocytes	Reduced the breakdown of type II collagen. Reduced IL-6 and TNF-α expression.	Li et al, 2019¹⁰⁷
Various long-acting GLP-1 mimetics	Obesity	Enhanced bone growth and prevented bone loss.	Iepsen et al, 2015¹⁰⁸
(D-Ala²) GIP	Human peripheral blood mononuclear cells	Directly inhibited osteoclast formation and resorption. Reduction in CTX levels.	Mabilleau et al, 2016²³
N-AcGIP	Human peripheral blood mononuclear cells	Reduced osteoclast formation and resorption. Reduction in osteoclast count and CTX levels.	Mabilleau et al, 2016²³

GLP-2 and related analogues

Multiple peptides with overlapping functions that support the absorption and assimilation of nutrients are encoded by the proglucagon gene.^65,66 Of these, GLP-2 is a 33 amino acid polypeptide secreted gut L-cells that was initially reported to exert an intestinal growth-promoting action.⁶⁷ Similar to other endogenous regulatory peptides, GLP-2 has a short biological half-life and is readily broken down in the circulation by the enzyme DPP-4, to yield and inactive peptide metabolite.⁶⁸ However, the half-life of GLP-2 can be extended from approximately 7 minutes to around 2 to 3 hours by simple substitution of the N-terminal Ala² amino acid with Gly², to effectively mask the DPP-4 binding site.⁶⁸ In 2012, the FDA approved (Gly²)GLP-2, known as teduglutide, for use in people with short bowel syndrome.^63,69 Further investigation has demonstrated that in patients with short bowel syndrome, a 5-week dosing regimen with GLP-2 markedly enhanced spinal BMD, intestinal calcium absorption rates and plasma calcium concentrations.^70,71 In agreement with this, in postmenopausal women, GLP-2 administration results in a dose-dependent decrease in bone resorption markers.⁷² Several other studies have confirmed that GLP-2 is able to supress bone resorption both in rodents and humans.^73
-75 Indeed, clinical trials in postmenopausal women support a stimulatory impact of GLP-2 on bone growth.^75
-77 Moreover, GLP-2 has recently been shown to ameliorate age-related bone loss in mice and augment the expression of genes directly involved in bone formation.⁷⁸

Despite this, GLP-2 receptors have only been evidenced on osteoblast-like cell lines such as MG-63 and TE-85, with identification in osteoblasts in the in vivo setting still to be fully confirmed.^79,80 That said, the GLP-2 receptor was shown to be expressed in human osteoclast cells, confirming presence of the receptor in the setting of bone.⁸¹ Intriguingly, GLP-2 has also been demonstrated to be locally produced within rodent and human pancreatic islets,⁸² where it may function as an important cell-to-cell messenger and in adaptations to pancreatic islet cell stress present in obesity and diabetes. Thus, benefits of GLP-2 in bone could be linked to the gut-pancreas-bone axis.⁶⁴ The GLP-2 receptor is clearly evident in the parathyroid gland, suggesting that effects on parathyroid hormone (PTH) secretion and/or activity may be linked to GLP-2-induced benefits on bone⁷³ (Figure 2), since PTH is well recognised to be directly involved in the bone remodelling process.⁸³ Indeed, consistent with this view, the antiresorptive effect of GLP-2 was shown to be abolished in patients with hypoparathyroidism.⁸¹ There is also a suggestion that intact gut function, especially the jejunum, is required for GLP-2 mediated benefits on bone via PTH signalling.⁸⁴ Notably, long-acting GLP-2 receptor agonists have recently been described with effects on both rodent and human bone⁸⁵ (Table 1), that may ultimately help fully uncover the potential of GLP-2 for the treatment of bone disorders.

Incretins

The incretin hormones, GIP and GLP-1, play a crucial role in glucose-stimulated insulin secretion and regulation of glucose metabolism.⁸⁶ Similar to GLP-2, both GIP and GLP-1 are GIT-derived, but also now believed to be locally produced under metabolic stress within alpha cells in pancreatic islets,⁸⁷ as well as exerting either direct and/or indirect effects on bone health^88,89 (Figure 2). For example, in osteoblasts, GLP-1 has been shown to promote proliferation and differentiation, enhancing their survival and inhibiting apoptosis.⁸⁸ Additionally, GLP-1 has also been noted to inhibit osteoclast formation and activity, together helping to prevent bone loss and maintain optimal bone quality.^66,90 In keeping with this, GLP-1 receptor KO mice present with a significant reduction in cortical bone thickness and collagen matrix maturity.⁹¹ Accordingly, GLP-1 receptor activation has recently been shown to improve fracture healing in a rat model of osteoporosis.⁹² However, as with GLP-2, the presence of functional GLP-1 receptors on bone remains a contentious issue,⁹³ suggesting effects may be indirect and perhaps linked to its prominent insulin secretory actions (Figure 2). In support of this, GLP-1 had no effect on bone turnover in patients with T1DM.⁹⁴

