The Effects of Incretin Mimetic Therapies on Muscle and Bone Health in Older Adults: A Narrative Review

ABSTRACT

Incretin mimetics are increasingly prescribed for the treatment of overweight and obesity, resulting not only in significant weight reduction but also co‐occurring improvements in cardiovascular health and quality of life. Incretin mimetic use among older adults is expected to increase as the population ages into obesity. However, older adults experience accelerated losses in skeletal muscle mass and bone mineral density, and it remains unclear how incretin mimetics affect these processes. This review outlines the age‐associated changes in muscle and bone and explores current evidence reporting the effects/associations of incretin mimetics on these tissues, as well as on physical function and fragility fracture risk. We identified several incretin mimetic weight reduction trials that demonstrated significant losses in lean soft tissue (n = 6 studies) and/or indices of bone (n = 3); however, the clinical significance of these decrements on physical function and/or fragility fracture remains unclear. Considering a rising trend in the prescription of incretin mimetics to treat obesity in older adulthood, a more robust characterization of the impact of these medications on lean soft tissue, physical function, and fragility fracture is needed to support future clinical decision‐making in older adults with overweight/obesity.

Study Importance

• What is already known?

  • ○
    Incretin mimetics are highly efficacious medications used in the treatment of overweight and obesity. Weight reduction in older adulthood is often accompanied by decrements in muscle and/or bone mass, potentially exacerbating the risk of adverse health outcomes. However, changes in body composition following incretin mimetic obesity therapy in older adults, as well as the downstream consequences on physical function and fragility fracture, are unclear.
• What does this review add?

  • ○
    Concomitant losses in muscle‐based indices (e.g., lean soft tissue) following incretin mimetic therapy are common, accounting for as much as 40% of total weight reduction in some randomized controlled trials. Limited data also suggest that significant decrements in central site (e.g., hip, lumbar spine) bone mineral density may also be a consequence of incretin mimetic therapy. However, the magnitude of these effects in older adults is unclear, and the implications of these therapies on physical functional and fragility fracture risk are poorly characterized.
• How might these results change the direction of research or the focus of clinical practice?

  • ○
    The proportion of older adults receiving incretin mimetics for the treatment of overweight and obesity is expected to rise. Therefore, a more robust characterization of how these therapies influence changes in body composition and whether such changes contribute to physical dysfunction and/or fragility fracture is needed to elucidate long‐term safety.

1. Introduction

Obesity is a chronic condition of excess adiposity that contributes to adverse health outcomes, particularly in older adulthood, where the effects of obesity may accelerate aging [1]. Routinely characterized using a body mass index (BMI) ≥ 30 kg/m², obesity affects roughly 40% of older adults in the United States (US), who are in turn disproportionately burdened by chronic conditions including cardiovascular disease [2], cancer [3], and type 2 diabetes mellitus (T2DM) [4]. Lifestyle interventions that promote healthy nutritional behaviors and increase physical activity serve as the cornerstone of obesity prevention and treatment [5]. However, evidence suggests that weight reduction from lifestyle interventions is difficult to sustain over the long term, with nearly half of individuals regaining initial weight within 1 year [6]. This reality has driven an increase in the use of obesity medications in the US, particularly the glucagon‐like peptide‐1 (GLP‐1) receptor agonists (also called “incretin mimetics”), which saw an eightfold increase in prescription between 2016 and 2022 [7].

Harnessed originally for its potent blood glucose clearance properties, GLP‐1 receptor agonists were prescribed almost exclusively to individuals with T2DM following Food and Drug Administration (FDA) approval of exenatide in 2004 [8]. By 2014, the FDA approved incretin mimetics for the treatment of obesity in adults, independent of diabetes status [9], with semaglutide, tirzepatide, and liraglutide representing the approved obesity medications in the US at the time of writing (December 2025) [10]. Incretin mimetics potentiate insulin secretion from the pancreas following glucose ingestion (the so‐called “incretin effect”) [11], contributing to weight reduction by suppressing appetite and limiting energy intake [12]. The reductions in total body weight (particularly fat mass) following incretin mimetic therapy are broadly associated with favorable health outcomes in persons with obesity, including reduced cardiovascular disease risk and improvements in person‐centered outcomes such as body weight‐ and health‐related quality of life [13, 14]. However, their potential deleterious effects on muscle and bone mass may exacerbate the risk of adverse outcomes in older adults, a demographic expected to see increased rates of incretin mimetic prescription [15].

While the general side effects of incretin mimetic therapy are well documented in the literature (e.g., nausea, diarrhea, vomiting) [16], comparatively less is known about the changes in muscle and bone mass, particularly among older adults. The gradual losses in both skeletal muscle mass (SMM) and bone mineral density (BMD) after peak attainment in early adulthood is a natural facet of aging, with older adulthood serving as a distinct period of the life‐span with appreciable declines in each [17]. However, weight reduction from incretin mimetics may compound age‐associated decrements in muscle and bone in older adults, a demographic with greater susceptibility to functional impairment and frailty. Future therapies may therefore require additional considerations for older adults that recognize and/or mitigate the potential hazards associated with the loss of SMM and BMD during incretin‐induced obesity therapy. We therefore conducted a narrative review of pertinent randomized controlled trials (RCTs) and observational studies to summarize the current knowledge about the relationship between incretin mimetic obesity therapy on SMM and BMD in individuals with overweight or obesity. To facilitate understanding, we first provide a brief overview of the phenotypical changes in body composition experienced with aging.

2. Body Compositional Changes With Aging

Aging is typified by increased total body adiposity, a reduction in skeletal muscle mass and strength, and a gradual loss in bone mineral density. Figure 1 illustrates the interrelationship between adiposity, skeletal muscle, and bone during aging, highlighting the interconnected adipose–muscle–bone axis. There is a generalized redistribution of fat from subcutaneous regions toward the visceral region where adipocytes (fat cells) are more metabolically active and proinflammatory in nature, exacerbating cellular senescence and increasing morbidity risk [19]. Biological aging is also a trigger for increased fat infiltration into skeletal muscle (myosteatosis) [20], a phenomenon that reduces local muscle quality and is associated with adverse outcomes such as cardiovascular morbidity and all‐cause mortality [21, 22]. Likewise, aging is accompanied by increased fat infiltration of bone marrow, the body's third largest deposit of adipose tissue, hindering bone homeostasis and hematopoiesis (blood cell production) [23].

FIGURE 1.

Changes in body composition accompany aging. Adapted from Ormsbee et al. [18] and created in BioRender by Saavedra, J. (2026) https://BioRender.com/ubt4aa9.

