Regulation of bone remodeling: impact of novel therapies

Abstract

The kidneys serve as both an endocrine organ and as a target of endocrine action, with the aim of controlling mineral and water balance. Hormones and other key metabolites regulate mineral homeostasis by altering gene function directly or by initiating a sequence of events, leading ultimately to a change in enzyme function. Two of these hormones, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D), interact in multiple tissues in the body to regulate the flux of calcium and phosphorus between extra- and intracellular compartments. Changes in the concentration of PTH and vitamin D, or the interaction of these with other factors, lead to the aberrant regulation of calcium and phosphorus. Among other effects, this aberrant regulation leads to pathologic changes in bone metabolism. The pathology of renal bone disease varies along a spectrum from disorders of low turnover to those of high turnover. This spectrum reflects the results of therapeutic intervention, hormone balances, and other causes. Effective management of renal bone disease therefore requires thorough evaluation of relevant risk factors, measurement of biochemical markers of bone remodeling, and determination of the physical status of bone tissue either by bone mineral density or bone biopsy. Subsequent therapeutic intervention with newer vitamin D compounds, novel phosphate binders, calcimimetics, and the use of alternative dialysis modalities offer hope in normalizing bone remodeling and mineral balance. The human skeleton functions in two capacities: the storage of minerals and structural support of the body. It is the only tissue that behaves as both a major source and a sink of calcium (Ca) and phosphorus (P). Healthy bone is a composite of a collagenous matrix embedded with crystals of hydroxyapatite. On the surface of bone and within the calcified matrix are specialized cells that build and maintain the tissue, and facilitate the movement of Ca and P into and out of serum. Bone undergoes remodeling in response to either damage from mechanical strain or as part of the normal cycle of bone renewal. The process involves distinct steps of cellular activation, bone resorption, and subsequent bone formation. It is a relatively slow process that takes several months, and at any one time occurs at many different sites along the bone surface. Systemic factors, such as PTH and vitamin D, regulate the resorption and formation of bone, and thus the systemic movement of Ca and P. However, during conditions of stress and disease, other factors may also play a role. In patients with chronic renal disease, the balance of Ca and P is profoundly disturbed. This disruption and the compensatory changes that occur in response alter the normal processes of bone metabolism.