sign in sign up
<<
Home , Osteomalacia, Osteosclerosis, Renal osteodystrophy

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 disease and some clinical management of chronic renal failure. Many patients manifestations of disturbed 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 and Skeletal deformity, bone fibrosa , pruritis? anaemia, effects of the treatments (drugs, dialysis and trans- impotence, neuropathy etc plantation). Major factors which influence the 2 and decreased Skeletal deformity, bone morbidity and mortality of this population include availability of 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 Pathological fracture, years concerning the pathophysiology and treatment skeletal deformity renal . This has been due to advances 4 Osteonecrosis Joint pain of copyright. in our understanding of hormone metabolism, 5 and periosteal None known particularly that of , and of skeletal new bone formation physiology. Tn addition, large populations of 6 Extraskeletal Depends on site-skin dialysis-or transplant-treated patients have now been ulcers, , 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 , 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 , 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 and , where surface osteoid may be tenderness, and proximal muscle weakness. 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 on 1 November 1981. Downloaded from

Osteomalacia and chronic renalfailure 1297

Osteoid area Calcification front Osteoid index 80 r /o ( mean osteoid seain 100 sectonal area) (1/. trcbecular width ) surface

601- 0O 0 o 0 a

OS 1 0 rC 0t10 a&& (.2 00Wo00

0 cPo °O *0 O 40 10- OPo ~ 40 Oxford 0 040 00 a. do 01 CL 000 0 0 * 0 0 100IW 0 0 0 20 0 e 1-1 00 00 o OM 0 o OF OM * OF o 'N-orOP 0 2 4 6 >6 D u of Fig. 1 Histological indices ofosteomalacia (OM) in 51 ration hoemodialysis (yecrs) patients with end-stage chronic renal failure. Patients Fig. 2 The prevalence ofosteomalacia in patients were subdivided according to the presence (right hand established on long-term intermittent haemodialysis, as columns) or absence (left hand columns) of osteomalacia assessed by repeated bone biopsy. Note the large as judged by the maximum number of osteoid lamellae difference in prevalence between Newcastle (a high visible on sections under polarised light. Note the lack of aluminium area) and Oxford (low aluminium in the discrimination of the calcification front, the osteoid dialysate fluid) but a similar prevalence ofosteomalacia volume, and the osteoid index in distinguishing patients at the time ofstarting dialysis. Patients from the Oxford with and without osteomalacia. Each of the indices Renal Unit do not invariably develop osteomalacia even copyright. discriminates patients with normal bone histology after many years ofhaemodialysis. (N or OP) from those with osteomalacia (OF + OM), but discrimination is lost when patients with osteitis fibrosa (OF) are included. deficiency (though it may appear so radiographically because of metaphyseal resorption below the growth plate: Fig. 3). These changes are more likely to particularly of the ribs, spine, pelvis and femoral reflect secondary hyperparathyroidism than vitamin neck, occur with a variable frequency and are more D deficiency.14

common in those dialysis centres with a high Few biochemical findings are characteristic of http://jcp.bmj.com/ prevalence of osteomalacia. osteomalacia in chronic renal failure. Plasma Radiographic features are usually absent and a concentrations of calcium are lower in chronic renal negative radiographic survey is therefore not helpful failure than in health, particularly in children, and in excluding osteomalacia. Looser's zones (Fig. 3) may be lower in patients with osteomalacia than are characteristic of osteomalacia and are most those without.'5 These differences are still present in frequently seen in the pelvis, but in dialysis-treated patients on intermittent haemodialysis though the

patients are a relatively infrequent finding. Many differences are less marked (Fig. 4). on September 30, 2021 by guest. Protected patients with osteomalacia have radiographic A proportion of patients with histologically changes which are associated with hyperparathy- proven osteomalacia have normal or high con- roidism. These changes include subperiosteal erosions centrations of plasma calcium but without evidence and intracortical porosity. Coarse trabecular mark- of hyperparathyroidism. In such cases, the bone ings, periosteal new bone formation and osteosclerosis often shows the absence of active-looking bone cells, appear to be more consistently associated with which is a characteristic of aluminium-induced bone osteomalacia than with osteitis fibrosa. disease (discussed later). Children are particularly prone to renal bone Plasma phosphate concentrations tend to increase disease and may show radiographic features which as the glomerular filtration rate falls below 30 resemble . A rachitic appearance on x-ray ml/min. The level of plasma phosphate is also examination does not always mean that osteomalacia determined by the diet, the use of oral phosphate- is present. Thus, in uraemia there is often no binding agents, and the dialysis regimen in patients widening of the metaphyseal zone and the width of with end-stage renal failure. Patients with severe the growth plate is not as thick as in vitamin D chronic renal failure also malabsorb phosphate and J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

1298 Kaniis

Fig. 3 Radiographic appearance.s of renal bone disease. Left: Characteriitic radiographic features of osteomalacia ini a child. Note the Looser's zonte of the tibial shaft, the metaphyseal splaying of the and the increased width of the growth plate. Centre: Appearances resembling rickets at the wrist of a patient with hyperparathyroid bone disease. Note metaphyseal . Right: Markedfeatures of hyperparathyroid bone disease of the wrist. copyright.

