Assessing and Modifying Bone Quality in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) results in an increased fracture risk, partially due to elevations in parathyroid hormone (PTH) that lead to substantial bone loss. On its own, bone loss does not explain bone fragility in CKD, suggesting that changes in skeletal tissue (bone quality) may also be present. Understanding the factors that lead to fracture in these patients will have a substantial impact on patient care and could lead to a better understanding of how to reduce their fracture risk. Due to their suppression of PTH, calcitriol and its analogues are the current standard of care for bone disease in CKD. Yet, surprisingly little is known of their effects on bone. Agents effective in treating osteoporosis are not recommended in advanced CKD due to the lack of data regarding their efficacy and safety in these patients. The goals of the current study were to determine (1) the impact of CKD on bone quality, (2) the ability of calcitriol to improve skeletal parameters, and (3) the efficacy of various pharmacological interventions (calcium, bisphosphonates, anti-sclerostin antibody, and raloxifene) on bone mass, quality, and mechanical properties in CKD bone disease. Using a slowly progressive rat model of CKD, renal and mineral metabolism, bone morphology, bone quality, and bone mechanics (at several length scales) were assessed. Primarily due to elevated PTH, mechanical testing and tissue-level assessments revealed compromised bone quantity (high cortical porosity and low trabecular volume) and quality (high collagen cross-linking and low matrix bound water). Despite clinically relevant reductions in PTH, calcitriol treatment had no positive impact on skeletal properties. Most agents were only effective when PTH levels were normal. Raloxifene, however, led to greater whole bone and material toughness (the ability of bone to tolerate existing damage) despite modest PTH suppression. While the examination of bone quality in CKD is still in its infancy, these results indicate that enhancing bone quality with raloxifene may be an effective means to compensate for bone loss in CKD.