Original Article
Effects of Therapy in X-Linked Hypophosphatemic Rickets
N Engl J Med 1991; 325:1843-1848December 26, 1991
- Abstract
- Abstract
Background.
Patients with X-linked hypophosphatemic rickets, which is clinically manifested by growth failure and bowing of the legs, are usually treated with phosphate and a vitamin D preparation. However, the efficacy of this treatment has been disputed, and nephrocalcinosis is a recognized complication of therapy.
Methods.
We studied 24 patients with X-linked hypophosphatemic rickets (9 boys and 15 girls) ranging in age from 1 to 16 years (median, 5.3). The duration of combination therapy ranged from 0.3 to 11.8 years (median, 3.0). We measured height as a standard-deviation (SD) score (the number of SDs from the mean height for chronologic age). Measurements made before the age of two years or after the onset of puberty were excluded. We compared the results with those reported in 1971 for 16 untreated prepubertal Australian patients. We also determined the severity of nephrocalcinosis (on a scale of 0 to 4, with 0 indicating no abnormalities and 4 stone formation) with renal ultrasonography and whether it could be related to the dosage of phosphate or vitamin D or to other factors.
Results.
Patients treated for at least two years before the onset of puberty (n = 19) had a mean height SD score of -1.08, as compared with -2.05 in the untreated historical controls. The 13 patients who had been treated with calcitriol and phosphate for at least two years had an increase in the mean height SD score of 0.33, from -1.58 to -1.25 (95 percent confidence interval, 0 to 0.67; P = 0.05).
Nineteen of the 24 patients (79 percent) had nephrocalcinosis detected on renal ultrasonography. The grade of nephrocalcinosis was significantly correlated with the mean phosphate dose (r = 0.60, P = 0.002), but not with the dose of vitamin D or the duration of therapy. All patients had normal serum creatinine concentrations.
Conclusions.
Therapy with calcitriol and phosphate may increase the growth of children with X-linked hypophosphatemic rickets. Nephrocalcinosis in these children represents a complication of therapy and is associated with the dose of phosphate received. (N Engl J Med 1991;325:1843–8.)
Article Activity
- Article
X-LINKED hypophosphatemic rickets involves two defects, impaired proximal tubular reabsorption of phosphate and a relative deficiency of 1,25-dihydroxyvitamin D production.1 The clinical manifestations include growth failure, bowing of the legs, hypophosphatemia, and radiographic changes of rickets. Treatment is aimed at correcting the clinical, biochemical, and radiologic abnormalities. The use of either a preparation of vitamin D or phosphate alone is not successful, but their simultaneous administration (combination therapy) raises the serum phosphate concentration, causes radiographic healing of the rickets, and improves the histologic abnormalities in bone.2 3 4 5 However, the effectiveness of therapy has been questioned, and nephrocalcinosis has developed in some patients during treatment; a recent report described three patients in their 20s in whom end-stage renal failure developed.6 We undertook this study to assess the value of therapy in terms of its effect on linear growth and to investigate whether the severity of nephrocalcinosis could be related to the dosage of phosphate and vitamin D or to other factors.
Methods
Patients
We studied all 24 patients with X-linked hypophosphatemic rickets who were being treated at the Children's Hospital, Camperdown, Sydney, Australia. There were 9 boys and 15 girls, ranging in age from 1 to 16 years (median, 5.3) at the time of the study. Their age at the time of diagnosis and the start of combination therapy ranged from 0.2 to 11.7 years (median, 1.8). The duration of therapy ranged from 0.3 to 11.8 years (median, 3.0). The diagnosis was based on the finding of hypophosphatemia, elevated serum alkaline phosphatase levels, increased urinary phosphate excretion, normal serum calcium and bicarbonate levels, and the absence of aminoaciduria. The patients came to medical attention either because of typical clinical features or because of a family history of the disorder. Twenty of the patients had a family history compatible with linkage to the X chromosome. The other four patients satisfied the above diagnostic criteria but had no family history of the disorder.