Peak muscle mass is attained in early midlife, declining thereafter at an average rate of 1% per year (Figure 2) [26]. These decrements are driven by reductions in both muscle fiber size (atrophy) and muscle fiber number (hypoplasia) [26], culminating in a loss of up to 50% of peak muscle mass by the eighth decade of life [27]. Muscle strength likewise declines with aging, though this typically occurs at a faster rate than the age‐related losses in skeletal muscle mass (~3% to 4% per year) [28, 29]. The presence of muscle weakness (specifically, poor grip strength) in the absence of low muscle mass is referred to as dynapenia [30], while the coexistence of both phenotypes typically confirms the syndrome of sarcopenia [31]. Muscle weakness in older Americans has a prevalence between 23% and 66% [32], while sarcopenia prevalence ranges from 9% to 18% [33], with estimates varying due to heterogeneity in the manner each is operationalized across populations; standardization of this syndrome is a major objective of the Global Leadership Initiative for Sarcopenia [34]. Importantly, however, both low grip strength and sarcopenia are robust indicators of future adverse events, including frailty and all‐cause mortality [33, 35]. Furthermore, sarcopenia is often comorbid with excess adiposity (i.e., sarcopenic obesity) in older adulthood, with an estimated prevalence of 20.0% for those aged 60–69 years in the US [36], and the occurrence of both conditions is often more disadvantageous for health than either condition alone [29].

FIGURE 2.

The decline in muscle strength and muscle mass with age. Data from Ferruci et al. [24], and image from Cruz‐Jentof and Sayer [25], by permission of Elsevier.

Another age‐associated change in body composition is the loss of bone volume and an increase in bone fragility. Bone mass is accrued over the initial two decades of life, peaking between the ages of 20 and 30 years in both men and women, after which skeletal tissue undergoes varying degrees of architectural remodeling, a process that is distinctly accelerated in women at the onset of menopause [37]. Lifetime losses of cortical skeletal tissue (the compact, outer surface of bone) approximate 18% and 25% for men and women, respectively, while lifetime losses of trabecular skeletal tissue (the porous, inner structure of bone) are roughly 46% and 54% for men and women, respectively [38]. Older adults are therefore at elevated risk of osteopenia and osteoporosis, conditions that affect roughly 50% and 20% of those aged over 65 years in the US, respectively [39]. The process of bone remodeling leading to greater bone fragility reflects a general imbalance between the activity of cells responsible for bone formation (osteoblasts) relative to those responsible for bone resorption (osteoclasts), such that the latter outpaces the former. Osteoblast senescence is intertwined with an increase in the deposition of adipocytes in aging bone marrow, with the appendicular and axial skeletal sites (distal forearm, femoral neck, vertebrae) being notable for significant increases in adiposity [40]. These sites of compromised bone quality are prone to osteoporotic fracture, an outcome that affects roughly 20% of men and 50% of women with osteoporosis [41].

The age‐associated changes in fat, muscle, and bone may exacerbate the risk of adverse outcomes such as frailty and fragility fractures, underscoring the importance of decelerating fat‐free mass losses that accompany aging. Weight reduction through incretin mimetic therapies may in turn potentiate reductions in muscle and bone mass and further compromise health and physical function in older adulthood. Considering the proportion of older adults receiving incretin mimetics for obesity treatment and management is rising [42], there is a need to highlight current gaps in knowledge to stimulate future research into safeguarding older adults from adverse outcomes resulting from incretin‐based obesity therapies.

3. Incretin Mimetics

Liraglutide, semaglutide, and tirzepatide are marketed as Saxenda (2014), Wegovy (2021), and Zepbound (2023), respectively, and are administered through weekly or daily subcutaneous injections, though oral semaglutide options are also available. Differences in dosing frequency are influenced by differing pharmacokinetic properties: semaglutide and tirzepatide exhibit half‐lives of 160 and 120 h, respectively, compared to an upper limit of 15 h for liraglutide [43]. Weight reduction from incretin mimetic therapies is driven by the achievement of a negative energy balance over the course of treatment [44], facilitated by appetite suppression, and delayed gastric emptying to prolong the sensation of “fullness” (satiety), reducing the drive to overconsume. The stimulatory effects on satiety and inhibitory effects on hunger reflect the potent neurohormonal influence of incretin mimetics on the central nervous system, particularly on the hypothalamus where these sensations are coordinated [45]. These medications have been recently reviewed in the context of older adult prescriptions in a recent issue of Obesity [46].

4. Effects on Muscle‐Based Indices

4.1. Liraglutide Trials

A summary of the changes in muscle‐based indices, defined as quantitative measures derived from body composition or imaging techniques that reflect changes in SMM, related lean tissue compartments, or muscle volume [47], is provided in Table 1. Clinical trials featured in this review use various methods to estimate changes in muscle mass, including dual‐energy x‐ray absorptiometry (DXA), air displacement plethysmography, and magnetic resonance imaging (MRI). Because these techniques quantify related but non‐identical constructs and do not directly measure contractile muscle tissue, we use the umbrella term muscle‐based indices to harmonize reporting across studies, as emphasized by Prado et al. [59]. When DXA is used, outcomes are reported as DXA‐derived lean soft tissue, which reflects the non‐fat, non‐bone components of body composition and is commonly used as a proxy for SMM. Throughout this section, DXA‐derived lean soft tissue is treated as a muscle‐based index rather than a direct measure of skeletal muscle. All liraglutide trials used DXA, which analyzes DXA‐derived lean soft tissue as a muscle‐based index to approximate muscle mass [60].

TABLE 1.

Summary of incretin mimetic effects on lean soft tissue mass, fat‐free mass, and muscle volume in recent clinical trials.

