Effects of Glucagon-Like Peptide-1 receptor agonists on bone health in people living with obesity

Abstract

Medications like liraglutide 3.0 mg daily (Saxenda®; Novo Nordisk) and semaglutide 2.4 mg weekly (Wegovy®; Novo Nordisk), which are glucagon-like peptide-1 receptor agonists (GLP-1Ra), have been sanctioned for prolonged weight management in people living with obesity (PwO). Although GLP-1 might enhance bone metabolism and quality, the impact of these receptor agonists on bone health remains uncertain and is the subject of this review. Data on bone health in the context of calorie restriction and bariatric surgery were also summarized. A comprehensive search of the literature on preclinical studies and human data published in English was performed from Jan 2013 to Dec 2024 to identify the various effects of GLP-1Ra on bone health. The effects of intentional weight loss procedures in PwO are well documented; significant weight reduction (~ 7–10%) through calorie restriction, with or without exercise, and bariatric/metabolic surgery results in high turnover bone loss. In different rodent models, liraglutide seems to positively influence bone material properties despite notable weight loss. However, the most favorable effects on bone mineral density and microarchitecture were noted at concentrations much higher than those approved for human obesity treatment. Current evidence on the effects of GLP-1Ra on bone health in PwO is limited. Although initial findings suggest that GLP-1Ra leads to a slight reduction in bone mineral density and promotes bone remodeling, favoring resorption similar to calorie restriction effects, further research is needed to explore the effects of GLP-1Ra on bone metabolism and fracture-related outcomes, as well as dual- and triple-receptor agonists of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon in PwO. The impact of glucagon-like peptide-1 receptor agonists (GLP-1Ra) on bone health remains unclear. Although preliminary findings indicate that GLP-1Ra causes modest bone mineral density reduction and enhances bone remodeling, favoring resorption similar to the effects of calorie restriction, further research is needed on fracture-related outcomes in people living with obesity.

Introduction

Obesity is a global epidemic, as defined by the World Health Organization (WHO), and its prevalence is increasing worldwide. It is defined as a body mass index (BMI) of 30 kg/m² or more and affects more than 890 million adults globally, 340 million adolescents, and 30 million children. Its prevalence is estimated to increase to 1.02 billion by 2030 [1].

Obesity has many metabolic consequences, such as type 2 diabetes mellitus (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), hypercholesterolemia, chronic kidney disease (CKD), cardiovascular disease, and an increased risk of certain types of cancer [2, 3].

It has been demonstrated that weight loss improves many consequences of obesity, and this improvement is greater when weight loss is more important. With a weight loss of 15%, there is a remarkable reduction in CKD progression, heart failure outcomes, MASLD, cardiovascular events, cancers, cancer mortality, and overall mortality [4, 5].

Obesity can be treated in various ways (Fig. 1). First, traditional treatment is based on calorie restriction with or without physical activity. Second, metabolic/bariatric surgery has been proven to be the most effective treatment in terms of weight loss and improvement in all associated comorbidities. Third, anti-obesity drugs developed by pharmaceutical companies in the early 2010 s include glucagon-like peptide-1 receptor agonists (GLP-1Ra), which cause significant weight loss [6].

Fig. 1.

Obesity treatment strategies

Weight loss procedures such as calorie restriction and metabolic/bariatric surgery are known to affect bone health because they elevate bone turnover markers (BTMs) and reduce bone mineral density (BMD) [7–9]. Metabolic/bariatric surgery also modifies bone microarchitecture and strength, and increases the risk of fracture [10–12].

Although GLP-1Ra and other medications for weight loss have transformed obesity treatment, their impact on bone health remains largely unexplored [13]. Consequently, this comprehensive review sought (i) to investigate the existing research regarding the effects of GLP-1Ra on bone metabolism, encompassing both preclinical studies and human trials and (ii) the current knowledge related to the impact on bone metabolism of weight loss following calorie restriction and metabolic/bariatric surgery. These data on changes in bone metabolism are important because they allow us to put things into perspective in the context of GLP-1Ra for obesity care.

