Clinical Endocrinology (1977) 7 , Suppl., 51s-57S.
F A C T O R S INFLUENCING THE RESPONSE TO l a - H Y D R O X Y V I T A M I N D , IN PATIENTS WITH RENAL BONE DISEASE J . A. K A N I S , R . G. G . R U S S E L L , R . B. N A I K , M . E A R N S H A W , R . SMITH, G. HEYNEN A N D C. G. WOODS Renal Unit, Churchill Hospital and Nuffeld Orthopaedic Centre, Oxford, U.K.
SUMMARY
Twenty-three patients with bone disease and chronic renal failure were treated for periods of 4-28 months with la-hydroxyvitamin D3 ( 1a-OHD3). Improvements in bone histology were consistently seen in patients with features both of osteitis fibrosa and osteomalacia but were not invariably observed in patients with osteitis fibrosa or osteomalacia alone (37 and 50% improved respectively). Several factors influencing the outcome of treatment were assessed on the basis of histological responses in bone. A low level of plasma calcium before treatment, rather than the dose of la-OHD3 tolerated, was the major detectable factor which favourably affected the histological outcome. Other factors examined, including initial plasma concentrations of phosphate, immunoreactive parathyroid hormone and alkaline phosphatase, and treatment with haemodialysis or dietary supplements of calcium did not apparently influence the response.
In the preceding paper we described the relation between symptomatic, biochemical, radiographic and histological responses to la-hydroxyvitamin D3 ( la-OHD3) in thirty-five patients with bone disease due to chronic renal failure. This paper examines in more detail some of the factors that contribute to the histological response. PATIENTS AND METHODS The twenty-three patients studied were those described in the previous paper, in whom a hstological diagnosis was made before and during the 4th-28th month of treatment. Histological responses were graded on a 4 point scale (+ 2 = ‘cure’; + 1 = good response; 0 = little response; - 1 = adverse or no response) as previously described in greater detail.
RESULTS
Of the twenty-three patients who had bone biopsies taken before and after treatment, eleven patients showed improvements of bone histology in their second biopsy (grade + 2 and + 1) Correspondence: Dr J . A. Kanis, Renal Unit, Churchdl Hospital, Oxford, U.K
51s
5 2s
J. A . Kanis e t al.
whereas twelve showed little or no change (grade 0 and - 1). These patients were termed good and poor responders, respectively. Despite the arbitary division of patients on the basis of their histological scores there were distinct biochemical differences between poor and good responders (Fig. 1). Mean plasma calcium before treatment was significantly higher in the poor responders, and individual pre-treatment values correlated with hstological score (r = + 0.62; P < 0.001, Fig. 2 ) . Administration of la-OHD,, was associated with an increase in plasma calcium ultimately requiring a reduction in dose in both groups. The dose had to be reduced earlier in the course of treatment in the poor responders (mean time t SEM = 4.6 f 1.3 months) than in the other group (mean = 9.4 k 1.7 months; P < 0.05) when the decrement in plasma alkaline phosphase was also less (Fig. 3). Though plasma calcium increased in both groups, the increment in plasma calcium and the dose required to maintain thls increment were lower in the poor responders so that there was a correlation between the initial plasma calcium and the percentage change in plasma calcium effected by treatment (r = - 0.48; P < 0.02). There were no statistical differences in mean plasma phosphate, alkaline phosphatase or immunoreactive parathyroid hormone (iPTH) between groups before treatment though responders showed a greater and more persistent decrement in plasma phosphate. During treatment the responses of iPTH did not differ significantly, but plasma alkaline phosphatase fell to normal in the responders and changed little in the other group (Fig. 1). Patients treated by haemodialysis had higher initial levels of plasma calcium than patients not on dialysis (mean 2 SEM, 2.39 f 0.05 vs. 2.08 t 0.09; P < 0.01) though no significant difference was noted in other biochemical or histological variables. Of the patients not on dialysis who had repeat histological assessments, two showed good and two showed poor responses suggesting that response may not have been dependent upon treatment with haemodialysis or degree of renal insufficiency. Before treatment plasma levels of phosphate correlated negatively with both osteoid area ( r = - 0.39; P < 0.05) and surface osteoid (r = - 0.58; P < 0.001) but there was no correlation between the change in plasma phosphate and the change in these two variables. Indeed the inverse relationship between plasma phosphate and these indices of osteomalacia (OM) was not found in the biopsies taken during treatment. There were differences in the degree of histological response between patients of differing diagnostic groups. Improvement was limited to four of eight patients with OM and to four of eleven patients with osteitis fibrosa (OF). This contrasted with improvements observed in all four patients with OF + OM (Fig. 2 ) . Factors of possible relevance might have included the relative mildness of both OF and OM in these patients in the sense that mean measurements (for example osteoid area and active resorption surface, plasma phosphate and alkaline phosphatase,) were of intermediate value when compared to patients with OF or OM alone. It is also notable that patients with OF + OM had the lowest mean pre-treatment plasma calcium compared with other diagnostic groups (Fig. 4). The increment induced in plasma calcium associated with treatment was therefore proportionately greater. The dose of 1 a-OHD, tolerated also decreased more rapidly in patients with OM + OF than in others, and between the 7th and 9th month of treatment the mean dose was significantly lower (P< 0.05) than that for patients with OM and indeed were lower than in ‘poor responders’ from the 6th month onwards. Good responses were noted in five of ten patients taking calcium supplements which did not therefore appreciably affect the histological outcome of treatment.
