Collagen metabolism, uremia and bone

Acquired alterations in renal function characterized by a progressive decrease in the normal amount of renal tissue and a decline in glomerular filtration rate lead to the "uremic syndrome". The latter is characteristically attended by a metabolic acidosis, intestinal malabsorption of amino acids and calcium, hypocalcemia, hyperphosphatemia, alterations in vitamin D metabolism and elevations in circulating parathyroid hormone levels and uremic toxins such as free phenols, indican and guanidines [1-3]. These changes either singularly or in concert result in a form of bone disease which, because of its varied histological manifestations, is often termed "renal osteodystrophy". Bone formation by individual osteoblasts is reduced in untreated uremic patients with secondary hyperparathyroidism [4] although the area of surface forming new bone and the total rate of bone formation are increased [4]. Radiographs of these patients may demonstrate diffuse osteopenia, pseudo-fractures, osteitis fibrosa cystica or osteosclerosis. The latter when apparent in the vertebral processes imparts a typical "rugger jersey" pattern (see Fig. 12 in the article of Drs. Eastwood, Bordier and DeWardener in this symposium), so-called since the alternating radiolucent intervertebral discs and radiopaque sclerotic vertebral end-plates simulate the black and white horizontally striped jersey pattern of English rugby players. The decrease in total bone mass and increments in un-mineralized osteoid which characterize the more advanced states of renal osteodystrophy have been variably attributed to the progressive hyperphosphatemia, elevations in circulating parathyroid hormone concentration, defective generation of the biologically active triol-vitamin D metabolite and an intestinal malabsorption of calcium. Although considerable attention has been focused on the abnormalities of parathyroid secretion and metabolism in uremia [5-9], calcium malabsorption and disordered metabolism of vitamin D [10, 11] and changes in bone mineral content [12-15], relatively little information exists on the effect of the uremic syndrome on the metabolism of organic bone matrix. Nichols et al and Nichols, Flanagan and van der Sluys Veer have demonstrated increased metabolic activity and collagen turnover in bone obtained from uremic patients [16, 17]. In addition, there have been reports of elevated plasma levels of free proline and hydroxyproline and the appearance of a plasma peptide-bound proline moiety [18-20] as well as histological evidence of osteoid accumulation and an increase in total bone mass in azotemic subjects [21]. The osteosclerosis usually encountered in terminal uremic states has been associated with an excess of unmineralized osteoid tissue and the replacement of lamellar bone by woven bone under the stimulus of abnormally high circulating parathyroid hormone levels [22]. The osteosclerosis has also been attributed to a dialyzable "collagen stimulating factor" [23]. Conversely, changes in collagen metabolism in chronic uremia and lower than normal values for urinary hydroxyproline have been attributed to a gradual replacement of collagen by elastin-like fibers [24] which are relatively deficient in hydroxy-proline (Table 1).