this may be the explanation for the osteomalacia and PATHOGENESIS OF OSTEOMALACIA IN marked hypophosphataemia seen in some patients CHRONIC RENAL FAILURE not taking phosphate-binding agents. Plasma Many factors are thought to be important in the concentrations of phosphate tend to be lower in pathophysiology of osteomalacia (Table 3). The patients with osteomalacia but osteomalacia cannot evidence incriminating these factors is frequently be diagnosed from this alone, since the presence of circumstantial but their consideration is valuable in http://jcp.bmj.com/ normal or high plasma concentrations do not exclude devising strategies for treatment. osteomalacia (Fig. 4). Plasma and plasma hydroxy- Metabolism of vitamini D proline are commonly raised in chronic renal Deficiency of vitamin D in man retards skeletal failure. An increase in alkaline phosphatase activity growth and results in defective mineralisation of may not always be due to an increase in bone- matrix produced both by chondrocytes and by derived phosphatase but may be due to increased osteoblasts. Reversal of these abnormalities by on September 30, 2021 by guest. Protected activities ofthe gut and liver isoenzymes. In population vitamin D provides convincing evidence for the studies, plasma activities of alkaline phosphatase importance of vitamin D in skeletal homeostasis. correlate well with histological indices of bone cell However, it is not yet clear whether formation and activity-for example, counts. Hence, mineralisation of bone and cartilage are direct alkaline phosphatase activity is usually increased in actions of vitamin D metabolites or whether these patients with osteomalacia combined with secondary processes are secondary to the actions of vitamin D hyperparathyroidism, but is normal or low in many at non-skeletal sites of calcium and phosphate patients with osteomalacia alone (Fig. 4). transport such as the gut and kidney. In addition, Since osteomalacia can rarely be diagnosed with- vitamin D metabolites may regulate the secretion of out histological assessment of bone, studies of its other hormones such as and pathogenesis and the assessment of treatment calcitonin, which themselves modify calcium and regimens must include the study of biopsy material, phosphate concentrations and bone metabolism. and require a critical awareness of the meaning of In the past decade the major thrust in vitamin D the histological variables measured. research has been directed to studies of its metabolism J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

Osteomalacia and chronic renalfailure 1299 (n=32) (n=27) (n=28) (n=30) Table 3 Some factors thought to be important in the 3 0 - 0 pathogenesis ofosteomalacia in chronic renalfailure Disturbed vitamin D metabolism 0 Inadequacy of intake of vitamin D or exposure to UV light Defective production of 1,25(OH),-D, 0 Excessive urinary losses of 25-OHD () ccoo ? Defective production of z 5 - 24,25(OH),-D, Plasma Accelerated metabolism of 25-OHD (anticonvulsants etc) calcium Toxic effects on bone (mmolI1) Aluminium intoxication-dialysate and ? aluminium-containing o _ phosphate-binding agents ? Fluoride o Anticonvulsants (target organ resistance to vitamin D 2-0- metabolites) 0 Availability of calcium and phosphate ______Low plasma phosphate (, hyperparathyroidism, 3-0 - steroids, phosphate-binding agents, lengthy dialysis schedules) 0 Very low calcium diets 0 8 F f t ~~~~~t9 Uncertain 0 9 Total Uraemic inhibitors (? pyrophosphate) ? Acidosis Plasma 2 0- phosphate -8 c~%'X (mml/11) bone disease in renal failure is "vitamin D-resistant" in the sense that the doses of vitamin D required to -aTo- _, q- produce a biological response are greater than those required to satisfy physiological needs in normal 1 0 - individuals. There is now considerable evidence that this resistance in renal failure is due to a defect in the copyright. metabolism ofvitamin D.17 700 - The first step in the metabolism of vitamin D3 is its 0 0 conversion to 25-hydroxy vitamin D3 (25-OHD3) 0 400 - which occurs mainly in the liver (Fig. 5). Is renal bone disease due to defective production, accelerated PLasma 0 20- _0_ metabolism, or impaired action of this metabolite? alkaline 200 Certainly plasma concentrations of 25-OHD (D2 and

phosphatase http://jcp.bmj.com/ D3) may be low in patients with the nephrotic (lIU/) 100- syndrome and be associated with bone disease.20 Apart from this exception, there is little evidence that 50 - 0 low concentrations of 25-OHD are due to defects in vitamin D metabolism, despite suggestions to the 0 contrary. Certain drugs, such as anticonvulsants and Normal OM OM OF OF barbiturates, induce hepatic microsomal enzymes,

and might, therefore, increase the metabolism of on September 30, 2021 by guest. Protected Fig. 4 Biochemical findings in plasma (predialysis 25-OHD to inert products, but there is little direct values) in patients on dialysis treatment. Patients have evidence for this. A more important effect of been grouped according to the type ofbone disease. anticonvulsants may be to block the action of OM = osteomalacia, OF = osteitis fibrosa. The broken vitamin D metabolites on gut and bone.2' Low lines denote the limits the normal of range. concentrations, when present, may therefore be due either to inadequate diet or reduced exposure to to active products.'6-'8 The kidney is involved sunlight and might be expected to contribute to critically in this process since it is the major site of osteomalacia particularly when the degree of renal production of 1,25-dihydroxy vitamin D3 (1 ,25(OH)2- failure is modest. The usual experience is that, when D3) and 24,25(OH)2-D3. anticonvulsants are avoided and patients allowed to It has been recognised for a long time that large eat normal diets (for example on dialysis treatment), doses of vitamin D may increase the intestinal plasma 25-OHD concentrations are normal.5 absorption of calcium and heal osteomalacia and It is commonly thought that most of the actions of osteitis fibrosa in patients with renal failure.19 The vitamin D3 are mediated by metabolism of 25-OHD3 J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

1300 Kanis f--O OH OH I/ OH

Liver ?

