In the JournalsPerspective

Influence of HbA1c on fracture risk differs in type 1, type 2 diabetes

Adults with type 1 diabetes and an HbA1c of at least 8% were more likely to sustain a low-trauma fracture in the 4 years after diabetes diagnosis than similar adults with an HbA1c of less than 7%, according to findings from a case-control study.

In an analysis of more than 47,000 adults, researchers did not observe the same fracture association for adults with type 2 diabetes; however, the risk for fracture was elevated in adults with type 2 diabetes prescribed rosiglitazone (Avandia, GlaxoSmithKline) or pioglitazone, independent of glycemic control.

“In patients diagnosed with [type 1 diabetes] during adolescence and early adulthood, deficiencies in insulin and insulin-like growth factor I seem to impair osteoblast function leading to lower bone mass, smaller bone size and alterations in bone microstructure,” Janina Vavanikunnel, MD, a research fellow in the division of endocrinology, diabetes and metabolism at University Hospital Basel, Switzerland, and colleagues wrote in the study background. “In contrast, patients with [type 2 diabetes], who usually suffer from obesity-related insulin resistance and hyperinsulinemia, present[ed] with normal to increased bone mass and preserved or even increased trabecular bone volume, but with increased cortical porosity. This pattern is found particularly in patients with fractures and microvascular complications.”

Vavanikunnel and colleagues analyzed data from adults with type 1 (n = 3,329) or type 2 diabetes (n = 44,275) diagnosed between 1995 and 2015, using data from the United Kingdom-based Clinical Practice Research Datalink. Cases were defined as patients with a low-trauma fracture sustained after diabetes onset (n = 9,531). Researchers matched each case with four controls by age, sex, general practice, fracture date and diabetes type and duration (n = 38,073). Exposure of interest was glycemic control after diabetes onset, defined by HbA1c levels. Researchers used conditional logistic regression analysis to assess the association between HbA1c values and the risk for low-trauma fractures, expressed as odds ratios.

Among patients with type 1 diabetes, 672 sustained a fracture after diagnosis during a median of 4.5 years (46% women). Researchers found that patients with 3-year mean HbA1c levels of at least 8% were 39% more likely to sustain a fracture vs. those with 3-year mean HbA1c levels of less than 7% (adjusted OR = 1.39; 95% CI, 1.06-1.83). Researchers did not observe an association between HbA1c and fracture risk in adults with type 1 diabetes and moderate glycemic control, defined as an HbA1c between 7% and 8% (aOR = 0.99; 95% CI, 0.72-1.35).

Among patients with type 2 diabetes, 8,859 sustained a fracture after diagnosis during a median of 4.5 years (71% women). In these patients, glycemic control was not associated with fracture risk; however, researchers observed increased fracture risk when patients were stratified by antidiabetes therapies. Compared with nonusers, adults prescribed pioglitazone (OR = 1.36; 95% CI, 1.25-1.49) or rosiglitazone (OR = 1.32; 95% CI, 1.2-1.46) were more likely to sustain a low-trauma fracture, independent of glycemic control, according to researchers.

“The impact of glycemic control on the risk of nonvertebral low-trauma fractures differed in [type 1 diabetes] and [type 2 diabetes] patients with short-term disease,” the researchers wrote. “While poor glycemic control elevated the risk of fracture in [type 1 diabetes] patients, we observed no such association in patients with [type 2 diabetes]. This might be attributed to a protective effect of insulin resistance in early disease.” – by Regina Schaffer

Disclosures: The Swiss National Science Foundation supported this study. The authors report no relevant financial disclosures.

Adults with type 1 diabetes and an HbA1c of at least 8% were more likely to sustain a low-trauma fracture in the 4 years after diabetes diagnosis than similar adults with an HbA1c of less than 7%, according to findings from a case-control study.

In an analysis of more than 47,000 adults, researchers did not observe the same fracture association for adults with type 2 diabetes; however, the risk for fracture was elevated in adults with type 2 diabetes prescribed rosiglitazone (Avandia, GlaxoSmithKline) or pioglitazone, independent of glycemic control.