Therapy
Most patients were treated with calcitriol (Rocaltrol, Hoffmann-LaRoche, Basel, Switzerland), in a mean (±SD) dose of 25.6± 16.9 ng per kilogram of body weight per day, but very young patients requiring small doses received a suspension of ergocalciferol (Roussel, Paris). This was switched to calcitriol as the patients became old enough to take the 250-ng capsules. All patients were given oral phosphate supplements (Phosphate Sandoz, Sandoz, Frimley, Surrey, United Kingdom) every four hours five or six times per day. The mean dose was 100±34 mg per kilogram per day. No dietary modification was made. The goal of therapy was to normalize serum phosphate and alkaline phosphatase concentrations while avoiding hypercalcemia, hypercalciuria, and hyperparathyroidism. Treatment was temporarily suspended if hypercalcemia occurred. Two of the patients received diuretics (a combination of amiloride and hydrochlorothiazide) in addition to combination therapy.7 None of the patients underwent osteotomy.
Clinical and Laboratory Assessment
The patients were evaluated in the hospital every three months after the initiation of treatment. During each hospitalization we obtained an interim history, performed a physical examination, and measured height, weight, and head circumference. Height was measured with a Harpenden stadiometer (Holtain, Crymmych, United Kingdom). Blood was taken for measurement of serum electrolytes, urea, creatinine, calcium (reference range, 2.25 to 2.75 mmol per liter), and alkaline phosphatase (reference ranges: 60 to 320 U per liter for patients less than 6 months of age, 40 to 300 U per liter for those 6 months to 15 years of age, and 15 to 125 U per liter for those over 15 years of age). Serum phosphate levels were measured before and once an hour for four hours after the administration of oral phosphate in the morning. The age-related reference ranges for serum phosphate were 1.6 to 2.4 mmol per liter (for patients less than 6 months of age), 1.3 to 1.9 mmol per liter (for those 6 months to 12 years of age), and 0.8 to 1.6 mmol per liter (for those more than 12 years of age). Serum parathyroid hormone levels were measured every six months by radioimmunoassay8 (reference value, <0.6 μg per liter). Twenty-four-hour urine samples were collected for measurement of calcium and phosphate excretion, or random urine samples were collected for measurement of the ratio of urinary calcium to urinary creatinine during alternate admissions. Hypercalciuria was defined as urinary calcium excretion of more than 0.15 mmol per kilogram per day or a ratio of urinary calcium to urinary creatinine of more than 0.6 (both elements of the ratio are expressed in millimoles per liter). There were no urinary data on five patients because of difficulties with sample collection. Serum and urine calcium concentrations were measured by atomic absorption spectrophotometry. Serum alkaline phosphatase levels and serum and urine phosphate concentrations were measured with a Synchron CX5 machine (Beckman Instruments, Brea, Calif.).
Glomerular Filtration Rate
Within 18 months of the treatment period analyzed, 20 patients had their glomerular filtration rate measured by diethylenetriamine pentaacetic acid labeled with technetium-99m. The results were corrected for surface area.
Analysis of Linear Growth
Each annual height measurement was converted into a height standard-deviation (SD) score, defined as the number of standard deviations from the mean height for chronologic age, according to data from the U.S. National Center for Health Statistics.9 The change in the height SD score during combination therapy was then examined. To exclude the effects of variation in the onset of puberty and the difficulties encountered in measuring small infants, the first measurement performed after the age of 2 years was compared with the most recent measurement performed before the age of 10 years in girls and 12 years in boys. If these two measurements were less than two years apart, then the interval was considered too short to evaluate any effect of therapy and the patient was excluded from the analysis of growth. This left 13 patients (4 boys and 9 girls) with a mean (±SD) interval of 5.0±2.3 years during which therapy was evaluated.
