Calcium therapy for calcitriol-resistant rickets Z e e v H o c h b e r g , MD, DSc, Dov Tiosano, MD, a n d Lea Even, MD From the Departments of Pediatrics, Rambam Medical Center and B'nai Zion Medical Center, Haifa, Israel Ten patients with calcitriol-resistant rickets c a u s e d by a d e f e c t in the Ugandbinding d o m a i n of the vitamin D r e c e p t o r are described. Eight patients, 1.7 to 13.8 years of age, received high doses of elemental calcium (range, 0.4 to 1.4 g m / m 2) through indwelling intracaval catheters for periods of 1.8 to 3.8 years. Two other patients, a g e d 1.1 and 2.2 years, were given oral calcium therapy as the sole m o d e of treatment. In five of the intravenously treated patients, oral calcium therapy was initiated after r a d i o l o g i c e v i d e n c e of healing of the rickets. To maintain normal serum calcium concentration, the patients required daily doses of elemental calcium of 3.5 to 9 g m / m 2 b o d y surface area. Clinical improvement was observed within a w e e k of the start of intravenous therapy, with d i s a p p e a r a n c e of b o n e pain; several of the y o u n g e r patients started to walk for the first time. Growth velocity increased within 2 to 3 months, from a pretreatment rate of - 0 . 8 to - 6 . 3 standard deviation score (SDS), to a posttreatment rate of +0.1 to +5.1 (SDS). Serum calcium, parathyroid hormone, phosphorus, and alkaline phosphatase values returned to normal within a year. Radiologic signs of healing occurred more rapidly in the intravenous treatment groups and in y o u n g e r patients. Episodes of septicemia occurred frequently in those receiving parenteral therapy and required r e p l a c e m e n t of the catheter. We recommend that in the treatment of calcitriol-resistant rickets, oral calcium therapy b e started at the youngest possible age, in doses to the limit of intestinal tolerance. When rickets is present, calcium should be infused through a large vessel in doses high e n o u g h to p r o d u c e n o r m o c a l c e m i a , normophosphatemia, and suppression of parathyroid hormone. Only after r a d i o l o g i c healing has been observed can oral calcium therapy be introduced. (J PEDIATR1992;121:803-8)
Calcitriol-resistant rickets is a group of autosomal recessive abnormalities of the vitamin D receptor that result in severe rickets from early infancy, severe growth retardation, generalized alopecia, and resistance to therapy with calcitriO1.1-7 These entities share a defective VDR, s14 resulting from a series of point mutations in the VDR gene. 15-~8Some patients undergo spontaneous healing of the rachitic bone changes,19 and high-dose vitamin D therapy can be helpful in others. 4, 20 Those with extreme receptor-negative muta-
tions and truncated VDR have no response to therapy, despite extremely high serum calcitriol levels of 1000 to 1500 pg/ml (normal, 20 to 60 pg/ml), obtained by giving daily doses of lc~-hydroxyvitamin D3 as high as 60 #g/m2.19 A study of intestinal absorption of calcium in patients
Submitted for publication Feb. 19, 1992; accepted June 1, 1992. Reprint requests: Zeev Hochberg, Technion Faculty of Medicine, P.O. Box 9649, Haifa 31096, Israel. 9/25/39906
with CRR revealed reduced absorption, but only to 50% to 60% of control values, and enhanced bone uptake of the absorbed calcium.5,21 To bypass the interrupted intestinal absorption of calcium, the major role of vitamin D affected
CCR PTH SDS VDR
Calcitriol-resistant rickets Parathyroid hormone Standard deviation score Vitamin D receptor
803
804
Hochberg, Tiosano, and Even
The Journal of Pediatrics November 1992
T a b l e . Calcium therapy, growth response, and radiologic outcome in 10 patients with calcitriol-resistant rickets Patient No. 1
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Growth velocity'l" (SDS)
0.6-1.7 1.7-3.5 3.5-4.0 0.3-1.l 1.1-3.0 0.9-2.0 2.0-4.8 4.8-5.5 1.0-2.2 2.2-4.0 2.5-3.9 3.9-7,0 7.0-9.2 4.0-5.8 5.8-9.0 8.8-10.7 10.7-14.5 7.0-11.5 11.5-15.0 9.9-13.7 13.7-16.8 16.8-17.8 10.9-13.8 13.8-17.0 17.0-18.2
-2.3 + 1.3 +0.2 -3.1 +2.3 -0.8 +0.7 + 1.6 -4.0 +2.2 -4.6 +3.5 +0.3 -6.3 +2.9 -3.9 +5.1 -4.0 +0.1 -2.4
Radiologic outcome Healed Healed Improved Healed Healed Improved Healed Healed Improved Healed Healed Healed Healed Healed Healed
*The letters and subscript numbers refer to the pedigree as detailed in reference 18 and the family designation in the other references noted. "~For the previous 1 to 2 years.
in CRR, some have used intravenous calcium infusion therapy; the short-term results have been reported for four patients. 2~23 It seemed possible that early initiation of therapy with high oral doses of calcium, before the establishment of severe rickets or after healing of rickets by intravenous calcium infusions, might be effective in these patients. This report summarizes our long-term experience in giving therapy for CRR with intravenous calcium infusions and with high oral doses of calcium.