Methods

References for the review were identified through PubMed searches for articles and reviews published from January 2013 to December 2024, although older references were used when appropriate. We used the search terms “fracture”, “osteoporosis”, “semaglutide”, “calorie restriction”, “bariatric surgery”, “bone density”, “bone turnover markers”, “liraglutide”, “tirzepatide”, “Glucagon-like peptide 1”, and “glucagon-like peptide receptor analogues” in combination with the terms “obesity” and “diabetes”. Articles revealed by these searches and the relevant references cited in these articles were reviewed. Only articles published in English were included in the present study.

GLP-1 Receptor Agonists for obesity care

Incretin hormones

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by enteroendocrine L-cells located in the distal small intestine and colon when nutrients are consumed [14, 15]. Additionally, it is produced by certain neuronal cells in the brainstem. GLP-1 originating from the gut has a very short circulating half-life of only 1–2 min due to its rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4) and subsequent clearance through the kidneys. GLP-1 exerts its effects through the GLP-1 receptor, which is found in various tissues, including the brain, pancreas, stomach, heart, kidneys, and adipose tissue [14, 15]. Incretin hormones, such as GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are involved in several functions such as regulating glucose levels, delaying gastric emptying, and reducing food intake [16, 17].

GLP-1Ra

GLP-1Ra were first marketed for the treatment of T2D (at a lower dose and as daily SC injections), then as weekly injections and finally, at larger doses for the treatment of obesity; indeed, the effect of GLP-1RA on weight loss is dose dependent. The history of GLP-1Ra started in 2005 with exenatide (Byetta®) developed by Amylin Pharma and Eli Lilly being the first GLP-1Ra to be approved on the market in 2005. It was then followed by liraglutide 1.8 mg (Victoza®, Novo Nordisk) in 2009, dulaglutide 1.5 mg (Trulicity®, Eli Lilly) in 2014, and liraglutide 3.0 mg (Saxenda®, Novo Nordisk) in 2014.

In 2017, Novo Nordisk created semaglutide 1 mg once weekly (Ozempic®), a GLP-1Ra, as an injectable treatment for T2D. Patients presented the largest weight loss reported to date with that drug class, prompting Novo Nordisk to conduct additional studies on semaglutide and other GLP-1Ra in people living with obesity (PwO) [18, 19]. When the dose was increased from 1 mg to 2.4 mg per week, PwO without T2D lost on average 15% of their starting weight [18, 19]. GLP-1Ra have revolutionized the treatment of obesity and the 2024 Lasker ~ DeBakey Clinical Medical Research Award has recently honored three scientists for their discovery on GLP-1Ra.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved liraglutide 3.0 mg once daily (Saxenda®; Novo Nordisk) and semaglutide 2.4 mg once weekly (Wegovy®; Novo Nordisk) as treatments for chronic weight management in PwO with a BMI of > 30 kg/m² or > 27 kg/m² who have weight-related health problems. Semaglutide has been taken by literally millions of people in the US in the last three years [20].

In France, the semaglutide 2.4-mg (Wegovy®) was part of an early-access initiative from July 2022 to September 2023. A recent publication has detailed the user profile of semaglutide 2.4-mg in real-world settings during this timeframe, which helps identify if this group is at risk for osteoporosis [21]. Out of the 6990 adult patients who began the treatment, 65.8% were female, and the median age was 49.0 years (interquartile range, 39.0–58.0 years). The predominant age category was 45–54, accounting for 28.1% of the cohort; 11.3% of patients had an age ≥ 65 years old. The proportion of patients with comorbidities associated with fracture risk such as T2D (26.7%), cardiac disease (16.3%), and liver disease (11.2%) was also reported. Metabolic/bariatric surgery in the past 5 years was found in 5.4% of patients. Unfortunately, no data on bone metabolism were available [21].

Tirzepatide and oral GLP-1Ra

Unsurprisingly, the broader biotech and pharmaceutical sectors have taken notice. Eli Lilly has created tirzepatide (Zepbound®), which incorporates the activity of another incretin-like peptide, GIP, into the GLP-1 framework [22]. The effectiveness of tirzepatide for treating obesity is being evaluated in the SURMOUNT series of phase 3 RCTs, which, for the first time, demonstrated average weight reductions exceeding 20% with pharmacotherapy [23]. In people without diabetes, tirzepatide achieved an average weight reduction of 21% and received FDA approval for weight loss in 2023 [24]. Oral versions of GLP-1Ra are still under investigation for the treatment of obesity, though they thus far have lower efficacy [25].

