Clinical Endocrinology (1977) 7, Suppl., 25s-30s.
THE R O L E O F VITAMIN D I N R E N A L BONE DISEASE S . W . STANBURY Department of Medicine, Royal Infirmaty, Manchester, England
There have been few fundamental advances since this topic was reviewed 5 years ago (Stanbury, 1972) but there has been promulgated in the recent literature a variety of illogicalities that warrant critical comment. To be provocative and t o put a personal viewpoint, I still believe that lack of the biological effects of vitamin D (Lumb et al., 1971) is probably the most important single factor in the pathogenesis of renal bone disease; when, that is, the renal failure is allowed to evolve spontaneously and is not complicated by iatrogenic measures that may cause deficiencies of calcium, phosphorus or protein; and when it is uncomplicated by various forms of inadvertent or therapeutic poisonings. And, when invoking ‘vitamin D’ in t h s pathogenetic role what is implied is a quantitative deficiency of its hormonal metabolite, 1,25-d1hydroxyvitamin D3 (1,25-(oH),D,). Having taken personal pains to rebut the dogma of Albright that ‘renal rickets is not rickets at all but renal osteitis fibrosa’, it is disconcerting to find that some are interpreting the observations of Krempien ef al. (1974), on slipped epiphyses in renal osteodystrophy, to imply that Albright was right. There is no doubt that hyperparathyroidism can produce a picture resembling rickets, nor that the histological changes described by Krempien were predominantly those of hyperparathyroidism. Indeed, it has been accepted for decades that hyperparathyroidism is the principal cause of epiphyseal dislocation in chddren with renal osteodystrophy. But the bones in chddren of the ages studied by Krempien are especially liable to respond exuberantly to hyperparathyroidism and the contemporary osteopathologist rarely has the opportunity to examine the metaphyses from adolescents with ‘renal rickets’ as did ~ L Scolleagues in the past. Some 25 years ago one was able to witness the progressive development of radiographic signs of rickets during the last year or two of life in adolescents with chronic uraemia. These appearances could be inhtinguishable from those seen in adolescents with late nutritional rickets. Moreover, since all these patients died, it was possible to demonstrate histological changes in the growth apparatus indistinguishable from those of nutritional rickets. There was, in these cases, abundant evidence of hyperparathyroidism, with erosion of metaphyseal trabeculae and osteitis fibrosa, but it must be emphasized that this is not necessarily different from nutritional rickets. One cannot biopsy Correspondence: Professor S. W. Stanbury. Department of Medicine, Manchester Royal I n f i i a r y . Manchester M13 9WL.
26s
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the growth plate in patients with nutritional rickets but, in florid cases, bone from the iliac crest may show, in addtion to osteomalacia, gross osteitis fibrosa. marrow fibrosis and formation of woven bone; and t h s evidence of bony hyperparathyroidism is reflected in the appearance of classical erosions in the digital phalanges. Simple vitamin D deficiency provides many analogies with renal osteodystrophy and, in a personal experience of about 150 affected adolescents and adults, we have encountered most of the syndromes and bony changes that occur in azotaemia. These include acquired ‘pseudohypoparathyroidism’ with profound hypocalcaemia, hyperphosphataemia and renal unresponsiveness to the phosphaturic action of parathyroid hormone (Stanbury et al., 1976): also cases of hypercalcaemic osteomalacia with osteitis fibrosa analogous to the infrequent hypercalcaemic cases in renal failure (Lumb & Stanbury, 1974). In almost all patients with vitamin D deficiency the serum iPTH is raised and it can be ten to twenty-five times the average normal (Stanbury & Lumb, 1976). Thus vitamin D deficiency in patients with normal renal function can produce a secondary hyperparathyroidism as severe as occurs in renal failure. This suggests that the conditioned deficiency of 1 ,2S-(0H)2D3 in renal failure could be as important in causing secondary hyperparathyroidism as is ‘phosphate retention’ due to reduced glomerular filtration. Evidence of hyperparathyroidism, with osteitis fibrosa, raised serum alkaline phosphatase and increased serum iPTH, appears to be an intrinsic component of the osteodystrophy of vitamin D deficiency. A form of histological osteomalacia without these accompanying features, as described in some chronically dialysed patients (Ellis, 1977, this Symposium), is thus unlikely to be due to lack of the biological effects of vitamin D. The Newcastle experience that such cases have proved refractory to treatment with all available vitamin D sterols is compatible with this interpretation. Observations on privational vitamin D deficiency in man are also relevant to recent claims that defective osseous mineralization in renal failure is due to simple vitamin D