METHODS Patients. We studied 10 patients with CRR caused by a defect in the ligand-bindingdomain of the VDR, verified in every case by binding studies, by a bioassay of vitamin D activity,6, s, 16, 18, 19, 24 and by polymerase chain reaction analysis of the VDR. 16' 18 Eight of the patients belong to seven branches of an extended Arab family with a high degree of consanguinity, as previously reported 6, 18, 19 and detailed in the Table. The other two patie'nts (Nos. 6 and 8) are brothers of a different Arab family, though the proximity of their residence and the identical point mutations suggest a distant relationship. The clinical course of patients 6 through 10 was previously reported. 6' 19 The first year of
therapy with intravenously administered calcium has been reported for patient 5. 2z Intravenous calcium therapy. An intracaval catheter was inserted through a branch of the jugular vein under general anesthesia. The infusion solution consisted of calcium glucono-galacto-gluconate (Sandoz Laboratories, Basel, Switzerland) in 0.9% sodium chloride. The calcium solution was given continuously in the hospital, under cardiac monitoring, for the first 1 to 2 months. It was continued at home for 12 hours daily. After periods of 1 to 3 months of home nursing care, the mothers and the older patients were trained to administer calcium intravenously. The dosage was adjusted frequently to give a serum calcium concentration of 2.1 to 2.5 mmol/L (8.4 to 10 rag/all). After 2 years of daily infusions and with radiologic signs of improvement, the dosage was divided into two to four weekly infusions. Oral calcium therapy. Calcium was given in effervescent tablets of calcium lactate-gluconate (Sandoz), containing 500 mg elemental calcium. The dosage was increased gradually to maximal gastrointestinal tolerance, as reported by the patients and the parents, in four or five daily doses. Analytic methods. Serum calcium, phosphorus, and alkaline phosphatase values were determined by using an automatic analyzer. Serum immunoreactive parathyroid hor-
Volume 121 Number 5, Part 1
Calcium f o r calcitriol-resistant rickets
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Figure. Effect of intravenous or oral calcium therapy on serum calcium, phosphorus, alkaline phosphatase, and plasma PTH levelsin 10 patients with CRR. Each string of lines indicates a single patient and correspondingpatient number (from the Table). Lines indicate results before any therapy (dotted line), after intravenouscalcium therapy (solid line), and after oral calcium therapy (dashed line)9
mone was measured with a radioimmunoassay kit for the C-terminal PTH (Sorin Biomedica, Fleures, Belgium). The normal adult levels are 6 to 20 pmol/L. RESULTS Intravenous calcium therapy. As detailed in the Table, intravenous calcium therapy started at age 1.7 to 13.8 years
and extended for a period of 1.8 to 3.8 years. To maintain normal serum calcium levels, the patients required a daily dose of 0.4 to 1.4 gm elemental calcium ions per square meter of body surface area. Within 4 to 13 months of therapy, when the serum calcium concentration approached the lower limit of normal, mild hypercaleiuria developed, with urinary calcium/creatinine ratio of 0.3 to 0.5 and urinary
806
Hochberg, Tiosano, and Even
excretion that amounted to as much as 20% of the infused calcium. Hypercalciuria persisted throughout intravenous therapy in all the patients. Periodic ultrasonography of the kidneys showed no evidence of nephrocalcinosis. Clinical improvement was observed within a week of initiation of therapy, with disappearance of bone pain; several of the younger patients started to walk for the first time. Acceleration of growth velocity was evident within 2 to 3 months. Growth velocity increased from a pretreatment rate of -0.8 to -6.3 standard deviation score (according to the normative data of Tanner et al.) 24 to +0.1 to +5.1 SDS. The patients with the slowest pretreatment velocity had a maximal response to therapy. The changes in serum calcium, phosphorus, alkaline phosphatase, and plasma PTH values are summarized in the Figure. The results for PTH do not always coincide with the age at therapy, as indicated in the Table, because these were obtained at different times. The serum calcium concentration became normal within 6 to 11 months. Plasma PTH was measured too infrequently to permit a summary of the time course of its normalization, but low serum phosphorus concentrations, which can be regarded as a result of hyperparathyroidism, became normal within 7 to 15 months of the initiation of therapy. Serum alkaline phosphatase activity decreased significantly within 7 to 13 months of therapy and became normal within 13 to 38 months. Radiologic signs of healing were seen sooner in the younger patients than in the older ones. Delivery of calcium through a central vein for such long periods was accompanied by significant morbidity. During the initial week of therapy, cardiac arrhythmias, mostly bradycardia, were often observed. Episodes of septicemia occurred in all patients, with a mean frequency of one every 8 months (range, 3 to 37 months), and required hospitalization, cessation of calcium therapy, and intravenous antibiotic therapy. The central catheter had to be replaced at a mean frequency of once every 14 months, a procedure that required general anesthesia. Oral calcium therapy. Oral calcium therapy was started in two patients, aged I. 1 and 2.2 years, as the sole mode of treatment and has continued for 1.9 and 1.8 years, respectively. In five other patients, aged 3.5 to 17 years, oral calcium therapy was initiated after radiologic evidence of healing of the rachitic bone changes during intravenous therapy. To maintain normal serum calcium levels, the patients required daily doses of elemental calcium of 3.5 to 9 gm/m 2 body surface area. Urinary calcium excretion was monitored regularly only in the youngeF patients and occasionally in the older; urinary calcium/creatinine ratio was normal (less than 0.22) in all cases. Clinical improvement was slower than that after intravenous calcium therapy. Growth velocity increased in the two
