Fracture risks, benefits vary with different diabetes drugs
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Clinicians should be cautious when prescribing certain antihyperglycemic agents for people with type 2 diabetes at risk for fracture, particularly when a patient is older with long disease duration or complications, according to a speaker.
Data demonstrate long-term exposure to type 2 diabetes leads to changes in bone metabolism and impaired bone microarchitecture, whereas glycemic control, diabetes complications and fall risk are also fracture risk factors, Christian Meier, MD, senior physician in the division of endocrinology, diabetes and metabolism at University Hospital Basel, Switzerland, said during a virtual presentation at the European Association for the Study of Diabetes annual meeting.
“The question that now remains is, what is the influence of glucose-lowering therapies on fracture risk?” Meier said.
Meier highlighted fracture risks and benefits associated with various classes of diabetes therapies:
Metformin — There are few clinical studies reporting the skeletal effects of metformin; however, preclinical studies indicate metformin has a positive effect on osteoblast differentiation, Meier said. In a systematic review and meta-analysis published in 2019 in Osteoporosis International, researchers observed a significant inverse association between metformin use and risk for fracture across six studies, with an RR of 0.82 (95% CI, 0.72-0.93) and no between-study heterogeneity, Meier said.
“Clearly, there was beneficial effect with a decrease in relative risk of about 18%,” Meier said. “Overall, metformin is certainly a first-line drug to be used with no major negative impact on fracture risk.”
Thiazolidinediones — There is “clear evidence” that TZDs have a negative impact on bone, with data showing TZD use is associated with increased bone resorption, decreased bone mineral density and increased fracture risk, Meier said. In a nested case-control analysis assessing the use of TZDs and other diabetes medications on fracture risk conducted by Meier and colleagues, the OR for users of eight or more TZD prescriptions (corresponding to approximately 12-18 months of therapy) compared with nonuse was 2.43 (95% CI, 1.49-3.95). Rosiglitazone and pioglitazone were used more frequently by case patients with fracture, with predominantly hip and wrist fractures, vs. controls. The association was independent of patient age and sex and tended to increase with TZD dose.
“Interestingly, we observed that the risk was independent of age, drug use and also independent of dose used,” Meier said. “This has been confirmed in a meta-analysis including randomized controlled trials, and, interestingly, the negative effect on fracture risk has only been observed in postmenopausal women and there was no increased risk for men. There are data showing that estrogens might have a protective effect on glitazone-induced bone loss. In this respect, postmenopausal women with low estrogen levels might lose the protective effect.”
Sulfonylureas — Data on associations between fracture risk and sulfonylurea use are limited. Despite some studies showing “no major effect” on fracture risk, a meta-analysis of seven studies published in 2021 (n = 464,121) showed the pooled risk ratio for developing fracture in sulfonylurea users with type 2 diabetes aged at least 65 years was 1.26 (95% CI, 1.15-1.39).
“The question is, what is the reason?” Meier said. “In most studies, it has been associated with risk for hypoglycemia and, thereby, fall risk. We know already that hypoglycemia is related to more fractures.”
Incretin-based therapies — GLP-1 receptor agonists have a direct effect on bone metabolism with a positive effect on bone formation and an inhibitory effect on bone resorption, Meier said. A large meta-analysis indicate fracture risk is decreased in GLP-1 users
“It seems that we have another drug with protective, or at least neutral, in patients with type 2 diabetes,” Meier said. “That is also true with the use of DPP-IV inhibitors, which do not increased the risk for fracture in studies. That is reassuring when using these drugs in patients with high fracture risk.”
SGLT2 inhibitors — There are biochemical changes in patients prescribed SGLT2 inhibitors, with an increase in phosphate and fibroblast growth factor-23 and parathyroid hormone. Few studies show an effect on bone turnover and hip BMD. In a meta-analysis analyzing the effects of combination therapy with SGLT2 inhibitors and metformin on fracture risk across 25 randomized controlled trials (n = 19,500), SGLT2 inhibitors combined with metformin use did not influence fracture risk compared with metformin monotherapy or other comparators in people with type 2 diabetes, with an OR of 0.97 (95% CI, 0.71-1.32).
Data from the CANVAS program suggested there may be increased risk with the SGLT2 inhibitor canagliflozin (Invokana, Janssen); however, the CREDENCE study, which Meier called “reassuring,” showed no skeletal-related adverse events related to canagliflozin vs. placebo during a median 2.6 years of follow-up.
‘Do no major harm’
Meier said adults with type 2 diabetes at high risk for fracture risk should be prescribed metformin as first-line therapy in addition to lifestyle modification.
“Incretin-based therapies should be the next step, specifically where we want to minimize hypoglycemia, such as in frail, elderly people, starting with DPP-IV inhibitors or GLP-1 receptor agonists,” Meier said. “Whereas in patients where we want to promote weight loss, start them on GLP-1 receptor agonists. With this [therapy] combination, we do no major harm in terms of fracture risk.”
With older adults with type 2 diabetes, particularly those with long treatment duration and complications, clinicians should try to avoid agents that cause hypoglycemia, Meier said.
“Specifically, be cautious in using treatments like sulfonylureas or insulin and not be too stringent in glycemic control, thereby avoiding falls and fractures,” Meier said.
References:
Meier C, et al. Arch Intern Med. 2008;doi:10.1001/archinte.168.8.820.
Qian BB, et al. Osteoporos Int. 2020;doi:10.1007/s00198-020-05590-y.
Tao Y, et al. Aging Clin Exp Res. 2021;doi:10.1007/s40520-020-01734-4.
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Meier C. The impact of diabetes on fracture risk. Presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 27-Oct. 1, 2021 (virtual meeting).
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