Type 1 diabetes (T1D) is associated with increased risk of fracture throughout the lifespan. As individuals with T1D now live to older ages, when morbidity and mortality from fracture are greatest, it is crucial to understand this skeletal fragility and identify strategies to mitigate fracture risk. Bone mineral density is reduced, but fracture is elevated out of proportion to this reduction, indicating that other factors??bone quality??also contribute to the skeletal fragility. These may include low bone turnover and compromised bone geometry and microstructure. The presence of a diabetes microvascular complication is associated with particular skeletal fragility, but studies to date have been unable to disentangle specific contributions of each complication, nor to determine whether associations are independent of glycemic control. Of the microvascular complications, diabetic kidney disease may be especially detrimental, as other skeletal effects of T1D may be compounded by bone and mineral derangements of chronic kidney disease, including abnormal bone turnover and vitamin D metabolism. Our central hypothesis is that diabetic kidney disease particularly affects the already vulnerable T1D skeleton and plays a key role in the pathophysiology of diabetic skeletal fragility. The PERL trial presents a unique opportunity to understand the overlapping impact of these effects, as it has extensively characterized the kidney function of adult participants with T1D and diabetic kidney disease of varied severity. This 3-year trial of the effects of allopurinol vs. placebo on kidney function has ended, and participants are enrolled in an observational post-trial cohort study. In the 148 participants at 7 PERL centers, we propose an ancillary study that will add skeletal imaging for bone density (with dual-energy X-ray absorptiometry) and bone microstructure and estimated strength (with high-resolution peripheral quantitative computed tomography). We will also add analyses on stored serum specimens from 3 time points during PERL. A subset of participants (N=25) will undergo tetracycline-labeled bone biopsy. We will estimate relationships of gold-standard iohexol GFR and albuminuria?measured longitudinally?with skeletal parameters (Aim 1a). Then, we will determine if those relationships vary across a wider spectrum of kidney function, by combining data from PERL with consistently-acquired skeletal imaging data from 220 adults in the EDIC study, many of whom have normal GFR and no albuminuria (Aim 1b). We will next determine if glycemic control is independently associated with skeletal parameters in PERL (Aim 2). Finally, we will examine whether high or low parathyroid hormone and bone turnover marker levels are associated with skeletal parameters, and whether altered vitamin D metabolites partially explain the kidney-bone relationship (Aim 3). In the biopsy subset, we will explore whether PTH and bone turnover markers correlate with histomorphometric turnover. This research has the potential to shape the care of patients with T1D by informing screening approaches and interventions. Ultimately, it could help reduce fracture risk in our aging T1D population.

Public Health Relevance

Type 1 diabetes is associated with lower bone mass and heightened fracture risk, but the underlying reasons are not known, hampering prevention efforts. The proposed research will determine if diabetic kidney disease?across its broad spectrum of severity?is a factor contributing to the reduced bone density and strength in type 1 diabetes. The results are expected to positively impact clinical care by directly shaping evidence-based recommendations for screening and treatment to prevent diabetic skeletal fragility.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Malozowski, Saul N
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Northern California Institute Research & Education
San Francisco
United States
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