The Journal of Pediatrics November 1992
younger patients from a pretreatment rate of -3.1 and - 4 . 0 SDS to +2.3 and +2.2 SDS, respectively. In the three older patients who had had intravenous treatment and who still had growth potential, growth velocity (as determined by positive SDS) was maintained, though at a slower pace. In the two patients who had not received intravenous calcium therapy, serum calcium concentrations became normal within 7 and 11 months, plasma PTH levels within 15 and 17 months, serum phosphorus levels within 16 and 19 months, and serum alkaline phosphatase activity within 18 and 22 months of initiation of therapy. Radiologic signs of rickets show improvement, but complete healing has not occurred. Oral calcium treatment was accompanied during the first months by significant abdominal discomfort, which required a slow increase of the dosage. After this period of adjustment, there were no further complaints or physical side effects of therapy. DISCUSSION Calcitriol-resistant rickets of the subtype described here is the most severe form of rickets, with no clinical response to calcitriol in doses that are 100-fold higher than normal. 19 In our patients it resulted from a complete absence of calcitriol binding and biologic activity8, I4, 16, 18, 19, 24 as a result of truncation of the receptor, which in turn was caused by a stop codon on the VDR gene. 16, 18 The main function of calcitriol is to enhance intestinal absorption of calcium, and the early reports of CRR did describe malabsorption of calcium in this condition), 5 To bypass the limited intestinal absorption of calcium, Balsan et al., 22 Weisman et al., 23 and Bliziotes et al. 21 suggested the intravenous route to deliver high quantities of calcium. Their reports on the short-term outcome of such therapy in four patients seemed promising, albeit not without hazards. Our long-term experience with intracaval infusion of high doses of calcium to a larger cohort of patients with CRR shows that outcome" is satisfactory, with normalization of serum calcium, PTH, phosphorus, and alkaline phosphatase values (in that succession), in growth acceleration, and in radiologic healing of the rachitic bone changes. However, the procedure is complicated for both the patients and their parents, and risky in terms of cardiac arrhythmias (which we observed during the initial week of therapy only) and recurrent septicemia. After normalization of the serum calcium concentration, hypercalciuria was evident in every case, though nephrocalcinosis was not seen on sonograms or on plain abdominal radiographs. Calcitriol has its greatest effects in the intestine, where it enhances calcium absorption.25 However, hormones are stimulators of existing mechanisms, and intestinal calcium absorption is not altogether lost in the absence of calcitriol.
Volume 121 Number 5, Part 1
In two patients with C R R who were described, 47Ca or stable 44Ca absorption was about 40% of values obtained in healthy children. 5, 23 Similar findings were present in three of our patients (Yergey AL, Hochberg Z: personal communication, 1991 ). Thus high oral doses of calcium may offer the potential to move calcium into plasma by passive absorption in sufficient amounts to return serum calcium levels to normal. On the other hand, we have tried oral calcium therapy unsuccessfully in the past. ~9 The protocol described in this report differs from our previous treatment in two ways. Therapy was initiated either at a very young age, when rachitic damage was not as extensive as in older patients, or after healing by intravenous calcium therapy. In both cases the bones were not as "hungry" for calcium as is true in the severe rickets observed in patients with C R R . Our other aim was to deliver massive doses of calcium. We prescribed gradually increasing doses, limited only by intestinal tolerance. The implications of these results for the understanding of the role of calcitriol in normal physiology are interesting, and are in agreement with a previous report 26 on a limited endocrine role for vitamin D other than in the gut. The principal effect of calcitriol is in regulating intestinal calcium absorption. In rats, infusion of calcium and phosphorus prevents rickets in vitamin D-deficient animals. 27 The same holds true for the effects of calcium and calcitriol on P T H suppression. The results of calcium administration indicate that secondary hyperparathyroidism is fully suppressed even in the absence of a VDR-mediated calcitriol effect. On the basis of our limited experience with 10 patients, we recommend that oral calcium therapy be started at the youngest possible age, in substantial doses, and to the limit of intestinal discomfort. When rickets has already commenced and advanced, calcium should be infused through a large vessel in a dosage high enough to allow resumption of normocalcemia, P T H suppression, and normophosphatemia. After radiologic healing has been observed, oral calcium therapy can be introduced. With both routes of therapy, periodic monitoring of serum calcium, P T H , and phosphorus levels, and of urinary calcium excretion, should be done to ensure that calcium is given at the lowest sufficient dosage. With the progress of therapy and the saturation of bone minerals, the dosage can be reduced according to the results of monitoring. REFERENCES
1. Brooks MH, Bell NH, Love L, et al. Vitamin D-dependent rickets type II: resistance of target organs to 1,25-dihydroxyvitamin D. N Engl J Med 1978;298:996-9. 2. Rosen JF, Fleischman AR, Finberg L, Hamstra A J, DeLuca HF. Rickets with alopecia: an inborn error of vitamin D metabolism. J PED~ATR1979;94:729-35.
