J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from J Clin Pathol 1981 ;34:1295-1 307 Osteomalacia and chronic renal failure JOHN A KANIS From the Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Beech Hill Road, Sheffield S1O 2RX Dialysis and transplantation have revolutionised the Table 1 Features of renal bone disease and some clinical management of chronic renal failure. Many patients manifestations of disturbed calcium and phosphate with end-stage chronic renal failure are surviving for metabolism in chronic renalfailure a long time, but there are some penalties attached to Feature Clinical consequence this survival, namely the complications associated with prolonged renal failure as well as the side I Hyperparathyroidism and osteitis Skeletal deformity, bone fibrosa pain, pruritis? anaemia, effects of the treatments (drugs, dialysis and trans- impotence, neuropathy etc plantation). Major factors which influence the 2 Osteomalacia and decreased Skeletal deformity, bone morbidity and mortality of this population include availability of vitamin D, pain and tenderness, anaemia, accelerated cardiovascular disease, dis- calcium, and phosphate pathological fracture, proximal myopathy, turbances in gonadal function, hypertension and haemolytic anaemia abnormalities in lipid and skeletal metabolism. Significant progress has been made in the past few 3 Osteoporosis Pathological fracture, years concerning the pathophysiology and treatment skeletal deformity renal bone disease. This has been due to advances 4 Osteonecrosis Joint pain of copyright. in our understanding of hormone metabolism, 5 Osteosclerosis and periosteal None known particularly that of vitamin D, and of skeletal new bone formation physiology. Tn addition, large populations of 6 Extraskeletal calcification Depends on site-skin dialysis-or transplant-treated patients have now been ulcers, vascular disease, studied for more than a decade with the result that cardiac failure etc the natural history of this bone disease is more clearly understood. Renal bone disease is a constellation of skeletal abnormalities (Table 1), none of which is specific for Paget's disease, hyperparathyroidism, fracture repair http://jcp.bmj.com/ chronic renal failure. These disorders are frequently, and hyperthyroidism, indicating that an increase in though not invariably, found in combination, and osteoid volume alone (hyperosteoidosis) is an consideration of one of these in isolation has obvious inadequate criterion for osteomalacia.6 7 limitations. Nevertheless, the emphasis of this The amount of osteoid present in bone depends review is on the aetiology and management of upon several factors including the rate of apposition osteomalacia, but several more thorough and of osteoid by osteoblasts, upon the rate of its integrated approaches have appeared recently as calcification, and upon the area of the bone surface on September 30, 2021 by guest. Protected reviews or proceedings of symposia.'-5 involved. When considering osteomalacia it is therefore important to distinguish hyperosteoidosis HISTOLOGICAL DEFINITIONS OF OSTEOMALACIA due to an increase in the proportion of bone surfaces Osteomalacia can have a variety of meanings. The on which osteoid is being deposited, as seen in clinician may apply the term to the syndrome hyperparathyroidism, from that due to a delay or associated with vitamin D deficiency, whereas to the absence of mineralisation-particularly in chronic bone histologist it implies defective mineralisation of renal failure where osteomalacia and hyperpara- bone. There is, however, a need for precision, even in thyroidism often coexist. Much confusion and histological definitions since, for example, a histo- apparently conflicting reports exist in the published logical characteristic of vitamin D deficiency in man is reports concerning the pathophysiology of osteo- an increase in the amount of unmineralised bone malacia and its response to various treatments. A matrix; but increased amounts of osteoid are also notable factor contributing to this confusion has associated with many other disorders with normal or been the lack of precision in defining osteomalacia, augmented rates of mineralisation. These include particularly in appreciating the significance of 1295 J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from 1296 Kanis hyperosteoidosis in hyperparathyroid bone disease The double labelling of bone with tetracyclines (Table 2). provides a direct method for measuring mineralis- ation in man,7 9 although the technique is time Table 2 Some of the quantitative measurements made consuming to perform. Nevertheless, care must be on bone biopsies which have been used (often erroneously) taken in