Hip fractures are common, costly, and strongly associated with morbidity and mortality. For patients with chronic kidney disease (CKD), fracture risk and post-fracture mortality are double what they are in the general population; and dialysis patients sustain hip fractures 10-15 years younger than their age-matched counterparts. Treatment for hip fracture in CKD is particularly challenging because these patients have multiple different pathologies of bone disease, and the distinct pathologies have different treatments. Patients with CKD can have age-related osteoporosis similar to non-CKD patients, but may also have CKD-related metabolic bone disease reflecting low turnover disease, high turnover disease (typically driven by hyperparathyroidism) or mixed lesions, even at the same level of bone mineral density. Low bone turnover in CKD patients appears to be increasing in frequency, and is problematic as most standard anti-fracture medications may exacerbate low turnover bone disease. On the other hand, there are now several FDA approved treatments that stimulate, rather than suppress, bone turnover. Thus, it is particularly timely to understand bone turnover in CKD patients, and ultimately see if this information can guide clinicians to improve patient outcomes. Bone biopsy and histomorphometry are the gold standard for determining bone turnover. These methods are not widely available and are rarely obtained due to only a few specialized centers performing them. When available, however, bone histomorphometry is typically evaluated at the iliac crest, which is poorly correlated with bone turnover at other bone sites including the hip. In order to better understand bone turnover at the hip, we propose histomorphometry using hip bone tissue taken during surgical repair of hip fracture in CKD patients as it may deliver relevant information about bone metabolism and structure. Specifically, we will determine the prevalence and risk factors for low bone turnover in hip fracture patients with CKD (Aim 1). Without biopsy, clinicians are limited in their ability to identify a subset of patients with low bone turnover. Our preliminary data suggest biomarkers hold promise to identify low bone turnover with high specificity in CKD patients. Yet, the optimal biomarker panel to define low bone turnover at the hip does not currently exist. We propose to develop a panel using serum biomarkers based on findings from hip bone biopsy and histomorphometry indicative of low bone turnover (Aim 2). Our recent findings suggest that using serum biomarkers that are specific for low bone turnover based on iliac crest histomorphometry can be applied to community-living individuals with CKD and provide important information on future fracture risk. Thus, we will apply these biomarkers based on bone turnover at the hip to a cohort of women with CKD who are well- characterized for bone mineral density and fractures (in the Study of Osteoporotic Fractures) to determine hip fracture risk in this subset of individuals (Aim 3).

Public Health Relevance

In chronic kidney disease, fracture is common and morbid, but with complex pathophysiology that is often difficult to detect. Bone biopsy at the iliac crest is the gold standard method to evaluate bone pathology, but is infrequently available to clinicians, and is poorly correlated with other bone sites. We propose to evaluate bone pathology at the hip in kidney patients who undergo surgical repair for a hip fracture to determine the risk factors for different bone pathologies, biomarkers that can identify these pathologies non-invasively, and test the significance of these biomarkers for future fracture risk.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Joseph, Lyndon
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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