Emerging antiobesity drugs in development

Numerous novel treatments for obesity are currently in the pipeline, including triple agonists that target GLP-1, GIP, and glucagon receptors [26]. The majority of these therapies aim to replicate or inhibit the effects of various gut hormones such as GLP-1, GIP, amylin, and glucagon [27, 28]. Initial clinical trials have shown remarkable results, with several of these agents demonstrating unprecedented weight reduction and improvements in blood glycemic control. In the short term, these outcomes appear similar to those achieved through bariatric/metabolic surgical procedures.

These developments raised several questions, including concerns about the direct and indirect impacts of these anti-obesity drugs on bone metabolism, particularly in PwO experiencing a massive amount of weight loss.

Effects of intentional weight-loss on bone health in humans

Although not the focus of this review, numerous studies have examined alterations in bone metabolism in PwO following weight loss interventions such as calorie restriction and bariatric/metabolic surgery [8]. A brief overview of the key findings is provided below. Understanding these changes is crucial, as it provides a context for evaluating the impact of GLP-1Ra on bone metabolism.

Intervention studies have shown that weight reduction in PwO through caloric restriction alone or in combination with low-impact aerobic exercise results in increased levels of BTMs and decreased BMD values [29, 30]. In most studies, significant reductions in total hip BMD, but not in lumbar spine BMD, were observed [31, 32]. Procollagen type I N-terminal propeptide (PINP) levels also increased to a lesser extent than cross-laps (CTX) [7, 9]. Importantly, weight loss does not systematically change bone metabolism, and the observed changes in BTMs and BMD may be associated with the amount of weight loss. Evidence supports a weight loss threshold of approximately 7–10% for changes in bone metabolism [7, 9]. Moreover, continued bone metabolism impairment over time in the aftermath of weight loss has been reported in postmenopausal women despite maintaining a stable weight, suggesting a progressive or even delayed effect [7]. Fracture assessment has rarely been performed in weight loss interventions through calorie restriction, largely because of the requirement for large study populations and long-term follow-up. In the LOOK-AHEAD study, 5145 participants aged 45–76 years (mean BMI 36 kg/m²) with T2D were randomized to either calorie restriction or diabetes support and education intervention (controls) [33]. Weight loss over the intervention period (median 9.6 years) was 6.0% for calorie restriction and 3.5% for controls. A total of 731 participants had confirmed incident fractures (358 with controls vs. 373 with calorie restriction). There were no significant differences in the incidence of total or hip fracture between the calorie restriction and control groups. However, compared to the controls, the calorie restriction group had a statistically significant 39% increased risk of major osteoporotic fractures (hazard ratio [HR], 1.39; 95% CI, 1.02 1.89) [33]. The paucity of data prevents us from concluding that there is a possible increase in the fracture risk following calorie restriction. Moreover, bone microarchitecture/strength changes assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) are lacking.

It is increasingly recognized that bariatric/metabolic surgery adversely affects bone metabolism [8, 34] (Fig. 2). The extent of high-turnover bone loss suggests severe bone impairment; this phenomenon is much more important than that observed with calorie restriction alone [8]. This is likely related, at least in part, to the magnitude of weight loss following bariatric/metabolic surgery. Changing patterns in BTMs and BMD are similar to those found in calorie restriction interventions: CTX levels increased to a greater extent compared to those of PINP, and total hip BMD decreased to a greater extent compared to lumbar spine BMD [35, 36]. Following Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), PwO often experience significant declines in bone microarchitecture and strength, as measured by HR-pQCT [37, 38]. There is a clear link between bariatric/metabolic surgery and an increased risk of fractures, typically becoming apparent in the third year of follow-up [39, 40]. While the exact mechanisms remain unclear, several factors are implicated, including nutritional aspects, mechanical unloading, loss of lean mass, and alterations in the secretion of gut hormones and adipokines [8, 10]. Evidence is mounting that RYGB is linked to a more pronounced decrease in BMD, a greater rise in BTMs, and a higher fracture risk compared to SG [8, 10].

Fig. 2.

