Osteoporosis Risk in Type 2 Diabetes Patients

"…there is now substantial evidence that T2D is an independent risk factor for fractures."

Type 2 diabetes mellitus (T2D) is an exceedingly common chronic metabolic disorder that has an enormous impact on public health. Currently, T2D affects over 366 million adults worldwide and is projected to reach 552 million by 2030.^[101] Until recently, the list of target organs affected by T2D did not include the skeleton. Yet, there is now substantial evidence that T2D is an independent risk factor for fractures,^[1,2] which is not attributable to increased BMI or the other classical osteoporosis risk factors. New data from pathophysiologic and epidemiologic reports, as well as from studies employing state-of-the-art investigational tools, have recently increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.

The evidence that older adults with T2D have a higher risk of fractures^[3,4] is substantial. A meta-analysis of 12 studies reported a relative risk (RR) of 1.7 (95% CI: 1.3–2.2) for hip fracture in both men and women with T2D.^[3] The risk of all clinical fractures was also increased with a summary RR of 1.2 (95% CI: 1.0–1.5).^[3] Subsequent studies have reported similar results,^[5,6] with a direct association between the duration of diabetes and increased fracture risk.^[7]

Given this increased fracture risk, it is perhaps surprising that BMD is generally higher in those with T2D compared with those without.^[4] In a meta-analysis, Vestergaard reported an increased Z-score of +0.41 at the spine and +0.27 at the hip associated with T2D.^[4] The paradox of higher BMD in association with increased fractures might be attributed to more frequent trauma, as diabetes is associated with an increased frequency of falls. However, in studies of diabetes and fracture that controlled for fall frequency, diabetes still remained independently associated with increased fracture risk.^[5,8] Thiazolidinediones (TZD) use might also be considered as an explanation, since it has been proposed that these agents divert mesenchymal stem cells from the osteogenic to the adipocytic lineage and are associated with bone loss and increased fracture risk, particularly in women.^[9] However, TZD use cannot fully account for the increased risk of fracture observed with diabetes, since most studies included substantial observation time prior to the widespread use of these medications. Rather, it appears that other bone properties, which are undetectable by DXA, are probably contributing to fracture risk in diabetes.

An important factor that may contribute to the paradox of increased fractures despite normal areal BMD is microarchitectural abnormality. Increased cortical porosity, a key determinant of bone fragility ,^[10] has been reported at the radius and tibia in female diabetics who have fractured, as measured by intracortical pore volume fraction via high-resolution peripheral quantitative computed tomography.^[11] When analyzed with finite element analysis under axial loading, the increased porosity was associated with significant biomechanical deficits, namely more pore-related deficits in stiffness.^[11]

Alterations in the trabecular compartment of bone might also play a role. Leslie et al. have recently shown that a novel trabecular measurement, the lumbar spine trabecular bone score (TBS), accounts for a component of the increased fracture risk in diabetes.^[12] This technique, which evaluates pixel gray-level variations in spine DXA, predicted osteoporotic fractures in women with diabetes independently of BMD. Over 29,000 women, 2356 of whom had diabetes, underwent both BMD and TBS measurement, with nearly 5 years of follow-up for fractures. Lumbar spine TBS captured a large portion of the diabetes-associated fracture risk that BMD did not detect, with an adjusted hazard ratio of 1.27 per standard deviation reduction (95% CI: 1.10–1.46) among women with diabetes ,^[12] consistent with the presence of microarchitectural deterioration.

Marcroarchitectural deficits in bone geometry are another potential explanation for reduced bone strength in diabetes. Strength-to-load ratios (QCT) at the spine and femoral neck were not improved in older adults with diabetes although areal BMD (DXA) was higher.^[13] In a study of older men, volumetric BMD (pQCT) was higher, but bone area was smaller at the distal radius and tibia.^[14] Smaller cross-sectional area suggests that stimulation of periosteal apposition, normally observed with greater loading, may be reduced in diabetes. These data seem to suggest that the higher areal BMD in diabetics does not result in biomechanical advantage.