Calcium f o r calcitriol-resistant rickets
807
3. Zerwekh JE, Glass K, Jowsey J, Pak CYC. A unique form of osteomalacia associated with end organ refractoriness to 1,25hydroxyvitamin D and apparent defective synthesis of 25-bydroxyvitamin D. J Clin Endocrinol Metab 1979;49:171-5. 4. Liberman UA, Samuel R, Halabe A, et al. End organ resistance to 1,25-dihydroxycbolecalciferol. Lancet 1980; 1:504-7. 5. Tsuchiya Y, Matsuo N, Cho H, et al. An unusual form of vitamin D-dependent rickets in a child: alopecia and marked end-organ hyposensitivity to biologically active vitamin D. J Clin Endoerinol Metab 1980;51:685-90. 6. Beer S, Tieder M, Kohelet D, et al. Vitamin D resistance to 1,25-dihydroxyvitamin D. Clin Endocrinol (Oxf) 1981;14:395402. 7. Marx S J, Spiegel AM, Brown EM, et al. A familial syndrome of decrease in sensitivity to 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 1978;47:1303-10. 8. Feldman D, Chen T, Cone C, Hirst M, Shani S, Benderly A, Hochberg Z. Vitamin-D-resistant rickets with alopecia: cultured skin fibroblasts exhibit defective cytoplasmic receptors and unresponsiveness to 1,25(OH)2D3. J Clin Endocrinol Metab 1982;55:1020-2. 9. Liberman UA, Ell C, Marx SJ. Resistance to 1,25-dihydroxyvitamin D: association with heterogeneous defects in cultured skin fibroblasts. J Clin Invest 1983;71:192-200. 10. Clemens TL, Adams JA, Horiuchi N, et al. Interaction of 1,25-dihydroxyvitamin D3 with keratinocytes and fibroblasts from skin of normal subjects and a subject with vitamin-Ddependent rickets, type II: a model for study of the mode of action of 1,25-dihydroxyvitamin D 3. J Clin Endocrinol Metab 1983;56:824-30. 11. Koren R, Ravid A, Liberman UA, Hochberg Z, Weisman Y, Novogrodski A. Defective binding and function of 1,25-dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end-organ resistance to 1,25(OH)2D3. J Clin Invest 76;2012-5, 1985. 12. Gamblin GT, Liberman UA, Ell C, Downs RW Jr, Deghrange DA, Marx SJ. Vitamin D-dependent rickets type II: defective induction of 1,25-dihydroxyvitamin D3, in cultured skin fibroblasts..I Clin Invest 1985;75:954-60. 13. Liberman UA, Ell C, Marx SJ. Receptor-positive hereditary resistance to 1,25-dihydroxyvitamin D: chromatography of hormone receptor complexes on deoxyribonucleic acid-cellulose shows two classes of mutation. J Clin Endocrinol Metab 1986;62:122-6. 14. MaUoy P J, Hochberg Z, Pike JW, Feldman D. Abnormal binding of vitamin D receptors to deoxyribonucleic acid in a kindred with vitamin D-dependent rickets, type II. J Clin Endocrinol Metab 1989;68:263-9. 15. Hughes MR, Malloy P J, Kieback DG, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 1988;242:1702-5. 16. Ritchie HH, Hughes MR, Thompson ET, et al. An ochre mutation in the vitamin D receptor gene causes hereditary 1,25dihydroxyvitamin D3-resistant rickets in three families. Proc Natl Acad Sci USA 1989;86:9783-7. 17. Sone T, Scott RA, Hughes MR, et al. Mutant vitamin D receptors which confer hereditary resistance to 1,25-dihydroxyvitamin D3 in humans are transcriptionally inactive in vitro. J Biol Chem 1989;264:20230-4. 18. Matloy P J, Hochberg Z, Tiosano D, Pike JW, Hughes MR, Feldman D. The molecular basis of hereditary 1,25-dihydroxy-
808
19. 20.
21.
22.
23.