Study	Summary of effects	Group characteristics and pre‐post changes in body composition
		Treatment group	Comparator group
Author (year): Feng et al. (2019) [48] Incretin mimetic: Liraglutide Population: Type 2 diabetes with nonalcoholic fatty liver disease Total randomized: 93 Duration: 24 weeks	Change in lean soft tissue (DXA): No significant treatment effect of liraglutide	N = 30 (28% female) Mean (SD) age: 46.8 (9.9) years Mean (SD) BMI: 28.1 (3.3) kg/m2 Treatment dose: 1.8 mg/day Mean (%) body weight: −5.6 kg (−6.9%) Mean (% change from baseline) lean soft tissue (DXA): −0.20 kg (−0.40%), ~4% of the total loss in body weight†	N = 32 (25% female) Mean (SD) age: 48.2 (13.0) years Mean (SD) BMI: 27.5 (2.6) kg/m2 Treatment dose: Gliclazide 30 to 120 mg/day, plus lifestyle education Mean (% change from baseline) body weight: −0.59 kg (−0.75%) Mean (% change from baseline) lean soft tissue (DXA): −0.80 kg (−1.59%)
Author (year): Kadouh et al. (2020) [49] Incretin mimetic: Liraglutide Population: Overweight or obesity Total randomized: 40 Duration: 16 weeks	Change in lean soft tissue (DXA): No significant treatment effect of liraglutide	N = 19 (95% female) Median (IQR) age: 42 (32–51) years Median (IQR) BMI: 37.2 (33.6–41.0) kg/m2 Treatment dose: 3.0 mg/day Median (IQR) body weight: −5.8 (−6.9 to −4.45) kg* Median (IQR) lean soft tissue (DXA): −1.3 (−1.75 to −0.1) kg, ~22% of total loss in body weight†	N = 21 (86% female) Median (IQR) age: 37 (26–51) years Median (IQR) BMI: 34.6 (33.4–38.9) kg/m2 Condition: Placebo injection Median (IQR) body weight: −1.0 (−3.5 to 2.53) kg Median (IQR) lean soft tissue (DXA): −0.65 (−1.13 to 1.13) kg, ~65% of total loss in body weight†
Author (year): Ghanim et al. (2020) [50] Incretin mimetic: Liraglutide Population: Overweight and obesity Total randomized: 84 Duration: 26 weeks	Change in lean soft tissue (DXA): No significant treatment effect of liraglutide	N = 42 (65% female) Mean (SD) age: 47.0 (12.2) years Mean (SD) BMI: 33.3 ± 7.3 kg/m2 Treatment dose: 1.8 mg/day Mean (%) total body weight: −3.9 kg (−4.1%)* Mean (% change from baseline) lean soft tissue (DXA): −0.20 kg (−0.4%), ~5% of total weight lost†	N = 42 (59% female) Mean (SD) age: 45.0 (15.6) years Mean (SD) BMI: 29.5 (6.8) kg/m2 Condition: Placebo injection Mean (%) total body weight: 0.4 kg (+0.5%) Mean (% change from baseline) lean soft tissue (DXA): No within‐group change reported
Author (year): Lundgren et al. (2021) [51] Incretin mimetic: Liraglutide Population: Obesity Total randomized: 195 Duration: 52 weeks	Change in lean soft tissue (DXA): Liraglutide preserved lean soft tissue mass compared to placebo	N = 49 (63% female) Mean (SD) age: 43 (12) years Mean (SD) BMI: 32.7 (3.1) kg/m2 Treatment dose: 3.0 mg/day Mean (95% CI) total body weight: −0.7 (−3.2 to 1.8) kg Mean (95% CI) lean soft tissue (DXA): 0 (−1.0 to 1.1) kg	N = 49 (63% female) Mean (SD) age: 43 (12) years Mean (SD) BMI: 32.3 (3.0) kg/m2 Condition: Placebo injection Mean (95% CI) total body weight: +6.1 (3.5 to 8.7) kg Mean (95% CI) lean soft tissue (DXA): +2.9 (1.8 to 4.0) kg
Author (year): Schmidt et al. (2022) [52] Incretin mimetic: Liraglutide Population: Overweight or obesity and type 1 diabetes Study sample size: 44 Duration: 26 weeks	Change in lean soft tissue (DXA): Liraglutide significantly reduced lean soft tissue mass compared to placebo	N = 22 (68% female) Median (IQR) age: 54 (37–61) years Mean (SD) BMI: 30.2 (2.0) kg/m2 Treatment dose: 1.8 mg/day Mean (95% CI) total body weight: −7.0 (−8.5 to −5.5) kg* Mean (95% CI) lean soft tissue (DXA): −2.5 (−3.2 to −1.7) kg*, equivalent to ~36% of total weight lost	N = 22 (68% female) Median (IQR) age: 45 (34–52) years Mean (SD) BMI: 29.0 (3.0) kg/m2 Condition: Placebo injection Mean (95% CI) total body weight: −0.3 (−1.7 to 1.1) kg Mean (95% CI) lean soft tissue (DXA): 0 (−0.7 to 0.7) kg
Author (year): Mok et al. (2023) [53] Incretin mimetic: Liraglutide Population: 1 year post bariatric surgery in patients with poor weight loss Study sample size: 70 Duration: 24 weeks	Change in lean soft tissue (DXA): Liraglutide significantly reduced lean soft tissue mass compared to placebo	N = 35 (74% female) Mean (SD) age: 46.7 (10.8) years Mean (SD) BMI: 41.6 (6.9) kg/m2 Treatment dose: 3.0 mg/day Mean (SD) change in total body weight: −9.5 (5.1) kg* Mean (SD) change in lean soft tissue (DXA): −4.2 (3.0) kg*, ~44% of total weight lost†	N = 35 (74% female) Mean (SD) age: 48.4 (10.6) years Mean (SD) BMI: 44.6 (8.3) kg/m2 Condition: Saline placebo Mean (SD) change in total body weight:‐0.4 (3.9) kg Mean (SD) change in lean soft tissue (DXA): −1.2 (3.3) kg
Author (year): McCrimmon et al. (2020) [54] Incretin mimetic: Semaglutide Population: Type 2 diabetes Study sample size: 178 Duration: 52 weeks	Change in lean soft tissue (DXA): No significant treatment effect of semaglutide	N = 88 (% female unknown) Mean (SD) age: 57.8 (9.9) years Mean (SD) BMI: 32.6 (6.4) kg/m2 Treatment dose: 1.0 mg/week Mean change in total body weight: −5.7 kg Mean (SE) change in lean soft tissue (DXA): −2.3 (0.30) kg, ~40.4% of total body weight lost†	N = 90 (% female unknown) Mean (SD) age: 58.6 (10.1) years Mean (SD) BMI: 32.3 (5.5) kg/m2 Condition: Canagliflozin, 300 mg/day Mean change in total body weight: −4.1 kg Mean (SE) change lean soft tissue (DXA): −1.5 (0.28) kg, ~36% of total body weight lost†
Author (year): Wilding et al. (2021) [55] Incretin mimetic: Semaglutide Population: Obesity without diabetes Study sample size: 1961 Duration: 68 weeks	Change in lean soft tissue (DXA): Semaglutide significantly reduced lean soft tissue mass compared to placebo	N = 1306 (73% female) N = 95 (76% female) in the DXA substudy Mean (SD) age: 46.0 (13.0) years Mean (SD) BMI: 37.8 (6.7) kg/m2 Treatment dose: 2.4 mg/week Mean (%) change in total body weight: −15.3 kg (−14.9%)* Mean (%) change in lean soft tissue (DXA): −5.3 kg (−10.0%)*, ~36% of total weight lost†	N = 655 (76% female) N = 45 (76% female) in the DXA substudy Mean (SD) age: 47.0 (12.0) years Mean (SD) BMI: 38.0 (6.5) kg/m2 Condition: Placebo injection Mean (%) change in total body weight: −2.6 kg (−2.4%) Mean (%) change in lean soft tissue (DXA): −1.8 kg (−3.6%), ~57% of total weight lost†
Author (year): Heise et al. (2023) [56] Incretin mimetic: Semaglutide Population: Type 2 diabetes Study sample size: 117 across 3 treatment arms Duration: 28 weeks	Changes in fat‐free mass (air displacement plethysmography): Semaglutide led to significant reductions in fat‐free mass; however, statistical comparisons with the placebo group were not reported	N = 44 (23% female) Mean (SD) age: 63.7 (5.9) years Mean (SD) BMI: 30.8 (3.8) kg/m2 Treatment dose: 1.0 mg/week Mean (%) change in total body weight: −6.9 kg (−7.4%)*† Mean (%) change in fat‐free mass (air displacement plethysmography): −0.8 kg (−1.4%), ~12% of total weight lost†	N = 28 (25% female) Mean (SD) age: 60.4 (7.6) years Mean (SD) BMI: 32.2 (4.0) kg/m2 Treatment dose: Placebo Mean (change in total body weight: 0 kg) Mean (%) change in fat‐free mass (air displacement plethysmography): −0.1 kg (−0.2%)
Author (year): Heise et al. (2023) [56] Incretin mimetic: Tirzepatide Population: T2DM Study sample size: 117 across 3 different treatment arms Duration: 28 weeks	Change in fat‐free mass (air displacement plethysmography): Tirzapetide significantly reduced fat‐free mass compared to the placebo group	N = 45 (31% female) Mean (SD) age: 61.1 (7.1) years Mean (SD) BMI: 31.3 (5.0) kg/m2 Treatment dose: 15 mg/week Mean (%) change in total body weight: ~11.0 kg (~12.0%)* Mean (%) change in fat‐free mass (air displacement plethysmography): −1.6 kg (−2.8%)*, ~14% of total weight lost†	N = 28 (25% female) Mean (SD) age: 60.4 (7.6) years Mean (SD) BMI: 32.2 (4.0) kg/m2 Condition: Placebo Mean change in total body weight: 0 kg Mean (%) change in fat‐free mass (air displacement plethysmography): −0.1 kg (−0.2%)
Author (year): Look et al. (2025) [57] Incretin mimetic: Tirzepatide Population: Obesity Study sample size: 160 Duration: 72 weeks	Change in lean soft tissue (DXA): Tirzepatide significantly reduced lean soft tissue mass compared to placebo	Pooled group size: 124 (74% female) Mean (SD) age: 45.5 (13.4) years Mean (SD) BMI: 37.5 (6.1) kg/m2 Treatment dose: Pooled data for 5 mg, 10 mg, and 15 mg/week Mean (%) change in total body weight: −21.3 kg† (−21.3%)* Mean (%) change in lean soft tissue (DXA) (pooled estimate): −5.6 kg (−10.9%)*, ~26% of total weight lost	Pooled group size: 36 (69% female) Mean (SD) age: 48.3 (14.2) years Mean (SD) BMI: 39.7 (7.4) kg/m2 Condition: Injectable placebo Mean (%) change in total body weight: −5.6† (−5.3%) kg* Mean (%) change in lean soft tissue (DXA) (pooled estimate): −1.2 kg (−2.6%), ~25% of total weight lost
Author (year): Sattar et al. (2025) [58] Incretin mimetic: Tirzepatide Population: Type 2 diabetes Study sample size: 246 Duration: 52 weeks	Changes in muscle thigh volume: Tirzepatide significantly reduced thigh muscle volume compared to insulin degludec, with the magnitude of decline consistent with population‐based expectations for the degree of weight loss (adaptive response)	Pooled group size: 190 (39% female) Mean (SD) age: 56.0 (9.8) years Mean (SD) BMI: 33.7 (4.8) kg/m2 Treatment dose: Pooled data for 5 mg, 10 mg, and 15 mg/week Mean (95% CI) change in total body weight: −9.6 (−10.6 to −8.5) kg* Mean (95% CI) change in thigh muscle volume (MRI) (pooled estimate): −0.64 (−0.74 to −0.54) L*; representing −6.0% (95% CI: −6.9% to −5.1%) decline in muscle thigh volume	N = 56 (45% female) Mean (SD) age: 56.1 (10.2) years Mean (SD) BMI: 32.7 (4.5) kg/m2 Condition: Once daily insulin degludec Mean (95% CI) change in total body weight: +3.2 (1.8 to 4.7) kg Mean (95% CI) change in thigh muscle volume (MRI): +0.16 (0.01 to 0.31) L; representing +1.6% (95% CI: 0.2% to 3.0%) increase in thigh muscle volume