Impaired bone health following bariatric/metabolic surgery

Effects of GLP-1 receptor agonists on bone health in preclinical models

The first indications of a GLP-1 effect on the skeleton were derived from phenotype assessments of GLP-1R knockout (KO) mice. These mice exhibited reduced trabecular bone mass due to increased osteoclast activity, suggesting lower biomechanical strength [41]. In rodents, but not in humans, GLP-1R is expressed by the C cells of the thyroid gland, and its activation stimulates calcitonin secretion [42, 43]. Therefore, the observed decrease in bone mass in GLP-1R KO mice could be linked to reduced calcitonin secretion [41]. Additionally, significant changes were noted in the composition of the bone matrix of these animals, with decreased enzymatic cross-linking of the collagenous matrix, which clearly worsened the compromised biomechanical strength and contributed to the observed bone fragility [44]. Double knockout animals for both GIPR and GLP-1R (DIRKO) showed in cortical bone the same bone alterations seen in single GLP-1R KO animals [45].

In vitro studies on bone cells supported the expression of the conventional GLP-1R in osteoblasts and confirmed that liraglutide, at nanomolar concentrations, promoted osteoblast differentiation and reduced osteoblast apoptosis via activation of the PI3K/Akt/GSK3K, MAPK, and cAMP/PKA/β-catenin intracellular pathways [46–48]. Furthermore, liraglutide treatment drove osteogenic differentiation in human adipose-derived stem cells, human periodontal ligament cells, and dental pulp stem cells [49–52]. Administration of liraglutide, still at nanomolar concentrations, to bone marrow macrophages or the pre-osteoclast Raw264.7 cell line resulted in a reduction in osteoclast formation and osteoclast-mediated resorption [53], suggesting a decoupling effect on bone formation and resorption.

Liraglutide, semaglutide, and more recently tirzepatide, have been tested in various animal models of obesity, type 1 diabetes and T2D, osteoporosis, and diabetes-induced osteoporosis. A previous study on GLP-1R activation in several species reported approximately 50% and 30% potency of liraglutide at the mouse and rat receptors, respectively [54]. Therefore, dose adjustment is necessary in preclinical animal models. Table 1 summarizes the dose adjustment of human doses. It is worth noting that only a few preclinical studies have been conducted with a dose range similar to that used in human clinical settings, and most of them used doses far above the tolerated human dose.

Table 1.

Daily dose adjustment of GLP-1RA used in humans and in preclinical rodent models

	Type 2 diabetes mellitus		Obesity
	Human	Rodent	Human	Rodent
Liraglutide	22	43–72	28	57–94
	(6)	(12–20)	(7.5)	(15–25)
Semaglutide	1.5	3–5	3.3	6.5–11
	(0.4)	(0.7–1.2)	(0.8)	(1.6–2.6)
Tirzepatide	23	46–76	20	41–68
	(4.7)	(9.5–16)	(4.2)	(8.4–14)

The values represent concentrations in µg/kg/day, and the values in parentheses correspond to the same concentrations expressed in nmoles/kg/day

In ovariectomy (OVX)-induced osteoporosis in rat and mouse models, liraglutide was administered at doses ranging from ~ 80 nmol/kg/day to ~ 530 nmol/kg/day. At these doses, liraglutide caused weight loss in rat models [55, 56]. However, despite significant weight loss, liraglutide-treated animals displayed increased bone mass, trabecular number, and cortical thickness in the appendicular and axial skeletons, with marked improvement in bone formation parameters [55–57]. It is also worth noting that these effects of liraglutide in OVX animals occurred relatively quickly, with positive outcomes observed after just four weeks of treatment, consistent with in vitro data [57]. In OVX rat, administration of semaglutide at ~ 21 and 43 µg/kg/day resulted in body weight loss in the animals, but also to improvement in BMD at the axial and appendicular skeleton associated with a reduction in BTMs [58]. However, none of the above studies investigated whether bone biomechanic and resistance to fracture were improved following administration of GLP-1Ra. In the glucocorticoid-induced osteoporosis (GIOP) rat model, administration of liraglutide at a dose of ~ 53 nmol/kg/day did not result in significant weight loss [59]. However, liraglutide-treated animals showed increases in trabecular BMD and trabecular thickness, two parameters that were dramatically reduced in GIOP controls [59], and which are hallmarks of human GIOP [60].