In terms of GIP effects on bone, there is conclusive evidence for the presence of GIP receptors on osteoblast and osteoclast cells⁹⁵ (Figure 1), where GIP was revealed to reduce osteoclast activity and improve osteoblast survival of primary human bone cells.⁹⁶ Moreover, GIP has been shown to stimulate osteoblast proliferation, differentiation and mineralisation to help promote bone formation in rodents.⁹⁷ In keeping with this, selective KO of the GIP receptor in mice leads to reduced bone strength and quality^98,99 In terms of related mechanisms, GIP is believed to directly modulate various signalling pathways in bone, including the cAMP/PKA pathway, the MAPK/ERK pathway and the PI3K/Akt pathway, that are crucial for bone matrix synthesis and mineralisation.¹⁰⁰ There is also well-defined translation of beneficial GIP effects on bone, with GIP deceasing bone resorption in healthy volunteers.¹⁰¹ Unlike GLP-1, such effects are preserved in people with T1DM further highlighting the direct nature on the positive impact of GIP on bone.⁹⁴ Indeed, positive effects of GIP on bone metabolism in humans are blocked by administration of a specific GIP receptor antagonist.¹⁰² These various observations suggest that GIT hormones, and particularly GIP which exerts positive metabolic effects directly on bone, may provide attractive therapeutic opportunities.

Incretin analogues

As noted above, the relatively short half-life of naturally occurring peptide hormones such as GIP, GLP-1 and GLP-2 precludes clinical utilisation, leading to the requirement for enzymatically stable analogues to harness therapeutic effectiveness.⁶⁶ In this regard, long-acting analogues of the incretin peptides, GIP and GLP-1, have been generated and examined in depth for usefulness in obesity and diabetes.^65,103 Exendin-4 was the first GLP-1 mimetic approved for the treatment of T2DM in 2005,¹⁰⁴ and studies with this peptide in an ovariectomised (OVX) rat model of bone loss revealed GLP-1 receptor mediated promotion of osteoblast activation, enhanced bone strength and partial amelioration of deterioration of trabecular microarchitecture¹⁰⁵ (Table 1). In addition to this, STZ-induced diabetic OVX rats administered with the longer-acting GLP-1 mimetic, liraglutide, for 8 weeks presented with decreased osteoclast numbers, increased serum osteocalcin, protection against femoral bone mineral loss and deterioration of bone microarchitecture¹⁰⁶ (Table 1). Liraglutide also exerted benefits on bone in STZ-diabetic mice, related to improvements in microarchitecture and overall bone strength²⁴ (Table 1). Additionally, the GLP-1 mimetic lixisenatide reduced degradation of type II collagen and the expression of IL-6 and TNF-α in primary human chondrocytes¹⁰⁷ (Table 2). Full translatability of this beneficial bone effect to the obesity-diabetes setting is provided from observations of increased bone formation in obese women treated with various clinically approved long-acting GLP-1 receptor agonists^90,108 (Table 2), with similar findings also noted in obese men.¹⁰⁹ In addition, the GLP-1 analogues exenatide and dulaglutide were shown to increase BMD and reduce fracture risk in patients with T2DM¹¹⁰ (Table 2).

Long-acting GIP analogues have also been demonstrated to exert key benefits on bone health in obesity and diabetes. For example, in STZ-diabetic mice, the well characterised enzyme resistant GIP analogue, (D-Ala²) GIP,¹¹¹ augmented bone quality and effectively halted degradation of bone matrix to improve bone fracture resistance¹¹² (Table 1). This finding is particularly important given that the majority of T2DM patients have normal BMD, but still present with increased bone fracture risk.¹¹³ This phenomenon, known as the ‘bone fragility diabetes paradox’, suggests that factors other than BMD, such as bone quality and microarchitecture, may be important in determining overall fracture risk in T2DM.¹¹⁴ To this end, the National Bone Health Alliance advises using indices of bone strength, such as changes in cortical pore and trabecular microstructure in bone, to determine osteoporosis-like disease risk in T2DM.⁹⁰ Encouragingly, other enzymatically stabilised and long-acting GIP analogues, beyond (D-Ala²) GIP, have been created and characterised, including N-AcGIP.¹¹⁵ Treatment with N-AcGIP for 4 weeks improved tissue material properties of bone in normal rats, and in particular collagen maturation¹¹⁶ (Table 1). Moreover, both (D-Ala²) GIP and N-AcGIP reduced osteoclast formation and the extent of osteoclast resorption in vitro, an effect mediated by a reduction in intracellular calcium concentrations²¹ (Table 2). Reassuringly a similar effect of GIP on osteoclasts has also been observed in human bone cells.^96,117

Interestingly, the dual GIP/GLP-1 receptor activating drug tirzepatide has an amino acid sequence with strong parallels to the native GIP sequence, and subsequently exhibits preference for GIP over GLP-1 receptor binding.⁶⁰ In this regard, tirzepatide may offer an exciting new option for improving bone health in obesity and diabetes, linked to the combined direct and indirect benefits of GLP-1, and especially GIP, at the level of the skeleton.¹¹⁸ Although the precise nature of tirzepatide-receptor interactions is under debate,¹¹⁹ it is interesting to note that other dual- and triple-acting peptide molecules that tend to have GLP-1 receptor signalling as their mainstay have also been developed,¹²⁰ with some already progressed to clinical trials.^121,122 The overall impact of these compounds on bone in the setting of obesity and diabetes will also be of particular interest, as described below. That said, such compounds are known to induce significant weight loss, with reductions of obesity conventionally being linked to bone loss.³⁵ Accordingly, bariatric surgeries that are considered gold-standard to manage obesity have been associated with increased bone fracture risk,¹²³ although this finding has been questioned by others.¹²⁴ This is interesting given that alterations in the secretion and action of gut hormones such as GIP, GLP-1 and GLP-2, are known to play a key role in the benefits of many bariatric surgeries.¹²⁵ Thus, it is conceivable that even with weight loss induction by GLP-1 and related compounds in the clinic, direct and/or indirect benefits of these treatments on bone health could offset any potential bone loss.

