New concepts in renal osteodystrophy.

number, and an increase in the number of osteoclastic Introduction resorption bays demonstrating the increased rates of bone resorption in osteitis fibrosa. Renal osteodystrophy is the term used to describe the In addition, osteitis fibrosa is characterized by a skeletal complications of end-stage renal disease. It is prominent accumulation of fibroblastic cells around a multifactorial disorder of bone remodelling. Some of the trabecular surfaces in the bone-marrow cavity. the factors contributing to the disorder, are known These cells produce a peritrabecular fibrosis which is substances whose actions are well defined, and strata hallmark of osteitis fibrosis cystica. The pathogenesis egies have been developed to treat these abnormalities and nature of the fibroblastic cells and their extracelluin end-stage renal disease. As a result, the nature of lar matrix has not been defined. renal osteodystrophy has changed in the last two From the histological features of osteitis fibrosa, the decades. For instance, the identification of secondary conclusion that bone remodelling is increased in this hyperparathyroidism and 1, 25a-dihydroxycholecalciform of renal osteodystrophy is straightforward. Bone ferol (calcitriol ) deficiency as major contributors to remodelling consists of the selection of site for remodelrenal osteodystrophy has led to the development of ling activity followed by the activation of the process. treatment regimens which maintain normal serum calRemodelling activation consists of a complex stimulacium and phosphate concentrations, reduced paration of two differentiation programmes, one of the thyroid hormone secretion, and correct low calcitriol osteoblast differentiation programme and one of the levels. These improvements in the treatment of renal osteoclast differentiation programme (Figure 1). osteodystrophy have resulted in a decrease in the Osteoclastic differentiation proceeds and concludes frequency and severity of osteitis fibrosa, the most more rapidly resulting in the stimulation of bone common and important type of renal osteodystrophy. resorption. Parathyroid hormone and locally produced The removal of aluminium from both water used for or systemic activating factors including interleukin-1 dialysis and aluminium phosphate binders has treand tumour necrosis factor a stimulate release of mendously diminished the incidence of osteomalacia soluble factors from stromal cells and the haematopoiand aluminium intoxication as a cause of the adynamic etic tissue which induce the proliferation and differenbone disorder. The frequency of aluminium-related tiation of osteoclast precursors. As a result, there is an bone disease has waned only to be replaced by increasactivation of osteoclastic bone resorption by an eleving prevalence of the adynamic bone disorder. As a ated number of multinucleated highly polarized osteoresult of these developments new hypotheses related to clasts. The soluble factors involved in the development the pathogenesis of renal osteodystrophy have been generated and tested, at least on a preliminary basis. of osteoclasts are many, including macrophage colonyThis review will discuss these new hypotheses and stimulating factor (m-CSF), granulocyte–macrophage suggest future directions for study and treatment. colony-stimulating factor (gm-CSF) interleukin-6, interleukin-11, leukaemia induction factor (LIF) and others. Parathyroid hormone, tumour necrosis factor Pathogenesis of osteitis fibrosa a, and interleukin-1 stimulate production of osteoclasts at different stages of cell differentiation, leading to synergism when the concentrations of cytokines and The histological features of osteitis fibrosa cystica parathyroid hormone are both elevated, as in chronic include a proliferation of osteoblasts leading to an increase in bone surfaces covered by osteoblast and an renal failure [1]. The actions of parathyroid hormone, increase in osteoblastic cells with a cuboidal type of and calcitriol on osteoclast differention occur late in cellular morphology. There is an increase in osteoclast the programme. Recent studies suggest the calcitriol may be a factor regulating substances that function at Correspondence and offprint requests to: Keith Hruska MD, Renal the multinucleation stage. In addition, new information Division, Barnes-Jewish Hospital North, Washington University demonstrates that a soluble circulating molecule of the School of Medicine, 216 S. Kingshighway, St Louis, MO 63110, USA. TNF receptor family, named osteoprotegerin, inhibits