Some of these patients had received calcitriol between the two measurements, whereas others had received ergocalciferol followed by calcitriol. To account for this difference, a second analysis was performed in which, for each patient, only the period of calcitriol and phosphate therapy was included (Table 1Table 1
Height SD Scores of 24 Patients with X-Linked Hypophosphatemic Rickets.*). The mean interval during which combination therapy with calcitriol was evaluated in this way was 3.8±2.0 years.We also compared the growth of our patients with that of 16 untreated prepubertal Australian patients with X-linked hypophosphatemia, whose height SD scores (according to the standards of Tanner et al.10) were reported in 1971 by Steendijk and Latham.11 For the purposes of this comparison, we converted the most recent measurement performed on each of our prepubertal patients (before the age of 10 years in girls and 12 in boys) into a height SD score according to the standards of Tanner et al.,10 so that the scores would be comparable with those of the 16 untreated patients. Any of our patients who had received combination therapy for less than two years at the time of the height measurement was excluded. The age and sex distributions of the two groups were comparable (Table 2Table 2
Mean Height SD Scores of Treated Patients and Untreated Patients with X-Linked Hypophosphatemic Rickets.*). The results were analyzed with Student's t-test.Renal Imaging
Renal ultrasonography was performed every 6 to 12 months beginning in 1986 with an Acuson 128 ultrasound machine (Mountain View, Calif.). The most recent renal ultrasonogram for each patient was reviewed by an investigator who was not aware of the patient's identity. The degree of echogenicity of the renal pyramids was graded on a scale from 0 to 4, according to the method of Patriquin and Robitaille12 (Table 3Table 3
Classification of Medullary Nephrocalcinosis, According to Grade.* and Fig. 1Figure 1
Renal Ultrasonograms from Four Patients with X-Linked Hypophosphatemic Rickets.). Five of the 24 patients had renal CT performed in addition to ultrasonography. For comparison, we performed renal ultrasonography on three adults with hypophosphatemia who had never received medical therapy for their rickets. These three adults were unrelated and were the parents of three of our patients.On a subsequent occasion the reproducibility of the grading of the ultrasonograms was assessed as follows. The ultrasonograms of 12 patients with X-linked hypophosphatemic rickets (with various grades of nephrocalcinosis) were interspersed in random order with the ultrasonograms of 12 normal children (obtained for other reasons, such as a history of urinary tract infection). The ultrasonograms were reevaluated, and the grade assigned to each one was compared with that determined previously. The two readings corresponded within one grade in every instance, and there was exact concordance in 17 instances (71 percent).
Analysis of Factors Associated with Nephrocalcinosis
The following potential risk factors for nephrocalcinosis were determined for each patient: duration of therapy, age at which therapy was begun, mean and total doses of vitamin D and phosphate, mean serum calcium level, number of episodes of hypercalcemia, mean and maximal levels of urinary calcium and phosphate excretion, number of episodes of hypercalciuria, and the mean and maximal products of urinary calcium and phosphate concentrations. The doses of ergocalciferol were converted into equivalent amounts of calcitriol, according to the formula 68 U of ergocalciferol = 1 ng of calcitriol.13 With respect to the number of episodes of hypercalcemia, we counted the number of measurements of serum calcium in which the concentration was greater than 2.50 mmol per liter and the number in which the concentration was greater than 2.75 mmol per liter.
These factors were analyzed for their association with the grade of nephrocalcinosis by calculating Pearson's and Spearman's correlation coefficients and by multiple linear regression analysis. In addition, the patients were divided into two groups according to whether or not they had had one or more episodes of hypercalciuria. These two groups were compared, in terms of the other variables, with Wilcoxon's two-sample rank-sum test. Probability values of more than 0.05 were considered not to indicate statistical significance.
Results
Growth
After the effects of puberty were excluded from the analysis, the patients treated with combination therapy for at least two years had a mean height SD score (Tanner) of -1.08, as compared with a score of -2.05 for the group of untreated Australian patients reported on by Steendijk and Latham11 (Table 2). The 0.97 difference in the SD score between the two groups was statistically significant (95 percent confidence interval, 0.22 to 1.75; P = 0.01).
After we excluded measurements made when the patients were ≤2 years old and when the girls were ≥10 and the boys ≥12, the change in the height SD score of the 13 patients treated for at least two years with combination therapy ranged from a decrease of 1.77 to an increase of 1.68 (National Center for Health Statistics data). The mean effect was an increase of 0.17 (from a mean height SD score of -1.42 to -1.25), which is not significantly different from zero (P = 0.5).
When the change in the height SD score was analyzed to include only the period of calcitriol and phosphate therapy (Table 1), the score improved in 10 of the 13 patients. The change in the height SD score ranged from a decrease of 0.35 to an increase of 1.68. The mean change in the height SD score was a statistically significant increase of 0.33 (95 percent confidence interval, 0 to 0.67; P = 0.05), from a mean score of -1.58 to -1.25. There was no significant correlation between the change in the height SD score and the duration of treatment or the age at which it commenced. Figure 2Figure 2
Change in Height SD Score as a Function of the Duration of Therapy with Calcitriol and Phosphate in 13 Patients with X-Linked Hypophosphatemic Rickets. shows the change in height SD score plotted against the duration of treatment with calcitriol and phosphate (r = 0.38, P = 0.2).Nephrocalcinosis
Nineteen of the 24 patients (79 percent) had nephrocalcinosis on renal ultrasonography (Table 3). Of these, 37 percent had grade 1 changes, 26 percent had grade 2, 37 percent had grade 3, and none had grade 4. Of the five patients who had renal CT scans, three had renal calcification (their ultrasonograms showed nephrocalcinosis of grades 2, 3, and 3) and two had equivocal patches of increased attenuation in the renal medulla (their ultrasonograms showed nephrocalcinosis of grades 0 and 1). None of three affected, untreated parents had any evidence of nephrocalcinosis.