Unimolecular peptides with established effects on bone

Given recent approval of tirzepatide for T2DM,^61,118 alongside current clinical evaluation of other similar dual- and triple-acting entities,¹²⁰ it seems clear that the same rationale could be applied to bone-targeting unimolecular peptides. Consequently, the powerful, and likely complementary effects of GIP and GLP-2 on bone turnover,^89,126 support this paradigm. Thus, GL-0001, a first in class GIP/GLP-2 dual-acting analogue, positively modified biomechanical parameters of bone in mice by increasing fracture resistance, preventing trabecular bone degradation and augmenting collagen cross-linking¹²⁶ (Table 1). Moreover, GIP-GLP-2 receptor co-agonists for use in the human setting have also recently been described, that reassuringly were shown to possess similar efficacy at the level of the bone as combined treatment with respective parent peptides,⁸⁹ suggesting translation of benefits to the clinic is conceivable. Furthermore, a peptide known as (D-Ala²)GIP-Oxm that co-activates GIP, GLP-1, and glucagon receptors, ameliorated reductions in bone strength following 21 days treatment in db/db mice¹¹ (Table 1). Finally, a long-acting GLP-1/GIP/glucagon triple agonist (HM15211) protected against bone loss and significantly increased the expression of type 1 collagen-α1, -α2, and carboxylated osteocalcin in OVX rats¹²⁷ (Table 1).

DPP-4 inhibitors

GIP, GLP-1, GLP-2, as well as numerous other regulatory peptides, act as substrates for the ubiquitous enzyme DPP-4.¹²⁸ Owing to the distinct benefits of GIP and GLP-1 on insulin secretion and glucose homoeostasis, drugs that inhibit DPP-4 activity are approved for the treatment of T2DM.¹²⁹ However, unsurprisingly it has been demonstrated that DPP-4 inhibitors can lower the risk of bone fracture.¹³⁰ Sitagliptin, a potent and selective DPP-4 inhibitor, has been shown to elevate BMD and bone quality in mice.¹³⁰ Further investigation of the effect of sitagliptin on bone quality in diabetic rodents reveals promotion of cortical bone volume, trabecular architecture and overall bone strength.^131
-133 In high fat fed mice, once daily administration of sitagliptin for 3 weeks positively modified bone composition and improved overall bone strength and resistance to fracture.¹¹² In a similar model of obesity, DPP-4 inhibition alongside metformin administration also exerted clear benefits on diabetic osteoporosis, through modulation of bone morphogenetic protein-2 (BMP-2) and sclerostin signalling.¹³⁴ Reassuringly, in patients with T2DM, use of DPP-4 inhibitor drugs appears to be associated with favourable effects on bone health.¹³⁰

Potential Impact of Other Peptide Hormones and Related Drugs on Bone in Obesity and Diabetes

PTH is employed as an osteoporotic medication and established to reduce fracture risk following daily injection.¹³⁵ Moreover, human PTH(1-34) imparts a favourable impact on bone in rodents with T2DM, linked to improved fracture healing through increased proliferation of mesenchymal stem cells.¹³⁶ Further to this, calcitonin (CT) is a 32-amino acid hormone secreted by thyroid C cells that regulates calcium concentrations.¹³⁷ CT is known to inhibit the resorptive activity of osteoclast cells and essentially oppose the action of PTH.¹³⁸ In OVX rats, CT was demonstrated to promote bone formation by upregulating the expression of Wnt10b in osteoclasts,¹³⁹ whilst CT receptor KO mice exhibit augmented bone formation.¹⁴⁰ However, to date, there is a lack of clinical evidence on the overall efficacy of PTH or CT for bone disorders in the setting of obesity and diabetes. Ghrelin, a peptide that is now recognised to be synthesised within pancreatic islets as well as the stomach,¹⁴¹ is interestingly demonstrated to directly enhance osteoblast proliferation and differentiation in vitro,¹⁴² but further confirmation of this positive bone effect is still required. In addition, the adipocyte-derived hormone leptin, that plays a crucial role in regulating energy homoeostasis,¹⁴³ may also be directly involved in the regulation and bone metabolism.¹⁴⁴ As such, the presence of leptin receptors in adult primary osteoblasts and chondrocytes fully supports this view.¹⁴⁵ Leptin may affect bone formation by activating fibroblast growth factor 23 (FGF-23), where FGF-23 is known to suppress phosphate reabsorption and vitamin D synthesis in the kidney and lately has emerged as a potential regulator of bone mineralisation.^146,147 Leptin may also be produced locally by bone marrow adipocytes, further highlighting an important direct function on bone.¹⁴⁸ Indeed, the impact of leptin on bone is thought to be independent from the action of this adipokine on energy homoeostasis.¹⁴⁹ Furthermore, growth hormone (GH) is crucial for healthy bone remodelling and is known to promote osteoblast activity and bone turnover.¹⁵⁰ In harmony with this, MK-677, a GH secretagogue, has been shown to elevate circulating levels of biochemical markers linked to bone production and bone resorption in humans.¹⁵¹ In women with postmenopausal osteoporosis, treatment of MK-677, either alone or in combination with a bisphosphonate, improved bone formation.¹⁵¹ However, whilst these observations are encouraging, clarification of similar benefits on bone in humans with obesity and diabetes, together with potential involvement of other peptides from the gut-bone axis, is still required. In that regard, there is emerging evidence that GIT peptides beyond GIP, GLP-1 and GLP-2, such as xenin, PYY as well as the neuroendocrine peptide vasoactive intestinal polypeptide (VIP) can also impact bone turnover,^152,153 and these regulatory peptides merit investigation in terms of effects on bone in humans with obesity and diabetes.

