Longitudinal associations of insulin resistance with change in bone mineral density in midlife women

Abstract

Although there is wide recognition that type 2 diabetes mellitus (DM2) is a risk factor for fractures (1), the effects of insulin resistance (a key pathophysiologic mechanism in DM2) on bone remain uncertain. In vitro, insulin signaling promotes osteoblast differentiation, proliferation, and function (2-4). However, in the in vivo models of insulin resistance, insulin signaling leads to expansion of bone marrow adipose tissue, decreased trabecular bone mineral density (BMD), and decreased cortical thickness (5). In states of insulin resistance, osteoblasts may also be resistant to insulin signaling (6, 7). Results from human studies of the relation between insulin resistance and BMD are similarly inconclusive, with studies reporting positive (8-11), negative (12-16), or no association (17)(18)(19)(20). Notably, to our knowledge, all published human investigations on this topic are cross-sectional (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).The objective of this study was, therefore, to examine the longitudinal associations of insulin resistance with BMD in midlife women before, during, and after the menopause transition (MT). BMD decreases rapidly in a 3-year window spanning 1 year before to 2 years after the final menstrual period (FMP). We define this period as the MT; premenopause (more than 1 year prior to the FMP) precedes the MT, and postmenopause BACKGROUND. The effects of insulin resistance on bone mineral density (BMD) are unclear. METHODS.In Study of Women's Health Across the Nation (SWAN) participants, we used multivariable regression to test average insulin resistance (homeostatic model assessment of insulin resistance, HOMA-IR) and rate of change in insulin resistance as predictors of rate of change in lumbar spine (LS) and femoral neck (FN) BMD in 3 stages: premenopause (n = 861), menopause transition (MT) (n = 571), and postmenopause (n = 693). Models controlled for age, average BW, change in BW, cigarette use, race and ethnicity, and study site. RESULTS.The relation between HOMA-IR and BMD decline was biphasic. When average log 2 HOMA-IR was less than 1.5, greater HOMA-IR was associated with slower BMD decline; i.e., each doubling of average HOMA-IR in premenopause was associated with a 0.0032 (P = 0.01, LS) and 0.0041 (P = 0.004, FN) g/cm 2 per year slower BMD loss. When greater than or equal to 1.5, average log 2 HOMA-IR was not associated with BMD change. In women in whom HOMA-IR decreased in premenopause, the association between the HOMA-IR change rate and BMD change rate was positive; i.e, slower HOMA-IR decline was associated with slower BMD loss. In women in whom insulin resistance increased in premenopause, the association was negative; i.e, faster HOMA-IR rise was associated with faster BMD decline. Associations of average HOMA-IR and HOMA-IR change rate with BMD change rate were similar in postmenopause, but weaker during the MT. CONCLUSION.When it decreases, insulin resistance is associated with BMD preservation; when it increases, insulin resistance is associated with BMD loss.

Prediabetes and skeletal health

“…In a cross-sectional examination of participants in the Korean National Health and Nutrition Examination Study, greater serum insulin was associated with higher BMD when insulin resistance (estimated using HOMA-IR) was in the lowest quartile; in contrast, at higher HOMA-IR levels, greater serum insulin correlated with lower BMD [19]. We reported similar findings in a longitudinal analysis of insulin resistance and BMD in the Study of Women's Health Across the Nation (SWAN) [20 ▪ ]. At lower levels, greater HOMA-IR over time was associated with slower bone loss.…”

Prediabetes and Fracture Risk Among Midlife Women in the Study of Women’s Health Across the Nation

“…Several recent SWAN analyses showed that prediabetes was associated with worse trabecular bone microarchitecture 8 and that greater insulin resistance was associated with diminished bone strength 10 and faster BMD loss. 22 In other cohorts, prediabetes was associated with lower bone turnover, 6,7 which can contribute to an accumulation of advanced glycation end products in bone and suboptimal bone material properties. [28][29][30][31] Establishing whether prediabetes is a risk factor for fractures has potential public health implications.…”

“…Our results add to a body of data suggesting that prediabetes is detrimental to bone health. Several recent SWAN analyses showed that prediabetes was associated with worse trabecular bone microarchitecture and that greater insulin resistance was associated with diminished bone strength and faster BMD loss . In other cohorts, prediabetes was associated with lower bone turnover, which can contribute to an accumulation of advanced glycation end products in bone and suboptimal bone material properties …”

“…Lumbar spine and FN areal BMD were measured by dual x-ray absorptiometry using Hologic Inc instruments. SWAN’s protocols for cross-site calibration, cross-calibration after machine upgrades, and quality control have been described previously …”

Bone Health in People Living with HIV/AIDS: An Update of Where We Are and Potential Future Strategies

“…Whether these metabolic changes can have an influence on the bone structure in PLWHIV is an issue that remains to be elucidated. However, diabetes, insulin resistance and NAFLD have all been reported to be associated with an increased risk of osteoporosis and fracture in individuals without HIV [ 64 , 65 , 66 , 67 ]. Xu et al studied the association between NAFLD and BMD in 89 HIV-infected patients receiving long-term TDF-based ARV for more than three years.…”