In type 1 diabetes mouse models, these effects appeared to be dose-dependent. At ~ 25 nmol/kg/day, only slight improvements in tissue biomechanics and a reduction in collagen degradation were observed [61]. However, at ~ 160 nmol/kg/day, both trabecular and cortical BMD improved after liraglutide treatment [62]. In type 2 diabetes rat models, where bone mass is often reduced, contrary to humans, where bone mass is often normal or increased, liraglutide administration in the range of ~ 110–160 nmol/kg/day resulted in increased trabecular BMD and restoration of trabecular microarchitecture parameters in the appendicular and axial skeleton [63–67]. Improvement in bone phenotype was also observed as early as four weeks after treatment initiation. Only one study examined the effect of liraglutide (~ 25 nmol/kg/day) on bone material properties in a T2D mouse model. Indeed, liraglutide significantly restored the degree of mineralization, tissue water content, hydroxyapatite crystal size, and enzymatic collagen cross-linking [68]. Administration of semaglutide at the dose regimen of ~ 90 µg/kg/day failed to evidence significant weight loss but more importantly, led to alteration of cortical bone microarchitecture, represented by lower cortical thickness, and ultimately to a significant decrease in bone strength [69]. On the other hand, administration of tirzepatide at a dose of 70 nmol/kg/day, resulted in a significant weight loss associated with shorter femur compared to saline-treated diabetic mice, but no evident alterations of bone microarchitecture or strength [69].

In the rodent high fat fed male mice model, administration of semaglutide at the dose of 2800 µg/kg/day resulted in a significant weight loss attributed to a decreased food intake [70]. Interestingly, appendicular BMD, but not axial BMD, was not reduced despite significant weight loss in the semaglutide group and no changes in BTMs or bone microarchitecture was encountered [70].

Research involving GLP-1R KO mouse models and in vitro bone cell studies indicated that GLP-1Ra could be advantageous for bone health, even when weight loss is pharmacologically induced. Liraglutide appears to positively influence bone metabolism in various preclinical models. Although the therapeutic dose of liraglutide appeared to enhance bone material properties, the most significant improvements in BMD and microarchitecture were noted at doses much higher than those used for weight loss in PwO. Currently, preclinical studies examining the impact of semaglutide on bone metabolism are limited.

Effects of GLP-1 receptor agonists on bone metabolism in humans

Until recently, there were no randomized controlled trials assessing the effects of GLP-1Ra on bone metabolism during the weight loss phase using standard BMD measurement sites (i.e., lumbar spine and proximal femur) [71, 72]. Two randomized controlled trials are now available [73, 74].

Researchers have investigated the impact of semaglutide on bone health in adults at elevated fracture risk, but without T2D [73]. The study involved 64 participants, predominantly female (86%), with a mean age of 63 years and a BMI ranging from 21 to 39 kg/m². Subjects were randomly assigned to receive either semaglutide (1.0 mg or the highest tolerated dose) or placebo weekly for 52 weeks. Semaglutide treatment resulted in a significant average weight reduction of 9.4% (p < 0.001), whereas no change was observed in the placebo group. Although serum PINP levels remained similar between groups from baseline to week 52, the semaglutide group exhibited a 54.8% greater increase in CTX than the placebo group (Fig. 3). Semaglutide administration led to a decrease in BMD: 2.1% in the lumbar spine (p = 0.01), 2.6% in the total hip (p = 0.001), and 1.5% in the tibial volumetric BMD (p = 0.003). The effects of semaglutide, including weight loss, slight bone loss, and increased CTX, resembled to those observed with calorie restriction interventions [73]. However, the study design did not allow for the assessment of the effects of semaglutide on bone metabolism, independent of weight loss, as the control group did not experience comparable weight reduction. It is also worth mentioning that this study included participants with a BMI lower than recommended for this molecule in people without diabetes, and this might influence the generalizability of the results.

Fig. 3.

Comparison of changes in PINP (A), and CTX (B) from baseline to week 52 between the semaglutide group (n = 32) and the placebo group (n = 32)