Conclusion

It is evident that obesity and diabetes significantly compromise bone health, disrupting the delicate balance between bone formation and resorption. This issue becomes even more significant in ageing populations with diminishing bone strength and given that the general diagnostic criteria for osteoporosis does not appear to be adequate for patients with obesity and diabetes. However, it is increasingly clear that drugs engineered to promote bioactivity of regulatory peptide hormones such as GIP, GLP-1 and GLP-2, can offer hope with regards to both preserving and building bone strength. These peptides have proven direct and/or indirect benefits on bone health in obesity and diabetes (Figure 2), both in the preclinical and clinical setting, although full translation of the obvious benefits in rodents is still required. Indeed, continuing advances in GIT hormone knowledge and peptide synthesis may allow for development of highly efficacious drugs that can simultaneously target multiple receptors to harness additive benefits on bone health, bringing further optimism to this field of therapeutics.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Nigel Irwin

References

Lafferty

Flatt

Irwin

GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy. Expert Opin Pharmacother. 2023;24:587-597.

Sun

Saeedi

Karuranga

, et al. IDF Diabetes Atlas: Global, regional, and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.

Magliano

Boyko

, eds. IDF Diabetes Atlas 10th Edition Scientific Committee. IDF DIABETES ATLAS [Internet]. 10th ed. International Diabetes Federation; 2021.

World Obesity, author. World obesity atlas 2022 [Internet]. World Obesity Federation; 2022. Accessed December 10, 2022. https://s3-eu-west-1.amazonaws.com/wof-files/World_Obesity_Atlas_2022.pdf .

Almarshad

Algonaiman

Alharbi

Almujaydil

Barakat

Relationship between ultra-processed food consumption and risk of diabetes mellitus: A mini-review. Nutrients. 2022;14:2366.

Bouvard

Annweiler

Legrand

Osteoporosis in older adults. Joint Bone Spine. 2021;88:105135.

Compston

Type 2 diabetes mellitus and bone. J Intern Med. 2018;283:140-153.

Palui

Pramanik

Mondal

Ray

Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus. World J Diabetes. 2021;12:706-729.

Datta

Walker

Tuck

Varanasi

SS.

The cell biology of bone metabolism. J Clin Pathol. 2008;61:577-587.

10.

Costantini

Conte

Bone health in diabetes and prediabetes. World J Diabetes. 2019;10:421-445.

11.

Mansur

Mieczkowska

Flatt

, et al. A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus. Bone. 2016;87:102-113.

12.

Kearns

Khosla

Kostenuik

PJ.

Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29:155-192.

13.

Xing

Zhang

RANKL inhibition: a new target of treating diabetes mellitus?

Ther Adv Endocrinol Metab. 2023;14:6039.

14.

Kondegowda

Fenutria

Pollack

, et al. Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-κB ligand pathway. Cell Metab. 2015;22:77-85.

15.

Wang

Gao

Liu

, et al. Denosumab improves glycaemic parameters in postmenopausal osteoporosis patients with combined type 2 diabetes mellitus. Cell Mol Biol. 2023;69:185-191.

16.

Kobayashi

Takahashi

Jimi

, et al. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 2000;191:275-286.

17.

Marahleh

Kitaura

Ohori

, et al. TNF-α directly enhances osteocyte RANKL expression and promotes osteoclast formation. Front Immunol. 2019;10:2925.

18.

García-Hernández

Arzate

Gil-Chavarría

Rojo

Moreno-Fierros

High glucose concentrations alter the biomineralization process in human osteoblastic cells. Bone. 2012;50:276-288.

19.

Roforth

Fujita

McGregor

, et al. Effects of age on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in humans. Bone. 2014;59:1-6.

20.

Tanaka

Yamaguchi

Kanazawa

Sugimoto

Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun. 2015;461:193-199.

21.

Walle

Whittier

Frost

Müller

Collins

CJ.

Meta-analysis of diabetes mellitus-associated differences in bone structure assessed by high-resolution peripheral quantitative computed tomography. Curr Osteoporos Rep. 2022;20:398-409.

22.

Picke

Campbell

Napoli

Hofbauer

Rauner

Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties. Endocr Connect. 2019;8:R55-R70.

23.

Mabilleau

Perrot

Flatt

Irwin

Chappard

High fat-fed diabetic mice present with profound alterations of the osteocyte network. Bone. 2016;90:99-106.