Responsiveness to la-hydroxyvitamin D 3
0 U 0
3Ql
2-6
E 0 -
a
2.2
t
2'ol I .6
4001 3001
'"1 100
I
I
0
6
I2
D u r a t i o n o f treatment (months1
Fig. 1. Doses used of la-OHD, and biochemical responses in twenty-three patients. Patients were divided into good responders (n = 12) and those in whom less favourable responses were seen ( n = 11). Shaded areas indicate the ranges described by the mean t 1 SEM in poor responders, and unshaded areas. those in good responders ( * and * * denote significanf differences between these groups;P < 0.0 1 ;P < 0.05,respectively).
00
ace
a a
a
C
3
I
I
I
-I
0
I
I
2
Histoloqical score
Fig. 2. Histological responses to la-OHD, in relation to plasma calcium levels before treatment. The scoring of histological response is described in detail elsewhere (p. 46s. this volume). The different symbols refer to the histological diagnosis before treatment. 0 , Osteomalacia; 0 , osteomalacia with osteitis fibrosa; 0 , osteitis fibrosa.
53s
J. A . Kanis et al.
54s
I L
I
1
I
0
6
I2
18
Duration o f treotment (months1
Fig. 3. Responses of plasma alkaline phosphatase when hypercalcaemia ( > 3.0 mmol/l) occured requiring a reduction in dose of l a a H D , from 2-2.5 b g daily. A t this time patients with good histological responses ( 0 ) showed suppression of plasma a l k a h e phosphatase to within the normal range (horizontal dashed line). Patients with poor histological responses ( 0 ) became hypercalcaemic earlier during treatment when the f d in plasma levels of alkaline phosphatase was less.
Osteomolocla
I1-10 -In "
L
-
2.
0
\ V
s e\
Osteitis llbrosa
I
I 0
J
I
6
-10
I 12
Durotion of treatment
(months)
Fig. 4. Mean levels of plasma calcium (Circles. f 1 SEM) and mean daily doses of lo-OHD, (continuous lines) during the first year of treatment in patients with osteomalacia ( n = 8). osteo fibrosa ( n = 11). or a combination of OF and OM (n = 4).