Note: Asterisks (*) indicate significant between‐group difference (treatment group vs. comparator group); daggers (^†) indicate derived values (i.e., not directly reported by the study).

Abbreviations: DXA, dual x‐ray absorptiometry; MRI, magnetic resonance imaging; SD, standard deviation; SE, standard error.

In their trial of primarily middle‐aged adults with T2DM and nonalcoholic fatty liver disease (mean [SD] age: 46.8 [9.9] years, N = 30), Feng et al. found that 24 weeks of 1.8 mg daily liraglutide resulted in a loss of 0.2 kg in lean soft tissue (roughly 4% of the total weight lost) [48], though this was not greater than the loss experienced in the comparator group (−0.8 kg). Kadouh et al. evaluated the effects of 3.0 mg/day of liraglutide in middle‐aged adults (median age 42 years, N = 19) with overweight or obesity, noting a median (interquartile range [IQR]) change in lean soft tissue of −1.3 (−1.75 to −0.10) kg over 16 weeks, constituting ~22% of the total weight lost [49], though this was not significantly greater than the median change experienced in the comparator group: −0.65 (IQR: −1.13 to 1.13) kg. Ghanim et al. reported a slight reduction in lean soft tissue of 0.20 kg after 26 weeks of therapy (1.8 mg/day) in middle‐aged adults with obesity (mean [SD] age: 47.0 [12.2] years, N = 42), a change that the authors state did not differ significantly from the change in the comparator group (though the these changes were not presented in the paper) [50]. In their 52‐week study (3.0 mg/day) of middle‐aged adults (mean [SD] age: 43.0 [12.0] years, N = 49) with obesity, Lundgren et al. noted a mean (95% confidence interval [95% CI]) change in lean soft tissue of 0 (−1.0 to 1.1) kg compared to a mean (95% CI) change of 2.9 (1.8 to 4.0) kg experienced in the comparator arm [51]. In their 26‐week study (1.8 mg/day) on middle‐aged adults with overweight or obesity and type 1 diabetes (median age [IQR] age: 54 years [37–61], N = 22), Schmidt et al. recorded a mean (95% CI) change in lean soft tissue of −2.5 (−3.2 to −1.7) kg, decrements that significantly exceeded those experienced by the comparator arm (mean [95% CI] change: 0 [−0.7 to 0.7] kg) [52]. Mok et al. reported a mean (SD) change in lean soft tissue of −4.2 (3.0) kg in their 24‐week (3.0 mg/day) study of middle‐aged adults (mean [SD] age: 46.7 [10.8] years, N = 35) who were 1 year post bariatric surgery [53]. These decrements were significantly greater than the mean (SD) change experienced by the comparator arm: −1.2 (3.3) kg.

