Bone Fractures and Hypoglycemic Treatment in Type 2 Diabetic Patients
Bone Fractures and Hypoglycemic Treatment in Type 2 Diabetic Patients
Objective: 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, rather all oral treatments as a whole. The 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.
Research Design and Methods: A case-control study nested within a cohort of 1,945 diabetic outpatients with a follow-up of 4.1 ± 2.3 years was performed, comparing 83 case subjects of bone fractures and 249 control subjects matched for age, sex, duration of diabetes, BMI, A1C, comorbidity, smoking, and alcohol abuse. Exposure to hypoglycemic drugs during the 10 years preceding the event (or matching index date) was assessed.
Results: In a model including treatment with insulin secretagogues metformin and insulin for at least 36 months during the previous 10 years, no significant association was observed between bone fractures and medications. In an alternative model considering treatments at the time of fracture, insulin treatment was significantly associated with bone fractures in men (OR 3.20 [95% CI 1.32-7.74]) but not in women (1.41 [0.73-2.73]).
Conclusions: 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 a reduction of insulinemia. 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.
Type 2 diabetes is associated with an increased risk for bone fractures with no reduction of bone density; several factors, including frequency of falls, diabetes complications, and comorbidities, could contribute to the higher risk of fractures.
Hypoglycemic treatments could modulate the risk for fractures in many ways. A higher incidence of fractures has been reported in insulin-treated patients in comparison with non-insulin-treated type 2 diabetic individuals, although some studies disagree. This could be due to a higher risk of hypoglycemic episodes and falls. However, a higher prevalence of diabetes complications and comorbid conditions could also contribute to the apparent increase of the incidence of fractures in insulin-treated patients; in fact, most available studies did not provide adjustments for comorbidities.
Recent evidence from an epidemiological study and an exploratory clinical trial suggests that the use of the insulin-sensitizing agents thiazolidinediones is associated with a decrease in bone density in postmenopausal women; similar results have been reported by an observational retrospective study exploring variations of bone density in older men with type 2 diabetes. This could explain the increased incidence of bone fractures in patients treated with rosiglitazone in a large randomized trial. Manufacturers of pioglitazone have also sent a letter to health professionals to inform them of the risk of fracture associated with this drug. Thiazolidinediones, which act as stimulators of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ, could reduce bone density through the inhibition of osteoblast differentiation and activity; in fact, PPAR-γ activation induces the differentiation of multipotent mesenchimal stem cells into adipocytes, rather than osteoblasts, and increases osteoblast apoptosis. On the other hand, the insulin-sensitizing effect of thiazolidinediones reduces circulating insulin levels and therefore the insulin anabolic effect on the bone. If this second hypothesis should be true, other insulin-sensitizing agents, such as metformin, could also be associated with an increased risk of bone fractures. Most available epidemiological studies have not explored the effect of individual oral hypoglycemic agents on the incidence of bone fractures but rather considered all oral treatments for diabetes only as a whole. The 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.
Objective: 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, rather all oral treatments as a whole. The 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.
Research Design and Methods: A case-control study nested within a cohort of 1,945 diabetic outpatients with a follow-up of 4.1 ± 2.3 years was performed, comparing 83 case subjects of bone fractures and 249 control subjects matched for age, sex, duration of diabetes, BMI, A1C, comorbidity, smoking, and alcohol abuse. Exposure to hypoglycemic drugs during the 10 years preceding the event (or matching index date) was assessed.
Results: In a model including treatment with insulin secretagogues metformin and insulin for at least 36 months during the previous 10 years, no significant association was observed between bone fractures and medications. In an alternative model considering treatments at the time of fracture, insulin treatment was significantly associated with bone fractures in men (OR 3.20 [95% CI 1.32-7.74]) but not in women (1.41 [0.73-2.73]).
Conclusions: 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 a reduction of insulinemia. 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.
Type 2 diabetes is associated with an increased risk for bone fractures with no reduction of bone density; several factors, including frequency of falls, diabetes complications, and comorbidities, could contribute to the higher risk of fractures.
Hypoglycemic treatments could modulate the risk for fractures in many ways. A higher incidence of fractures has been reported in insulin-treated patients in comparison with non-insulin-treated type 2 diabetic individuals, although some studies disagree. This could be due to a higher risk of hypoglycemic episodes and falls. However, a higher prevalence of diabetes complications and comorbid conditions could also contribute to the apparent increase of the incidence of fractures in insulin-treated patients; in fact, most available studies did not provide adjustments for comorbidities.
Recent evidence from an epidemiological study and an exploratory clinical trial suggests that the use of the insulin-sensitizing agents thiazolidinediones is associated with a decrease in bone density in postmenopausal women; similar results have been reported by an observational retrospective study exploring variations of bone density in older men with type 2 diabetes. This could explain the increased incidence of bone fractures in patients treated with rosiglitazone in a large randomized trial. Manufacturers of pioglitazone have also sent a letter to health professionals to inform them of the risk of fracture associated with this drug. Thiazolidinediones, which act as stimulators of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ, could reduce bone density through the inhibition of osteoblast differentiation and activity; in fact, PPAR-γ activation induces the differentiation of multipotent mesenchimal stem cells into adipocytes, rather than osteoblasts, and increases osteoblast apoptosis. On the other hand, the insulin-sensitizing effect of thiazolidinediones reduces circulating insulin levels and therefore the insulin anabolic effect on the bone. If this second hypothesis should be true, other insulin-sensitizing agents, such as metformin, could also be associated with an increased risk of bone fractures. Most available epidemiological studies have not explored the effect of individual oral hypoglycemic agents on the incidence of bone fractures but rather considered all oral treatments for diabetes only as a whole. The 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.