CH2 CH2 OCH2 HO D 3 25-OH -D3 25,26 -(OH)2 D3 1.

dney Kidney

H OH

CH2

HO ^' copyright. (24R)-24, 25-(OH)2 D3

Fig. 5 Some of the major steps in the metabolism of vitamin D. to 1,25(OH)2-D3. Since the kidney is probably the endogenous production rate in health, suggesting

sole site of synthesis of 1,25(OH)2-D3 (apart from the that target organs are sensitive to physiological http://jcp.bmj.com/ placenta in ), the development of osteo- amounts of1 ,25(OH)2-D3incontrast to 25-OHD3.1322 malacia and its resistance to vitamin D and to The view that lack of 1,25(OH)2-D3 is the major 25-OHD may result from impaired production of cause of osteomalacia in renal failure may be an 1,25(OH)2-D3 due to loss of renal tissue and perhaps oversimplification. Thus not all patients with severe also to the inhibitory effects of hyperphosphataemia chronic renal failure have osteomalacia, and its on the renal 1-alpha hydroxylase.'6-18 incidence does not invariably increase with time on The evidence for a causal relation between vitamin dialysis despite defects in the metabolism of vitamin D resistance, defective 1-alpha hydroxylation, and D.23 The incidence of osteomalacia varies widely on September 30, 2021 by guest. Protected osteomalacia, is based on several observations. between dialysis units (Fig. 2) suggesting the im- Firstly, plasma concentrations of 1,25(OH)2-D3 and portance of dialysis-related factors in its aetiology. its rate of formation decrease when the glomerular Moreover, the prevalence of osteomalacia is not filtration rate is less than 40 ml/min, and 1,25(OH)2- increased markedly in anephric patients, and in some D3 is usually undetectable in end-stage chronic such patients the rates of mineralisstion and bone renal failure.'7 Secondly, x-ray and histological formation are normal. Treatment with 1-alpha appearances of renal bone disease have features hydroxylated metabolites may improve radiographic which resemble nutritional vitamin D deficiency. and biochemical indices of osteomalacia, but this is Thirdly, administration of 1,25(OH)2-D3 or its not invariable, particularly when histological indices synthetic analogue 1-alpha hydroxy vitamin D3, of response are used.'3 22 23 Radiographic criteria of reverses many of the biochemical and radiographic healing may be inadequate, particularly in children features of osteomalacia. Moreover, the doses of where the so-called rachitic appearances of the 1 ,25(OH)2-D3 required to maintain remission epiphyses may be due to hyperparathyroidism rather (0 25-0 5 ,ug daily) are close to its estimated daily than to osteomalacia. These data suggest that factors J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

Osteomalacia and chronic renal failure 1301 (n=2) (ii=21)(n=22)(n=lg)(n=19)tn.-7)(n=12) other than defective production of 1,25(OH)2-D3 T must contribute significantly to the osteomalacia of chronic renal failure. 201 The production of 24,25(OH)2-D3 may also be deficient in renal failure since the kidney has an enzyme system capable of converting 25-OHD3 to 0 this metabolite. In chronic renal failure, plasma -aE concentrations of 24,25(OH)2-D3 are, in some E patients, lower than would be predicted from the a 1-5 circulating concentration of 25-OHD3.24 25 Pre- E liminary observations suggest that patients with renal failure and osteomalacia may have the lower concentrations of 24,25(OH)2-D3.25 The administra- tion of 24,25(OH)2-D3 alone in doses sufficient to restore plasma concentrations to normal has a. 0. .I metabolic effects but does not heal osteomalacia 10. (unpublished observations). There is increasing evidence that both 1,25(OH)2-D3 and 24,25(OH)2-D3 1 3 5 70or more are required for the actions of vitamin D on bone to Maximum number of lamel be complete.26 27 However, the relation between Fig. 6 Relation between plasma phosphateo decreased synthesis of 24,25(OH)2-D3 and osteo- (Pi; mean of values taken immediately beforeme malacia in chronic renal failure will be clarified only dialysis treatment ± SEM) and the number of when we know whether or not the kidney is the sole osteoid lamellae seen in histological sections. site of production of this metabolite (a controversial Osteomalacia (five or more lamellae) was issue) since nephrectomydoes not appear to aggravate uncommon in patients with high concentrations renal bone disease.23 ofplasma phosphate. Evidence ofosteomalacia was commonly noted in patients whose plasma copyright. phosphate concentration lay below the upper Calcium and phosphate metabolism limit of the normal range (indicated by broken It is possible that the skeletal effects of vitamin D are lines). not dependent upon direct actions of the metabolites on bone itself but are due to consequent changes in the plasma concentration of calcium, phosphate and shown recently that the delayed rate of osteoid parathyroid hormone. One of the reasons why this maturation in D-deficient rats is correctable when question remains open is the difficulty in studying hypocalcaemia is reversed by dietary calcium mineralisation in vitro, while the effects of vitamin D supplements.28 There is controversy as to whether http://jcp.bmj.com/ metabolites in vivo are complex. calcium deficiency alone in the presence of adequate In many disorders, including renal failure, the vitamin D nutrition can cause osteomalacia in man. level of plasma phosphate appears to be an important The most convincing demonstration of calcium determinant of osteomalacia. The concentration of deficiency rickets is in Bantus who have normal plasma phosphate in dialysis-treated patients has vitamin D status.29 In chronic renal failure it has been been shown to correlate inversely with the degree of reported that severe calcium deficiency may render osteomalacia, such that those patients with normal the patient unresponsive to 1,25(OH)2-D3, whereas on September 30, 2021 by guest. Protected amounts of osteoid have the higher plasma phosphate healing of osteomalacia occurs when the diet is concentrations (Fig. 6).23 It may be relevant that adequately supplemented with calcium.30 phosphate concentrations in such patients are considerably higher than the upper limit of normal in Trace elements and water contaminants health, and hyperphosphataemia may therefore A number of trace elements accumulate in chronic protect the patient from osteomalacia, despite renal failure due either to impaired excretion or to defective vitamin D metabolism. If such a protective absorption from the dialysate. These include arsenic, mechanism exists, hyperphosphataemia may mask strontium, molybdenum, magnesium, manganese, the true importance of disturbed vitamin D metab- copper, aluminium and fluoride, but, with the olism in renal bone disease. possible exception of fluoride and aluminium, their The case for the phosphate effect on mineralisation role in the evolution of dialysis bone disease is is greater than for calcium. Calcium deficiency in unclear. Patients with osteomalacia do not respond some experimental models leads to osteoporosis uniformly to treatment with 1,25(OH)2-D3 or its rather than to osteomalacia. However, it has been synthetic analogue, 1-alpha-OHD313 22 despite J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