deficiency. Investigators in France (Bayard et al., 1973) and in London (Eastwood er al., 1976) have claimed that azotaemic osteomalacia is associated selectively and causally with low levels of serum 2s-hydroxyvitamin D (25-OHD). Other workers in Germany and the U.S.A. found no such relationshp and, most recently, Neilsen et af. (1977) in Denmark have studied groups of patients essentially similar to those of Eastwood et al. (1976) and shown conclusively that the presence of azotaemic osteomalacia is unrelated to the serum 25-OHD. If one invokes deficiency of vitamin D (or of 25-oHD3) to account for osseous phenomena in renal failure (Eastwood et al., 1976) it is essential to know and understand the characteristics of human privational deficiency. An oral dose of 4SOiu (11.2pg) per day of vitanun D is sufficient to correct all manifestations of clinical vitamin D deficiency and even this small amount is probably overdosage. Human vitamin D deficiency is a most difficult condition to investigate since it tends to be corrected ‘spontaneously’ after admission to hospital. If bone biopsy is delayed for 4-5 days after admission, tetracycline is found to be bound at calcification fronts in most patients, even in those with florid clinical and radiographic signs of rickets or osteomalacia. If allowed to equilibrate with a metabolic diet for 6-10 days, most patients with ‘clinical vitamin D deficiency’ are found t o be in positive mineral balance by amounts of 200-800 mg of calcium per day. (In azotaemic osteomalacia, impaired calcium absorption can be demonstrated after weeks or months in hospital.) In vitamin D deficient patients with profound hypocalcaemia, the serum calcium may increase by as much as 3mg/dl w i t h days of entering hospital. This may be accompanied by a change of serum 25-OHD3 as small as from 2 to 5 ng/ml (5-1 2 nmol/l). Thus in simple
Vitamin D and renal osteodystrophy
27s
vitamin D deficiency it is possible to detect evidence of the correction of the deficiency at levels of serum 25-OHD3 lower than in the azotaemic cases of Eastwood et af. (1976) with the most severe histological osteomalacia. It is of interest to enquire what quantity of vitamin D is likely to be responsible for producing these effects in simple vitamin D deficiency. The evidence suggests that the correction of vitamin D deficiency in hospital is simply due to eating the hospital diet, w h c h provides little more than 2-3 pg per day of vitamin D. Oral dosage with 25-OHD3 may increase the serum 25-OHD3 by up to ten times the increment produced by an equimolar amount of oral vitamin D. Thus the correction of simple vitamin D deficiency may be achieved by the equivalent of 0.2-0.3 pg per day of 25-OHD3 or, to overestimate generously the vitamin D content of the hospital diet, by no more than 0.5 puglday. Such quantitative considerations have many implications, one of which is to suggest that 1 pgjday of 1,25-(OH)2D3 is a pharmacological dose in man. In the present context, the most important implication is that correction of the mineralization defect in azotaemic osteodystrophy by intravenous doses of 20-40pglday of 25-OHD3 (Eastwood et af., 1976) does not prove the existence of vitamin D deficiency; it simply demonstrates that pharmacological doses of this sterol can substitute for smaller (and possibly still pharmacological) doses of 1 ,25-(OH)*D3 in renal failure. More than 5 years ago, Verberckmoes was able to heal osteomalacia in anephric patients by treatment with vitamin D; he proved thereby that la-hydroxylation was not essential for this therapeutic effect. We have long insisted that the beneficial effects of large doses of vitamin D in azotaemic osteomalacia must be attributable to metabolically produced 25-OHD, (Stanbury, 1972), which can reach concentrations as high as 200-600ng/ml (0.5-1.5pmoI/I) in the serum of treated patients. The minimum concentration of serum 25-OHD3 that is effective in azotaemia is unknown and it could vary from patient to patient. It is also unknown whether the luxus consumption of vitamin D by some populations provides sufficient 25-OHD3 to protect against the development of osteomalacia in renal failure. Despite continued assertion to the contrary, there is no evidence that the hepatic metabolism of vitamin D is disturbed in uraemic or anephric man and the survival of metabolically produced 25-OHD3 is normal (Mawer er af., 1971). It might be questioned whether hydroxylated derivatives of 25-OHD3 other than 1 ,25-(OH)2D3 could be responsible for the biological effects of pharmacological doses of vitamin D in renal failure. In normal individuals the serum concentration of 24,25-(OH)$ increases with that of 25-OHD3 (Taylor et al., 1976) but the anephric patient is unable to form 24,25-(OH)2D (Taylor, 1977). Thus the latter sterol cannot implement the action of administered 25-(OH)D3 (or vitamin D) in anephric patients. Patients with renal farlure appear to produce normal, or possibly even increased, amounts of 25,26-(OH)zD3 from a pulse dose of vitamin D3 (Mawer