Regression analysis revealed a significant association between the mean phosphate dose (expressed as milligrams per kilogram per day) during the treatment period and the grade of nephrocalcinosis (r - 0.60, P = 0.002) (Fig. 3Figure 3
Relation between the Mean Phosphate Dose and the Grade of Nephrocalcinosis in 24 Patients with X-Linked Hypophosphatemic Rickets Treated with Combination Therapy.). The association between the total phosphate dose and the grade of nephrocalcinosis was not as strong (r = 0.47, P = 0.02). There was no significant association between the degree of nephrocalcinosis and any of the other factors studied.The mean serum calcium concentrations in the 24 patients during treatment ranged from 2.15 to 2.53 mmol per liter. Three patients had serum calcium concentrations of more than 2.75 mmol per liter on 1 or more occasions (range, 1 to 4 occasions). Fifteen patients had serum calcium concentrations of more than 2.50 mmol per liter on 1 or more occasions (range, 1 to 11). Five patients had transient borderline elevations in serum parathyroid hormone concentrations (highest, 1.6 μg per liter), but no patient had persistent secondary hyperparathyroidism.
The mean urinary calcium excretion ranged from 0.0007 to 0.12 mmol per kilogram per day, and the mean ratio of urinary calcium to urinary creatinine ranged from 0.015 to 0.89. Eight of the 19 patients (42 percent) for whom urinary measurements were available had one or more episodes of hypercalciuria. This group had received significantly more calcitriol (median dose, 29.9 vs. 17.3 ng per kilogram per day; P = 0.007) than the group of patients who never had documented hypercalciuria. However, there was no significant difference between these two groups in terms of the grade of nephrocalcinosis, whether nephrocalcinosis of any grade was present or absent, or whether diuretic therapy had been given.
All the patients had normal serum creatinine concentrations throughout the study period. The mean (±SD) glomerular filtration rate was 1.9±0.4 ml per second per 1.73 m2 of body-surface area (range, 1.2 to 2.4), and 4 of 20 patients had a rate of less than 1.7 ml per second per 1.73 m2. One patient with grade 3 nephrocalcinosis became hypertensive and was treated with an angiotensin-converting—enzyme inhibitor. This patient was found to have a glomerular filtration rate of 1.4 ml per second per 1.73 m2. Treatment was discontinued; two years later the patient's grade of nephrocalcinosis on ultrasonography and glomerular filtration rate were unchanged.
Discussion
X-linked hypophosphatemic rickets is a benign disease, compatible with a normal life span. The high incidence of the potentially serious side effect of nephrocalcinosis during treatment calls for an evaluation of the effectiveness of the treatment.
The aims of therapy in children with X-linked hypophosphatemic rickets are to correct deformity, to minimize symptoms in adult life, and to increase the child's ultimate height. Although it has been difficult to document this objectively, combination therapy with calcitriol and phosphate appears to help the deformity, since few patients require surgical intervention, whereas before the introduction of combination therapy the majority of such patients required osteotomies. With regard to symptoms in later life, two studies have shown that previous or ongoing therapy is of no benefit to adult patients.6 , 14 With regard to height, our data suggest that combination therapy has a slight beneficial effect. Previous studies failed to demonstrate a definite beneficial effect 2 , 4 , 6 , 15 16 17 Balsan and Tieder found that height SD scores increased in 10 of 16 patients receiving 1α-hydroxyvitamin D and phosphate — results that are similar to our findings — but no test of statistical significance was reported.18 In view of the unresponsiveness of renal 1α-hydroxylase in the disorder, the use of a 1α-hydroxylated vitamin D preparation, such as calcitriol, has theoretical advantages over other vitamin D preparations. In addition, treatment with ergocalciferol and phosphate does not allow histologic healing of the rickets.3
The growth pattern of untreated patients has not been well documented. If it entails a progressive decline in height SD scores during childhood, then the true effect of treatment may not be appreciated by studying only treated patients. To date no prospective controlled trial of combination therapy has been undertaken to evaluate its effect on linear growth. However, our treated patients had significantly better height SD scores than a comparable group of untreated Australian patients reported on in 1971.11 A small secular increase in the height of Australian children that averaged 1.2 cm between 1971 and 1983 was reported by Hitchcock et al.,19 but this would not account for the size of the difference we found.