Responsiveness to I a-hydroxy vitamin D
55s
Table 1. Factors of possible importance in influencing the responses to IaaHD, (a) Variations in dose and metabolism of l a a H D ,
1. lntestinal absorption 2. Frequency of adminstration (short half-life) 3 . Hepatic conversion t o 1, W O H ) , D , (liver disease, anticonvulsants) 4 . Conversion of l a a H D , and 1,25-(OH),D, to further metabolites (degree of renal impairment, extra-renal metabolism of vitamin D, residual D-status of patient) (b) Variations ir? target organ responses to I o e H D , 1. Intestine: (uraemia. dietary calcium and phosphate, drugs e.g. anticonvulsants, steroids, phosphate binding agents) 2. Bone: type of bone disease and bone-cell responsiveness (effects of hormones, e.g. PTH, calcitonin, prolactin. etc., drugs And ‘uraemic toxins’) 3. Muscle 4. Parathyroid gland (size and degree of ‘autonomy’, drugs) 5 . ‘C’ cells of thyroid
DISCUSSION Some of the factors which might be expected to contribute to variations in response are shown in Table 1. Many have not yet been adequately investigated in man, but the importance of further metabolism of Ia-OHD3 is suggested by observations (Plerides er al., 1976b) that the doses needed for the treatment of renal bone disease are increased in patients taking drugs such as anticonvulsants which induce microsomal enzyme systems and may thereby increase the hepatic metabolism of 25-OHD3. With regard to varying effects on target organs, no differences in the responses of plasma iPTH were observed in the present study, although one should be cautious about interpreting the results of radioimrnunoassay in chronic renal failure. The major determinant of skeletal response appeared to be the pre-treatment level of plasma calcium in our patients (Figs 1 and 2 ) . Patients with the higher levels responded less favourably to la-OHD3 independently of the duration of treatment, concurrent supplements of calcium or of the presence of OF or OM in the bone biopsy. During treatment, mean levels of plasma calcium increased in both poor and good responders, though the increment induced was significantly less in the poor responders since treatment policy dictated that the dose be reduced at a futed value of serum calcium, which was of course independent of the pre-treatment value. This suggests that la-OHD3 and possibly 1 ,25-(0H)2D3 (Coburn ef al., 1977) act in a manner which is not solely dependent upon attaining a high plasma calcium. The responsiveness to treatment may therefore be related to the increment in plasma calcium attainable rather than to the final value. In favour of this hypothesis, patients with OF + OM, in whom initial values for plasma calcium were among the lowest of the histologcal categories (Fig. 4), responded most favourably to la-OHD,. In these patients it was also necessary to decrease the dose of la-OHD3earlier and to a greater extent than in others, suggesting that low dose tolerance and poor histologcal responses seen in other patients (Fig. 1) were not causally related. The pathophysiologcal mechanisms by which plasma calcium is maintained at higher
56s
J. A . Kanis et al.
levels in some patients with chronic renal failure than in others are fl-understood and not fully investigated. The belief that a degree of parathyroid autonomy is the predominant factor may be an over-simplification since other relevant factors include the prevailing rate of intestinal absorption of calcium and the use of dialysis fluid with hlgh levels of calcium. Factors of possible importance such as variations in intestinal secretion of calcium, the balance between calcium accretion and resorption from bone, and changes in pH during dialysis require further investigation. Modifications in one or more of these processes may be of therapeutic importance in altering the responsiveness of patients to la-OHD3. Differences in response may reflect the relative importance of different pathogenic factors in the induction of renal bone disease. For example there is evidence, based on radioimmunoassay, to suggest that renal bone disease may be modified by changes in the secretion of calcitonin (Kanis et al., 1977b), but the role of calcitonin in the responses to la-OHD, has not yet been investigated. Several recent reports (Baker ef al., 1974; Mahony et al., 1976) have suggested that phosphate restriction may induce and that phosphate repletion may heal OM in chronic renal failure implying that defective mineralization and plasma phosphate are causally related. In this respect it should be noted that changes in osteoid area seen in our patients did not correlate with changes in plasma phosphate nor did the correlation between phosphate and surface osteoid, present in our patients before treatment, persist at the time of the second biopsy. These data do not therefore provide evidence that the beneficial effects of la-OHD3 in OM associated with hypophosphataemia are mediated by changes in plasma phosphate. Treatment of renal bone disease with la-hydroxylated metabolites may be associated with a decrease in plasma phosphate during the first few months of treatment (Fig. 1 ; Coburn et al., 1977) despite no apparent change in the dose of phosphate binding agent used. l h s might reflect the incorporation of phosphate into bone. However, plasma phosphate may rise during episodes of drug overdose which could be due either to increased intestinal absorption of phosphate, (Peacock er al., this Symposium) or to its release from bone. In contrast to our own observations, others (Davison et ul., Peacock et al., t h s Symposium) have observed rises in plasma phosphate throughout treatment which may have been due to the avoidance of phosphate binding agents or to more frequent toxicity as judged by the higher levels of plasma calcium that were maintained in these studies. Observations by others (Pierides et al., 1976a) have suggested that OM associated with hypophosphataemia may be resistant to treatment with la-OHD3, but in our patients the prevding plasma phosphate did not appear to influence the histological outcome of treatment in the population as a whole or in patients with OM. Several lines of evidence suggest that the role of deficient production of la-hydroxylated metabolites in the pathogenesis of renal bone disease may not be as important as hitherto supposed. Although production of 1,2540H)2D3 is defective in chronic renal failure (Mawer et a/., 1973; Haussler ef al., 1976), OM and OF are not universally found in patients with end-stage chronic renal failure. The incidence of OF and OM does not invariably increase with time on dialysis or indeed after nephrectomy (Kanis et al., 1977a), and extra-renal metabolism of vitamin D might conceivably be important in determining the type of bone disease. The present study suggests that renal bone disease is not invariably improved by la-OHD,, and that this drug does not reverse renal bone disease by simply replacing a deficiency of 1 ,25-(OH)?D3. The reason it is effective in some patients may be related more to the changes in plasma calcium and PTH it produces than to a direct effect on bone.