Finally [52, 53], only the studies of Lundgren et al. [51] and Mok et al. [53] reported pre‐post indices of functionality. In the former, self‐reported physical functioning (as determined by the SF‐36 questionnaire) showed no significant within‐ or between‐group change from baseline to follow‐up [51]. Interestingly in the latter, those in the liraglutide group experienced a mean (SD) change in the five‐times sit‐to‐stand test of −1.84 (3.69) seconds, relative to a mean (SD) change of 0.44 (3.26) seconds experienced by the comparator (indicating an improvement in physical function in the liraglutide group, despite significant losses in lean soft tissue).

4.2. Semaglutide Trials

There are a limited number of controlled trials that have evaluated changes in muscle‐based indices following semaglutide obesity therapy (Table 1). McCrimmon et al. found that middle‐aged adults with T2DM (mean [SD] age: 57.8 [9.9] years, N = 88) treated with 1.0 mg/week of semaglutide for 52 weeks experienced a mean (SE) change in lean soft tissue of −2.3 (0.30) kg [54]. While this decrement represented approximately 40% of the total reduction in body weight, it was not significantly greater than the mean (SE) change experienced in the comparator group: −1.5 (0.28) kg (~36% of the total reduction in body weight). In their 68‐week trial of middle‐aged adults with obesity treated with 2.4 mg/week of semaglutide (mean [SD] age: 46.0 [13.0] years, N = 1306), Wilding et al. noted a mean (%) change in lean soft tissue of −5.3 (−10.0%) kg, equating to approximately 36% of the total reduction in body weight [55]. Further, this decrement was significantly greater than the mean (%) change in lean soft tissue experienced by the comparator arm: −1.8 (−3.6%) kg (approximately 57% of the total reduction in body weight). Heise et al. evaluated the effects of 1.0 mg/week of semaglutide over 28 weeks in older adults with T2DM (mean [SD] age: 63.7 [5.9] years, N = 44), reporting a mean (%) change in fat‐free mass (derived from air displacement plethysmography) of −0.8 (−1.4%) kg, corresponding to ~12% of total reduction in body weight [56]. This change was not significantly different from the mean (%) change in fat‐free mass in the comparator arm: −0.1 (−0.2%) kg. Finally, only the trial of Wilding et al. reported pre‐post changes in physical functioning, using two self‐reported measurement tools: (1) the SF‐36 Physical Function score and (2) the Impact of Weight on Quality of Life‐Lite Physical Function score [55]. Here, estimated treatment differences (95% CI) were 1.80 (1.18–2.42) and 9.43 (7.50–11.35) for each tool, respectively, indicating a significant improvement in physical function among those in the semaglutide group despite significant losses in lean soft tissue.

4.3. Tirzepatide Trials

There is a dearth of randomized controlled trials testing the effects of tirzepatide on muscle‐based indices of body composition (Table 1). In their study of older adults with T2DM treated with 15 mg/week of tirzepatide for 28 weeks (mean [SD] age: 61.1 (7.1) years, N = 45), Heise et al. noted a mean (%) change in fat‐free mass (derived from air displacement plethysmography) of −1.6 (−2.8%) kg, equating to ~14.0% of the total reduction in body weight [56]. This decrement was significantly greater than the mean (%) change experienced by the comparator arm of the study: −0.1 (−0.2%) kg. In a 72‐week trial of middle‐aged adults with obesity (mean [SD] age: 45.5 [13.4] years, N = 124), in which the effects of three different treatment arms (5 mg, 10 mg, and 15 mg/week) were pooled into a single estimate, Look et al. reported a mean (%) change in lean soft tissue of −5.6 (−10.9%) kg, representing ~26% of the total reduction in body weight [57]. This decrement was significantly greater than the mean (%) change experienced by the comparator arm of the study: −1.2 (−2.6%) kg. In a separate, 52‐week pooled effects trial (5 mg, 10 mg, and 15 mg/week tirzepatide) consisting of primarily middle‐aged adults with T2DM (mean [SD] age: 56.0 [9.8] years, N = 190), Sattar et al. found a mean (95% CI) change in MRI‐derived muscle thigh volume of −0.64 (−0.74 to −0.54) L, equating to a ~ 6% decline between baseline and follow‐up [58]. This change was significantly greater than the mean (95% CI) change experienced by the comparator arm of the study: 0.16 (0.01 to 0.31) L. None of the [56, 58] studies explored the pre‐post changes in self‐reported or objectively assessed physical function.

5. Effects on Bone Health

5.1. Liraglutide Trials

Several liraglutide clinical trials have reported pre‐post changes in bone mineral density and/or markers of bone turnover (Table 2). In their 52‐week study (1.3 mg/day) of middle‐aged adults with obesity (mean [SD] age: 46.0 [2.0] years, N = 18), Ipsen et al. reported a mean (%) change in whole body bone mineral density of −0.004 (−0.3%) g/m², which did not differ significantly from the mean change of −0.005 g/m² experienced in the comparator arm [61]. In the same study, the mean (95% CI) change in type 1 collagen cross‐linked C‐telopeptide (CTX, a plasma derived marker of bone resorption) among the treatment and comparator arms did not differ significantly: 0.06 (−0.02 to 0.14) ng/mL vs. −0.03 (−0.06 to 0.06) ng/mL, respectively. Conversely, the mean (95% CI) change in propeptide of type 1 collagen (P1NP, a plasma derived marker of bone formation) was significantly greater in the treatment arm compared to the comparator arm: 6.5 (1.4 to 11.6) μg/L vs. −0.8 (−8.05 to 6.45) μg/L, respectively. In their 52‐week study (1.8 mg/day) of middle‐aged and older adults with T2DM (mean [SD] age: 54.0 [8.5] years, N = 20) Gilbert et al. found negligible decrements in the mean (%) change in whole body bone mineral density in both the treatment and comparator arms: −0.002 (−0.16%) g/cm² vs. −0.008 (−0.68%) g/cm², respectively [59]. Ghanim et al. reported no significant within‐ or between‐group changes in whole body bone mineral density following 26 weeks of liraglutide therapy (1.8 mg/day) in middle‐aged adults with obesity (mean [SD] age: 47.0 [12.2] years, N = 42) [50], and similar null changes in whole body bone mineral density were noted by Mok et al. in their 24‐week trial (4.0 mg/day) of middle‐aged adults who were 1 year post bariatric surgery (mean [SD] age: 46.7 [10.8] years, N = 35) [53].

