Intensive Glycemic Control and Thiazolidinedione Use: Effects on Cortical and Trabecular Bone at the Radius and Tibia

Abstract

Factors that contribute to bone fragility in type 2 diabetes are not well understood. We assessed the effects of intensive glycemic control, thiazolidinediones (TZDs), and A1C levels on bone geometry and strength at the radius and tibia. In a substudy of the Action to Control Cardiovascular Risk in Diabetes trial, peripheral quantitative computed tomographic (pQCT) scans of the radius and tibia were obtained 2 years after randomization on 73 participants (intensive n = 35, standard n = 38). TZD use and A1C levels were measured every 4 months during the trial. Effects of intervention assignment, TZD use, and A1C on pQCT parameters were assessed in linear regression models. Intensive, compared with standard, glycemic control was associated with 1.3 % lower cortical volumetric BMD at the tibia in men (p = 0.02) but not with other pQCT parameters. In women, but not men, each additional year of TZD use was associated with an 11 % lower polar strength strain index (SSIp) at the radius (p = 0.04) and tibia (p = 0.002) in models adjusted for A1C levels. In women, each additional 1 % increase in A1C was associated with an 18 % lower SSIp at the ultradistal radius (p = 0.04) in models adjusted for TZD use. There was no consistent evidence of an effect of intensive, compared with standard, glycemic control on bone strength at the radius or tibia. In women, TZD use may reduce bone strength at these sites. Higher A1C may also be associated with lower bone strength at the radius, but not tibia, in women.

The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis

“…Animal studies have also demonstrated that TZD exposure results in increased cortical porosity and decreased cortical thickness in the absence of significant changes in volumetric BMD [38,39]. In women using TZDs, reduction in polar strength strain index at highly cortical sites has been observed [40]. Therefore, while TZD-mediated declines in BMD may result in an increased propensity for fracture, particularly if bone loss is sustained with long-term treatment, the excess distal extremity fractures observed in patients taking TZDs may be better explained by changes in microarchitecture at cortical sites.…”

“…The majority of fractures in patients taking TZDs in randomised trials occur at cortical sites (humerus, distal forearm, tibia) [4,5], but we did not observe a greater magnitude of bone loss at cortical sites than trabecular sites. Studies in both rodents and humans indicate that TZD exposure is associated with changes in cortical microarchitecture, which will not necessarily be evident on dual-energy x-ray absorptiometry [38][39][40]. Animal studies have also demonstrated that TZD exposure results in increased cortical porosity and decreased cortical thickness in the absence of significant changes in volumetric BMD [38,39].…”

Claimed effects, outcome variables and methods of measurement for health claims proposed under Regulation (EC) 1924/2006 in the framework of bone health

“…Even if these measures are directly correlated with bone stability, a better estimation of bone strength can be obtained using engineering theory through calculation of polar strength strain index and other mechanical indices, such as moments of inertia or section moduli. Hence, polar strength strain index of the radius is evaluated in growth studies to investigate the relationship existing between body size, muscle size, and bone structural development [102,103]. Moreover, a decrease in polar strength strain index of the distal radius, measured by pQCT, can be considered a parameter of loss of strength in bones, thus allowing the detection of individuals at risk of osteoporotic fractures late in life.…”

Effects of Incretin-Related Diabetes Drugs on Bone Formation and Bone Resorption

“…Several studies also showed that patients with inadequate glycemic control have a high risk of fracture [ 11 , 12 , 13 ]. However, a randomized clinical trial indicated little difference in the effect on risk of fracture between intensive treatment, with a median HbA1c of 6.4%, and normal treatment, with a median of HbA1c 7.5%, in patients with type 2 diabetes [ 14 ]. However, it has also been reported that intensive control of hyperglycemia is related to elevated risk of fracture [ 15 ].…”