24.

Mansur

Mieczkowska

Bouvard

, et al. Stable incretin mimetics counter rapid deterioration of bone quality in type 1 diabetes mellitus. J Cell Physiol. 2015;230:3009-3018.

25.

Miazgowski

Andrysiak-Mamos

Czekalski

Pynka

Obnizona gestość mineralna kości u chorych zcukrzyca insulinozalezna [Decreased bone mineral density in patients with insulin-dependent-diabetes]. Pol Tyg Lek. 1995;50:14-15.

26.

Thong

Herath

Weber

, et al. Fracture risk in young and middle-aged adults with type 1 diabetes mellitus: a systematic review and meta-analysis. Clin Endocrinol. 2018;89:314-323.

27.

Kemink

Hermus

Swinkels

Lutterman

Smals

AG.

Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. J Endocrinol Invest. 2000;23:295-303.

28.

Schwartz

Backlund

de Boer

, et al. Risk factors for lower bone mineral density in older adults with type 1 diabetes: a cross-sectional study. Lancet Diabetes Endocrinol. 2022;10:509-518.

29.

Rosen

Luben

Multiple hormonal mechanisms for the control of collagen synthesis in an osteoblast-like cell line, MMB-1. Endocrinology. 1983;112:992-999.

30.

Ituarte

Halstead

Iida-Klein

Ituarte

Hahn

TJ.

Glucose transport system in UMR-106-01 osteoblastic osteosarcoma cells: regulation by insulin. Calcif Tissue Int. 1989;45:27-33.

31.

Ferron

Wei

Yoshizawa

, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142:296-308.

32.

Fulzele

Riddle

DiGirolamo

, et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142:309-319.

33.

Liu

Lan

Liang

Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets. Clin Transl Immunol. 2020;9:e1122.

34.

Amarasekara

Rho

Bone loss triggered by the cytokine network in inflammatory autoimmune diseases. J Immunol Res. 2015;2015:832127.

35.

Hou

, et al. Obesity and bone health: a complex link. Front Cell Dev Biol. 2020;8:600181.

36.

Tarantino

Sinatti

Citro

Santini

Balsano

Sarcopenia, a condition shared by various diseases: can we alleviate or delay the progression?

Intern Emerg Med. 2023;18:1887-1895.

37.

Scott

Shore-Lorenti

McMillan

, et al. Associations of components of sarcopenic obesity with bone health and balance in older adults. Arch Gerontol Geriatr. 2018;75:125-131.

38.

Cao

JJ.

Effects of obesity on bone metabolism. J Orthop Surg Res. 2011;6:30.

39.

Ellulu

Patimah

Khaza'ai

Rahmat

Abed

Obesity and inflammation: the linking mechanism and the complications. Arch Med Sci. 2017;13:851-863.

40.

Shapses

Lee

Sukumar

Durazo-Arvizu

Schneider

SH.

The effect of obesity on the relationship between serum parathyroid hormone and 25-hydroxyvitamin D in women. J Clin Endocrinol Metab. 2013;98:E886-E890.

41.

Cashman

Hill

Lucey

, et al. Estimation of the dietary requirement for vitamin D in healthy adults. Am J Clin Nutr. 2008;88:1535-1542.

42.

Trivedi

Doll

Khaw

KT.

Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326:469.

43.

Mohammadi

Sameri

Najafi

Insight into adipokines to optimize therapeutic effects of stem cell for tissue regeneration. Cytokine. 2020;128:155003.

44.

Pastrello

Understanding the role of adipokines in bone metabolism. Bone Res. 2023;11:225.

45.

Greco

Lenzi

Migliaccio

The obesity of bone. Ther Adv Endocrinol Metab. 2015;6:273-286.

46.

Steppan

Crawford

Chidsey-Frink

Swick

AG.

Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept. 2000;92:73-78.

47.

Holloway

Collier

Aitken

, et al. Leptin inhibits osteoclast generation. J Bone Miner Res. 2002;17:200-209.

48.

Williams

Callon

Watson

, et al. Skeletal phenotype of the leptin receptor-deficient db/db mouse. J Bone Miner Res. 2011;26:1698-1709.

49.

Saito

Marumo

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.

50.

Strieder-Barboza

Baker

Flesher

, et al. Advanced glycation end-products regulate extracellular matrix-adipocyte metabolic crosstalk in diabetes. Sci Rep. 2019;9:19748.

51.

Alikhani

Boyd

, et al. Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone. 2007;40:345-353.

52.

Okazaki

Yamaguchi

Tanaka

, et al. Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis. Calcif Tissue Int. 2012;91:286-296.

53.

Singh

Bali

Singh

Jaggi

AS.

Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014;18:1-14.

54.

Zanner

Goff

Ghatan

, et al. Microvascular disease associates with larger osteocyte lacunae in cortical bone in type 2 diabetes mellitus. JBMR Plus. 2023;7:e10832.

55.

Siddiqui

Partridge

NC.

Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology. 2016;31:233-245.

56.

Irwin

Flatt

PR.

New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J Diabetes. 2015;6:1285-1295.

57.