“In patients diagnosed with [type 1 diabetes] during adolescence and early adulthood, deficiencies in insulin and insulin-like growth factor I seem to impair osteoblast function leading to lower bone mass, smaller bone size and alterations in bone microstructure,” Janina Vavanikunnel, MD, a research fellow in the division of endocrinology, diabetes and metabolism at University Hospital Basel, Switzerland, and colleagues wrote in the study background. “In contrast, patients with [type 2 diabetes], who usually suffer from obesity-related insulin resistance and hyperinsulinemia, present[ed] with normal to increased bone mass and preserved or even increased trabecular bone volume, but with increased cortical porosity. This pattern is found particularly in patients with fractures and microvascular complications.”

Vavanikunnel and colleagues analyzed data from adults with type 1 (n = 3,329) or type 2 diabetes (n = 44,275) diagnosed between 1995 and 2015, using data from the United Kingdom-based Clinical Practice Research Datalink. Cases were defined as patients with a low-trauma fracture sustained after diabetes onset (n = 9,531). Researchers matched each case with four controls by age, sex, general practice, fracture date and diabetes type and duration (n = 38,073). Exposure of interest was glycemic control after diabetes onset, defined by HbA1c levels. Researchers used conditional logistic regression analysis to assess the association between HbA1c values and the risk for low-trauma fractures, expressed as odds ratios.

Among patients with type 1 diabetes, 672 sustained a fracture after diagnosis during a median of 4.5 years (46% women). Researchers found that patients with 3-year mean HbA1c levels of at least 8% were 39% more likely to sustain a fracture vs. those with 3-year mean HbA1c levels of less than 7% (adjusted OR = 1.39; 95% CI, 1.06-1.83). Researchers did not observe an association between HbA1c and fracture risk in adults with type 1 diabetes and moderate glycemic control, defined as an HbA1c between 7% and 8% (aOR = 0.99; 95% CI, 0.72-1.35).

Among patients with type 2 diabetes, 8,859 sustained a fracture after diagnosis during a median of 4.5 years (71% women). In these patients, glycemic control was not associated with fracture risk; however, researchers observed increased fracture risk when patients were stratified by antidiabetes therapies. Compared with nonusers, adults prescribed pioglitazone (OR = 1.36; 95% CI, 1.25-1.49) or rosiglitazone (OR = 1.32; 95% CI, 1.2-1.46) were more likely to sustain a low-trauma fracture, independent of glycemic control, according to researchers.

“The impact of glycemic control on the risk of nonvertebral low-trauma fractures differed in [type 1 diabetes] and [type 2 diabetes] patients with short-term disease,” the researchers wrote. “While poor glycemic control elevated the risk of fracture in [type 1 diabetes] patients, we observed no such association in patients with [type 2 diabetes]. This might be attributed to a protective effect of insulin resistance in early disease.” – by Regina Schaffer

Disclosures: The Swiss National Science Foundation supported this study. The authors report no relevant financial disclosures.

    Perspective

    Author Name

    Both type 1 and type 2 diabetes have detrimental effects on skeletal health. The mechanisms behind the increased risk for fragility fractures in patients with type 1 diabetes differs from that in patients with type 2 diabetes. In addition, diabetes-specific factors, such as duration of diabetes, glycemic control, the presence of diabetes complications and hypoglycemia, may also contribute to increased fracture risk.

    There remains controversy regarding the extent to which glycemic control impacts fracture risk in patients with diabetes. To date, only a few, relatively small studies have assessed the impact of glycemic control on fracture risk, and they yielded varied results.

    In this trial, the authors evaluated the association between glycemic control and risk for nonvertebral, low-trauma fractures in patients with newly diagnosed diabetes. They found no association between poor glycemic control (HbA1c > 8%) and fracture risk in patients with type 2 diabetes — a possible explanation for this finding is that the study population included a high proportion of patients with well-controlled type 2 diabetes.

    From a clinical standpoint, it is important to note that patients with type 2 diabetes have an increased fracture risk irrespective of sex, race or ethnicity. The mechanism behind this increased risk is likely multifactorial. Adequate glycemic control prevents or reduces the risk for microvascular complications, which have also been linked to increased fracture risk, whereas diabetic vascular complications may directly contribute to bone fragility and an increased risk of falls. Further, glycemic control may reduce the non-enzymatic glycosylation of collagen.

    It is clear that more clinical research is needed to better establish the role of glycemic control in fracture risk in patients with diabetes.

    Matthew P. Gilbert, DO, MPH

    Associate Professor of Medicine,
    Division of Endocrinology & Diabetes,
    College of Medicine, The University of Vermont, Burlington, Vermont

    Disclosure: Gilbert reports he has received consulting fees from Corcept Therapeutics, Novo Nordisk and Sanofi..