Sodium-Glucose Co-Transporter 2 Inhibitors and Fracture Risk
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Patients with type 2 diabetes mellitus (T2DM) appear to have increased risk for fractures. In this context, the finding that canagliflozin, a sodium-glucose co-transporter-2 (SGLT) inhibitor, increased the risk for fracture compared with placebo in the Canagliflozin Cardiovascular Assessment Study (CANVAS), a large randomized controlled trial (RCT) in patients with established cardiovascular disease or multiple cardiovascular risk factors, created concern. In the present review, we summarize the data regarding the association between SGLT2 inhibitors and fracture risk in patients with T2DM. In contrast to the findings reported in CANVAS, canagliflozin did not affect the risk of fracture in a more recent, large RCT in patients with diabetic nephropathy. In addition, empagliflozin and dapagliflozin, other members of this class, also do not appear to affect the incidence of fracture. Moreover, there is no clear pathogenetic mechanism through which SGLT2 inhibitors increase the risk for fractures. Therefore, available data are inconclusive to attribute to these drugs a direct responsibility for bone fractures.
KeywordsCanagliflozin Dapagliflozin Empagliflozin Fracture Sodium-glucose co-transporter-2 inhibitors Type 2 diabetes mellitus
Key Summary Points
Patients with type 2 diabetes mellitus appear to have increased risk for fractures.
Canagliflozin, a sodium-glucose co-transporter-2 (SGLT) inhibitor, increased the risk for fracture compared with placebo in a large randomized controlled trial (RCT) in patients with established cardiovascular disease or multiple cardiovascular risk factors but not in a more recent, large RCT in patients with diabetic nephropathy.
Empagliflozin and dapagliflozin, other members of this class, also do not appear to affect the incidence of fracture.
There is no clear pathogenetic mechanism through which SGLT2 inhibitors increase the risk for fractures.
Overall, available data are inconclusive to attribute to SGLT2 inhibitors a direct responsibility for bone fractures.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the newest class of oral medications for the management of type 2 diabetes mellitus (T2DM) . Canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin have already been approved by the US Food and Drug Administration (FDA) for the management of T2DM [2, 3], whereas luseogliflozin, tofogliflozin, and ipragliflozin have been approved in Japan [4, 5, 6]. The SGLT2 inhibitors can be used either as monotherapy or in combination with other antidiabetic agents. In randomized clinical trials, canagliflozin, dapagliflozin, and empagliflozin reduced the risk for hospitalization for heart failure and empagliflozin also reduced cardiovascular and all-cause mortality [7, 8, 9]. Accordingly, in patients with T2DM and established cardiovascular disease, SGLT2 inhibitors and glucagon-like peptide 1 receptor agonists with proven reduction of the cardiovascular risk are proposed as the preferred add-on therapy to metformin, when combination treatment is needed .
Despite these beneficial effects of SGLT2 inhibitors on cardiovascular events, an increased risk of fractures was observed in the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial in patients treated with canagliflozin . In contrast, the incidence of fractures did not differ between patients treated with placebo and either dapagliflozin or empagliflozin in the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58) and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients trial (EMPA-REG OUTCOME), respectively [8, 9]. These findings have potential implications in patients with T2DM, who appear to be at increased risk for fractures [11, 12]. In the present review, we summarize the data regarding the association between SGLT2 inhibitors and fracture risk in patients with T2DM. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
The PubMed database was reviewed for papers using the terms “diabetes”, “sodium-glucose co-transporter 2 inhibitors”, “canagliflozin” “dapagliflozin”, “empagliflozin”, “fracture”, and “bone”. The references of pertinent articles were also hand-searched for relevant papers. Only studies published in English were considered.