1302 Kanis adequate control of plasmaphosphate concentrations skeletal aluminium. and the administration of calcium supplements. Indeed the failure to respond to 1,25(OH)2-D3 may Acidosis be one method of separating patients in whom The role of acidosis in contributing to renal bone osteomalacia is due to other causes. It is also the disease has been advocated for many years. It has impression of many groups that osteomalacia more been suggested that bone acts as a buffer by releasing commonly fails to respond to vitamin D treatment in alkaline bone salts and this is supported by the patients on intermittent haemodialysis that in finding of a decrease in the bicarbonate content of patients managed conservatively, and this has led bone from uraemic patients.36 The acute administra- to renewed interest in the possibility that disturbances tion of acid loads to normal man results in a neg- induced by haemodialysis itself may give rise to ative calcium balance37 and it has been noted that the osteomalacia. rate of mineralisation increases acutely when The possible role of fluoride has been the most alkalis are administered to acidotic patients with extensively studied. Fluoride accumulates in chronic osteomalacia.38 The long-term effects of metabolic renal failure during haemodialysis and is deposited acidosis on bone are, however, less clear and it has in bone. It is also known that high doses in man not been regarded as a major factor, since the induce the formation of excessive amounts of correction of acidosis appears to influence renal bone osteoid. Several groups have attempted to find a disease in only a minority of patients.39 Chronic correlation between fluoride and bone disease where- acidosis in the absence of uraemia or hypophos- as others have looked at the effects of reducing the phataemia-for example, chronic respiratory disease, fluoride content of the dialysate. However, there is diabetes mellitus, Gaucher's disease, is not character- no consensus view to be obtained from the many ised by osteomalacia. studies performed3' and it is now recognised that the bone disease attributed to fluoride may have been Parathyroidectomy due to other factors not recognised at the time. Total parathyroidectomy may be associated with the

There is an increasing body of evidence that development of osteomalacia when osteitis fibrosacopyright. aluminium retention may be an important factor in has healed.' 10 It is interesting that, apart from the pathogenesis of osteomalacia in dialysis- patients with aluminium toxicity, a high proportion treated patients. A form of osteomalacia associated of patients with recognised osteomalacia and renal with a high incidence of bone pain and fractures is disease who fail to respond to treatment with common in certain geographical locations with a vitamin D metabolites have had previous parathy- high aluminium content in the water (Fig. 2), and its roidectomies.'3 22 In some instances this lack of incidence appears to decrease with deionisation ofthe response may be related to persistent hypophos- water. There is also a good correlation (in the UK) phataemia, but this is not invariably the case. The between osteomalacia associated with fractures and relative ease with which woven osteoid, present in http://jcp.bmj.com/ the aluminium content of the water used for hyperparathyroidism, calcifies in the absence of dialysis.3233Flendriget al.34 showed that the incidence vitamin D (compared with lamellar osteoid) may of fractures (and of dialysis dementia) in their unit explain the appearance of osteomalacia only after was associated with a source of aluminium in the parathyroidectomy when lamellar bone is laid down. dialysate lines whereas other patients using the same A corollary is that osteitis fibrosa may protect tap water did not develop this complication. This against osteomalacia. suggests that either aluminium or some factor on September 30, 2021 by guest. Protected associated with aluminium is responsible for the Otherfactors high prevalence of osteomalacia seen in some centres. A number of years ago Yendt et al40 noted that The question arises whether or not phosphate- uraemic plasma contained a factor which inhibited binding agents containing aluminium salts may give the calcification of rat cartilage. The nature of this rise to aluminium toxicity, since there is good uraemic factor has not been elucidated. One candi- evidence that oral aluminium is absorbed.35 One of date might be pyrophosphate which is an inhibitor of the difficulties of investigating this problem is that calcium phosphate nucleation in vitro. Increased skeletal retention of aluminium may remain for concentrations are found in patients with hypo- many years after the source has been withdrawn and phosphatasia and in patients with chronic renal aluminium toxicity may take many years to develop. failure, and it is conceivable that these might cause Thus, it is difficult to assess the relative importance failure of mineralisation in both conditions. In of oral and water-borne aluminium. The evidence to population studies there does not appear to be a date suggests that water-borne, rather than oral clear relation between histological indices of aluminium, is most commonly the major source of osteomalacia and plasma pyrophosphate4' but this J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