Irwin

Pathak

Flatt

A novel CCK-8/GLP-1 hybrid peptide exhibiting prominent insulinotropic, glucose-lowering, and satiety actions with significant therapeutic potential in high-fat-fed mice. Diabetes. 2015;64:2996-3009.

58.

Nauck

Quast

Wefers

Meier

JJ.

GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102.

59.

Wang

Yang

, et al. GLP-1 receptor agonists for the treatment of obesity: role as a promising approach. Front Endocrinol. 2023;14:1085799.

60.

Nauck

D'Alessio

. 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.

61.

Garvey

Frias

Jastreboff

, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402:613-626.

62.

Seino

Fukushima

Yabe

GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Invest. 2010;1:8-23.

63.

Jeppesen

PB.

Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome. Therap Adv Gastroenterol. 2012;5:159-171.

64.

Schiellerup

Skov-Jeppesen

Windeløv

, et al. Gut hormones and their effect on bone metabolism. potential drug therapies in future osteoporosis treatment. Front Endocrinol. 2019;10:75.

65.

Müller

Finan

Bloom

, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130.

66.

Lafferty

O'Harte

FPM

Irwin

Gault

Flatt

PR.

Proglucagon-derived peptides as therapeutics. Front Endocrinol. 2021;12:689678.

67.

Bell

Santerre

Mullenbach

GT.

Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature. 1983;302:716-718.

68.

Marier

Mouksassi

Gosselin

, et al. Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn's disease. J Clin Pharmacol. 2010;50:36-49.

69.

Thymann

Stoll

Mecklenburg

, et al. Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr Gastroenterol Nutr. 2014;58:694-702.

70.

Haderslev

Jeppesen

Hartmann

, et al. Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon. Scand J Gastroenterol. 2002;37:392-398.

71.

Choi

Lee

Park

, et al. HM15912, a novel long-acting glucagon-like peptide-2 analog, improves intestinal growth and absorption capacity in a male rat model of short bowel syndrome. J Pharmacol Exp Ther. 2023;384:277-286.

72.

Henriksen

Alexandersen

Bjarnason

, et al. Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res. 2003;18:2180-2189.

73.

Gottschalck

Jeppesen

Hartmann

Holst

Henriksen

DB.

Effects of treatment with glucagon-like peptide-2 on bone resorption in colectomized patients with distal ileostomy or jejunostomy and short-bowel syndrome. Scand J Gastroenterol. 2008;43:1304-1310.

74.

Gottschalck

Jeppesen

Holst

Henriksen

DB.

Reduction in bone resorption by exogenous glucagon-like peptide-2 administration requires an intact gastrointestinal tract. Scand J Gastroenterol. 2008;43:929-937.

75.

Henriksen

Alexandersen

Hartmann

, et al. 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;45:833-842.

76.

Henriksen

Alexandersen

Byrjalsen

, et al. Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2. Bone. 2004;34:140-147.

77.

Henriksen

Alexandersen

Hartmann

, et al. Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone. 2007;40:723-729.

78.

Huang

Kuai

, et al. Glucagon-like peptide-2 ameliorates Age-Associated bone loss and gut barrier dysfunction in senescence-accelerated mouse prone 6 mice. Gerontology. 2023;69:428-449.

79.

Yusta

Huang

Munroe

, et al. Enteroendocrine localization of GLP-2 receptor expression in humans and rodents. Gastroenterology. 2000;119:744-755.

80.

Pacheco-Pantoja

Ranganath

Gallagher

Wilson

Fraser

WD.

Receptors and effects of gut hormones in three osteoblastic cell lines. BMC Physiol. 2011;11:12.

81.

Skov-Jeppesen

Hepp

Oeke

, et al. The antiresorptive effect of GIP, but not GLP-2, is preserved in patients with Hypoparathyroidism-A randomized crossover study. J Bone Miner Res. 2021;36:1448-1458.

82.

Khan

Vasu

Moffett

Irwin

Flatt

PR.

Differential expression of glucagon-like peptide-2 (GLP-2) is involved in pancreatic islet cell adaptations to stress and beta-cell survival. Peptides. 2017;95:68-75.

83.

Dobnig

Turner

RT.

The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology. 1997;138:4607-4612.

84.

Holst

Hartmann

Gottschalck

, et al. Bone resorption is decreased postprandially by intestinal factors and glucagon-like peptide-2 is a possible candidate. Scand J Gastroenterol. 2007;42:814-820.

85.

Gadgaard

Windeløv

Schiellerup

, et al. Long-acting agonists of human and rodent GLP-2 receptors for studies of the physiology and pharmacological potential of the GLP-2 system. Biomed Pharmacother. 2023;160:114383.

86.

Nauck

Meier

JJ.

Incretin hormones: their role in health and disease. Diabetes Obes Metab. 2018;20 Suppl 1:5-21.

87.

Rebello

Henne

, et al. GLP-2 is locally produced from human islets and balances inflammation through an inter-islet-immune cell crosstalk. Front Endocrinol. 2021;12:697120.

88.

Zhao

Liang

Yang

The impact of glucagon-like peptide-1 on bone metabolism and its possible mechanisms. Front Endocrinol. 2017;8:98.

89.

Gabe

MBN

Skov-Jeppesen

Gasbjerg

, et al. 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.

90.

