(model 84, Ohio-Nuclear Inc., Solon, Ohio) with 10% background subtraction and 10% contrast enhan- cement. Approximately 2.5 hours before the test the.
C. VELENTZAS, MD; D.G. OREOPOULOS, MD, PH D, FRCP[C], A. PIERRATOS, MD; H.E. MEEMA, MD, FRCP[C]; S. RABINOVICH, MD, FRCP[CJ; H. MEINDOK, MB, BS, MRC P, FRCP[C]; H. HUSDAN, PH D. T.M. MURRAY, MD, FRCP[C]; R. OGILVIE, PH D A. KATIRTZOGLOU, MD Nine patients with renal osteodystrophy were treated for 6.5 to 35 months with I ,25-dihydroxycholecalciferol (1,25DHCC). A close biochemical follow-up was performed during the first 6 months of treatment, including biweekly deter. minations of serum calcium, phosphorus, magnesium, alkaline phosphatase and creatinine levels. A bone biopsy, radiologic investigations and determinations of plasma levels of immunoreactive parathyroid hormone (iPTH) and intestinal absorption of calcium 47 were performed before and after the 6 months. Although the five patients with osteitis fibrosa showed a significant improvement, the four with predominantly osteomalacic lesions showed no response to treatment. These four had a normal initial plasma iPTH level, higher serum calcium levels than the other five patients, extreme sensitivity to I ,25-DHCC, with frequent episodes of hypercalcemia, and only a slightly increased serum alkaline phosphatase level, which remained unchanged during treatment. All but one of the patients, irrespective of the histologic abnormality, showed a decrease in the uptake of the radionuclide by bone after treatment. The renal function of one patient, a man with long-standing stable renal failure who had not undergone dialysis, deteriorated during treatment. Neuf patients atteints d'osteodystrophie d'origine renale ont re.u du I ,25-dihydroxycholecalciferol (I ,25-DHCC) pendant des periodes allant de 6.5 a 35 mois. Un contr6le biochimique suivi a ete effectue pendant les premiers 6 mois de traitement comprenant des determinations bi-hebdomadaires des taux seriques du calcium, du phosphore, du magnesium, de Ia phosphatase alcaline et de Ia creatinine. Une biopsie osseuse, des examens radiologiques et des determinations des taux plasmatiques de Ia parathormone immunoreactive (PTHi) et de l'absorption intestinale du calcium 47 ont ete pratiques avant et apres cette periode de 6 mois. Bien que les cinq malades souffrant de dysplasie fibreuse des os aient manifeste une amelioration significative, les quatre ayant surtout des lesions osteomalaciques n'ont montr6 aucune reponse au traitement. Ces quatre derniers presentaient a l'origine un taux plasmatique de PTHi normal, une calcemie superieure a celle des cinq autres patients, une sensibilit6 excessive au I ,25-DHCC, ayant de frequents episodes d'hypercalcemie, et une phosphatase alcaline legerement augmentee seulement, qul est demeuree inchangee pendant le traitement. Tous les malades sauf un, quelle que soit leur anomalie histologique, ont manifeste une diminution de Ia captation osseuse du radionucl6ide apres traitement. La fonction renale d'un patient, un homme souffrant d'une insuffisance r6nale d'un patient, mais stable qui n'avait pas subi de dialyse, s'est d6t6rior6e durant le traitement. From the metabolic-renal laboratory and the departments of medicine, radiology, pathology and clinical biochemistry, Toronto Western Hospital and University of Toronto Reprint requests to: Dr. D.G. Oreopoulos, Rm. A44, Research wing, Toronto Western Hospital, 399 Bathurst St., Toronto, Ont. M5T 2S8
After the initial impressive reports on the effect of 1 ,25-dihydroxycholecalciferol (1 ,25-DHCC) on intestinal calcium absorption and bone disease in patients with chronic renal failure1 it was expected that the administration of this renal metabolite of vitamin D:i to anephric patients and those with chronic renal failure would correct all the effects of vitamin D:1 defiency, especially those in bone. Surprisingly, although some investigators have found this drug to be effective in controlling renal osteodystrophy,24 others have found it to have only limited effect or none at all.5-'0 In this report we present our findings in nine patients with renal osteodystrophy undergoing long-term treatment with I ,25-DHCC. Materials and methods Nine patients with renal osteodystrophy, eight receiving maintenance dialysis and one with stable longstanding renal failure, were treated with 1 ,25-DHCC (Table 1). Each patient was informed of the purpose and nature of the study and gave informed consent. The drug was given for 6.5 to 35 months in a daily dose of 0.25 to 1.00 ,.tg, adjusted according to the serum calcium level. Two of the patients had undergone parathyroidectomy before treatment with I ,25-DHCC was started; one of them entered the trial because of persistent hypocalcemia and the other because of bone pain. Two patients were asymptomatic but showed progressive radiologic features of bone disease. The remaining five complained