Aside from potential structural abnormalities, other anomalies related to the material properties of bone and dynamics may contribute to fracture risk in T2D. Accumulation of advanced glycation endproducts (AGEs) in the organic bone matrix leads to more biomechanically brittle bone that has lost its toughness and is less able to deform before fracturing.^[15] Urinary pentosidine, the best studied AGE, was associated with a 42% increase in clinical fracture incidence in T2D.^[16] Whether reversal of hyperglycemia attenuates fracture risk is unknown. In the ACCORD randomized trial, there was no difference in the rate of fractures between the intensive and standard glycemic control groups, with median A1C levels of 6.4 and 7.5%, respectively.^[17] In an observational study, poor glycemic control (A1C: >7.5%) was associated with increased risk of clinical fracture.^[18] Other data suggest that bone marrow fat composition is altered in T2D women who have fractured, regardless of BMD, with an increase in the proportion of saturated lipids.^[19] Small histomorphometry studies suggest that the rate of bone formation is reduced in T2D.^[20,21] Studies of bone turnover markers have also identified reduced skeletal dynamics in T2D, with a disproportionate reduction in bone formation.^[22] Interestingly, circulating levels of sclerostin, the osteocyte product that inhibits the anabolic Wnt β-catenin pathway, are increased in T2D ,^[23] perhaps suggesting a derangement in mechanosensation.

Thus, there is considerable evidence for multifactorial skeletal abnormalities in diabetic patients. Yet, it remains unclear whether clinical assessment of fracture risk should be modified in individuals with T2D. BMD, central to fracture risk prediction in older adults, is indeed predictive of fractures in those with diabetes. However, individuals with diabetes tend to be at higher fracture risk for a given BMD t-score.^[1] Similarly, the WHO fracture risk assessment tool – FRAX, a key clinical instrument – has been shown to underestimate fracture risk in diabetes in several US study cohorts and in a large clinical cohort in Manitoba, Canada.^[1,2] In the Canadian study, diabetes was a significant predictor of subsequent major osteoporotic fracture (adjusted hazard ratio [aHR]: 1.61; 95% CI: 1.42–1.83) and hip fractures (aHR: 6.27, 95% CI: 3.62–10.87 in those aged <65 years; aHR: 2.22, 95% CI: 1.71–2.90 in those ≥65 years) even when adjusted for competing mortality. These data have led to discussion of how to accommodate the risk associated with T2D in the FRAX algorithm.^[24]

Whether treatment with antiresorptive agents decreases fracture risk in T2D to the same extent as in postmenopausal osteoporosis is uncertain. Post hoc analyses from the Fracture Intervention Trial suggest that alendronate increases lumbar spine and hip BMD regardless of diabetes status.^[25] With regard to fracture outcomes, in a nationwide cohort study from Denmark, users of antiresorptive drugs (n = 103,562) were compared with age- and gender-matched controls from the general population (n = 310,683).^[26] Patients on bisphosphonates and raloxifene had a higher risk of hip, spine and forearm fractures. No difference was observed on the effects of treatment between patients with diabetes and nondiabetic controls. Randomized clinical trials powered to demonstrate a reduction in fracture risk in individuals with diabetes and elevated fracture risk have not been performed to date and may well be unethical.

As the incidence of diabetes continues to increase, it is necessary to understand the increased fracture risk in this population. With current treatments for T2D improving, affected patients are likely to live longer and skeletal concerns may become more prevalent. It is timely for skeletal complications to become part of the discussion of the long-term outlook in T2D in order to offset serious challenges in this population as they age. Continuing investigation into the underlying mechanisms promises to advance our understanding of osteoporosis and diabetes.

Expert Rev Endocrinol Metab. 2013;8(5):423-425. © 2013  Expert Reviews Ltd.