Using a sensitive and reproducible ultrasonographic grading system to detect early changes, we found a high incidence (79 percent) of nephrocalcinosis in patients with X-linked hypophosphatemic rickets who were receiving combination therapy. This figure is higher than previously reported,13 , 15 although 37 percent of our patients with nephrocalcinosis had minimal changes (grade 1).
We found a significant association between the severity of nephrocalcinosis and the dose of phosphate that the patients had received. Furthermore, the absence of nephrocalcinosis in the affected but untreated adult relatives of our patients supports the hypothesis that nephrocalcinosis is a consequence of therapy, rather than part of the natural history of the disease. Our results confirm those of previous investigators who found a consistent association with large doses of phosphate.13 , 15 Calcitriol could theoretically contribute to the development of nephrocalcinosis by causing hypercalciuria, especially in view of the fact that untreated patients with X-linked hypophosphatemic rickets have reduced calcium excretion.5 However, none of the other factors we studied, including the dose of calcitriol and the duration of therapy, were associated with nephrocalcinosis.
The administration of phosphate causes nephrocalcinosis in rats.20 In patients with X-linked hypophosphatemic rickets, oral phosphate supplementation could increase the severity of the phosphaturia caused by the basic proximal tubular defect. Precipitates of calcium and phosphate could then form even in the presence of normocalciuria if the urinary excretion of phosphate were sufficiently high.21 Although we found no relation between the grade of nephrocalcinosis and the product of urinary calcium and phosphate concentrations, the recent finding of hyperoxaluria in treated patients (but not in untreated patients) suggests a role for calcium oxalate precipitation.22 Reusz et al. found that the extent of oxalate excretion correlated with the oral phosphate dose in these patients and proposed that the formation of calcium phosphate in the lumen of the gut causes enteric hyperabsorption of oxalate as a result of the reduced availability of calcium ions that would otherwise bind oxalate in the gut.22
Ultrasonographic findings similar to ours have been reported in neonates receiving long-term furosemide therapy; histologic study of the kidneys revealed interstitial calcium deposits in the medulla as well as mild focal calcification in the subcapsular cortex.23 The decreased glomerular filtration rate that we found in some patients with X-linked hypophosphatemic rickets may be explained by a similar mechanism of cortical calcium deposition, although the calcium seen on imaging is in the medulla, rather than the cortex. Goodyer and coworkers could not demonstrate any impairment of concentrating ability related to medullary calcification in patients with X-linked hypophosphatemic rickets.13 Little is known about the reversibility of nephrocalcinosis in X-linked hypophosphatemic rickets if therapy is stopped, but in one patient whose therapy was discontinued, we found that the glomerular filtration rate stabilized. In neonates with nephrocalcinosis due to furosemide therapy, the changes seen on ultrasonography regressed over a period of approximately 16 months.24
We conclude that nephrocalcinosis in children with X-linked hypophosphatemic rickets is a complication of therapy, associated with larger doses of phosphate. The slight increase in the height of children with X-linked hypophosphatemic rickets during therapy with calcitriol and phosphate has to be balanced against this potential complication. We recommend conservative use of phosphate and calcitriol and regular monitoring for nephrocalcinosis with renal ultrasonography and measurements of the glomerular filtration rate. Consideration should be given to discontinuing therapy in patients who have completed their growth or who have decreased renal function.
We are indebted to the staff of Sailing League Ward at the Children's Hospital, Camperdown, for collecting the samples; to our institute's information-systems manager, Mr. P. Greenacre, for assistance with the data analysis; to Dr. C. Quigley, who set in place a system for data collection; to the Endocrine Laboratory, Royal North Shore Hospital, for performing the serum parathyroid hormone assays; and to Dr. K.J. Gaskin, Dr. J. Knight, and Prof. H.H. Bode for critically reviewing the manuscript.
Source Information
From the Ray Williams Institute of Paediatric Endocrinology, Diabetes and Metabolism (C.F.V., C.T.C., N.J.H., M.S.) and the Department of Radiology (A.L.), Children's Hospital, and the Department of Public Health, University of Sydney (J.M.S.), both in Sydney, Australia. Address reprint requests to Dr. Verge at the Ray Williams Institute of Paediatric Endocrinology, Diabetes and Metabolism, Children's Hospital, Camperdown NSW 2050, Australia.
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