Responsiveness to I a-hydroxyvitamin D3
5 7s
ACKNOWLEDGMENTS
We are grateful to the Wellcome Trust, the National Kidney Research Fund, the National Fund for Research into Crippling Diseases and the Peel Medical Research Trust for their support in this work. REFERENCES BAKER, L.R.I., ACKRILL, P., CATELL. W.R., STAMP, T.C.B. & WATSON, L. (1974) Iatrogenic osteomalacia and myopathy due to phosphate depletion. British Medical Journal. iii, 150-152. COBURN, J.W., BRICKMAN, AS.. SHERRARD, D.J., SINGER,F.R., BAYLINK, D.J., WONG,E.G.C.. MASSRY, S.G. & NORMAN, A.W. (1977) Clinical efficacy of 1.2Sdihydroxyvitamin D, in renal osteodystrophy. 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. 6 5 7 4 6 6 . Walter d e Gruyter, Berlin. HAUSSLER, M.R.. BAYLINK, D.J., HUGHES, M.R., BRUMBAUGH, P.F., WERGEDAL, J.E., SHEN, F.H., NIELSEN. R.L., COUNTS. S.J., BURSAC, K.M. & MCCAIN, T.A. (1976) The assay of 1,25dihydroxyvitamin D,: Physiologic and pathologic modulation of circulating hormone levels. Clinical Endocrinology,5 , 1 5 1 ~ 1 6 5 s . KANIS, J.A., ADAMS, N.D., EARNSHAW,M., HEYNEN,G., LEDINGHAM, J.G.G., OLIVER, D.O.. RUSSELL, R.G.G. & WOODS, C.G. (1977a) Vitamin D, osteomalacia and chronic renal failure. 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. Crigoleit and D. von Herrath), pp. 6 7 1 4 7 3 . Walter de Gruyter, Berlin. KANIS, J.A., EARNSHAW. M., HEYNEN.G., LEDINGHAM, J.G.G., OLIVER, D.O., RUSSELL, R.G.G., WOODS, C.C., FRANCHIMONT, P. & GASPAR, S. (1977b) Changes in histologic and biochemical indexes of bone turnover after bilateral nephrectomy in patients on haemodialysis. Evidence for a possible role of endogenous calcitonin. New England Journal of Medicine, 296, 1073-1079. MAHONEY, J.F., HAYES, J.M.. INGHAM, J.P. & POSEN, S. (1976) Hypophosphataemic osteomalacia in patients receiving haemodialysis. British Medical Journal, u, 142-144. MAWER. E.B.. BACKHOUSE, J., TAYLOR, C.M., LUMB, G.A. & STANBURY, S.W. (1973) Evidence for failure of formation of 1,25dihydroxycholecalc~erolin chronic renal failure. Lancet, i, 6 2 6 4 2 8 . PIERIDES,A.M., ELLIS, H.A., SIMPSON, W., DEWAR. J.H., WARD,M.K. & KERR, D.N.S. (1976a) Variable response to long-term la-hydroxycholecalciferol in haemodialysis osteodystrophy. Lancet, i, 1092-1095. PIERIDES, A.M., KERR, D.N.S., ELLIS, H.A., PEART, K.M., O’RIORDAN, J.L.H. & DELUCA, H.F. (1976b) la-hydroxycholecdciferol in haemodialysis renal osteodystrophy. Adverse effects of anticonvulsant therapy. Clinical Nephrology, 5 , 189-196.