TABLE 2.

Summary of incretin mimetic effects on bone mineral density and bone turnover markers in recent clinical trials.

Study	Summary of effects	Group characteristics and pre‐post changes in body composition
		Treatment group	Comparator group
Author (year): Ipsen et al. (2015) [61] Incretin mimetic: Liraglutide Population: Obesity without diabetes Study sample size: 37 Duration: 52 weeks	Change in whole body bone mineral density: No significant treatment effect of liraglutide Change in bone turnover markers: Liraglutide significantly increased plasma P1NP (a marker of bone formation) compared to lifestyle education	N = 18 (100% female) Mean (SD) age: 46.0 (2.0) years Mean (SD) BMI: 31.4 (0.8) kg/m2 Treatment dose: 1.3 mg/day Mean (approx. 95% CI) body weight: −0.2 (−3.5 to 3.1) kg Mean (% change from baseline) whole body bone mineral density (DXA): −0.004 g/m2 (−0.3%) Mean change (approx. 95% CI) in bone turnover markers: Plasma CTX: +0.06 (−0.02 to 0.14) ng/mL Plasma P1NP: +6.5 (1.4 to 11.6) μg/L *	N = 19 (100% female) Mean (SD) age: 45 ± 8.7 years Mean (SD) BMI: 29.0 (2.2) kg/m2 Condition: Lifestyle education Mean (approx. 95% CI) body weight: +1.7 (−1.4 to 4.8) kg Mean (% change from baseline) whole body bone mineral density (DXA): −0.005 g/m2 (−0.4%) Mean change (approx. 95% CI) in bone turnover markers: Plasma CTX: −0.03 (−0.06 to 0.06) ng/mL Plasma P1NP: −0.8 (−8.05 to 6.45) μg/L
Author (year): Gilbert et al. (2016) [59] Incretin mimetic: Liraglutide Population: Type 2 diabetes Study sample size: 61 in the bone mineral density subgroup analysis (N = 746 in parent trial) Duration: 52 weeks	Change in whole body bone mineral density: No significant treatment effect of liraglutide	N = 20 (50% female) Mean (SD) age: 54 (8.5) years Mean (SD) BMI: 33.4 (6.6) kg/m2 Treatment dose: 1.8 mg/day Mean (% change from baseline) body weight: Not reported Mean (%) change in whole body bone mineral density (DXA): −0.002 g/cm2 (−0.16%)	N = 18 (67% female) Mean (SD) age: 53.5 (13) years Mean (SD) BMI: 32.4 (5.0) kg/m2 Condition: Glimepiride 8 mg/day Mean (% change from baseline) body weight: Not reported Mean (%) change in whole body bone mineral density (DXA): −0.008 g/cm2 (−0.68%)
Author (year): Hygum et al. (2020) [62] Incretin mimetic: Liraglutide Population: Type 2 diabetes Study sample size: 60 Duration: 26 weeks	Change in total hip bone mineral density (DXA): Liraglutide preserved total hip bone mineral density despite significant weight loss Change in volumetric bone mineral density (QCT), bone microarchitecture (HRpQCT), and bone turnover markers: No significant treatment effect of liraglutide	N = 30 (47% female) Mean (SD) age: 62 (8.0) years Mean (SD) BMI: 33.0 (5.6) kg/m2 Treatment dose: 1.8 mg/day Mean (95% CI) body weight: −3.8 (−5.2 to −2.5) kg* Areal (DXA) and volumetric (QCT) bone mineral density (total hip, femoral neck, lumbar spine): No significant within‐group changes between baseline and week 26 Bone microarchitecture (HRpQCT): No significant changes Bone turnover markers: CTX, Mean (95% CI) change: +0.07 (0.03 to 0.10) μg/L P1NP, Mean (% change from baseline): +0.70 μg/L (+1.9%)	N = 30 (53% female) Mean (SD) age: 64 (8.0) years Mean (SD) BMI: 31.3 (5.6) kg/m2 Condition: Saline injection Mean (95% CI) body weight: −0.06 (−1.3 to 1.2) kg Areal (DXA) and volumetric (QCT) bone mineral density (total hip, femoral neck, lumbar spine): Mean total hip (95% CI): −0.006 (0.002 to 0.011) g/cm2 Mean femoral neck (95% CI): −0.009 (0.001 to 0.017) g/cm2 Bone microarchitecture (HRpQCT): No significant changes Bone turnover markers: CTX, Mean (95% CI) change: +0.03 (0.00 to 0.06) μg/L P1NP, Mean (% change from baseline): Not reported
Author (year): Ghanim et al. (2020) [50] Incretin mimetic: Liraglutide Population: Overweight and obesity Study sample size: 84 Duration: 26 weeks	Change in whole body bone mineral density: No significant treatment effect of liraglutide	N = 42 (65% female) Mean (SD) age: 47.0 (12.2) years Mean (SD) BMI: 33.3 ± 7.3 kg/m2 Treatment dose: 1.8 mg/day Mean (%) total body weight: −3.9 kg (−4.1%)* Whole body bone mineral density (DXA): No within‐group change reported	N = 42 (59% female) Mean (SD) age: 45.0 (15.6) years Mean (SD) BMI: 29.5 (6.8) kg/m2 Condition: Placebo injection Mean (%) total body weight: 0.4 kg (+0.5%) Whole body bone mineral density (DXA): No within‐group change reported
Author (year): Mok et al. (2023) [53] Incretin mimetic: Liraglutide Population: 1 year post bariatric surgery in patients with poor weight loss Study sample size: 70 Duration: 24 weeks	Change in whole body bone mineral density (DXA): No significant effect of liraglutide	N = 35 (74% female) Mean (SD) age: 46.7 (10.8) years Mean (SD) BMI: 41.6 (6.9) kg/m2 Treatment dose: 3.0 mg/day Mean (SD) change in total body weight: −9.5 (5.1) kg* Mean (SD) change in whole body bone mineral density (DXA): −0.01 (0.02) g/cm2	N = 35 (74% female) Mean (SD) age: 48.4 (10.6) years Mean (SD) BMI: 44.6 (8.3) kg/m2 Condition: Saline placebo Mean (SD) change in total body weight: −0.4 (3.9) kg Mean (SD) change in whole body bone mineral density (DXA): +0.01 (0.04) g/cm2
Author (year): Jensen et al. (2024) [63] Incretin mimetic: Liraglutide Population: Overweight or obesity Study sample size: 195 Duration: 52 weeks	Change in site‐specific body bone mineral density (DXA): Liraglutide significantly reduced total hip and lumbar spine bone mineral density compared to placebo	N = 49 (63% female) Mean (SD) age: 43.2 (11.6) years Mean (SD) BMI: 37.0 (3.3) kg/m2 Treatment dose: 3.0 mg/day Mean (95% CI) change in total body weight: −13.7 (−16.4 to −11.0) kg Mean (95% CI) change in bone mineral density (DXA): Total hip: −0.026 (−0.033 to −0.018) g/cm2 * Lumbar spine: −0.020 (−0.030 to −0.009) g/cm2* Distal forearm: +0.003 (−0.004 to 0.011) g/cm2	N = 49 (63% female) Mean (SD) age: 43.0 (11.5) years Mean (SD) BMI: 36.5 (2.9) kg/m2 Condition: Placebo injection Mean (95% CI) change in total body weight: −7.0 (−9.8 to −4.3) kg Mean (95% CI) change in bone mineral density (DXA): Total hip: −0.012 (−0.020 to −0.004) g/cm2 Lumbar spine: −0.001 (−0.012 to 0.010) g/cm2 Distal forearm: +0.003 (−0.005 to 0.010) g/cm2
Author (year): Hansen et al. (2024) [64] Incretin mimetic: Semaglutide Population: Individuals with DXA‐derived T‐scores < −1.0 in the hip or lower back and/or low energy fracture within the last 3 years Study sample size: 64 Duration: 52 weeks	Change in site‐specific bone mineral density: Semaglutide significantly reduced total hip and lumbar spine bone mineral density compared to placebo Change in bone turnover markers: Semaglutide significantly increased CTX (marker of bone resorption) compared to placebo; semaglutide did not significantly change P1NP (marker of bone formation) compared to placebo	N = 32 (87% female) Mean (SD) age: 62.7 (5.6) years Mean (SD) BMI: 27.9 (4.8) kg/m2 Treatment dose: 1.0 mg/week Mean (%) change in total body weight: −7.2 kg (−9.3%)* Mean (%) change in bone mineral density (DXA): Total hip: −0.021 g/cm2 (−2.7%)* Femoral neck: −0.010 g/cm2 (−1.5%) Lumbar spine: −0.013 g/cm2 (−1.6%)* Mean (%) change in bone turnover markers: CTX: +180.2 ng/L (+43.9%†)* P1NP: +0.5 μg/L (+0.8%†)	N = 32 (84% female) Mean (SD) age: 63.6 (5.4) years Mean (SD) BMI: 27.6 (4.3) kg/m2 Treatment dose: Saline placebo Mean (%) change in total body weight: −0.5 kg (−0.7%)* Mean (%) change in bone mineral density (DXA): Total hip: 0 g/cm2 Femoral neck: −0.003 g/cm2 (−0.5%) Lumbar spine: +0.005 g/cm2 (+0.6%) Mean (%) change in bone turnover markers: CTX: +13.7 ng/L (+3.3%†) P1NP: −3.3 μg/L (−5.0%†)