A secondary analysis of a randomized clinical trial examined changes in BMD at clinically significant sites following an 8-week low-calorie diet (800 kcal/day) for weight loss, followed by a year-long treatment with liraglutide (3.0 mg daily), exercise alone (a supervised and progressive resistance training program), a combination of both treatments (liraglutide + exercise), or a placebo [74]. A total of 195 participants (average [SD] age, 42.8 [11.9] years; 124 females [64%]; average [SD] BMI, 37.0 [2.9]) completed the low-calorie diet and were then randomly assigned to the exercise group (n = 48), liraglutide group (n = 49), combination group (n = 49), or placebo group (n = 49). None of the participants were on osteoporosis medications and no fractures were reported in any group. Following a weight loss of 13.1 kg induced by the low-calorie diet for the entire cohort, the placebo group regained weight, the exercise and liraglutide groups maintained their weight loss, and the combination group lost additional weight. As anticipated, the low-calorie diet led to an increase in CTX (+ 27%) and PINP (+ 7%), indicating increased bone turnover favoring bone resorption [74] (Fig. 4). After calorie restriction, CTX levels continued to rise in the combination group owing to further weight loss, but these levels decreased during the final phase of the intervention from week 26 to week 52 across all four groups. By week 52, PINP levels had returned to their initial values in all groups (Fig. 4). Throughout the study, a slight reduction in BMD was noted in all four groups at the lumbar spine and total hip. However, unlike the combination of exercise and liraglutide, liraglutide alone resulted in a decrease in hip and lumbar spine BMD compared to placebo. Therefore, after weight loss, incorporating exercise with liraglutide helps mitigate BMD loss at the hip and lumbar spine, similar to the pattern observed when weight loss from calorie restriction alone is combined with exercise [74] (Fig. 5).

Fig. 4.

Changes in Bone Turnover Markers During the Study

Fig. 5.

Changes in Bone Mineral Density (BMD) During the Study

In conclusion, the effects of GLP-1Ra (i.e., semaglutide and liraglutide), including weight loss, slight BMD loss, and increased CTX, resembled to those observed with calorie restriction interventions [7, 9]. However, we need more data to assess the effects of anti-obesity drugs on bone metabolism in PwO experiencing a massive amount of weight loss (≥ 15–20%).

Effects of GLP-1 receptor agonists on fracture risk in humans

The STEP program, consisting of phase 3 randomized controlled trials, has examined the effectiveness of semaglutide (Wegovy®) in treating obesity [18, 19]. Nevertheless, none of the published studies have provided information on fracture-related outcomes. The specific fracture risk associated with GLP-1Ra used for obesity treatment has not yet been evaluated. However, there are several ways to examine fracture-related outcomes under GLP-1Ra.

GLP-1Ra at doses intended for T2D management

Studies have examined the risk of fracture in both obese and non-obese individuals taking GLP-1Ra at doses intended for T2D (such as liraglutide 1.2 mg daily versus 3.0 mg daily for obesity) [75–77]. In T2D, GLP-1Ra typically result in a weight loss of 2–6 kg over 6 months, with subcutaneous semaglutide showing the most significant reduction. Multiple systematic reviews and meta-analyses have been conducted, with most indicating no significant difference in fracture risk between GLP-1Ra and placebo or other anti-diabetic medications [75–77]. Interestingly, one meta-analysis of RCTs, encompassing 38 studies and 39,795 patients with T2D, found that fractures occurred in 241 patients (107 patients in the GLP-1 Ra group and 134 patients in the control group). GLP-1Ra was linked to a decrease in fracture risk (overall response 0.71, 95% CI 0.56–0.91) compared to placebo or other anti-diabetic medications [78]. This positive effect was only observed after more than 52 weeks of treatment [78].

The SELECT study: a warning

In 2023, semaglutide was shown to reduce the rates of major adverse cardiovascular events by 20% among persons with a history of atherosclerotic cardiovascular disease and obesity or in persons with overweight and one or more weight-related complications [79]. In 2025, crucial safety data regarding semaglutide was disclosed. Notably, the cardiovascular outcomes study conducted on adults (SELECT study) revealed a higher incidence of hip and pelvic fractures among female patients receiving semaglutide compared to those on placebo: 1.0% (24/2448) versus 0.2% (5/2424) [80]. Similarly, in participants aged 75 years and above, the fracture rates were 2.4% (17/703) for semaglutide and 0.6% (4/663) for placebo, respectively [80].