Osteomalacia and chronic renal failure 1303 does not necessarily exclude a regulatory role for logues or metabolites, and the haemodialysis pyrophosphate or other inhibitors of skeletal treatment schedule prescribed. Profound hypo- metabolism. phosphataemia should also be avoided since it is associated with osteomalacia.43 If the relation TREATMENT OF OSTEOMALACIA IN CHRONIC between predialysis concentrations of phosphate and RENAL FAILURE histological indices of osteomalacia is causal (Fig. 6), The strategy of treatment should be based not only it isimportant to notethat theconcentrationsofplasma on the presence of osteomalacia or associated phosphate below which osteomalacia may be symptoms but also on a careful assessment of the inducedare considerably higher than those associated other skeletal abnormalities present, the other with impaired mineralisation in patients with normal consequences of disturbed mineral metabolism renal function. Thus the plasma phosphate con- (Table 1), and the mechanisms responsible for the centrations which best balance the risks of metastatic disorder. The proposed management of the chronic calcification and osteomalacia probably lie between renal disease itself should also be considered since, 1-4 and 2-4 mmol/l in dialysis-treated patients. for example, therapeutic approaches may depend on Phosphate therapy has been advocated as a the probability of subsequent transplantation. method of treating osteomalacia in chronic renal There are a number of preventative measures failure. This is not without risk and should only be which should be considered in all patients with attempted, and then cautiously, in patients with advanced renal impairment. It is probable that the tubular disorders. The infusion of phosphate during severe restriction of dietary protein, as sometimes the dialysis treatment does not appear to improve practised, is a greater factor in inducing morbidity osteomalacia and indeed may aggravate osteitis than it is in achieving beneficial effects. Though low fibrosa.44 protein diets restrict the amount of phosphate, this is better achieved with the use of phosphate-binding Treatment ofdisturbed cakcium metabolism agents. Protein-deficient diets also tend to restrict the Unlike the net intestinal absorption of phosphate intake ofvitamin C and pyridoxine which both act as which is largely dependent on the dietary load, the essential cofactors in the formation and maturation net absorption ofcalcium is more critically dependent copyright. of collagen. The relation between deficiency of these on the presence of the vitamin D metabolites, factors and osteomalacia is unclear and they may be particularly 1,25(OH)2-D3. Nevertheless, net in- more important in the pathogenesis of osteoporosis. testinal transport of calcium can be augmented by Both vitamin C and should be given as large amounts of (5-20 g daily) dietary supplements. and this may improve osteomalacia.45 It is often more practicable to give vitamin D or one of its Treatment ofdisturbedphosphate metabolism metabolites, but net intestinal absorption of calcium Despite compensatory decreases in tubular re- cannot be greatly augmented if the diet is severely http://jcp.bmj.com/ absorption of phosphate, plasma phosphate con- deficient in calcium. Moreover, marked calcium centrations are nearly always markedly increased in deficiency appears to impair the response to patients with severe renal impairment (Fig. 4). The 1,25(OH)2-D3.30 It is important, therefore, to ensure value of lowering plasma phosphate concentrations a normal dietary intake of calcium with the use of in preventing hyperparathyroid bone disease in man calcium supplements if necessary. is uncertain but the control of plasma phosphate is The dialysis membrane provides a site for the loss important in the management and prevention of of calcium or its incorporation into the body, but on September 30, 2021 by guest. Protected extraskeletal calcification,42 and is usually achieved there is no evidence that the dialysate calcium by the use of phosphate-binding agents, such as concentration influences the natural history of aluminium hydroxide. Calcium carbonate also binds osteomalacia. phosphate in the gut, and has potential advantages in that it corrects acidosis, increases the dietary calcium Use ofvitamin D and related compounds load, and enables the ingestion of aluminium to be A variety of vitamin D compounds is available for avoided; but in practice the amounts of calcium use in chronic renal failure. These include vitamin carbonate required are large. D2, D3, 25-OHD3, dihydrotachysterol (DHT), In order to avoid extraskeletal calcification, 1,25(OH)2-D3 and 1-alpha-OHD3. A great deal of predialysis concentrations of plasma phosphate clinical interest has focused on 1,25(OH)2-D3 and should be less than 2-4 mmol/1.42 Factors which its synthetic analogue 1-alpha-OHD3 since they influence the dose required of the phosphate- bypass the metabolic block caused by uraemia, but bindingagent include the dietaryintake ofphosphate, DHT is also biologically active without the necessity concurrent treatment with vitamin D and its ana- for l-alpha-hydroxylation by the kidney. DHT and J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

1304 Kanis 1-alpha-OHD3 undergo hepatic hydroxylation and appears to respond more readily when associated the 25-OHDHT or 1,25(OH)2-D3 so formed are the with osteitis fibrosa. Once again this may be related major circulating forms of these agents. It has been to the different pathogenic mechanisms. suggested that anticonvulsants interfere with the Although most patients with end-stage chronic hepatic production of these metabolites and these renal failure have histological evidence of bone drugs should therefore be avoided for this reason. disease, they are often symptomless. In patients on The clinical evidence for this is not clear though it dialysis treatment, considerable differences exist in should be remembered that anticonvulsants probably the incidence and natural history of osteomalacia also interfere with the target organ actions of all the between renal units. Whether to treat asymptomatic vitamin D compounds. patients with vitamin D metabolites will therefore All the vitamin D-like compounds available are depend on several factors. Our own policy at present effective in relieving symptoms of bone pain and is not to treat those patients with abnormal bone muscle weakness, in increasing plasma calcium histology unless they have symptoms, marked concentrations, and in the majority of patients they hypocalcaemia or radiographic or biochemical suppress raised plasma activities of alkaline phos- evidence of bone disease. Several trials are currently phatase and correct radiographic abnormalities underway to evaluate the efficacy of I-alpha-OHD3 (Figs. 7 and 8).13 19 22 Skeletal deformity in the young or 1,25(OH)2-D3 in preventing the development of can probably be prevented and growth partly overt bone disease and this view may therefore restored.46 47 require modification. The histological response to treatment is often Doses of the various agents required to maintain disappointing, particularly in patients maintained on the plasma calcium concentration within the normal intermittent haemodialysis, where factors other than range and to reverse bone disease are indicated in disturbed vitamin D metabolism presumably play a Table 4. In general, the maximal dose which avoids dominant role in the pathophysiology. Osteomalacia hypercalcaemia decreases with time (Fig. 7). The MT Renal bone disease copyright. + OF and OM 1 oc- HCC(g/day) l +Normalx-ray4 Normal bone biopsy 29 _ Plasma Ca2- 5

