PEDIATRICS Vol. 111 No. 4 April 2003, pp. 899-901
Oral Bisphosphonate Therapy for Vitamin D Intoxication of the Infant
Abdullah Bereket, MD and
Tulay Erdogan, MD
Department of Pediatrics
Division of Pediatric Endocrinology
Marmara University
School of Medicine
Istanbul 81030, Turkey
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ABSTRACT
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Vitamin D intoxication in infancy has serious consequences attributable to acute hypercalcemia and subsequent hypercalcuria/nephrocalcinosis. Current treatments of patients with vitamin D intoxication are unsatisfactory and associated with prolonged hypercalcemia. We now report the use of oral alendronate sodium in a 3-month-old infant with vitamin D intoxication. Short-term oral alendronate sodium treatment effectively corrected hypercalcemia/hypercalciuria, decreased the duration of hospitalization, and appears safe in 15 months of observation.
Key Words: bisphosphonates • hypercalcemia • hypervitaminosis D
Abbreviations: IV, intravenous
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INTRODUCTION
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Vitamin D intoxication is a well-known cause of hypercalcemia in children. Prompt and effective treatment of vitamin D intoxication is necessary because of the serious consequences of acute hypercalcemia in children.1,2 Hypercalcemia and hypercalciuria seen in Vitamin D intoxication is relatively resistant to treatment and takes a long time to resolve because of deposition of ingested vitamin D in fat tissue.3,4
Although intravenous (IV) hydration and diuretics are the first line of treatment for mild hypercalcemia, glucocorticoids and calcitonin have been used in severe cases to lower elevated serum calcium concentrations.2 Nevertheless, calcium-lowering effects of glucocorticoids are slow and calcitonin is intolerable for some patients because of hypersensitivity.4–7 In addition, both agents have considerable side effects.7,8
Bisphosphonates have been used in treatment of hypercalcemia in adults resulting from various etiologies. However, the experience in children is limited. In this article, we report, for the first time, the effect of oral bisphosphonate treatment in an infant with vitamin D intoxication.
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CASE REPORT
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A 3-month-old male infant was brought to the emergency department with vomiting, lethargy, and constipation. History revealed that he was fed breast milk and started on vitamin D 750 IU/d at 1 month of age, which was increased to 1500 IU/d at 2 months of age by his primary care physician. At 2.5 months of age, a Stoss therapy (300 000 IU vitamin D, single dose, orally) was prescribed by the same physician. The mother mistakenly gave the infant 1 ampule (300 000 IU) of vitamin D every day until the fourth day (a total of 1 200 000 IU) when the infant started to have decreased appetite, vomiting, lethargy, and constipation. The mother stopped giving vitamin D after the appearance of these symptoms. The patient was brought to our emergency department because of the persistence of the symptoms 10 days after the discontinuation of vitamin D.
On physical examination, he had constant vomiting, and was lethargic and hypertensive (blood pressure was 140/80). His height and weight was at between the 90th and the 97th percentile. The rest of the examination was unremarkable.
Laboratory investigation demonstrated serum calcium of 18.5 mg/dL (4.6 mmol/L); phosphorus, 3.2 mg/dL (1.03 mmol/L); alkaline phosphatase, 492 U/L; parathyroid hormone, <1.0 pg/ml; and 25 (OH)vitamin D 360 ng/mL (897 nmol/L) (Table 1). The patient was admitted to the intensive care unit and emergency treatment was initiated with IV hydration (150 mL/kg/d), furosemid (1.5 mg/kg), and nifedipine. Breast milk was discontinued to restrict dietary calcium intake. A repeat serum calcium level was still 17.6 mg/dL (4.4 mmol/L) on the following day. Alendronate sodium 5 mg/d given by mouth was added to treatment after obtaining informed consent from the parents. Breastfeeding restarted at the end of the same day. On the third day of admission, serum calcium was 16.7 mg/dL (4.2 mmol/L). The dose of alendronate sodium was increased to 10 mg/d. Serum calcium dropped rapidly to 13.7 mg/dL (3.4 mmol/L) on the fourth day and IV fluid was discontinued. Blood pressure was also normalized on the fourth day and nifedipine was discontinued. The following days serum calcium decreased gradually and the patient was discharged on the sixth day when serum calcium was 12.4 mg/dL (3.1 mmol/L).
Alendronate sodium was decreased to 5 mg/d on discharge and discontinued on 18th day when serum calcium was 9.9 mg/dL (2.5 mmol/L). Serum calcium levels remained normal thereafter.