et af.,1973). Such observations as have been made indicate that t h s trio1 is biologically less potent than its precursor; it is, therefore, u d k e l y to be responsible for the therapeutic benefits of vitamin D in renal failure. Kanis et al. (1977) have recently demonstrated that oral doses of 24,25-(OH)2D3 as small as 1 pg/day can promote intestinal absorption of calcium in man; and, since the same effect was found in anephric patients, it cannot be attributed to the formation in viuo of 1,24,25(OH)$,. From observations in hypoparathyroidism, it is known that an oral dose of 1 pg/day of 1,2540H)$, can increase calcium absorption and the serum calcium without producing detectable direct effects on bone or kidney (Davies et af., 1977). Observations by Mawer et af. ( 1 976) suggest that this action on the intestine may be direct and produced in the course of absorption of the orally adminstered sterol. It must be questioned whether
28s
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24,25-(OHhD3, reaching the intestine by this unphysiological oral route, might not initiate calcium absorption in the same way. An oral dose of 1 &day of 1,25-(0H)2D3 produces only a transient elevation of its serum concentration, with a rapid fall-off compatible with its very short half-life (Mawer er af., 1976). It is not yet known whether 24,25-(OH)& is as well absorbed by the intestine as are 25-OHD3 and 1,25-(OH)zD3, although th~sis likely. But 24,25-(OH)2D3 in serum has the longest half-life in man (- 40 days) of any of the biologically active vitamin D sterols. Consequently, the serum concentration produced by an oral dose of 24,25-(OH)2D3 4 1 not have decayed significantly by the time the next daily dose is given and oral therapy with this sterol is certain to produce progressively rising serum levels. Before it can be decided whether the observations of Kanis el ul. (1977) have any physiological significance or are simply another aspect of the pharmacology of ‘wtamin D’ much more information will be required. The short duration of action of 1 ,25-(0H)2D3 and la-OHD, makes these safer therapeutic agents than the native vitamins D or 25-OHD3; but it is a mistake to assume that their mode of therapeutic action is established or that the optimum method of their use has been defined. Some reports have claimed excellent results from the use of either agent; other reports describe patients who derived little benefit from an identical therapeutic regimen. This is not surprising. A slmilar experience might have been expected had vitamin D or 25-OHD3 been used in the same groups of patients; it has yet to be shown that 1 ,25-(OH)2D3 or la-OHD, produce any therapeutic effects that CaMOt be achieved with larger doses of vitamin D and its hepatic metabolites. There is considerable potential for error in extrapolating from the results of therapy with these new sterols - i n random groups of patients observed in the mass - to conclusions regarding the pathogenesis of renal osteodystrophy. Experience from earlier investigation of renal ‘osteodystrophy suggests that more will be learned from the intensive study of the individual patient than by the acquisition of statistical data from many. Thus, in exploring the responses of azotaemic patients with osteomalacia, one must be certain that the defective mineralization is a direct consequence of the underlying disease -and not the result of others of our therapeutic measures. It has been clear for many years that the injudicious use of aluminium hydroxide or of massive oral doses of non-phosphatic calcium salts, in uraemic patients receiving a low intake of dietary phosphorus, may induce the development of Pdeficiency osteomalacia. More recently it has become apparent that the chronic haemodialytic regimen may induce the same. It would be illogical to expect this type of osteomalacia to heal on treatment with 1,25-(0H)2D3 or la-OHD3; and equally illogical to infer that its development was a direct consequence of the renal disease. Having selected cases of azotaemic osteomalacia uncomplicated by other treatment, one must define what is expected of the new therapy. If h s is solely to promote intestinal absorption of calcium, the problem is relatively simple. The range of dosage of 1,25-(0H)21)3 and la-OHD3 that will produce this effect is already known; and simple means are avadable for detecting increased calcium absorption in the individual patient. By increasing the serum calcium this should reduce parathyroid secretion and the hyperparathyroid component of the bone disease. But if the full therapeutic effect requires some appropriate concentration of 1,25(OH)2D3 in other tissues the problem becomes more complicated. The scanty information avdable suggests that 1 &day of 1,25-(OH)2D3 orally increases its serum concentration only transiently and barely to ‘normal’ levels (Mawer er al., 1976). In a single uraemic patient, 1 pg of la-OHD, produced a serum 1,25-(0H)zD3 of 16 pg/ml at 1 2 h after the oral dose and this increase was also short-lived (Holick et al., 1977). Thus the presently adopted
