Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures

Abstract

The primary goal of this study was to assess peripheral bone microarchitecture and strength in diabetic postmenopausal women with fragility fractures (DMFx) and to compare them with diabetic women without fracture (DM). Secondary goals were to assess differences in non-diabetic women with (Fx) and without fragility fractures (Co) and in women with (DM) and without diabetes (Co). Eighty women (mean age 61.3±5.7 yrs) were recruited into these groups (n=20 per group). Participants underwent DXA and high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultradistal and distal radius and tibia. In the HR-pQCT images volumetric bone mineral density, cortical and trabecular structure measures, including cortical porosity, were calculated. Bone strength was estimated using micro-finite element analysis (μFEA). Differential strength estimates were obtained with and without open cortical pores. At the ultradistal and distal tibia, DMFx had greater intracortical pore volume (+52.6%, p=0.009; +95.4%, p=0.020), relative porosity (+58.1%; p=0.005; +87.9%, p=0.011) and endocortical bone surface (+10.9%, p=0.031; +11.5%, 0.019) than DM. At the distal radius DMFx had 4.7-fold greater relative porosity (p=0.000) than DM. At the ultradistal radius, intracortical pore volume was significantly higher in DMFx than DM (+67.8%, p=0.018). DMFx also displayed larger trabecular heterogeneity (ultradistal radius; +36.8%, p=0.035), and lower total and cortical BMD (ultradistal tibia: −12.6%, p=0.031; −6.8%, p=0.011) than DM. DMFx exhibited significantly higher pore-related deficits in stiffness, failure load and cortical load fraction at the ultradistal and distal tibia, and the distal radius than DM. Comparing non-diabetic Fx and Co, we only found a non-significant trend with increase in pore volume (+38.9%, p=0.060) at the ultradistal radius. The results of our study suggest that severe deficits in cortical bone quality are responsible for fragility fractures in postmenopausal diabetic women.

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

“…(65) In particular, miR-21 is of interest because miR-21 is not only known as "inflamma-miR," (66) but has been shown to mediate RANKL-induced osteoclast differentiation (67) and inhibit osteoclast apoptosis. (68) Given that we found significantly higher serum miR-21 serum levels in DMFx than in DM subjects and that DMFx were described to have more cortical porosity, (29) osteoclast dysfunction/or prolonged osteoclast survival might be a potential mechanisms that could explain the higher fracture risk in the DMFx patients. In this context it is remarkable that certain miRNAs, such as miR-223 and miR-125, which are known to be potent inhibitors of osteoclastogenesis, (69,70) were not altered in the serum of our DMFx subjects.…”

“…While both miRNAs did not exhibit any effect on cell proliferation, miR-550a-5p revealed to be a potent inhibitor of osteogenesis and adipogenesis. Given that we observed that levels of miR-550a-5p were about 22-fold upregulated in DMFx relative to DM subjects, it is noteworthy that clinically, the DMFx group presented with significantly lower areal and volumetric bone mineral density (BMD), (29,30) as well as with significantly higher peripheral cortical porosity relative to DM subjects. (29) Because circulating miRNAs can act as intercellular messengers (83,84) and have been found to be taken up by distant organs, (85,86) one might speculate that high systemic levels of miR-550a-5p as in the DMFx group may be taken up by bone tissue and may-in synergy with other factors (such as oxidative stress)-inhibit bone formation-potentially leading to reduced BMD and high fracture rates as observed in this DMFx group.…”

“…(29,30) We then investigated the role of the most promising miRNAs on osteogenesis, adipogenesis, and cell proliferation in vitro. miRNAs have been reported to master-regulate diverse physiologic cellular functions including differentiation, apoptosis, (55) oxidative stress, (56) and remodeling.…”

“…For diabetics, a minimum course of 3 years antidiabetic medication use (oral medication and/or insulin) was necessary and diagnosis of T2D had to be based on the guidelines of the American Diabetes Association. (31) Women from different racial backgrounds (White, African American, Asian) (29) were enrolled in similar proportions into each study group, reflecting the racial diversity of the San Francisco Bay Area. Fracture subjects (Fx, DMFx groups) were only included if the fracture met the definition of a fragility fracture, meaning a low-energy fracture as for example, sustained during a fall from standing height or less.…”

Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights

“…These include greater cortical porosity, smaller cortical area, decreased bone material strength measured by microindentation, and high bone marrow adiposity. (17)(18)(19) In addition, the composition of the skeletal matrix may be significantly altered by higher concentrations of advanced glycation end products (AGEs). (20) All may contribute to the higher frequency of fractures documented in epidemiologic studies.…”