Xie

Chen

, et al. The impact of glucagon-like peptide 1 receptor agonists on bone metabolism and its possible mechanisms in osteoporosis treatment. Front Pharmacol. 2021;12:697442.

91.

Mabilleau

Mieczkowska

Irwin

Flatt

Chappard

Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. J Endocrinol. 2013;219:59-68.

92.

Wang

Cheng

, et al. Effects of glucagon-like peptide-1 receptor agonists on fracture healing in a rat osteoporotic model. Exp Ther Med. 2023;26:412.

93.

Cho

Fujita

Kieffer

TJ.

Glucagon-like peptide-1: glucose homeostasis and beyond. Annu Rev Physiol. 2014;76:535-559.

94.

Christensen

Lund

Calanna

, et al. Glucose-dependent insulinotropic polypeptide (GIP) inhibits bone resorption independently of insulin and glycemia. J Clin Endocrinol Metab. 2018;103:288-294.

95.

Bollag

Zhong

Phillips

, et al. Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology. 2000;141:1228-1235.

96.

Hansen

Søe

Christensen

, et al. GIP reduces osteoclast activity and improves osteoblast survival in primary human bone cells. Eur J Endocrinol. 2023;188:lvac004.

97.

Vyavahare

Mieczkowska

Flatt

, et al. GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice. Peptides. 2020;125:170207.

98.

Zhong

Itokawa

Sridhar

, et al. Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab. 2007;292:E543-E548.

99.

Mieczkowska

Irwin

Flatt

Chappard

Mabilleau

Glucose-dependent insulinotropic polypeptide (GIP) receptor deletion leads to reduced bone strength and quality. Bone. 2013;56:337-342.

100.

McGonnell

Grigoriadis

Lam

Price

Sunters

A specific role for phosphoinositide 3-kinase and AKT in osteoblasts?

Front Endocrinol. 2012;3:88.

101.

Nissen

Christensen

Knop

, et al. Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans. J Clin Endocrinol Metab. 2014;99:E2325-E2329.

102.

Gasbjerg

Hartmann

Christensen

, et al. GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3–30)NH2. Bone. 2020;130:115079.

103.

Tatarkiewicz

Hargrove

Jodka

, et al. A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents. Diabetes Obes Metab. 2014;16:75-85.

104.

Kendall

Riddle

Rosenstock

, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-1091.

105.

Meng

Jia

, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, prevents osteopenia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats. J Bone Miner Res. 2013;28:1641-1652.

106.

Wen

Zhao

Wang

Liraglutide exerts a bone-protective effect in ovariectomized rats with streptozotocin-induced diabetes by inhibiting osteoclastogenesis. Exp Ther Med. 2018;15:5077-5083.

107.

Jia

Zhu

Huang

Lixisenatide attenuates advanced glycation end products (AGEs)-induced degradation of extracellular matrix in human primary chondrocytes. Artif Cells Nanomed Biotechnol. 2019;47:1256-1264.

108.

Iepsen

Lundgren

Hartmann

, et al. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J Clin Endocrinol Metab. 2015;100:2909-2917.

109.

Eastell

Rosen

Black

, et al. Pharmacological management of osteoporosis in postmenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2019;104:1595-1622.

110.

Cai

Jiang

, 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.

111.

Martin

Sutton

Willars

Dixon-Woods

Frameworks for change in healthcare organisations: a formative evaluation of the NHS Change Model. Health Serv Manage Res. 2013;26:65-75.

112.

Mansur

Mieczkowska

Flatt

, et al. Sitagliptin alters bone composition in high-fat-fed mice. Calcif Tissue Int. 2019;104:437-448.

113.

Starup-Linde

Lykkeboe

Gregersen

, et al. Bone structure and predictors of fracture in type 1 and type 2 diabetes. J Clin Endocrinol Metab. 2016;101:928-936.

114.

Samelson

Demissie

Cupples

, et al. Diabetes and deficits in cortical bone density, microarchitecture, and bone size: Framingham HR-pQCT study. J Bone Miner Res. 2018;33:54-62.

115.

Kerr

Irwin

O'Harte

, et al. Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties. Biochem Pharmacol. 2009;78:1008-1016.

116.

Mabilleau

Mieczkowska

Irwin

, et al. Beneficial effects of a N-terminally modified GIP agonist on tissue-level bone material properties. Bone. 2014;63:61-68.

117.

Chavda

Ajabiya

Teli

Bojarska

Apostolopoulos

Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: a mini-review. Molecules. 2022;27:4315.

118.

Gasbjerg

Rosenkilde

Meier

Holst

Knop

FK.

The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide. Diabetes Obes Metab. 2023;25:3079-3092.

119.

Seghieri

Christensen

Andersen

, et al. Future perspectives on GLP-1 receptor agonists and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD. Front Endocrinol. 2018;9:649.

120.

Coskun

Sloop

Loghin

, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3-14.

121.

Müller

Blüher

Tschöp

DiMarchi

RD.

Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21:201-223.

122.

Skov-Jeppesen

Veedfald

Madsbad

, et al. Subcutaneous GIP and GLP-2 inhibit nightly bone resorption in postmenopausal women: a preliminary study. Bone. 2021;152:116065.

123.

Stein

Silverberg

SJ.

Bone loss after bariatric surgery causes, consequences, and management. Lancet Diabetes Endocrinol. 2014;2:165-174.