F A C T O R S INFLUENCING THE RESPONSE TO l a - H Y D R O X Y V I T A M I N D , IN PATIENTS WITH RENAL BONE DISEASE J . A. K A N I S , R . G. G . R U S S E L L , R . B. N A I K , M . E A R N S H A W , R . SMITH, G. HEYNEN A N D C. G. WOODS Renal Unit, Churchill Hospital and Nuffeld Orthopaedic Centre, Oxford, U.K.
SUMMARY
Twenty-three patients with bone disease and chronic renal failure were treated for periods of 4-28 months with la-hydroxyvitamin D3 ( 1a-OHD3). Improvements in bone histology were consistently seen in patients with features both of osteitis fibrosa and osteomalacia but were not invariably observed in patients with osteitis fibrosa or osteomalacia alone (37 and 50% improved respectively). Several factors influencing the outcome of treatment were assessed on the basis of histological responses in bone. A low level of plasma calcium before treatment, rather than the dose of la-OHD3 tolerated, was the major detectable factor which favourably affected the histological outcome. Other factors examined, including initial plasma concentrations of phosphate, immunoreactive parathyroid hormone and alkaline phosphatase, and treatment with haemodialysis or dietary supplements of calcium did not apparently influence the response.
In the preceding paper we described the relation between symptomatic, biochemical, radiographic and histological responses to la-hydroxyvitamin D3 ( la-OHD3) in thirty-five patients with bone disease due to chronic renal failure. This paper examines in more detail some of the factors that contribute to the histological response. PATIENTS AND METHODS The twenty-three patients studied were those described in the previous paper, in whom a hstological diagnosis was made before and during the 4th-28th month of treatment. Histological responses were graded on a 4 point scale (+ 2 = ‘cure’; + 1 = good response; 0 = little response; - 1 = adverse or no response) as previously described in greater detail.
RESULTS
Of the twenty-three patients who had bone biopsies taken before and after treatment, eleven patients showed improvements of bone histology in their second biopsy (grade + 2 and + 1) Correspondence: Dr J . A. Kanis, Renal Unit, Churchdl Hospital, Oxford, U.K
51s
5 2s
J. A . Kanis e t al.
whereas twelve showed little or no change (grade 0 and - 1). These patients were termed good and poor responders, respectively. Despite the arbitary division of patients on the basis of their histological scores there were distinct biochemical differences between poor and good responders (Fig. 1). Mean plasma calcium before treatment was significantly higher in the poor responders, and individual pre-treatment values correlated with hstological score (r = + 0.62; P < 0.001, Fig. 2 ) . Administration of la-OHD,, was associated with an increase in plasma calcium ultimately requiring a reduction in dose in both groups. The dose had to be reduced earlier in the course of treatment in the poor responders (mean time t SEM = 4.6 f 1.3 months) than in the other group (mean = 9.4 k 1.7 months; P < 0.05) when the decrement in plasma alkaline phosphase was also less (Fig. 3). Though plasma calcium increased in both groups, the increment in plasma calcium and the dose required to maintain thls increment were lower in the poor responders so that there was a correlation between the initial plasma calcium and the percentage change in plasma calcium effected by treatment (r = - 0.48; P < 0.02). There were no statistical differences in mean plasma phosphate, alkaline phosphatase or immunoreactive parathyroid hormone (iPTH) between groups before treatment though responders showed a greater and more persistent decrement in plasma phosphate. During treatment the responses of iPTH did not differ significantly, but plasma alkaline phosphatase fell to normal in the responders and changed little in the other group (Fig. 1). Patients treated by haemodialysis had higher initial levels of plasma calcium than patients not on dialysis (mean 2 SEM, 2.39 f 0.05 vs. 2.08 t 0.09; P < 0.01) though no significant difference was noted in other biochemical or histological variables. Of the patients not on dialysis who had repeat histological assessments, two showed good and two showed poor responses suggesting that response may not have been dependent upon treatment with haemodialysis or degree of renal insufficiency. Before treatment plasma levels of phosphate correlated negatively with both osteoid area ( r = - 0.39; P < 0.05) and surface osteoid (r = - 0.58; P < 0.001) but there was no correlation between the change in plasma phosphate and the change in these two variables. Indeed the inverse relationship between plasma phosphate and these indices of osteomalacia (OM) was not found in the biopsies taken during treatment. There were differences in the degree of histological response between patients of differing diagnostic groups. Improvement was limited to four of eight patients with OM and to four of eleven patients with osteitis fibrosa (OF). This contrasted with improvements observed in all four patients with OF + OM (Fig. 2 ) . Factors of possible relevance might have included the relative mildness of both OF and OM in these patients in the sense that mean measurements (for example osteoid area and active resorption surface, plasma phosphate and alkaline phosphatase,) were of intermediate value when compared to patients with OF or OM alone. It is also notable that patients with OF + OM had the lowest mean pre-treatment plasma calcium compared with other diagnostic groups (Fig. 4). The increment induced in plasma calcium associated with treatment was therefore proportionately greater. The dose of 1 a-OHD, tolerated also decreased more rapidly in patients with OM + OF than in others, and between the 7th and 9th month of treatment the mean dose was significantly lower (P< 0.05) than that for patients with OM and indeed were lower than in ‘poor responders’ from the 6th month onwards. Good responses were noted in five of ten patients taking calcium supplements which did not therefore appreciably affect the histological outcome of treatment.