Vitamin D and renal osteodystrophy
29s
method of giving either of these new sterols may not reproduce physiological conditions, if these imply a relatively constant and optimum serum concentration of 1,25-(OH)2D3. If the purported (but unproven) direct effects of ’vitamin D’ on mineralization or on the parathyroid glands required such a normal circulating concentration of the hormone, t h ~ srequirement might not be met by the contemporary therapeutic regimen. The therapeutic requirement might be better met by higher concentrations of a less specific and less potent sterol with a longer biological life, such as 25-OHDS. Until more is known of the physiological concentrations and functions of 1,25-(OH)z& in the blood and other tissues it is premature to conclude, as some have done, that 25-OHD3 has an independent action on the bone. S d a r l y , the therapeutic problem would not necessarily be solved by increasing the oral dose of 1,25-(OH)2D, or la-OHD,, since this might produce hormonal concentrations exceeding the physiological. Hypothetically, the osteolytic action of 1,25-(OH)2D3 might then worsen the bone disease. The means are now available for measuring in man all the identified and biologically active metabolities of vitamin D. Before succumbing to the temptation to invoke direct actions of these individual sterols on various tissues, there is a need to document their concentrations - at least in the serum - in different physiological states, in disease and during therapy. REFERENCES BAYARD, F., BEC, P., TON THAT, H. & LOUVET, J.P. (1973) Plasma 25-hydrouycholecalciferol in chronic renal failure. European Journal of Clinical Investigarion, 3 , 447-450. DAVIES. M., HILL, L.F., TAYLOR, C.M. & STANBURY, S.W. (1977) 1,25-Dihydrouycholecalcirolin hypoparathyrodism. Lancet, i, 55-59. EASTWOOD, J.B., HARRIS, E., STAMP, T.C.B. & DE WARDENER, H.E. (1976) Vitamin D deficiency in the osteomalacia of chronic r e n d f d u r e . Lancet, ii, 1209-121 I . HOLICK, M.F.. DE BLANCO, M.C.. CLARK, M.B., HENLEY, J.W., NEER, R.M., DE LUCA, H.F. & POTTS, J.T. Jr. (1977) The metabolism of [6-’H] 1,hydroxycholecalciferol to [6-%H]l,25dihydroxycholecalciferol in man. Journal of Clinical Endocrinology and Metabolism. (In press.) KANIS, J.A., HEYNEN, G., RUSSELL, R.G.C., SMITH, R., WALTON, R.J. & WARNER, G.T. (1977) Biological effects of 24,25dihydroxycholecalciferol in man. Vitamin D: Biochemical, Chemical and Clinical Aspects Related t o Calcium Metabolism (Ed. by A.W. Norman, K. Schaefer, J.W. Coburn, H.F. DeLuca, D. Fraser, H.C. Crigoleit & D. yon Henath), pp. 793-795. Walter de Cruyter, Berlin. KREMPIEN, B.. MEHL, 0. & RITZ, E. (1974) Morphological studies o n pathogenesis of epiphyseal slipping in uraemic children. Virchows Archiv; Abtedung A: Pathologische Anatornie, 362, 129-143. LUMB, C.A.. MAWER, E.B. & STANBURY, S.W. (1971) The apparent vitamin D resistance of chronic renal failure. A study of the physiology of vitamin D in man. American Journal of Medicine, 50, 4 2 1 . 4 4 1. LIMB,C.A. & STANBURY, S.W. (1974) Parathyroid function in vitamin D deficiency and vitamin D deficiency in primary hyperparathyroidism. American J o u m l of Medicine, 56,833-839. MAWER, E.B., BACKHOUSE, J., DAWES, M., HILL, L.F. & TAYLOR, C.M. (1976) Metabolic fate of administered 1,254ihydroxycholecalciferol in controls and patients with hypoparathyroidism. lancer, i, 1203-1206. MAWER, E.B., BACKHOUSE, J., TAYLOR.C.M., LUMB, C.A. & STANBURY,S.W. (1973) Failure of formation of 1,25dihydroxycholecalciferol in chronic renal insufficiency. Luncer. i, 626-628. MAWER, E.B., LUMB, G.A., SCHAEFFER, K. & STANBURY, S.W. (1971) The metabolism of isotopically labelled vitamin D, in man; the influence of the state of vitamin D nutrition. clincal Science, 40.39-53. NIELSEN, H.E., MELSEN, F., LUND, B., S@RENSEN,O.H. & CHR1STENSEN;M.S. (1977) Serum 25hydroxycholecalciferol and renal osteodystrophy. Lancet, i, 754-755. STANBURY, S.W. (1972) Azotaemic rend osteodystrophy. Clinics in Endocrinology and Metabolism, 1, 26 7-304.
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STANBURY, S.W. & LUMB, G.A. (1976) Parathyroid function in chronic vitamin D deficiency: a model for comparison with chronic renal failure. Calcified Tissue Research, 21, Suppl., 185-201. STANBURY, S.W.. LUMB, G.A. & TORKINGTON, P. (1976) Interrelations of the parathyroid glands, the bone and the kidneys in human vitamin D deficiency. In: Calcium et Maladies Endocriniennes. (Ed. by D. J. Hioco.), pp. 3146. Sandoz, Paris. TAYLOR, C.M., HUGHES, S.E. & DE SILVA, P. (1976) Competitive protein-binding assay for 24.25dihydroxycholedciferol. Biochemical and Biophysical Research Communications, 70, 1243-1 249. TAYLOR, C.M. (1977) The measurement of 24,25dihydroxycholecalciferol in human serum. Vitamin D Biochemical. Chemical and Clinical Aspects Related to calcium metabolism. (Ed. by A.W. Norman, K. Schaefer. J.W.Coburn. H.F. DeLuca. D. Fraser, H.G. Grigoleit and D. von Herrath), pp. 531-543. Walter de Gruyter, Berlin.