T2DM and Fractures
Major observational studies that showed an association between type 2 diabetes mellitus (T2DM) and risk of fractures
Patients with T2DM had increased nonvertebral fracture risk than subjects without T2DM (hazard ratio 1.33, 95% confidence interval 1.00–1.77)
Patients with T2DM had higher bone mineral density than subjects without T2DM
The increased fracture risk was present only in treated patients with T2DM and not in newly diagnosed patients
T2DM was an independent risk factor for prevalent vertebral fracture
Bone mineral density was not associated with the presence of vertebral fracture in patients with T2DM
Several mechanisms have been proposed to explain the association between T2DM and fractures. Advanced glycation end products (AGEs) are accumulated in the bones and contribute to the low bone quality in diabetic patients . Indeed, serum levels of pentosidine appear to be associated with the risk of fracture in patients with T2DM . Moreover, insulin and insulin-like growth factor 1 (IGF1) have an important anabolic effect on bone metabolism. Low levels of IGF1 are associated with increased risk for fractures . Osteocalcin, which is mainly produced by osteoblasts, is a bone formation marker . Serum osteocalcin levels in women with T2DM are lower compared with nondiabetic women [17, 18]. Moreover, there is an inverse association between serum osteocalcin levels and both fasting glucose levels and insulin resistance . Incretins have also been implicated in the pathogenesis of increased fracture risk in patients with T2DM. The gastric inhibitory polypeptide (GIP) contributes to the promotion of bone formation and to the reduction of bone absorption and is reduced in patients with T2DM . Sclerostin, a protein that is expressed in osteocytes, is increased in T2DM and might also play a role in the poor bone quality of these patients [21, 22]. More specifically, sclerostin binds to its low-density lipoprotein receptor-related proteins 5 and 6, which are found in osteoblasts. This leads to the inhibition of the Wnt-β–catenin pathway, which results in inhibition of osteoblastogenesis and bone formation . Finally, the levels of vitamin D were also shown to be lower in patients with T2DM [24, 25].
SGLT2 Inhibitors and Fracture Risk
Characteristics of the major trials that evaluated sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes mellitus (T2DM)
T2DM duration (years
Established CVD or age ≥ 50 years with ≥ 2 cardiovascular risk factors
HR 1.26, 95% CI 1.04–1.52
Chronic kidney disease
HR 0.98, 95% CI 0.70–1.37
Established CVD or multiple cardiovascular risk factors
HR 1.04, 95% CI 0.91–1.18
New York Heart Association class II, III, or IV heart failure and ejection fraction ≤ 40%
2.1% in both placebo and dapagliflozin group
3.9% and 3.8% in the placebo and empagliflozin group, respectively
Meta-analyses of randomized controlled trials that evaluated the association between sodium-glucose co-transporter 2 (SGLT2) inhibitors and the risk of fracture
Number of studies
Number of patients
Similar incidence of bone fractures in patients receiving SGLT2 inhibitors and placebo
When the effects of canagliflozin, dapagliflozin, and empagliflozin on fractures were analyzed separately, none was associated with increased risk for fracture
Similar incidence of bone fractures in patients receiving SGLT2 inhibitors and placebo
In groups at higher risk for fracture, including women and the elderly, no increase in the incidence of fracture was noted in patients treated with SGLT2 inhibitors
In another recent meta-analysis of 27 randomized controlled trials (n = 20,895), SGLT2 inhibitors did not increase the risk of fracture compared with placebo (relative risk 1.02, 95% CI 0.81–1.28) . In groups at higher risk for fracture, including women and the elderly, no increase in the incidence of fracture was noted either . Moreover, three trials (n = 1303) evaluated the effects of SGLT2 inhibitors on BMD and did not show any change in the evaluated skeletal sites (lumbar spine, femoral neck, total hip, and distal forearm) (Table 3) .
Effects of SGLT2 Inhibitors on Bone Metabolism
Canagliflozin increased the risk for fracture in the CANVAS trial but not in the CREDENCE trial. In addition, empagliflozin and dapagliflozin do not appear to affect the incidence of fracture. Moreover, there is no clear pathogenetic mechanism through which SGLT2 inhibitors will result in increased risk for fractures. Therefore, available data are inconclusive to attribute to these drugs a direct responsibility for bone fractures.
No funding or sponsorship was received for this study or publication of this article.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Anastasia Erythropoulou-Kaltsidou and Georgios Polychronopoulos have nothing to disclose. Konstantinos Tziomalos is a member of the journal’s Editorial Board.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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