Responsiveness to la-hydroxyvitamin D 3
0 U 0
3Ql
2-6
E 0 -
a
2.2
t
2'ol I .6
4001 3001
'"1 100
I
I
0
6
I2
D u r a t i o n o f treatment (months1
Fig. 1. Doses used of la-OHD, and biochemical responses in twenty-three patients. Patients were divided into good responders (n = 12) and those in whom less favourable responses were seen ( n = 11). Shaded areas indicate the ranges described by the mean t 1 SEM in poor responders, and unshaded areas. those in good responders ( * and * * denote significanf differences between these groups;P < 0.0 1 ;P < 0.05,respectively).
00
ace
a a
a
C
3
I
I
I
-I
0
I
I
2
Histoloqical score
Fig. 2. Histological responses to la-OHD, in relation to plasma calcium levels before treatment. The scoring of histological response is described in detail elsewhere (p. 46s. this volume). The different symbols refer to the histological diagnosis before treatment. 0 , Osteomalacia; 0 , osteomalacia with osteitis fibrosa; 0 , osteitis fibrosa.
53s
J. A . Kanis et al.
54s
I L
I
1
I
0
6
I2
18
Duration o f treotment (months1
Fig. 3. Responses of plasma alkaline phosphatase when hypercalcaemia ( > 3.0 mmol/l) occured requiring a reduction in dose of l a a H D , from 2-2.5 b g daily. A t this time patients with good histological responses ( 0 ) showed suppression of plasma a l k a h e phosphatase to within the normal range (horizontal dashed line). Patients with poor histological responses ( 0 ) became hypercalcaemic earlier during treatment when the f d in plasma levels of alkaline phosphatase was less.
Osteomolocla
I1-10 -In "
L
-
2.
0
\ V
s e\
Osteitis llbrosa
I
I 0
J
I
6
-10
I 12
Durotion of treatment
(months)
Fig. 4. Mean levels of plasma calcium (Circles. f 1 SEM) and mean daily doses of lo-OHD, (continuous lines) during the first year of treatment in patients with osteomalacia ( n = 8). osteo fibrosa ( n = 11). or a combination of OF and OM (n = 4).