Note: Asterisks (*) indicate significant between‐group difference (treatment group vs. comparator group); daggers (^†) indicate derived values (i.e., not directly reported by the study).

Abbreviations: CTX, type 1 collagen cross‐linked C‐telopeptide (marker of bone resorption); DXA, dual x‐ray absorptiometry; P1NP, propeptide of type 1 collagen (marker of bone formation); SD, standard deviation.

Conversely, significant between‐group differences in the pre‐post change in bone mineral density at two central sites (total hip and lumbar spine) were noted by Jensen et al. in their 52‐week trial (3.0 mg/day) of primarily middle‐aged adults with overweight or obesity (mean [SD] age: 43.2 [11.6] years, N = 49) [63]. Hansen et al. also demonstrated significantly greater decrements in total hip and lumbar spine bone mineral density among the treatment arm relative to the comparator arm in their 52‐week study (1.0 mg/week) of primarily older adults at risk of fragility fracture (mean [SD] age: 62.7 years, N = 32) [64]. In the same study, there was a significant between‐group difference in the mean (%) change in plasma CTX: 180.2 (43.9%) ng/L vs. 3.7 (3.3%) ng/L for the treatment and comparator arms, respectively, while plasma P1NP remained relatively stable across the intervention period.

Findings from a 26‐week trial by Hygum et al. represent the most extensive evaluation of bone health following liraglutide obesity therapy [62]. Pre‐post metrics included both areal and volumetric bone mineral density using DXA and quantitative computed tomography (QCT), respectively, performed at the three central sites (total hip, femoral neck, and lumbar spine). The authors also evaluated bone microarchitecture and geometry of the radius and tibia using high resolution peripheral QCT and then additionally analyzed blood plasma for CTX and P1NP. Participants (N = 60) were individuals with T2DM and had a mean (95% CI) age of 62 (59–65) years, with those in the liraglutide group receiving a target dose of 1.8 mg/day. There were no significant within‐ or between‐group changes in areal or volumetric bone mineral density at either the hip, femoral neck, or lumbar spine. Furthermore, none of the radius or tibia microarchitecture variables (e.g., trabecular thickness) experienced significant changes after 26 weeks. The mean (95% CI) change in plasma CTX was 0.07 (0.03–0.10) μg/L and 0.03 (0.00–0.06) μg/L for the treatment and comparator arms, respectively, suggesting the absence of a significant treatment effect on bone resorption. P1NP remained relatively stable in both groups throughout the study period.

5.2. Semaglutide Trials

At the time of writing (December 2025), only one adequately designed RCT reported the effects of semaglutide obesity therapy on bone health. Hansen et al. evaluated the effects of once weekly semaglutide (1.0 mg) for 52 weeks in older adults with low bone mineral density and increased risk of fragility fracture (mean [SD] age: 62.7 [5.6] years N = 64) [64]. DXA‐derived changes in total hip, femoral neck, and lumbar spine bone mineral density were − 0.021 g/cm² (−2.7%), −0.010 g/cm² (−1.5%), and − 0.013 g/cm² (−1.5%), respectively, and were significantly greater than the losses experienced by the control group for the total hip and lumbar spine. There was a significant within‐group increase in plasma CTX (+180.2 μg/L, +43.9%) that was statistically superior to the increase reported in the control group, with P1NP remaining relatively stable across time points, suggesting a predominance of bone resorption over the course of treatment.

5.3. Tirzepatide Trials

Adequately powered clinical trials testing the effects of tirzepatide obesity therapy on bone health are lacking, representing a key area for future study (particularly considering the rise in tirzepatide prescription for the treatment of obesity) [65].