2-1 http://jcp.bmj.com/

Plasma alkaline 200 phosphatase (IU/ l) 100iol, ( o, {~~~~~~~~~~~~~~~~~~~~~~) 6-0r on September 30, 2021 by guest. Protected

Plasma iPTH (,Ug / ) 3-0

s a a I --i 0 6 12 18 24 Duration of treatment ( months) Fig. 7 Long-term treatment ofosteomalacia (OM) with I-alpha-hydroxy-vitamin D3 (1-alpha-HCC) in a dialysis-treated patient. Healing of osteomalacia occurred within 15 months. Episodes ofhypercalcaemia occurred suddenly and the dose of I-alpha-HCC tolerated decreased progressively once plasma alkaline phosphatase hadfallen to normal activities. Remission from bone disease was maintained using a dose of J-alpha-HCC of I ,ug thrice weekly. OF = osteitis fibrosa, i PTH = immunoreactive parathormone. J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

Osteomalacia and chronic renal failure 1305

:'3.1.78 o i Fig. 8 Radiographic responses to treatment ofosteomalacia with large doses of vitamin D. Table 4 Usual dose requirements of vitamin D3 (or vitamin D2), dihydrotachysterol (DHT), I a-OHD3, and 1,25(OH)2- D3 in dietary deficiency rickets and in vitamin D resistance due to chronic renalfailure. Note that, though larger amounts of DHT than vitamin D are required to treat simple rickets, for the treatment ofrenal bone disease only slightly higher doses of DHT (or I a-OHD3 or 1,25(OH)2-D3 up to x 4) are required in contrast to the much larger doses of vitamin D3 (up to x 400) that are required

D, DHT la-OHD3 1,25(OH),-D, copyright. Approximate daily dose required to treat or prevent rickets (,ug) 2 5-25 up to 200 up to 1 0 up to 0 5 Potency relative to vitamin D, 100 10 250 500 Approximate daily dose required to treat renal bone disease (,ug) 750-10 000 200-1000 0 5-2-0 0 25-2-0 Potency relative to vitamin D, 100 1000 500 000 500 000

Note I jig Ds or 1,25(OH)2-D3 is equivalent to approximately 40 IU. greatest risks of hypercalcaemia occur at the start of cautiously, if at all, since such patients often respond treatment, particularly in patients who respond poorly to treatment. Prolonged hypercalcaemia may http://jcp.bmj.com/ poorly to treatment (aplastic osteomalacia), and later also impair renal function, sometimes irreversibly, when biochemical responses are nearing completion. and there has been recent interest in the suggestion Plasma calcium concentrations should be monitored that vitamin D compounds may themselves be frequently during these risk periods. It is also impor- nephrotoxic.50 It is difficult, however, to be sure how tant to note that these agents increase the absorption much any deterioration of renal function reflects the of phosphate and the requirements for phosphate- natural history of the disorder or the effects of the binding agents may be increased. hypercalcaemia or hyperphosphataemia,51 and others on September 30, 2021 by guest. Protected Despite advocates to the contrary, there is no have not noted such adverse effects when plasma clinical evidence that 1,25(OH)2-D3, I-alpha-OHD3 calcium and phosphate are well controlled. These or DHT have any particular therapeutic actions considerations nevertheless re-emphasise the need not also possessed by other agents such as 25-OHD3 for close control of plasma calcium and phosphate, or vitamin D.1348 The advantages of the 1-alpha- and the serial measurement of plasma creatinine in hydroxylated metabolites of vitamin D lie in the ease patients not yet established on dialysis treatment. with which doses are titrated according to require- ments and the speed with which toxic effects are Aluminium toxicity reversed on withdrawal of treatment.49 This severely disabling condition does not respond to Treatment with vitamin D or its metabolites is not treatment with vitamin D or its metabolites. It may without risk. Prolonged raised plasma calcium and respond slowly to transplantation or adequate phosphate concentrations give rise to extraskeletal removal of aluminium from the dialysis fluid. This calcification. Patients with pre-existing hyper- slow response probably reflects the prolonged calcaemia and osteomalacia should be treated skeletal retention of aluminium and the difficulty J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