124.

Khalid

Omotosho

Spagnoli

Torquati

Association of bariatric surgery with risk of fracture in patients with severe obesity. JAMA Netw Open. 2020;3:e207419.

125.

Finelli

Padula

Martelli

Tarantino

Could the improvement of obesity-related co-morbidities depend on modified gut hormones secretion?

World J Gastroenterol. 2014;20:16649-16664.

126.

Gobron

Couchot

Irwin

, et al. Development of a first-in-class unimolecular dual GIP/GLP-2 analogue, GL-0001, for the treatment of bone fragility. J Bone Miner Res. 2023;38:733-748.

127.

Kim

Lee

Choi

, et al. Neuroprotective effects of HM15211, a novel long-acting GLP-1/glucagon/GIP triple agonist in the MPTP Parkinson’s disease mouse model. American Diabetes Association’s 77th Scientific Sessions; San Diego, CA; June 9-13, 2017.

128.

Richter

Bandeira-Echtler

Bergerhoff

Lerch

Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4:753-768.

129.

Gilbert

Pratley

RE.

GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: review of head-to-head clinical trials. Front Endocrinol. 2020;11:178.

130.

Lee

Kim

Yoo

, et al. Effect of dipeptidyl peptidase-4 inhibitors on bone health in patients with type 2 diabetes mellitus. J Clin Med. 2021;10:4775.

131.

Kyle

Willett

Baggio

Drucker

Grynpas

MD.

Differential effects of PPAR-{gamma} activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice. Endocrinology. 2011;152:457-467.

132.

Achemlal

Tellal

Rkiouak

, et al. Bone metabolism in male patients with type 2 diabetes. Clin Rheumatol. 2005;24:493-496.

133.

Kanda

Furukawa

Izumo

, et al. Effects of the linagliptin, dipeptidyl peptidase-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus in obese mice. Drug Discov Ther. 2020;14:218-225.

134.

Nirwan

Vohora

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. 2022;13:944323.

135.

Leder

O'Dea

LSL

Zanchetta

, et al. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2015;100:697-706.

136.

Alder

White

Chung

, et al. Systemic parathyroid hormone enhances fracture healing in multiple murine models of type 2 diabetes mellitus. JBMR Plus. 2020;4:e10359.

137.

Copp

Cameron

Cheney

Davidson

Henze

KG.

Evidence for calcitonin–a new hormone from the parathyroid that lowers blood calcium. Endocrinology. 1962;70:638-649.

138.

Keller

Catala-Lehnen

Huebner

, et al. Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts. Nat Commun. 2014;5:5215.

139.

Hsiao

Chen

Chu

, et al. Calcitonin induces bone formation by increasing expression of wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats. Front Endocrinol. 2020;11:613.

140.

Cornish

Reid

IR.

Effects of amylin and adrenomedullin on the skeleton. J Musculoskelet Neuronal Interact. 2001;2:15-24.

141.

Müller

Nogueiras

Andermann

, et al. Ghrelin. Mol Metab. 2015;4:437-460.

142.

Fukushima

Hanada

Teranishi

, et al. Ghrelin directly regulates bone formation. J Bone Miner Res. 2005;20:790-798.

143.

Maffei

Halaas

Ravussin

, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1:1155-1161.

144.

Upadhyay

Farr

Mantzoros

CS.

The role of leptin in regulating bone metabolism. Metabolism. 2015;64:105-113.

145.

Baldock

Sainsbury

Allison

, et al. Hypothalamic control of bone formation: distinct actions of leptin and y2 receptor pathways. J Bone Miner Res. 2005;20:1851-1857.

146.

Tsuji

Maeda

Kawane

Matsunuma

Horiuchi

Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1α,25-dihydroxyvitamin D3 synthesis in leptin-deficient ob/ob Mice. J Bone Miner Res. 2010;25:1711-1723.

147.

Erben

RG.

Physiological actions of fibroblast growth factor-23. Front Endocrinol. 2018;9:267.

148.

Laharrague

Larrouy

Fontanilles

, et al. High expression of leptin by human bone marrow adipocytes in primary culture. FASEB J. 1998;12:747-752.

149.

Turner

Kalra

Wong

, et al. Peripheral leptin regulates bone formation. J Bone Miner Res. 2013;28:22-34.

150.

Murphy

Weiss

McClung

, et al. Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women¹. J Clin Endocrinol Metab. 2001;86:1116-1125.

151.

Smith

Thorner

MO.

Growth hormone secretagogues as potential therapeutic agents to restore growth hormone secretion in older subjects to those observed in young adults. J Gerontol A. 2023;78:38-43.

152.

Gobron

Bouvard

Vyavahare

, et al. Enteroendocrine K cells exert complementary effects to control bone quality and mass in mice. J Bone Miner Res. 2020;35:1363-1374.

153.

Zahedi

Daley

Brooks

. The PYY/Y2R-deficient male mouse is not protected from bone loss due to Roux-en-Y gastric bypass. Bone. 2023;167:116608.

154.

Chen

, et al. The protective effects of dulaglutide against advanced glycation end products (AGEs)-induced degradation of type Ⅱ collagen and aggrecan in human SW1353 chondrocytes. Chem Biol Interact. 2020;322:108968.