of bone pain or muscular weakness or both. Blood samples for the measurement of calcium, magnesium, phosphorus, alkaline phosphatase and creatinine levels were obtained biweekly during the first 6 months. The calcium and magnesium concentrations were estimated by atomic absorption spectrometry, the phosphorus concentration was measured by the method of Fiske and SubbaRow" and the alkaline phosphatase and creatinine concentrations were determined by the Technicon AutoAnalyzer (Technicon Instruments Corp., Tarrytown, New York). Before and 6 months after the start of treatment we measured the plasma levels of immunoreactive parathyroid hormone (iPTH) by a radioimmunoassay recognizing sites for both the aminoterminal and carboxyterminal portions of the hormone,'2"3 and the intestinal absorption of calcium 47 by a modification of the 45Ca/47Ca double isotope method . All patients underwent a radiologic investigation, with special attention to bone resorption (subperiosteal, intracortical and endosteal), measured by Meema's technique.15" A bone scan was carried out with a dualprobe rectilinear scanner of focal length 12.7 cm CMA JOURNAL/MARCH 1, 1981/VOL. 124 577
Table
Patient no. 1 2
Clinical characteristics of nine patients treated with 1,25-dihydroxycholecalciterol (i,25-DHCC)
Age Diseases and (yr)/sex operations 63/F Chronic renal failure secondary to renal stone disease; parathyroidectomy 26/M Chronic glomerulonephritis
3 4
64/F 27/F
5
57/F
Polycystic kidneys Chronic glomerulonephritis
Type of dialysis*/ duration (yr) before i,25-DHCC treatment H/3; P/3 No dialysis P/3. P/34
Polycystic kidneys; P/2. angina 6 46/F Chronic glomerulonephritis P/2. 7 41/F Chronic renal failure P/2. secondary to ref lux; parathyroidectomy 8 45/F Chronicglomerulonephritis; P/i; H/i angina; vagotomy and pyloroplasty 9 55/F Polycystic kidneys P/i; H/3 *H = hemodialysis; P - peritoneal dialysis. tNA = not applicable, since the patient had no symptoms before treatment.
(model 84, Ohio-Nuclear Inc., Solon, Ohio) with 10% background subtraction and 10% contrast enhancement. Approximately 2.5 hours before the test the patient was given an intravenous injection of technetium 99m stannous methylene diphosphonate (Charles E. Frosst & Co., Dorval, PQ), 10 mCi/in2 of body surface. Bone biopsies were obtained from the anterior iliac crest of eight patients by means of a Vilaghy-Zellerman needle7 Undecalcified and decalcified sections were examined for severity of osteitis fibrosa and osteomalacia and graded semiquantitatively. Osteoid as a proportion of total bone (osteoid index) and the active osteoclastic resorptive surface as a percentage of the total endosteal surface were measured quantitatively. Results
Clinical response
i,25-DHCC treatment Duration (mo) Clinical resultst 25 No response
Indications Bone pain Radiologic evidence of renal osteodystrophy; asymptomatic Bone pain; rib fractures Progressive radiologic evidence of bone disease; asymptomatic Severe bilateral hip pain; muscular weakness Bone pain Persistent hypocalcemia; asymptomatic Persistenthypocalcemia; rib fractures; bone pain; muscular weakness Bone pain
7
NA
29 6.5
No response NA
9.5
No response
35 9
Free of symptoms inimonth NA
9
Slightimprovement after 6 months
7.5
No response
10.5 mg/dI (2.6 mmol/l); however, the maximum serum calcium level never exceeded 13.6 mg/dl (3.4 mmol/l). The maximum calcium X phosphorus product varied from 60.4 to 98.3. The four nonresponders had more hypercalcemic episodes (42 v. 37) and a significantly higher (P < 0.001) mean serum calcium level (10.7 ± 0.92 [standard error] v. 10.1 ± 0.88 mg/dl) than the other five patients. In addition, the mean serum magnesium level was lower in the nonresponders than in the responders, but it was above normal in both groups. The intestinal absorption of 47Ca (Fig. 2) was within the normal range (15% to 45%) before treatment in seven patients; in the other two, whose bone biopsies showed predominantly osteomalacia, it was below normal (12.3% and 9.0%). After treatment the absorpPatient 1* 11.6
Of the six symptomatic patients only one, with very troublesome hone pain, responded promptly to therapy with I ,25-DHCC: she became symptom-free by 1 month after the start of treatment. Of the other five symptomatic patients one reported slight lessening of bone pain and muscular weakness after 6 months of treatment, but the other four had no response; two continued to require a wheelchair after 9 and 25 months of treatment. In three of the four nonresponders the bone biopsy had shown predominantly osteomalacia. The patient with postparathyroidectomy hypocalcemia became normocalcemic during treatment, but drugrelated pruritus necessitated reduction of the dose of I ,25-DHCC. Biochemical response Five patients had frequent episodes of hypercalcemia (Fig. 1), with serum calcium levels greater than
*
2
Total episodes per patient 11 11.2
13.6
1
16
4
11.2
5
13.6
.