1306 Kanis with which it is removed by haemodialysis, and Imprimerie Fournie, 1976. the importance of prophylaxis. Thus, where 9 Frost HM. Relation between bone tissue and cell popula- indicates tion dynamics, histology and tetracycline labelling. Clin aluminium concentrations in the dialysate exceed 20 Orthop 1966;49:65-75. Mtg/l, the water should be treated by reverse osmosis 10 Ritz E, Krempien V, Mehls 0. Skeletal abnormalities in or possibly by deionisation.33 chronic renal insufficiency before and during haemo- dialysis. Kidney Int 1973;4:116-27. '1 Woods CG, Morgan DB, Patterson CR, Grossman HH. Parathyroidectomy Measurement of osteoid in bone biopsy. J Pathol Surgical removal of parathyroid glands is the most Bacteriol 1968 ;95 :441-7. effective and rapid method of treating hyper- 12 Ellis HA, Pierides AM, Feest TG, Ward MK, Kerr DNS. parathyroid bone disease. The place for parathy- Histopathology of with particular reference to the effects of 1 o-hydroxyvitamin D:i in roidectomy is beyond the scope of this review, but the patients treated by long-term haemodialysis. Clin occurrence (or unmasking) of osteomalacia following Endocrinol (Oxf ) 1977 ;7 :31-8. total parathyroidectomy is one of the reasons why 13 Kanis JA, Cundy T, Earnshaw M, et al. Treatment of partial parathyroidectomy may be preferred. renal bone disease with la-hydroxylated derivatives of vitamin D3. Clinical, biochemical, radiographic anid histological responses. Q J Med 1979;48:289-322. Renal transplantation 14 Krempein B, Mehls 0, Ritz E. Orthological studies on the Theoretically renal transplantation would be the pathogenesis of epiphyseal slipping in uraemic children. treatment of choice for patients with osteomalacia. Virchows Arch 1974;362:129-34. form 1,25(OH)2- 15 Stanbury SW, Lumb GA, Mawer EG. Osteodystrophy This rapidly restores the capacity to developing spontaneously in the course of chronic renal D3 and of course reverses uraemia. Osteomalacia is failure. Arch Intern Med 1969;124:274-81. often slow to reverse, particularly when associated 16 De Luca HF. Recent advances in our understanding of with aluminium retention. Bone disease, including the vitamin D endocrine system. J Lab Clin Med 1976; arise de novo in the transplanted 87 :7-26. osteomalacia, may 17 Haussler MR, McCain TA. Basic and clinical concepts population. There is a high incidence of hypophos- related to vitamin D metabolism and action. N Engl J phataemia in the transplant population52 and this Med 1977 ;297:974-83, 1041-50. Press. may be partly related to phosphate depletion by the 18 Lawson DEM, ed. Vitami1in D. London: Acadeniic copyright. use of antacids, to the persistence of hyperpara- 1978. 19 Stanbury SW, Lumb GA. Metabolic studies in renal thyroidism which is slow to regress after transplan- osteodystrophy. Medicine (Baltiniore) 1962 ;41 :1-31. tation, and to the effects of corticosteroids in de- 20 Malluche HH, Goldstein DA, Massry SG. Osteomalacia creasing renal tubular reabsorption of phosphate. and hyperparathyroid bone disease in patients with nephrotic syndrome. J Clin Invest 1979;63:494-500. 21 Jenkins MV, Harris M, Wills MR. The effect of phenytoini I am grateful to the National Kidney Research on parathyroid extract and 25-hydroxycholecalciferol Fund, the Wellcome Trust, the Medical Research induced bone resorption: Adenosine 3'-5'. cyclic Calcified Tissue Research Council and the Special Trustees of the Sheffield monophosphate production. http://jcp.bmj.com/ Area Health Authority for their generous support of 1974;16:163-7. 22 Coburn JW, Brickman AS, Sherrard DJ, et al. Clinical this work. efficacy of 1,25-dihydroxy-vitamin D: in renal osteo- dystrophy In: Norman AW, Schaefer K, Coburn JW, clinical References et al, eds. Vitamin D: biochemical, chemical and aspects related to calcium metabolisnm. Berlin: Walter lDavid DS, ed. Calcium metabolismi in renal failure and DeGruyter, 1977:657. nephrolithiasis. New York: John Wiley & Sons, 1977. 23 Kanis JA, Adams ND, Earnshaw M, et al. Vitamin D 2 on chronic renal failure. In: Norman AW. bone disease. osteomalacia on September 30, 2021 by guest. Protected Avioli LV. Renal osteodystrophy in metabolic bio- Vol 2. Avioli LV, Krane SM, eds. New York: Academic Schaefer K. Coburn JW, et ao, eds. Vitamin D: chemical, chemical and clinical aspects related to calcium Press, 1978. 1977:671. 3 Peacock M. The clinical uses of 1 tY-hydroxyvitamin D3. metabolism. Berlin: Walter DeGruyter, Clin Fndocrinol (Oxf) 1977 ;7, suppi. 21 Weisman Y, Eisenberg Z, Leib L, et al. Serum concentra- 4 Coburn JW, Massry SG, eds. Uses and actions of 1,25- tions of 24,25-dihydroxy-vitamin D in different degrees dihydroxyvitamin D3 in . Contrib Nephrol 1980; of chronic renal failure. Br MedJ 1980;281:712-3. 25 Andrade 18. Kanis JA, Russell RGG, Taylor CM, Cundy T, Kanis JA. Features and pathophysiology of renal bone A, Heynen G. The relationships between disturbed disease. In: Davies AM, ed. Haemodiali'sis review. metabolism of vitamin D and bone disease in chronic Tunbridge Wells: Pitman, 1978:182-204. renal failure. Proc Eur Dial Transplant As.soc 1979;16: 6 Meunier P, Edouard C, Richard D, Laurent, J. Histo- 630-6. morphometry of osteoid tissue: the hyperosteoidoses. 26 Malluche HH, Henry H, Meyer-Sabellek W, et al. Effects In: Meunier PJ, ed. Bone histomorphometryl. Toulouse: of interactions with 24R, 25-OHD3 and 1,25(OH)2-D: Societe de la Nouvelle Imprimerie Fournie, 1976 :249-62. on bone. Am JPhysiol 1980;283:494-8. 27 Bordier P, Rasmussen H, Marie P, et al. Vitamin D Frost HM. The bone dynamics in osteoporosis and Clin osteomalacia. Springfield: Charles C Thomas, 1966. metabolites and bone mineralisation in man. J Woods CG. Why count osteoblasts? In: Meunier PJ ed., Endocrinol Metab 1978 ;46:284-94. HistomorphometrY. Toulouse: Societe de la Nouvelle 2 8 Howard GA, Baylink DJ. Matrix formation and osteoid J Clin Pathol: first published as 10.1136/jcp.34.11.1295 on 1 November 1981. Downloaded from