Responsiveness to I a-hydroxy vitamin D
55s
Table 1. Factors of possible importance in influencing the responses to IaaHD, (a) Variations in dose and metabolism of l a a H D ,
1. lntestinal absorption 2. Frequency of adminstration (short half-life) 3 . Hepatic conversion t o 1, W O H ) , D , (liver disease, anticonvulsants) 4 . Conversion of l a a H D , and 1,25-(OH),D, to further metabolites (degree of renal impairment, extra-renal metabolism of vitamin D, residual D-status of patient) (b) Variations ir? target organ responses to I o e H D , 1. Intestine: (uraemia. dietary calcium and phosphate, drugs e.g. anticonvulsants, steroids, phosphate binding agents) 2. Bone: type of bone disease and bone-cell responsiveness (effects of hormones, e.g. PTH, calcitonin, prolactin. etc., drugs And ‘uraemic toxins’) 3. Muscle 4. Parathyroid gland (size and degree of ‘autonomy’, drugs) 5 . ‘C’ cells of thyroid
DISCUSSION Some of the factors which might be expected to contribute to variations in response are shown in Table 1. Many have not yet been adequately investigated in man, but the importance of further metabolism of Ia-OHD3 is suggested by observations (Plerides er al., 1976b) that the doses needed for the treatment of renal bone disease are increased in patients taking drugs such as anticonvulsants which induce microsomal enzyme systems and may thereby increase the hepatic metabolism of 25-OHD3. With regard to varying effects on target organs, no differences in the responses of plasma iPTH were observed in the present study, although one should be cautious about interpreting the results of radioimrnunoassay in chronic renal failure. The major determinant of skeletal response appeared to be the pre-treatment level of plasma calcium in our patients (Figs 1 and 2 ) . Patients with the higher levels responded less favourably to la-OHD3 independently of the duration of treatment, concurrent supplements of calcium or of the presence of OF or OM in the bone biopsy. During treatment, mean levels of plasma calcium increased in both poor and good responders, though the increment induced was significantly less in the poor responders since treatment policy dictated that the dose be reduced at a futed value of serum calcium, which was of course independent of the pre-treatment value. This suggests that la-OHD3 and possibly 1 ,25-(0H)2D3 (Coburn ef al., 1977) act in a manner which is not solely dependent upon attaining a high plasma calcium. The responsiveness to treatment may therefore be related to the increment in plasma calcium attainable rather than to the final value. In favour of this hypothesis, patients with OF + OM, in whom initial values for plasma calcium were among the lowest of the histologcal categories (Fig. 4), responded most favourably to la-OHD,. In these patients it was also necessary to decrease the dose of la-OHD3earlier and to a greater extent than in others, suggesting that low dose tolerance and poor histologcal responses seen in other patients (Fig. 1) were not causally related. The pathophysiologcal mechanisms by which plasma calcium is maintained at higher
56s
J. A . Kanis et al.
levels in some patients with chronic renal failure than in others are fl-understood and not fully investigated. The belief that a degree of parathyroid autonomy is the predominant factor may be an over-simplification since other relevant factors include the prevailing rate of intestinal absorption of calcium and the use of dialysis fluid with hlgh levels of calcium. Factors of possible importance such as variations in intestinal secretion of calcium, the balance between calcium accretion and resorption from bone, and changes in pH during dialysis require further investigation. Modifications in one or more of these processes may be of therapeutic importance in altering the responsiveness of patients to la-OHD3. Differences in response may reflect the relative importance of different pathogenic factors in the induction of renal bone disease. For example there is evidence, based on radioimmunoassay, to suggest that renal bone disease may be modified by changes in the secretion of calcitonin (Kanis et al., 1977b), but the role of calcitonin in the responses to la-OHD, has not yet been investigated. Several recent reports (Baker ef al., 1974; Mahony et al., 1976) have suggested that phosphate restriction may induce and that phosphate repletion may heal OM in chronic renal failure implying that defective mineralization and plasma phosphate are causally related. In this respect it should be noted that changes in osteoid area seen in our patients did not correlate with changes in plasma phosphate nor did the correlation between phosphate and surface osteoid, present in our patients before treatment, persist at the time of the second biopsy. These data do not therefore provide evidence that the beneficial effects of la-OHD3 in OM associated with hypophosphataemia are mediated by changes in plasma phosphate. Treatment of renal bone disease with la-hydroxylated metabolites may be associated with a decrease in plasma phosphate during the first few months of treatment (Fig. 1 ; Coburn et al., 1977) despite no apparent change in the dose of phosphate binding agent used. l h s might reflect the incorporation of phosphate into bone. However, plasma phosphate may rise during episodes of drug overdose which could be due either to increased intestinal absorption of phosphate, (Peacock er al., this Symposium) or to its release from bone. In contrast to our own observations, others (Davison et ul., Peacock et al., t h s Symposium) have observed rises in plasma phosphate throughout treatment which may have been due to the avoidance of phosphate binding agents or to more frequent toxicity as judged by the higher levels of plasma calcium that were maintained in these studies. Observations by others (Pierides et al., 1976a) have suggested that OM associated with hypophosphataemia may be resistant to treatment with la-OHD3, but in our patients the prevding plasma phosphate did not appear to influence the histological outcome of treatment in the population as a whole or in patients with OM. Several lines of evidence suggest that the role of deficient production of la-hydroxylated metabolites in the pathogenesis of renal bone disease may not be as important as hitherto supposed. Although production of 1,2540H)2D3 is defective in chronic renal failure (Mawer et a/., 1973; Haussler ef al., 1976), OM and OF are not universally found in patients with end-stage chronic renal failure. The incidence of OF and OM does not invariably increase with time on dialysis or indeed after nephrectomy (Kanis et al., 1977a), and extra-renal metabolism of vitamin D might conceivably be important in determining the type of bone disease. The present study suggests that renal bone disease is not invariably improved by la-OHD,, and that this drug does not reverse renal bone disease by simply replacing a deficiency of 1 ,25-(OH)?D3. The reason it is effective in some patients may be related more to the changes in plasma calcium and PTH it produces than to a direct effect on bone.