THE R O L E O F VITAMIN D I N R E N A L BONE DISEASE S . W . STANBURY Department of Medicine, Royal Infirmaty, Manchester, England
There have been few fundamental advances since this topic was reviewed 5 years ago (Stanbury, 1972) but there has been promulgated in the recent literature a variety of illogicalities that warrant critical comment. To be provocative and t o put a personal viewpoint, I still believe that lack of the biological effects of vitamin D (Lumb et al., 1971) is probably the most important single factor in the pathogenesis of renal bone disease; when, that is, the renal failure is allowed to evolve spontaneously and is not complicated by iatrogenic measures that may cause deficiencies of calcium, phosphorus or protein; and when it is uncomplicated by various forms of inadvertent or therapeutic poisonings. And, when invoking ‘vitamin D’ in t h s pathogenetic role what is implied is a quantitative deficiency of its hormonal metabolite, 1,25-d1hydroxyvitamin D3 (1,25-(oH),D,). Having taken personal pains to rebut the dogma of Albright that ‘renal rickets is not rickets at all but renal osteitis fibrosa’, it is disconcerting to find that some are interpreting the observations of Krempien ef al. (1974), on slipped epiphyses in renal osteodystrophy, to imply that Albright was right. There is no doubt that hyperparathyroidism can produce a picture resembling rickets, nor that the histological changes described by Krempien were predominantly those of hyperparathyroidism. Indeed, it has been accepted for decades that hyperparathyroidism is the principal cause of epiphyseal dislocation in chddren with renal osteodystrophy. But the bones in chddren of the ages studied by Krempien are especially liable to respond exuberantly to hyperparathyroidism and the contemporary osteopathologist rarely has the opportunity to examine the metaphyses from adolescents with ‘renal rickets’ as did ~ L Scolleagues in the past. Some 25 years ago one was able to witness the progressive development of radiographic signs of rickets during the last year or two of life in adolescents with chronic uraemia. These appearances could be inhtinguishable from those seen in adolescents with late nutritional rickets. Moreover, since all these patients died, it was possible to demonstrate histological changes in the growth apparatus indistinguishable from those of nutritional rickets. There was, in these cases, abundant evidence of hyperparathyroidism, with erosion of metaphyseal trabeculae and osteitis fibrosa, but it must be emphasized that this is not necessarily different from nutritional rickets. One cannot biopsy Correspondence: Professor S. W. Stanbury. Department of Medicine, Manchester Royal I n f i i a r y . Manchester M13 9WL.
26s
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W.Stanbury
the growth plate in patients with nutritional rickets but, in florid cases, bone from the iliac crest may show, in addtion to osteomalacia, gross osteitis fibrosa. marrow fibrosis and formation of woven bone; and t h s evidence of bony hyperparathyroidism is reflected in the appearance of classical erosions in the digital phalanges. Simple vitamin D deficiency provides many analogies with renal osteodystrophy and, in a personal experience of about 150 affected adolescents and adults, we have encountered most of the syndromes and bony changes that occur in azotaemia. These include acquired ‘pseudohypoparathyroidism’ with profound hypocalcaemia, hyperphosphataemia and renal unresponsiveness to the phosphaturic action of parathyroid hormone (Stanbury et al., 1976): also cases of hypercalcaemic osteomalacia with osteitis fibrosa analogous to the infrequent hypercalcaemic cases in renal failure (Lumb & Stanbury, 1974). In almost all patients with vitamin D deficiency the serum iPTH is raised and it can be ten to twenty-five times the average normal (Stanbury & Lumb, 1976). Thus vitamin D deficiency in patients with normal renal function can produce a secondary hyperparathyroidism as severe as occurs in renal failure. This suggests that the conditioned deficiency of 1 ,2S-(0H)2D3 in renal failure could be as important in causing secondary hyperparathyroidism as is ‘phosphate retention’ due to reduced glomerular filtration. Evidence of hyperparathyroidism, with osteitis fibrosa, raised serum alkaline phosphatase and increased serum iPTH, appears to be an intrinsic component of the osteodystrophy of vitamin D deficiency. A form of histological osteomalacia without these accompanying features, as described in some chronically dialysed patients (Ellis, 1977, this Symposium), is thus unlikely to be due to lack of the biological effects of vitamin D. The Newcastle experience that such cases have proved refractory to treatment with all available vitamin D sterols is compatible with this interpretation. Observations on privational vitamin D deficiency in man are also relevant to recent claims that defective osseous mineralization in renal failure is due to simple vitamin D deficiency. Investigators in France (Bayard et al., 1973) and in London (Eastwood er al., 1976) have claimed that azotaemic osteomalacia is associated selectively and causally with low levels of serum 2s-hydroxyvitamin D (25-OHD). Other workers in Germany and the U.S.A. found no such relationshp and, most recently, Neilsen et af. (1977) in Denmark have studied groups of patients essentially similar to those of Eastwood et al. (1976) and shown conclusively that the presence of azotaemic osteomalacia is unrelated to the serum 25-OHD. If one invokes deficiency of vitamin D (or of 25-oHD3) to account for osseous phenomena in renal failure (Eastwood et al., 1976) it is essential to know and understand the characteristics of human privational deficiency. An oral dose of 4SOiu (11.2pg) per day of vitanun D is sufficient to correct all manifestations of clinical vitamin D deficiency and even this small amount is probably overdosage. Human vitamin D deficiency is a most difficult condition to investigate since it tends to be corrected ‘spontaneously’ after admission to hospital. If bone biopsy is delayed for 4-5 days after admission, tetracycline is found to be bound at calcification fronts in most patients, even in those with florid clinical and radiographic signs of rickets or osteomalacia. If allowed to equilibrate with a metabolic diet for 6-10 days, most patients with ‘clinical vitamin D deficiency’ are found t o be in positive mineral balance by amounts of 200-800 mg of calcium per day. (In azotaemic osteomalacia, impaired calcium absorption can be demonstrated after weeks or months in hospital.) In vitamin D deficient patients with profound hypocalcaemia, the serum calcium may increase by as much as 3mg/dl w i t h days of entering hospital. This may be accompanied by a change of serum 25-OHD3 as small as from 2 to 5 ng/ml (5-1 2 nmol/l). Thus in simple
Vitamin D and renal osteodystrophy
27s
vitamin D deficiency it is possible to detect evidence of the correction of the deficiency at levels of serum 25-OHD3 lower than in the azotaemic cases of Eastwood et af. (1976) with the most severe histological osteomalacia. It is of interest to enquire what quantity of vitamin D is likely to be responsible for producing these effects in simple vitamin D deficiency. The evidence suggests that the correction of vitamin D deficiency in hospital is simply due to eating the hospital diet, w h c h provides little more than 2-3 pg per day of vitamin D. Oral dosage with 25-OHD3 may increase the serum 25-OHD3 by up to ten times the increment produced by an equimolar amount of oral vitamin D. Thus the correction of simple vitamin D deficiency may be achieved by the equivalent of 0.2-0.3 pg per day of 25-OHD3 or, to overestimate generously the vitamin D content of the hospital diet, by no more than 0.5 puglday. Such quantitative considerations have many implications, one of which is to suggest that 1 pgjday of 1,25-(OH)2D3 is a pharmacological dose in man. In the present context, the most important implication is that correction of the mineralization defect in azotaemic osteodystrophy by intravenous doses of 20-40pglday of 25-OHD3 (Eastwood et af., 1976) does not prove the existence of vitamin D deficiency; it simply demonstrates that pharmacological doses of this sterol can substitute for smaller (and possibly still pharmacological) doses of 1 ,25-(OH)*D3 in renal failure. More than 5 years ago, Verberckmoes was able to heal osteomalacia in anephric patients by treatment with vitamin D; he proved thereby that la-hydroxylation was not essential for this therapeutic effect. We have long insisted that the beneficial effects of large doses of vitamin D in azotaemic osteomalacia must be attributable to metabolically produced 25-OHD, (Stanbury, 1972), which can reach concentrations as high as 200-600ng/ml (0.5-1.5pmoI/I) in the serum of treated patients. The minimum concentration of serum 25-OHD3 that is effective in azotaemia is unknown and it could vary from patient to patient. It is also unknown whether the luxus consumption of vitamin D by some populations provides sufficient 25-OHD3 to protect against the development of osteomalacia in renal failure. Despite continued assertion to the contrary, there is no evidence that the hepatic metabolism of vitamin D is disturbed in uraemic or anephric man and the survival of metabolically produced 25-OHD3 is normal (Mawer er af., 1971). It might be questioned whether hydroxylated derivatives of 25-OHD3 other than 1 ,25-(OH)2D3 could be responsible for the biological effects of pharmacological doses of vitamin D in renal failure. In normal individuals the serum concentration of 24,25-(OH)$ increases with that of 25-OHD3 (Taylor et al., 1976) but the anephric patient is unable to form 24,25-(OH)2D (Taylor, 1977). Thus the latter sterol cannot implement the action of administered 25-(OH)D3 (or vitamin D) in anephric patients. Patients with renal farlure appear to produce normal, or possibly even increased, amounts of 25,26-(OH)zD3 from a pulse dose of vitamin D3 (Mawer et af.,1973). Such