Insulin and Not Metformin is Linked to Higher Rate of Fractures

Insulin-sensitizing treatment with metformin is not associated with a higher incidence of bone fractures, but current treatment with insulin increases the risk for fractures, according to the results of a nested case-control study.

Insulin treatment did not affect bone frailty in the long-term.
Edoardo Mannucci, MD, from the University of Florence and Azienda Ospedaliero-Universitaria Careggi in Florence, Italy, writes, "Hypoglycemic treatments could modulate the risk for fractures in many ways."  "Most studies have not explored the effect on the incidence of bone fractures of individual oral hypoglycemic agents, considering all oral treatments only as a whole. Aim of this case-control study, nested within a retrospective cohort, is the assessment of the risk for bone fractures associated with exposure to insulin or different oral hypoglycemic agents."

Within a cohort of 1945 outpatients with diabetes with a follow-up of 4.1 ± 2.3 years, this nested case-control study compared 83 cases of bone fractures and 249 controls matched for age, sex, duration of diabetes, body mass index, levels of hemoglobin A1c, comorbidity, smoking, and alcohol abuse. The investigators determined exposure to hypoglycemic drugs during the 10 years preceding the event or the matching index date.

A model that included treatment with insulin-secretagogues, metformin, and insulin for at least 36 months during the previous 10 years showed no significant association between bone fractures and medication use. An alternative model considering treatments at the time of fracture showed that insulin treatment was significantly associated with bone fractures in men (odds ratio [OR], 3.20; 95% confidence interval [CI], 1.32 – 7.74) but not in women (OR, 1.41; 95% CI, 0.73 – 2.73).

"Insulin-sensitizing treatment with metformin is not associated with a higher incidence of bone fractures, suggesting that the negative effect of thiazolidinediones is due to a specific action on bone metabolism, rather than to reduction of insulinemia," the study authors write. "Conversely, current treatment with insulin increases the risk of fractures; at the same time, exposure to this agent in the longer term does not appear to affect bone frailty."

Limitations of the study include very few patients receiving thiazolidinediones, preventing separate analysis for each agent; lack of a statistically significant effect of metformin possibly because of insufficient sample size; diagnosis of bone fractures obtained through coded diagnoses at hospital discharge; distinction among spontaneous, traumatic, and indeterminate fractures not considered; lack of data on bone density and frequency of falls; treatments affecting bone metabolism (eg, bisphosphonates, vitamin D, and calcium supplementation) not considered; and possible misclassification of treatments.
"Bone fractures deserve to be considered among treatment outcomes for the choice of hypoglycemic medication, particularly in older patients with type 2 diabetes," the study authors conclude.

Practice Pearls:

• In a nested case-control study, insulin-sensitizing treatment with metformin was not associated with a higher incidence of bone fractures, suggesting that the negative effect of thiazolidinediones was because of a specific action on bone metabolism and not reduction of insulinemia.
• Current treatment with insulin was associated with increased fracture risk in men but not in women. Longer-term exposure to insulin did not seem to affect bone frailty.

Diabetes Care. Published online November 16, 2007.

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