GLP-1 Therapies Linked to Lower Fragility Fracture Risk in Adults Living With Type 2 Diabetes
Key Takeaways:
- Adults aged 50 and over living with type 2 diabetes who started a GLP-1 receptor agonist had a 21% lower three-year risk of fragility fracture than those starting a DPP-4 inhibitor (HR 0.79).
- Reductions were strongest for vertebral (HR 0.68) and hip or femur fractures (HR 0.70), and appeared independent of changes in BMI and HbA1c – pointing to a possible direct skeletal effect.
- The findings do not extend to younger people using GLP-1 medications for weight management alone, or to those with osteoporosis; among adults without diabetes, fracture risk was higher (HR 1.13).
A large-scale look at bone health during GLP-1 treatment
Initiating a GLP-1 receptor agonist for type 2 diabetes was associated with a lower risk of fragility fractures in adults aged 50 and over, including fractures of the hip and spine, according to a large target trial emulation study published in JAMA Network Open.
Over three years of follow-up, adults who newly started a GLP-1 medication had a 21% lower risk of fragility fracture than those who newly started a DPP-4 inhibitor (HR 0.79, 95% CI 0.76–0.83), reported Christopher Hamad, MD, of the University of California Los Angeles, and colleagues.
The authors were careful to frame the size of the effect in context rather than overstate it.
“Although the absolute risk reduction at 3 years was modest (0.79%), this magnitude is clinically relevant given a baseline 3-year major osteoporotic fracture risk of approximately 3% to 4% in comparable populations and the substantial morbidity and mortality associated with hip and vertebral fractures,” the authors wrote.
Why a modest absolute reduction still matters
The clinical weight of these numbers rests on how serious the events being prevented are. Hip fractures, for example, are associated with one-year mortality rates of up to 25% in women and up to 36% in men.
Given the potential for such severe outcomes, Hamad’s group emphasised that even modest absolute reductions in fragility fractures – which stem from low-energy trauma, such as a fall from standing height – can prevent a meaningful number of events at population level.
The findings build on several smaller observational studies in people living with diabetes that have similarly linked the use of GLP-1 medications such as semaglutide (Ozempic, Wegovy) to a reduced fracture risk. Hamad’s team noted that their analysis drew on the largest dataset assembled on this question to date.
Which fractures showed the strongest signal
The protective association was most pronounced at precisely the sites that carry the highest morbidity and mortality:
- Vertebral fractures: HR 0.68, 95% CI 0.63–0.73
- Hip or femur fractures: HR 0.70, 95% CI 0.63–0.79
- Rib fractures: HR 0.83, 95% CI 0.77–0.91
No significant associations were identified for fractures of the distal radius or ulna, or of the proximal humerus.
Weight loss, glycaemic control and the question of a direct skeletal effect
One of the more striking elements of the analysis concerns the mechanism. Mediation analyses indicated that the associations were independent of changes in BMI and HbA1c, a pattern consistent with a potential direct skeletal effect of GLP-1 medications.
That matters because weight loss itself is associated with reduced bone mineral density and a higher fracture risk – a relationship reflected in the study’s own data, which found that cumulative BMI loss was tied to a 2% increase in fracture risk. In other words, the expected consequence of the weight reduction these medications produce would be a rise in fracture risk, not a fall.
“Yet, GLP-1 RA [receptor agonist] use was associated with lower fracture risk despite these changes, suggesting that potential direct skeletal effects may outweigh the adverse consequences of weight loss,” the authors wrote.
Reassessing the assumption of neutral skeletal effects
Current American Diabetes Association Standards of Care classify GLP-1 medications as having neutral effects on the skeleton. The researchers argued that their results suggest this assumption warrants reevaluation.
They also acknowledged the limits of what an observational design can establish, noting that the findings could still reflect unmeasured factors such as improved balance or greater physical activity among people taking these medications. Making sense of evidence like this – and of the mechanistic arguments used to interpret it – is the focus of professional training such as the College of Contemporary Health’s GLP-1RAs in Focus, a CPD-accredited online short course that grounds healthcare professionals in how these medications act on the body.
How the study was conducted
For this comparative effectiveness study, the researchers drew data from the TriNetX Research Network, analysing 66,803 matched pairs, or 133,606 people in total, aged between 50 and 90 years.
Mean age was approximately 63 years, roughly 53% of participants were male, 58% were White, and average baseline BMI was around 33.
All participants were living with type 2 diabetes and had newly initiated either a GLP-1 receptor agonist or a DPP-4 inhibitor between 2015 and 2022. Dulaglutide (Trulicity), semaglutide and liraglutide (Victoza) together accounted for 91% of index prescriptions in the GLP-1 group. Exclusion criteria included fractures resulting from high-energy trauma, as well as osteoporosis and osteopenia.
Where the protective association held – and where it did not
In subgroup analyses, the lower fracture risk was consistent across age groups, across sexes and across levels of frailty.
A separate matched cohort, however, evaluated participants according to diabetes status and produced a notably different picture. Among adults living with type 2 diabetes, GLP-1 use retained a protective association (three-year HR 0.91, 95% CI 0.88–0.95). Among adults without diabetes, it was associated with an increased fracture risk (HR 1.13, 95% CI 1.04–1.23, P<0.001 for interaction).
Consequently, the authors emphasised that the findings cannot be generalised to younger people using GLP-1 medications solely for weight management, nor to those with known osteoporosis or a previous fragility fracture, who were excluded from the study altogether.
What this means for practice
Overall, “the findings do not argue against GLP-1 RA use on the basis of fracture risk, though bone health monitoring remains prudent,” according to the researchers.
They called for prospective randomised trials to evaluate the associations observed, including among people with osteopenia or early osteoporosis, alongside preclinical work to understand the potential mechanisms involved.
CCH insight
For healthcare professionals, this study is a useful reminder that the skeletal consequences of GLP-1 treatment are not yet settled science – and that the answer appears to differ depending on who is being treated and why. Interpreting findings of this kind with confidence depends on a firm grasp of how these medications act in the first place, from gut hormones and appetite regulation through to their wider effects beyond glycaemic control. That is exactly what CCH’s GLP-1RAs in Focus – Why Drugs Like Ozempic Work CPD short course (2 CPD hours, fully online, CPD-accredited) is built to provide, giving clinicians a clear grounding in the mechanisms behind these therapies and the ability to appraise emerging evidence critically, whether or not they prescribe.
Read More