Hochberg, Tiosano, and Even
vitamin D3-resistant rickets in seven related families. J Clin Invest 1990;86:2071-9. HochbergZ, BenderlyA, LevyJ, et al. 1,25-dihydroxyvitamin D resistance, rickets and alopecia. Am J Med 1984;77:805-11. Castells S, Greig F, Fusi MA, et al. Severely deficient binding of 1,25-dihydroxyvitamin D to its receptors in a patient responsive to high doses of this hormone. J Clin Endocrinol Metab 1986;63:252-6. Bliziotes M, Yergey AL, Nanes MS, et al. Absent intestinal response to calciferols in hereditary resistance to 1,25-dihydroxyvitamin D: documentation and effective therapy with high dose intravenous calcium infusions. J Clin Endocrinol Metab 1988;66:294-300. Balsan S, Garabedian M, Larchet M, et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to i,25-dihydroxyvitamin D. J Clin Invest 1986;77:1661-7. Weisman Y, Bab I, Gazit D, Spirer Z, Jaffe M, Hochberg Z.
The Journal of Pediatrics November 1992
24.
25.
26.
27.
Long-term intracaval calcium infusion therapy in end-organ resistance to 1,25-dihydroxyvitamin D. Am J Med 1987; 83:984-90. Chen T, Hirst MA, Cone CM, Hochberg Z, Tietze HV, Feldman D. 1,25-Dihydroxyvitamin D resistance, rickets and alopecia: analysis of receptors and bioresponse in cultured fibroblasts from patients and parents. J Clin Endocrinol Metab 1984;59:383-91. Halloran BP, DeLuca HF. Evidence for two distinct mechanisms of action of 1,25-dihydroxyvitamin D. Arch Biochem Biophys 1981;208:477-82. Hochberg Z, Bor0chowitz Z, Benderly A, et al. Does 1,25-dihydroxyvitamin D3 participate in the regulation of hormone release from endocrine glands? J Clin Endocrinol Metab 1985;60:57-61. Underwood JL, DeLuca HF. Vitamin D is not directly necessary for bone growth and mineralization. Am J Physiol 1984;246:E493-8.
Calcitriol-resistant rickets is a group of autosomal recessive abnormalities of the vitamin D receptor that result in severe rickets from early infancy, severe growth retardation, generalized alopecia, and resistance to therapy with calcitriO1.1-7 These entities share a defective VDR, s14 resulting from a series of point mutations in the VDR gene. 15-~8Some patients undergo spontaneous healing of the rachitic bone changes,19 and high-dose vitamin D therapy can be helpful in others. 4, 20 Those with extreme receptor-negative muta-
tions and truncated VDR have no response to therapy, despite extremely high serum calcitriol levels of 1000 to 1500 pg/ml (normal, 20 to 60 pg/ml), obtained by giving daily doses of lc~-hydroxyvitamin D3 as high as 60 #g/m2.19 A study of intestinal absorption of calcium in patients
Submitted for publication Feb. 19, 1992; accepted June 1, 1992. Reprint requests: Zeev Hochberg, Technion Faculty of Medicine, P.O. Box 9649, Haifa 31096, Israel. 9/25/39906
with CRR revealed reduced absorption, but only to 50% to 60% of control values, and enhanced bone uptake of the absorbed calcium.5,21 To bypass the interrupted intestinal absorption of calcium, the major role of vitamin D affected
CCR PTH SDS VDR
Calcitriol-resistant rickets Parathyroid hormone Standard deviation score Vitamin D receptor
803
804
Hochberg, Tiosano, and Even
The Journal of Pediatrics November 1992
T a b l e . Calcium therapy, growth response, and radiologic outcome in 10 patients with calcitriol-resistant rickets Patient No. 1
Refer* J118
2
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10
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0.5-1.3 0.6 0.5-0.8 3.5
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1.0-1.4 4.7
Age (yr)
Growth velocity'l" (SDS)
0.6-1.7 1.7-3.5 3.5-4.0 0.3-1.l 1.1-3.0 0.9-2.0 2.0-4.8 4.8-5.5 1.0-2.2 2.2-4.0 2.5-3.9 3.9-7,0 7.0-9.2 4.0-5.8 5.8-9.0 8.8-10.7 10.7-14.5 7.0-11.5 11.5-15.0 9.9-13.7 13.7-16.8 16.8-17.8 10.9-13.8 13.8-17.0 17.0-18.2
-2.3 + 1.3 +0.2 -3.1 +2.3 -0.8 +0.7 + 1.6 -4.0 +2.2 -4.6 +3.5 +0.3 -6.3 +2.9 -3.9 +5.1 -4.0 +0.1 -2.4
Radiologic outcome Healed Healed Improved Healed Healed Improved Healed Healed Improved Healed Healed Healed Healed Healed Healed
*The letters and subscript numbers refer to the pedigree as detailed in reference 18 and the family designation in the other references noted. "~For the previous 1 to 2 years.
in CRR, some have used intravenous calcium infusion therapy; the short-term results have been reported for four patients. 2~23 It seemed possible that early initiation of therapy with high oral doses of calcium, before the establishment of severe rickets or after healing of rickets by intravenous calcium infusions, might be effective in these patients. This report summarizes our long-term experience in giving therapy for CRR with intravenous calcium infusions and with high oral doses of calcium.