the interpretation of findings when hyper- in the assessment ofosteomalacia parathyroidism is present. Thus, woven osteoid,* which may take up tetracycline more easily than I Surface osteoid proportion of trabecular surfaces covered by osteoid (depends on lamellar bone,10 is laid down in hyperparathyroidism resolving power of microscope) so that normal mineralisation measured in woven 2 Osteoid volume proportion of bone matrix (or bone may coexist with metabolic abnormalities sectional area) occupied by which might impair mineralisation in more normal non-mineralised bone matrix bone. 3 Osteoid index mean osteoid seam width: may be An alternative and simpler method of assessing derived indirectly from osteoid mineralisation is to measure the maximum number volume and surface osteoid of osteoid lamellae visible under polarised light." 4 Maximum number of semiquantitative In hyperparathyroidism the "hyperosteoidosis" is osteoid lamellae mainly due to an increase in osteoid surfaces (and 5 Calcification front the proportion of the trabecular sometimes an increase in lamellar thickness), rather surface (or osteoid surface) than toan increase in the number of osteoid lamellae.6 undergoing calcification as judged by stains in vitro-for Another simple method is to measure the thickness example, toluidine blue or in vivo of the osteoid seams themselves or to derive this -for example, tetracycline indirectly from the measurement of osteoid area and 6 Appositional rate mean thickness between two the bone surface covered by osteoid-the osteoid tetracycline markers laid down surface osteoid x per unit time index (osteoid area divided by 100).6 7 Bone formation rate derived from 5 and 6 The prevalence of "osteomalacia" according tocopyright. some of these histological criteria is shown in Fig. 1. The definition of osteomalacia as impairment of It is important to recognise that all these indices of mineralisation indicates that evidence for osteo- osteomalacia have their limitations, particularly in malacia should be obtained by indices of mineralis- the presence of hyperparathyroidism. However, ation rather than by the amount of osteoid present. without a clear understanding of what is meant by The extent of the bone surface undergoing calcifica- osteomalacia and the problems of its definition, tion can be measured by suitable staining techniques judgements about its pathophysiology and treatment such as toluidine blue in vitro or tetracycline can be misleading. labelling in vivo. A decrease in the calcification http://jcp.bmj.com/ front is commonly thought to reflect a decreased rate CLINICAL, BIOCHEMICAL AND RADIOGRAPHIC of mineralisation and hence osteomalacia. There are FEATURES OF OSTEOMALACIA several objections to this view. Thus, the calcification The diagnosis of osteomalacia in chronic renal front does not measure the rate of mineralisation failure depends mainly on the histological examin- but only its extent. Also the calcification front ation of bone, since most patients have no character- correlates well with the proportion of bone surface istic clinical, biochemical, or radiographic features. covered by active-looking osteoblasts in patients The frequency with which osteomalacia causes on September 30, 2021 by guest. Protected with chronic renal failure, and is therefore a better symptoms is very variable and in the Oxford Renal index of the number of functional osteoblasts than Unit, symptoms are confined to 10-20% of affected of the adequacy of bone mineralisation.8 Moreover, patients whereas in the Newcastle Renal Unit, where calcification fronts are commonly expressed as a the incidence of osteomalacia is greater12 (see Fig. 2), proportion of the non-mineralised (osteoid) bone symptoms appear also to be more frequent. surface, clearly an inadequate baseline in renal Symptoms of osteomalacia include bone pain and osteodystrophy, where surface osteoid may be tenderness, and proximal muscle weakness. Pains in increased because of augmented bone turnover due the lower limbs, pelvis and back are particularly to hyperparathyroidism. Indeed, reports that common and may be worse on exercise. It is our osteomalacia has improved in response to treatment experience'3 that bone pain occurs with equal such as vitamin D may be misleading where the frequency in osteomalacia and osteitis fibrosa and is "improvement"-that is, reduction in the calcifica- therefore not a diagnostic feature. Fractures, tion front, is due to a decrease in the amount of the *Osteoid is normally laid down in tight lamellar bundles and bone trabecular surface occupied by osteoid. woven osteoid requires a degree of structural disorganisation. J Clin Pathol: first published as 10.1136/jcp.34.11.1295