observations as have been made indicate that t h s trio1 is biologically less potent than its precursor; it is, therefore, u d k e l y to be responsible for the therapeutic benefits of vitamin D in renal failure. Kanis et al. (1977) have recently demonstrated that oral doses of 24,25-(OH)2D3 as small as 1 pg/day can promote intestinal absorption of calcium in man; and, since the same effect was found in anephric patients, it cannot be attributed to the formation in viuo of 1,24,25(OH)$,. From observations in hypoparathyroidism, it is known that an oral dose of 1 pg/day of 1,2540H)$, can increase calcium absorption and the serum calcium without producing detectable direct effects on bone or kidney (Davies et af., 1977). Observations by Mawer et af. ( 1 976) suggest that this action on the intestine may be direct and produced in the course of absorption of the orally adminstered sterol. It must be questioned whether
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24,25-(OHhD3, reaching the intestine by this unphysiological oral route, might not initiate calcium absorption in the same way. An oral dose of 1 &day of 1,25-(0H)2D3 produces only a transient elevation of its serum concentration, with a rapid fall-off compatible with its very short half-life (Mawer er af., 1976). It is not yet known whether 24,25-(OH)& is as well absorbed by the intestine as are 25-OHD3 and 1,25-(OH)zD3, although th~sis likely. But 24,25-(OH)2D3 in serum has the longest half-life in man (- 40 days) of any of the biologically active vitamin D sterols. Consequently, the serum concentration produced by an oral dose of 24,25-(OH)2D3 4 1 not have decayed significantly by the time the next daily dose is given and oral therapy with this sterol is certain to produce progressively rising serum levels. Before it can be decided whether the observations of Kanis el ul. (1977) have any physiological significance or are simply another aspect of the pharmacology of ‘wtamin D’ much more information will be required. The short duration of action of 1 ,25-(0H)2D3 and la-OHD, makes these safer therapeutic agents than the native vitamins D or 25-OHD3; but it is a mistake to assume that their mode of therapeutic action is established or that the optimum method of their use has been defined. Some reports have claimed excellent results from the use of either agent; other reports describe patients who derived little benefit from an identical therapeutic regimen. This is not surprising. A slmilar experience might have been expected had vitamin D or 25-OHD3 been used in the same groups of patients; it has yet to be shown that 1 ,25-(OH)2D3 or la-OHD, produce any therapeutic effects that CaMOt be achieved with larger doses of vitamin D and its hepatic metabolites. There is considerable potential for error in extrapolating from the results of therapy with these new sterols - i n random groups of patients observed in the mass - to conclusions regarding the pathogenesis of renal osteodystrophy. Experience from earlier investigation of renal ‘osteodystrophy suggests that more will be learned from the intensive study of the individual patient than by the acquisition of statistical data from many. Thus, in exploring the responses of azotaemic patients with osteomalacia, one must be certain that the defective mineralization is a direct consequence of the underlying disease -and not the result of others of our therapeutic measures. It has been clear for many years that the injudicious use of aluminium hydroxide or of massive oral doses of non-phosphatic calcium salts, in uraemic patients receiving a low intake of dietary phosphorus, may induce the development of Pdeficiency osteomalacia. More recently it has become apparent that the chronic haemodialytic regimen may induce the same. It would be illogical to expect this type of osteomalacia to heal on treatment with 1,25-(0H)2D3 or la-OHD3; and equally illogical to infer that its development was a direct consequence of the renal disease. Having selected cases of azotaemic osteomalacia uncomplicated by other treatment, one must define what is expected of the new therapy. If h s is solely to promote intestinal absorption of calcium, the problem is relatively simple. The range of dosage of 1,25-(0H)21)3 and la-OHD3 that will produce this effect is already known; and simple means are avadable for detecting increased calcium absorption in the individual patient. By increasing the serum calcium this should reduce parathyroid secretion and the hyperparathyroid component of the bone disease. But if the full therapeutic effect requires some appropriate concentration of 1,25(OH)2D3 in other tissues the problem becomes more complicated. The scanty information avdable suggests that 1 &day of 1,25-(OH)2D3 orally increases its serum concentration only transiently and barely to ‘normal’ levels (Mawer er al., 1976). In a single uraemic patient, 1 pg of la-OHD, produced a serum 1,25-(0H)zD3 of 16 pg/ml at 1 2 h after the oral dose and this increase was also short-lived (Holick et al., 1977). Thus the presently adopted