The SELECT study enrolled 17,604 individuals aged 45 years or older with existing cardiovascular disease, no T2D, and a BMI exceeding 27 kg/m². Only 27.7% and 7.8% of the enrolled patients were women or aged 75 years or older, respectively [81]. Participants were randomly divided into two groups: semaglutide 2.4 mg once weekly vs. placebo. Findings indicated that when added to standard care, semaglutide decreased the occurrence of a composite of cardiovascular-related deaths, non-fatal heart attacks, or non-fatal strokes over an average follow-up period of 39.8 ± 9.4 months in this group compared to the placebo group. In the semaglutide group, 569 out of 8803 patients (6.5%) experienced a primary cardiovascular end-point event, compared to 701 out of 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P < 0.001) [81].

Notably, the study did not mention an increased fracture risk associated with semaglutide, despite the fact that this information is currently reported elsewhere [80]. The duration of follow-up, the number of participants included, the older age and cardiovascular comorbidities may explain why an increased fracture risk was observed [81].

Future research related to GLP-1Ra and bone health

Observational studies with long-term follow-up of bone health for patients under GLP-1Ra are necessary because fracture risk remains to be determined. The risk of fracture associated with GLP-1Ra vs. controls with obesity undergoing surgical or non-surgical procedures should be further explored. In particular, fracture risk should be evaluated in populations at risk of fracture, such as postmenopausal women and men older than 50 years. Thus, ancillary bone health studies in randomized controlled trials of GLP-1Ra are required.

More data describing changes in BMD at various sites using DXA and BTMs following GLP-1Ra administration are needed to validate these preliminary findings. There is also a need to know if all GLP-1Ra have the same impact on bone outcomes. There is a need to assess the impact of GLP-1Ra on bone microarchitecture and strength by using HR-pQCT.

There is a knowledge gap in screening and management strategies for osteoporosis in patients undergoing GLP-1Ra. There is a need to identify who is at highest fracture risk among patients starting a GLP1-Ra. Additional research is necessary to determine the best clinical use of DXA, vertebral fracture assessment, and BTMs in those patients undergoing GLP-1Ra. We also need to evaluate other tools, such as the FRAX® and trabecular bone score (TBS) in this specific population.

The effects of pharmaceutical and non-pharmaceutical treatments on bone outcomes such as BTMs and/or BMD are warranted. The effects of interventions combining vitamin D and calcium supplementation with or without physical activity, as well as the effects of bisphosphonates or other treatments in patients with osteoporosis and treated by GLP-1Ra, remain to be determined.

Effects of treatment sequences for obesity management on bone metabolism need to be evaluated as obesity is a chronic disease requiring different sequences of treatment such as calorie restriction, bariatric/metabolic surgery, and anti-obesity drugs. Each of these therapeutic sequences has an impact on bone metabolism with a probable cumulative effect.

Conclusions

The field of bone health and GLP-1Ra is evolving rapidly. This review summarizes our current knowledge on bone metabolism in PwO treated by GLP-1Ra. Further data collection is essential to gain a deeper understanding of the effects of GLP-1Ra on bone outcomes. Although preliminary findings indicate that GLP-1Ra causes modest BMD reduction and enhances bone remodeling, favoring resorption similar to the effects of calorie restriction, further research is needed.

Additionally, incorporating exercise during and after weight reduction may help mitigate the BMD loss at the hip and lumbar spine. Calorie restriction with physical activity encompassing resistance exercise during weight loss has been shown to counteract high turnover bone loss compared with calorie restriction alone.

The substantial metabolic changes triggered by GLP-1Ra in PwO could potentially influence the fracture risk beyond its effects on BMD and BTMs. Moreover, it is crucial to gather more information on fracture-related outcomes associated with GLP-1Ra use considering body composition alterations. These changes may result in muscle mass reduction, potentially leading to osteosarcopenia, which could increase the risk of fracture owing to an elevated likelihood of falls. Beyond bone health, the effects of GLP-1Ra on musculoskeletal health remain to be elucidated [82].

These drugs exert systemic effects that are crucial for a thorough understanding their safety profile, particularly in the context of obesity management. Bone specialists should not overlook the significant psychiatric, ophthalmological and thyroid-related side effects of GLP-1Ra [83–86].

Funding

Open access funding provided by Centre Hospitalier Universitaire de Lille.

Declarations

Conflicts of interest

JP has received consulting fees from Kyowa Kirin, Eli Lilly, and Theramex; honoraria from Amgen, Besins, CDD, Kyowa Kirin, and Theramex; payment for expert testimony from UCB; and support for attending meetings from Kyowa Kirin and Theramex. GM and LK has no conflict of interest.