Osteomalacia and chronic renal failure 1307 maturation in vitamin D deficient rats made normo- of renal rickets. Bulletin of the Johns Hopkins Hospital calcaemic by dietary means. Min Elect Metab 1980;3:44- 1955;96:1-19. 50. 4] Bishop MC. Bone disease in the Oxford Renal Unit. 29 Pettifor JM, Ross FP, Moodley G, De Luca HF, Travers University of London: MD Thesis, 1976. R, Glosseux FH. Calcium deficiency rickets associated 42 Parafitt AM. Soft-tissue calcification in uraemia. Arch with elevated 1,25-dihydroxyvitamin D concentrations Intern Med 1969 ;124:544-56. in a rural black population. In: Norman AW, Schaefer 43 Ahmed KY, Varghese Z, Wills MR, et al. Persistent K, Herrath DV, et al, eds. Vitamin D: Basic research and hypophosphataemia and osteomalacia in dialysis its clinical application. Berlin: Walter DeGruyter, 1979: patients not on oral phosphate-binders: response to DHT 1125-7. therapy. Lancet 1976 ;ii :439. 30 Cundy T, Kanis JA, Heynen G, et al. Lack of direct effect 44 Feest TG, Ward MK, Ellis HA, Aljama P, Kerr DNS. of 1,25-dihydroxy vitamin D3 on mineralisation of bone Osteomalacic dialysis osteodystrophy: A trial of and secretion of parathyroid hormone. Clin Sci 1980;59: phosphate enriched dialysis fluid. Br MedJ 1978 :i : 18-20. 15P. 41 Meyrier A, Marsac J, Richet G. The influence of a high 31 Rao STK, Freidman EA. Fluoride and bone disease in calcium carbonate intake on bone disease in patients uraemia. Kidney Int 1975 ;7:125-9. undergoing haemodialysis. Kidney Int 1973;4:146-53. 32 Platts MM, Goode GC, Hislop JS. Composition of the 46 Kanis JA, Henderson RJ, Hevnen G, et al. Renal osteo- domestic water supply and the incidence of fractures and dystrophy in non-dialysed adolescents: long-term treat- encephalopathy in patients on home dialysis. Br Med J ment with l-alpha-hydroxycholecalciferol. Arch Dis 1977 ;ii :657-60. Child 1977;52:473-81. 33 Parkinson IS, Ward MK, Feest TG, Fawcett RPW, Kerr 4 Chesney RW, Moorthy AV, Eisman JA, et al. Increased DNS. Fracturing dialysis osteodystrophy and dialysis growth after long-term oral 1a, 25-vitamin D in child- encephalopathy. An epidemiological survey. Lancet hood renal osteodystrophy. NFnglJ Med 1978;298:238. 1979;i:406-9. 48 Prior JC, Cameron EC, Ballon HS, Lirenman LS, Moriarty 34 Flendrig JA, Kruis H, Das H. Aluminium and dialysis MV, Price JDE. Experience with 1,25-dihydroxychole- dementia. Lancet 1976;i:1235. calciferol therapy in undergoing haemodialysis patients 35 Clarkson EM, Luck VA, Hynson WV, et al. The effect of with progressive vitamin D2-treated osteodystrophy. aluminium hydroxide on calcium, and Am J Med 1979 ;67:583-9. aluminium balances, the serum parathyroid hormone 49 Kanis JA, Russell RGG. Rate of reversal of hypercalcaemia concentration and the aluminium content of bone in and hypercalciuria induced by vitamin D and its patients with chronic renal failure. Clin Sci 1972;53:519- 1-alpha-hydroxylated derivatives. Br MedJ 1977;i:78-81. 31. 10 Christiansen C, Rodbro P, Christensen MS, Hartnack B, 36 Pellegrino ED, Bilz RM. The composition of bone in Transbol I. Deterioration of renal function during uraemia. Observations on the reservoir functions of bone treatment of chronic renal failure with 1,25-dihydroxy- copyright. and demonstration of a labile fraction on carbonate. . Lancet 1978 ;ii :700-3. Medicine (Baltimore) 1965 ;44:397-418. 51 Naik RB, Cundy T, Robinson BHB, Russell RGG, Kanis 3 Leman J Jr, Litzow JR, Lennon EJ. The effect of acid JAK. Effects of vitamin D metabolism and analogues on levels in normal man: turther evidence for the partici- renal function. Nephron 1981:28:17-25. pation of bone mineral in the defence against chronic 52 Moorhead JF, Wills MR, Ahmed KY, Baillod RA, metabolic acidosis. J Clin Invest 1966:45:1608-14. Varghese Z, Tatler GLV. Hypophosphataemic osteo- 38 Cochran M, Hopkinson R. Effect of correction of metabolic malacia after cadaveric renal transplantation. Lancet acidosis on bone mineralisation rates in patients with 1974;i :694-7. renal osteomalacia. Nephron 1975;15:98-1 10. 39 Fletcher RF, Jones JH, Morgan DB. Bone disease and http://jcp.bmj.com/ chronic renal failure. Q J Med 1963;32:321-39. Requests for reprints to: Dr JA Kanis, Department of 40 Yendt ER, Connell TB, Howard JE. In vitro calcification Human Metabolism and Clinical Biochemistry, University of rachitic rat cartilage in normal and pathological of Sheffield Medical School, Beech Hill Road, Sheffield human sera with some observations on the pathogenesis S1O 2RX, England. on September 30, 2021 by guest. Protected