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method of giving either of these new sterols may not reproduce physiological conditions, if these imply a relatively constant and optimum serum concentration of 1,25-(OH)2D3. If the purported (but unproven) direct effects of ’vitamin D’ on mineralization or on the parathyroid glands required such a normal circulating concentration of the hormone, t h ~ srequirement might not be met by the contemporary therapeutic regimen. The therapeutic requirement might be better met by higher concentrations of a less specific and less potent sterol with a longer biological life, such as 25-OHDS. Until more is known of the physiological concentrations and functions of 1,25-(OH)z& in the blood and other tissues it is premature to conclude, as some have done, that 25-OHD3 has an independent action on the bone. S d a r l y , the therapeutic problem would not necessarily be solved by increasing the oral dose of 1,25-(OH)2D, or la-OHD,, since this might produce hormonal concentrations exceeding the physiological. Hypothetically, the osteolytic action of 1,25-(OH)2D3 might then worsen the bone disease. The means are now available for measuring in man all the identified and biologically active metabolities of vitamin D. Before succumbing to the temptation to invoke direct actions of these individual sterols on various tissues, there is a need to document their concentrations - at least in the serum - in different physiological states, in disease and during therapy. REFERENCES BAYARD, F., BEC, P., TON THAT, H. & LOUVET, J.P. (1973) Plasma 25-hydrouycholecalciferol in chronic renal failure. European Journal of Clinical Investigarion, 3 , 447-450. DAVIES. M., HILL, L.F., TAYLOR, C.M. & STANBURY, S.W. (1977) 1,25-Dihydrouycholecalcirolin hypoparathyrodism. Lancet, i, 55-59. EASTWOOD, J.B., HARRIS, E., STAMP, T.C.B. & DE WARDENER, H.E. (1976) Vitamin D deficiency in the osteomalacia of chronic r e n d f d u r e . Lancet, ii, 1209-121 I . HOLICK, M.F.. DE BLANCO, M.C.. CLARK, M.B., HENLEY, J.W., NEER, R.M., DE LUCA, H.F. & POTTS, J.T. Jr. (1977) The metabolism of [6-’H] 1,hydroxycholecalciferol to [6-%H]l,25dihydroxycholecalciferol in man. Journal of Clinical Endocrinology and Metabolism. (In press.) KANIS, J.A., HEYNEN, G., RUSSELL, R.G.C., SMITH, R., WALTON, R.J. & WARNER, G.T. (1977) Biological effects of 24,25dihydroxycholecalciferol in man. Vitamin D: Biochemical, Chemical and Clinical Aspects Related t o Calcium Metabolism (Ed. by A.W. Norman, K. Schaefer, J.W. Coburn, H.F. DeLuca, D. Fraser, H.C. Crigoleit & D. yon Henath), pp. 793-795. Walter de Cruyter, Berlin. KREMPIEN, B.. MEHL, 0. & RITZ, E. (1974) Morphological studies o n pathogenesis of epiphyseal slipping in uraemic children. Virchows Archiv; Abtedung A: Pathologische Anatornie, 362, 129-143. LUMB, C.A.. MAWER, E.B. & STANBURY, S.W. (1971) The apparent vitamin D resistance of chronic renal failure. A study of the physiology of vitamin D in man. American Journal of Medicine, 50, 4 2 1 . 4 4 1. LIMB,C.A. & STANBURY, S.W. (1974) Parathyroid function in vitamin D deficiency and vitamin D deficiency in primary hyperparathyroidism. American J o u m l of Medicine, 56,833-839. MAWER, E.B., BACKHOUSE, J., DAWES, M., HILL, L.F. & TAYLOR, C.M. (1976) Metabolic fate of administered 1,254ihydroxycholecalciferol in controls and patients with hypoparathyroidism. lancer, i, 1203-1206. MAWER, E.B., BACKHOUSE, J., TAYLOR.C.M., LUMB, C.A. & STANBURY,S.W. (1973) Failure of formation of 1,25dihydroxycholecalciferol in chronic renal insufficiency. Luncer. i, 626-628. MAWER, E.B., LUMB, G.A., SCHAEFFER, K. & STANBURY, S.W. (1971) The metabolism of isotopically labelled vitamin D, in man; the influence of the state of vitamin D nutrition. clincal Science, 40.39-53. NIELSEN, H.E., MELSEN, F., LUND, B., S@RENSEN,O.H. & CHR1STENSEN;M.S. (1977) Serum 25hydroxycholecalciferol and renal osteodystrophy. Lancet, i, 754-755. STANBURY, S.W. (1972) Azotaemic rend osteodystrophy. Clinics in Endocrinology and Metabolism, 1, 26 7-304.
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STANBURY, S.W. & LUMB, G.A. (1976) Parathyroid function in chronic vitamin D deficiency: a model for comparison with chronic renal failure. Calcified Tissue Research, 21, Suppl., 185-201. STANBURY, S.W.. LUMB, G.A. & TORKINGTON, P. (1976) Interrelations of the parathyroid glands, the bone and the kidneys in human vitamin D deficiency. In: Calcium et Maladies Endocriniennes. (Ed. by D. J. Hioco.), pp. 3146. Sandoz, Paris. TAYLOR, C.M., HUGHES, S.E. & DE SILVA, P. (1976) Competitive protein-binding assay for 24.25dihydroxycholedciferol. Biochemical and Biophysical Research Communications, 70, 1243-1 249. TAYLOR, C.M. (1977) The measurement of 24,25dihydroxycholecalciferol in human serum. Vitamin D Biochemical. Chemical and Clinical Aspects Related to calcium metabolism. (Ed. by A.W. Norman, K. Schaefer. J.W.Coburn. H.F. DeLuca. D. Fraser, H.G. Grigoleit and D. von Herrath), pp. 531-543. Walter de Gruyter, Berlin.