Responsiveness to I a-hydroxyvitamin D3
5 7s
ACKNOWLEDGMENTS
We are grateful to the Wellcome Trust, the National Kidney Research Fund, the National Fund for Research into Crippling Diseases and the Peel Medical Research Trust for their support in this work. REFERENCES BAKER, L.R.I., ACKRILL, P., CATELL. W.R., STAMP, T.C.B. & WATSON, L. (1974) Iatrogenic osteomalacia and myopathy due to phosphate depletion. British Medical Journal. iii, 150-152. COBURN, J.W., BRICKMAN, AS.. SHERRARD, D.J., SINGER,F.R., BAYLINK, D.J., WONG,E.G.C.. MASSRY, S.G. & NORMAN, A.W. (1977) Clinical efficacy of 1.2Sdihydroxyvitamin D, in renal osteodystrophy. 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. 6 5 7 4 6 6 . Walter d e Gruyter, Berlin. HAUSSLER, M.R.. BAYLINK, D.J., HUGHES, M.R., BRUMBAUGH, P.F., WERGEDAL, J.E., SHEN, F.H., NIELSEN. R.L., COUNTS. S.J., BURSAC, K.M. & MCCAIN, T.A. (1976) The assay of 1,25dihydroxyvitamin D,: Physiologic and pathologic modulation of circulating hormone levels. Clinical Endocrinology,5 , 1 5 1 ~ 1 6 5 s . KANIS, J.A., ADAMS, N.D., EARNSHAW,M., HEYNEN,G., LEDINGHAM, J.G.G., OLIVER, D.O.. RUSSELL, R.G.G. & WOODS, C.G. (1977a) Vitamin D, osteomalacia and chronic renal failure. 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. Crigoleit and D. von Herrath), pp. 6 7 1 4 7 3 . Walter de Gruyter, Berlin. KANIS, J.A., EARNSHAW. M., HEYNEN.G., LEDINGHAM, J.G.G., OLIVER, D.O., RUSSELL, R.G.G., WOODS, C.C., FRANCHIMONT, P. & GASPAR, S. (1977b) Changes in histologic and biochemical indexes of bone turnover after bilateral nephrectomy in patients on haemodialysis. Evidence for a possible role of endogenous calcitonin. New England Journal of Medicine, 296, 1073-1079. MAHONEY, J.F., HAYES, J.M.. INGHAM, J.P. & POSEN, S. (1976) Hypophosphataemic osteomalacia in patients receiving haemodialysis. British Medical Journal, u, 142-144. MAWER. E.B.. BACKHOUSE, J., TAYLOR, C.M., LUMB, G.A. & STANBURY, S.W. (1973) Evidence for failure of formation of 1,25dihydroxycholecalc~erolin chronic renal failure. Lancet, i, 6 2 6 4 2 8 . PIERIDES,A.M., ELLIS, H.A., SIMPSON, W., DEWAR. J.H., WARD,M.K. & KERR, D.N.S. (1976a) Variable response to long-term la-hydroxycholecalciferol in haemodialysis osteodystrophy. Lancet, i, 1092-1095. PIERIDES, A.M., KERR, D.N.S., ELLIS, H.A., PEART, K.M., O’RIORDAN, J.L.H. & DELUCA, H.F. (1976b) la-hydroxycholecdciferol in haemodialysis renal osteodystrophy. Adverse effects of anticonvulsant therapy. Clinical Nephrology, 5 , 189-196.