METHODS Patients. We studied 10 patients with CRR caused by a defect in the ligand-bindingdomain of the VDR, verified in every case by binding studies, by a bioassay of vitamin D activity,6, s, 16, 18, 19, 24 and by polymerase chain reaction analysis of the VDR. 16' 18 Eight of the patients belong to seven branches of an extended Arab family with a high degree of consanguinity, as previously reported 6, 18, 19 and detailed in the Table. The other two patie'nts (Nos. 6 and 8) are brothers of a different Arab family, though the proximity of their residence and the identical point mutations suggest a distant relationship. The clinical course of patients 6 through 10 was previously reported. 6' 19 The first year of
therapy with intravenously administered calcium has been reported for patient 5. 2z Intravenous calcium therapy. An intracaval catheter was inserted through a branch of the jugular vein under general anesthesia. The infusion solution consisted of calcium glucono-galacto-gluconate (Sandoz Laboratories, Basel, Switzerland) in 0.9% sodium chloride. The calcium solution was given continuously in the hospital, under cardiac monitoring, for the first 1 to 2 months. It was continued at home for 12 hours daily. After periods of 1 to 3 months of home nursing care, the mothers and the older patients were trained to administer calcium intravenously. The dosage was adjusted frequently to give a serum calcium concentration of 2.1 to 2.5 mmol/L (8.4 to 10 rag/all). After 2 years of daily infusions and with radiologic signs of improvement, the dosage was divided into two to four weekly infusions. Oral calcium therapy. Calcium was given in effervescent tablets of calcium lactate-gluconate (Sandoz), containing 500 mg elemental calcium. The dosage was increased gradually to maximal gastrointestinal tolerance, as reported by the patients and the parents, in four or five daily doses. Analytic methods. Serum calcium, phosphorus, and alkaline phosphatase values were determined by using an automatic analyzer. Serum immunoreactive parathyroid hor-
Volume 121 Number 5, Part 1
Calcium f o r calcitriol-resistant rickets
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Figure. Effect of intravenous or oral calcium therapy on serum calcium, phosphorus, alkaline phosphatase, and plasma PTH levelsin 10 patients with CRR. Each string of lines indicates a single patient and correspondingpatient number (from the Table). Lines indicate results before any therapy (dotted line), after intravenouscalcium therapy (solid line), and after oral calcium therapy (dashed line)9
mone was measured with a radioimmunoassay kit for the C-terminal PTH (Sorin Biomedica, Fleures, Belgium). The normal adult levels are 6 to 20 pmol/L. RESULTS Intravenous calcium therapy. As detailed in the Table, intravenous calcium therapy started at age 1.7 to 13.8 years
and extended for a period of 1.8 to 3.8 years. To maintain normal serum calcium levels, the patients required a daily dose of 0.4 to 1.4 gm elemental calcium ions per square meter of body surface area. Within 4 to 13 months of therapy, when the serum calcium concentration approached the lower limit of normal, mild hypercaleiuria developed, with urinary calcium/creatinine ratio of 0.3 to 0.5 and urinary
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excretion that amounted to as much as 20% of the infused calcium. Hypercalciuria persisted throughout intravenous therapy in all the patients. Periodic ultrasonography of the kidneys showed no evidence of nephrocalcinosis. Clinical improvement was observed within a week of initiation of therapy, with disappearance of bone pain; several of the younger patients started to walk for the first time. Acceleration of growth velocity was evident within 2 to 3 months. Growth velocity increased from a pretreatment rate of -0.8 to -6.3 standard deviation score (according to the normative data of Tanner et al.) 24 to +0.1 to +5.1 SDS. The patients with the slowest pretreatment velocity had a maximal response to therapy. The changes in serum calcium, phosphorus, alkaline phosphatase, and plasma PTH values are summarized in the Figure. The results for PTH do not always coincide with the age at therapy, as indicated in the Table, because these were obtained at different times. The serum calcium concentration became normal within 6 to 11 months. Plasma PTH was measured too infrequently to permit a summary of the time course of its normalization, but low serum phosphorus concentrations, which can be regarded as a result of hyperparathyroidism, became normal within 7 to 15 months of the initiation of therapy. Serum alkaline phosphatase activity decreased significantly within 7 to 13 months of therapy and became normal within 13 to 38 months. Radiologic signs of healing were seen sooner in the younger patients than in the older ones. Delivery of calcium through a central vein for such long periods was accompanied by significant morbidity. During the initial week of therapy, cardiac arrhythmias, mostly bradycardia, were often observed. Episodes of septicemia occurred in all patients, with a mean frequency of one every 8 months (range, 3 to 37 months), and required hospitalization, cessation of calcium therapy, and intravenous antibiotic therapy. The central catheter had to be replaced at a mean frequency of once every 14 months, a procedure that required general anesthesia. Oral calcium therapy. Oral calcium therapy was started in two patients, aged I. 1 and 2.2 years, as the sole mode of treatment and has continued for 1.9 and 1.8 years, respectively. In five other patients, aged 3.5 to 17 years, oral calcium therapy was initiated after radiologic evidence of healing of the rachitic bone changes during intravenous therapy. To maintain normal serum calcium levels, the patients required daily doses of elemental calcium of 3.5 to 9 gm/m 2 body surface area. Urinary calcium excretion was monitored regularly only in the youngeF patients and occasionally in the older; urinary calcium/creatinine ratio was normal (less than 0.22) in all cases. Clinical improvement was slower than that after intravenous calcium therapy. Growth velocity increased in the two