11.5
6
15 *
11
7
0 12.6
6' 9
21 18
13.3
. I 2
4
6
8
10
12
14
16
WEEKS OF TREATMENT
18
20
22
24
tion increased in five patients and decreased in three, slightly, while in the second group it decreased to near two of whom were nonresponders (their absorption normal by the end of 6 months' treatment (Fig. 4). values were 25% and 46% before, and 21 % and The first group included three nonresponders; the 41 % after treatment). second group included all responders and one nonThe serum phosphorus levels showed wide fluctua- responder whose alkaline phosphatase level decreased tions during treatment with I ,25-DHCC (Fig. 3); con- after an initial increase. trol by the use of phosphate binders was difficult. The serum levels of iPTH showed a similar pattern The serum alkaline phosphatase level was above nor- (Fig. 5): the patients with osteomalacia had normal mal in all patients before treatment. During treatment iPTH levels initially and after 6 months' treatment; the patients could be separated into two groups accord- the remaining patients, with one exception, had high ing to the alkaline phosphatase response. In the first iPTH levels before treatment, and the levels decreased group the level either did not change or increased after 6 months' treatment. Radiologic response 60 Photodensitometric measurements in the radius before and after 6 months of treatment did not show significant changes in bone mineral mass (392 ± 51.8 v. 397 ± 73.5 mg/cm1), cortical thickness (4.78 ± 0.70 v. 4.65 ± 0.36 mm) or bone mineral density (822.4 ± 83.6 v. 840.0 ± 52.5 mg/cm2). On the other hand, quantitative microradioscopy of the hand bones Ishowed a significant decrease in subperiosteal and 0. intracortical resorption but no apparent effect on endosteal resorption. 040 (I) Changes in bone scan m 4 In all but one patient the uptake of the radionuclide It was significantly lower (P < 0.025) after treatment than it had been before (65.7 v. 103 ..tCi), but it re.30 mained higher than in healthy controls (Table II). Histologic response Table III shows the changes with 1 ,25-DHCC treatment in the histologic grading of osteomalacia and 201-
z50 Q
101.
0
FIG. 2-Intestinal absorption of calcium 47 before and after 6 months of treatment with l,25-DHCC. In one patient, only the before-treatment value was available. Black circles represent values of patients with osteitis fibrosa, white circles values of patients with predominantly osteomalacia. 9.0
. 5.0 i>l/l\i.fl INTl , 11' \.j./Ni-r. ¼ 1 11 LU Co 3.0 11111 II 13 5 7
9
II III 11111 11 1315 17192023
WEEKS OF TREATMENT
Table II Uptake of technetium 99m stannous methylene diphosphonate by bone before and after treatment with 1,25-DHCC Uptake (p.CI)* Patient no. Before treatment After treatment 1 130 58 2 55 32 3 139 100 4 84 101 5 162 84 6 74 52 7 97 75 8 110 41 9 80 49 *Average for skull, mandible, lumbar spine, proximal and distal ends of both femurs and proximal ends of both tibias when compared with a phantom of known activity at the time of scanning. For 16 patients without bone disease the mean and standard error were 23.2 i4.6pCi.
Table Ill-Effect of treatment with 1,25-DHCC on bone lesions* Patient no. and time Osteoid Active resorptive of biopsy index, % surface, % of total in relation Osteo- (normal Osteitis endosteal surface to treatment malaciat