6. Associations With Fragility Fracture

At present, no RCTs have been specifically designed and powered to detect incident fractures as a primary endpoint following incretin mimetic obesity therapy in older adults. However, a large RCT (N = 17,604) did evaluate the safety profile of semaglutide (2.4 mg/day) vs. placebo in older adults (61.6 ± 8.9 years) with overweight or obesity and diabetes, in which fractures were counted as adverse events over ~3.5 years of follow‐up [66]. Investigators noted that while overall fracture rates between the treatment and control groups were similar (1.5% vs. 1.7%, respectively), an imbalance existed for those aged ≥ 75 years (2.4% and 0.6% for the treatment and placebo group, respectively), suggesting a four fold greater relative risk for the semaglutide group. However, no adjusted comparisons were made in this analysis, meaning the true risk of incident fracture following semaglutide treatment in older adults without diabetes remains unclear. Two recent meta‐analyses summarized clinical trials of the effects of incretin mimetics in individuals with T2DM and found primarily null associations between incretin mimetic treatment and subsequent fracture risk [67, 68]. However, the studies included in these analyses were likely underpowered and too short in duration to adequately capture cases of incident fracture (events that may occur several years after the initiation of incretin mimetic therapy). Thus, controlled trials that are properly powered for incident fracture endpoints in older adults with overweight or obesity are needed to better guide clinical decision‐making and to address the question: “do incretin mimetics causally influence fragility fracture risk?”.

There are a limited number of observational studies that have characterized fracture risk among individuals with a history of incretin mimetic use. For instance, in a population‐based study of 212,816 people from primary care practices in the UK (mean age: 53.5 years), Driessen and colleagues found that the risk of incident hip or vertebral fracture for individuals who had a history of least one incretin mimetic prescription was not associated with fracture risk over a ~5‐year follow‐up period (relative to those who had never had an incretin mimetic prescription) [69]. Conversely, in a retrospective analysis of 32,266 patients with T2DM in the Danish National Patient Registry (mean age: 57.5 years), Al‐Mashadi et al. showed that those with a history of liraglutide prescription had a 35% lower risk of vertebral fracture relative to those with no history, though no such association with vertebral fracture risk was evident [70]. Finally, in a retrospective analysis of 109,207 individuals with obesity (mean age: 45.0 years) in the Atropos Eos electronic health record dataset, Noreña et al. noted a 26% lower all‐cause fracture risk at any anatomical site (hand, wrist, femur, etc.) among those with a history of semaglutide prescription (compared to those with no semaglutide prescription history) [71]. While these observational findings provide some indication of a possible link between incretin mimetic use and subsequent fracture risk in real‐world settings, their heterogenic findings have limited clinical utility; therefore further prospective studies are needed to more robustly interrogate the influence of incretin mimetics on fragility fracture risk.

7. Interpretation

The current evidence paints a picture of heterogeneity regarding the effects of incretin mimetics on body composition in adults with overweight, obesity, and/or T2DM. The broad range of findings across studies likely reflects variability in study sample sizes, treatment dosages, study durations, concurrent lifestyle treatments (e.g., diet, physical activity), and/or other unknown factors. No RCTs have been adequately powered to test the effects of incretin mimetics on an exclusively older adult population with overweight or obesity without diabetes, and addressing this gap is important because the widespread adoption of incretin mimetic therapy for obesity management is likely to grow among the rapidly aging population. Since older adults face unique physiological vulnerabilities (particularly age‐related losses in muscle strength and mass), there is a heightened need for individualized risk–benefit assessment and comprehensive lifestyle support to ensure incretin mimetic therapy does not exacerbate age‐associated decrements in physiological reserve.

The existing data also highlight the need to better distinguish changes in skeletal muscle from changes in DXA‐ or plethysmography‐derived lean compartments. Of the studies reviewed herein, only one trial directly quantified muscle tissue [58], doing so with MRI. The remaining studies relied upon DXA and air displacement plethysmography, technologies that cannot delineate skeletal muscle from lean soft tissue [47], and reductions in muscle‐based indices may have differential implications for functionality and disease risk in older adults compared to decrements in directly measured muscle tissue. The scarcity of functional outcome data in the existing evidence base, such as grip strength and gait speed, means we are additionally limited in our understanding of how incretin mimetic obesity therapy impacts the longer‐term risks of adverse events associated with weakness and/or slowness in older adults. Muscular strength declines three times faster than muscle mass in older adulthood [28], and epidemiologic evidence suggests the loss of muscular strength is a stronger predictor of mortality than the loss of muscle mass alone [72]. Therefore, future studies should seek to better characterize the functional implications of incretin mimetic therapy in older adults to better inform clinical decision‐making and public health guidelines. Until long‐term trials clarify the trajectory of muscle, physical function, and bone responses, clinicians should proceed with vigilance: leveraging the metabolic promise of incretin mimetic therapy while safeguarding the musculoskeletal health that underpins independence in later life.

8. Conclusion

Existing evidence suggests that incretin mimetics are highly efficacious for eliciting reductions in body weight, and that their usage is associated to some degree with concurrent decrements in muscle‐based indices and bone mineral density. It is still unclear, however, how these body compositional changes affect long term outcomes such as physical function and the risk of fragility fracture in older adult populations because adequately powered studies are lacking. Older adults are expected to constitute a rising fraction of the incretin mimetic user base in the US the rapidly aging population and the stagnation of obesity rates within this population. Appropriately powered RCTs and real‐world observational studies are needed to robustly elucidate the relationship between incretin mimetics and body composition in older adult populations and to evaluate approaches (e.g., lifestyle modification) that mitigate decrements in skeletal muscle mass and bone during incretin mimetic obesity therapy. Such data will help inform future clinical guidelines for the pharmacological management of obesity in aging populations, potentially impacting longer term outcomes.

Author Contributions

Conceptualization: J.M.S., A.S.C., K.N.P.S., and J.A.B. Acquisition and interpretation of data: J.M.S., A.S.C., and K.N.P.S. Writing – original draft: J.M.S. Writing – review, editing, and critical review: A.S.C., K.N.P.S., and J.A.B. Final approval: J.M.S., A.S.C., K.N.P.S., and J.A.B.

Funding

J.M.S. is the recipient of the Ruth L. Kirschstein National Research Service Award from the National institute on aging (T3200270). A.S.C. is supported by the National Institute on Aging Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342), a Yale Physician Scientist Development Award, and CTSA Grant Number UL1 TR001863 from the National Center for Advancing Translational Science. K.N.P.S. is partially supported by the National Institute on Aging Claude D. Pepper Older Americans Independence Center at Duke University School of Medicine (P30AG028716) and a U.S. Department of Veterans Affairs Rehabilitation Research and Development grant I01RX003981. J.A.B. is partially supported by the National Institute on Aging, National Institutes of Health grant R01 AG071663, and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, P30DK056350‐23.

Conflicts of Interest

K.N.P.S. has received consultant fees from Abbott Nutrition Health Institute, Nestle, and Vivo. J.A.B. has received consultant fees from Regeneron, Abbott Nutrition, and MedaCorp. He owns equity in SynchroHealth LLC, a remote monitoring startup. The other authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.