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younger patients from a pretreatment rate of -3.1 and - 4 . 0 SDS to +2.3 and +2.2 SDS, respectively. In the three older patients who had had intravenous treatment and who still had growth potential, growth velocity (as determined by positive SDS) was maintained, though at a slower pace. In the two patients who had not received intravenous calcium therapy, serum calcium concentrations became normal within 7 and 11 months, plasma PTH levels within 15 and 17 months, serum phosphorus levels within 16 and 19 months, and serum alkaline phosphatase activity within 18 and 22 months of initiation of therapy. Radiologic signs of rickets show improvement, but complete healing has not occurred. Oral calcium treatment was accompanied during the first months by significant abdominal discomfort, which required a slow increase of the dosage. After this period of adjustment, there were no further complaints or physical side effects of therapy. DISCUSSION Calcitriol-resistant rickets of the subtype described here is the most severe form of rickets, with no clinical response to calcitriol in doses that are 100-fold higher than normal. 19 In our patients it resulted from a complete absence of calcitriol binding and biologic activity8, I4, 16, 18, 19, 24 as a result of truncation of the receptor, which in turn was caused by a stop codon on the VDR gene. 16, 18 The main function of calcitriol is to enhance intestinal absorption of calcium, and the early reports of CRR did describe malabsorption of calcium in this condition), 5 To bypass the limited intestinal absorption of calcium, Balsan et al., 22 Weisman et al., 23 and Bliziotes et al. 21 suggested the intravenous route to deliver high quantities of calcium. Their reports on the short-term outcome of such therapy in four patients seemed promising, albeit not without hazards. Our long-term experience with intracaval infusion of high doses of calcium to a larger cohort of patients with CRR shows that outcome" is satisfactory, with normalization of serum calcium, PTH, phosphorus, and alkaline phosphatase values (in that succession), in growth acceleration, and in radiologic healing of the rachitic bone changes. However, the procedure is complicated for both the patients and their parents, and risky in terms of cardiac arrhythmias (which we observed during the initial week of therapy only) and recurrent septicemia. After normalization of the serum calcium concentration, hypercalciuria was evident in every case, though nephrocalcinosis was not seen on sonograms or on plain abdominal radiographs. Calcitriol has its greatest effects in the intestine, where it enhances calcium absorption.25 However, hormones are stimulators of existing mechanisms, and intestinal calcium absorption is not altogether lost in the absence of calcitriol.
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In two patients with C R R who were described, 47Ca or stable 44Ca absorption was about 40% of values obtained in healthy children. 5, 23 Similar findings were present in three of our patients (Yergey AL, Hochberg Z: personal communication, 1991 ). Thus high oral doses of calcium may offer the potential to move calcium into plasma by passive absorption in sufficient amounts to return serum calcium levels to normal. On the other hand, we have tried oral calcium therapy unsuccessfully in the past. ~9 The protocol described in this report differs from our previous treatment in two ways. Therapy was initiated either at a very young age, when rachitic damage was not as extensive as in older patients, or after healing by intravenous calcium therapy. In both cases the bones were not as "hungry" for calcium as is true in the severe rickets observed in patients with C R R . Our other aim was to deliver massive doses of calcium. We prescribed gradually increasing doses, limited only by intestinal tolerance. The implications of these results for the understanding of the role of calcitriol in normal physiology are interesting, and are in agreement with a previous report 26 on a limited endocrine role for vitamin D other than in the gut. The principal effect of calcitriol is in regulating intestinal calcium absorption. In rats, infusion of calcium and phosphorus prevents rickets in vitamin D-deficient animals. 27 The same holds true for the effects of calcium and calcitriol on P T H suppression. The results of calcium administration indicate that secondary hyperparathyroidism is fully suppressed even in the absence of a VDR-mediated calcitriol effect. On the basis of our limited experience with 10 patients, we recommend that oral calcium therapy be started at the youngest possible age, in substantial doses, and to the limit of intestinal discomfort. When rickets has already commenced and advanced, calcium should be infused through a large vessel in a dosage high enough to allow resumption of normocalcemia, P T H suppression, and normophosphatemia. After radiologic healing has been observed, oral calcium therapy can be introduced. With both routes of therapy, periodic monitoring of serum calcium, P T H , and phosphorus levels, and of urinary calcium excretion, should be done to ensure that calcium is given at the lowest sufficient dosage. With the progress of therapy and the saturation of bone minerals, the dosage can be reduced according to the results of monitoring. REFERENCES
1. Brooks MH, Bell NH, Love L, et al. Vitamin D-dependent rickets type II: resistance of target organs to 1,25-dihydroxyvitamin D. N Engl J Med 1978;298:996-9. 2. Rosen JF, Fleischman AR, Finberg L, Hamstra A J, DeLuca HF. Rickets with alopecia: an inborn error of vitamin D metabolism. J PED~ATR1979;94:729-35.
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3. Zerwekh JE, Glass K, Jowsey J, Pak CYC. A unique form of osteomalacia associated with end organ refractoriness to 1,25hydroxyvitamin D and apparent defective synthesis of 25-bydroxyvitamin D. J Clin Endocrinol Metab 1979;49:171-5. 4. Liberman UA, Samuel R, Halabe A, et al. End organ resistance to 1,25-dihydroxycbolecalciferol. Lancet 1980; 1:504-7. 5. Tsuchiya Y, Matsuo N, Cho H, et al. An unusual form of vitamin D-dependent rickets in a child: alopecia and marked end-organ hyposensitivity to biologically active vitamin D. J Clin Endoerinol Metab 1980;51:685-90. 6. Beer S, Tieder M, Kohelet D, et al. Vitamin D resistance to 1,25-dihydroxyvitamin D. Clin Endocrinol (Oxf) 1981;14:395402. 7. Marx S J, Spiegel AM, Brown EM, et al. A familial syndrome of decrease in sensitivity to 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 1978;47:1303-10. 8. Feldman D, Chen T, Cone C, Hirst M, Shani S, Benderly A, Hochberg Z. Vitamin-D-resistant rickets with alopecia: cultured skin fibroblasts exhibit defective cytoplasmic receptors and unresponsiveness to 1,25(OH)2D3. J Clin Endocrinol Metab 1982;55:1020-2. 9. Liberman UA, Ell C, Marx SJ. Resistance to 1,25-dihydroxyvitamin D: association with heterogeneous defects in cultured skin fibroblasts. J Clin Invest 1983;71:192-200. 10. Clemens TL, Adams JA, Horiuchi N, et al. Interaction of 1,25-dihydroxyvitamin D3 with keratinocytes and fibroblasts from skin of normal subjects and a subject with vitamin-Ddependent rickets, type II: a model for study of the mode of action of 1,25-dihydroxyvitamin D 3. J Clin Endocrinol Metab 1983;56:824-30. 11. Koren R, Ravid A, Liberman UA, Hochberg Z, Weisman Y, Novogrodski A. Defective binding and function of 1,25-dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end-organ resistance to 1,25(OH)2D3. J Clin Invest 76;2012-5, 1985. 12. Gamblin GT, Liberman UA, Ell C, Downs RW Jr, Deghrange DA, Marx SJ. Vitamin D-dependent rickets type II: defective induction of 1,25-dihydroxyvitamin D3, in cultured skin fibroblasts..I Clin Invest 1985;75:954-60. 13. Liberman UA, Ell C, Marx SJ. Receptor-positive hereditary resistance to 1,25-dihydroxyvitamin D: chromatography of hormone receptor complexes on deoxyribonucleic acid-cellulose shows two classes of mutation. J Clin Endocrinol Metab 1986;62:122-6. 14. MaUoy P J, Hochberg Z, Pike JW, Feldman D. Abnormal binding of vitamin D receptors to deoxyribonucleic acid in a kindred with vitamin D-dependent rickets, type II. J Clin Endocrinol Metab 1989;68:263-9. 15. Hughes MR, Malloy P J, Kieback DG, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 1988;242:1702-5. 16. Ritchie HH, Hughes MR, Thompson ET, et al. An ochre mutation in the vitamin D receptor gene causes hereditary 1,25dihydroxyvitamin D3-resistant rickets in three families. Proc Natl Acad Sci USA 1989;86:9783-7. 17. Sone T, Scott RA, Hughes MR, et al. Mutant vitamin D receptors which confer hereditary resistance to 1,25-dihydroxyvitamin D3 in humans are transcriptionally inactive in vitro. J Biol Chem 1989;264:20230-4. 18. Matloy P J, Hochberg Z, Tiosano D, Pike JW, Hughes MR, Feldman D. The molecular basis of hereditary 1,25-dihydroxy-
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Long-term intracaval calcium infusion therapy in end-organ resistance to 1,25-dihydroxyvitamin D. Am J Med 1987; 83:984-90. Chen T, Hirst MA, Cone CM, Hochberg Z, Tietze HV, Feldman D. 1,25-Dihydroxyvitamin D resistance, rickets and alopecia: analysis of receptors and bioresponse in cultured fibroblasts from patients and parents. J Clin Endocrinol Metab 1984;59:383-91. Halloran BP, DeLuca HF. Evidence for two distinct mechanisms of action of 1,25-dihydroxyvitamin D. Arch Biochem Biophys 1981;208:477-82. Hochberg Z, Bor0chowitz Z, Benderly A, et al. Does 1,25-dihydroxyvitamin D3 participate in the regulation of hormone release from endocrine glands? J Clin Endocrinol Metab 1985;60:57-61. Underwood JL, DeLuca HF. Vitamin D is not directly necessary for bone growth and mineralization. Am J Physiol 1984;246:E493-8.