Urinary calcium/creatinine ratios were initially high (1.15; 2.22, 2.60, 1.67 at 4 different instances) but decreased later to normal levels (Table 1). Renal ultrasound examinations performed at admission, at 2 weeks, and 2 months after the admission did not show any evidence of nephrocalcinosis. A radiograph of the hand taken 4 months after the admission showed metaphyseal sclerosis (Fig 1).
On follow-up examination at 6 months after the admission, the patient was normocalcemic with normal urinary calcium excretion. His growth and development has been normal (height: 75%–90%, weight: 90%–97%) at 6 months after his admission. His most recent examination in 18 months of age demonstrated that he continues to grow at the same percentile with completely normal physical examination.
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DISCUSSION
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Vitamin D intoxication in children can cause severe hypercalcemia. When the total calcium concentration is >14 mg/dL, emergency intervention is necessary because of the adverse effects of hypercalcemia on cardiac, central nervous, renal, and gastrointestinal function.2 In a review of 24 children with vitamin D intoxication, 2 deaths and 23% of permanent renal damage has been reported.1 Rapid normalization of serum calcium is, therefore, necessary to prevent these acute complications. Maintaining normocalcemia is also important to prevent prolonged hypercalciuria and nephrocalcinosis seen in these patients. The latter may sometimes be difficult to achieve because of the storage of substantial amount of vitamin D in adipose tissue.3
Bisphosphonates are specific inhibitors of osteoclast mediated bone resorption. Bisphosphonates have been used extensively in adults for the treatment of hypercalcemia of malignancy and metabolic bone diseases. However, the experience in vitamin D intoxication is limited to a few adult case reports.5,6,9,10 Bisphosphonate treatment of a child with hypercalcemia attributable to vitamin D intoxication has not been reported previously. In general, less is known about the safety and the efficacy of bisphosphonate therapy in hypercalcemia of infants and children.11 Patient reports of hypercalcemic children (mostly attributable to malignancy) treated with IV pamidronate sodium has been appearing in the literature.12–14 Oral bisphosphonates are used rarely in hypercalcemia. A 14-year-old female with chronic hypercalcemia of unknown etiology was initially treated with IV pamidronate sodium, but a need for frequent pamidronate sodium infusions led to the decision to use oral alendronate treatment.12 Etidronate disodium was used effectively in an infant with hypercalcemia attributable to subcutaneous fat necrosis15 and another with familial hypocalciuric hypercalcemia.16 Thus, our patient is the first infant with vitamin D intoxication treated with oral alendronate sodium.
It has been demonstrated that hypercalcemia seen in hypervitaminosis D is predominantly related to increased bone resorption.5,6 Therefore, specific inhibitors of bone resorption might provide more effective treatment in hypervitaminosis D. Indeed, studies in adult patients with vitamin D intoxication, demonstrated that treatment with bisphosphonates was more effective than treatment with glucocorticoids. IV pamidronate sodium treatment resulted in a more rapid reduction in plasma calcium concentration compared with patients received corticosteroid.5 Rizzoli et al reported that IV administration of clodronate corrected hypercalcemia/hypercalciuria whereas prednisone therapy barely affected biochemical values.5
In the light of these studies, we decided to use a bisphosphonate because very high serum calcium concentrations did not show a significant reduction after treatment with IV fluids and diuretics. Experimental studies suggest that glucocorticoid treatment increases the risk for nephrocalcinosis by increasing urinary calcium excretion in hypervitaminosis D.17 IV bisphosphonate therapy is relatively expensive. Thus, we decided to use an oral bisphosphonate. Alendronate sodium offers continuous oral dosing with theoretically less risk to skeletal growth and mineralization. Alendronate treatment resulted in rapid reduction of serum calcium concentrations and resolution of symptoms such as vomiting, lethargy, and hypertension. We were able to restart breastfeeding at the end of second day and discharge patient on the sixth day. Hypercalciuria also normalized in a short time despite discontinuation of treatment.
Alendronate sodium has been well-tolerated with no gastrointestinal or other side effects observed during treatment and follow-up periods. After 6 months of observation, the patient remained normocalcemic with normal urinary calcium excretion and renal ultrasound examination. Weight gain and linear growth of the patient continues on 75th percentile at 18 months of age assuring for the long-term safety of the drug. Band-like metaphyseal sclerosis observed in our patient can be caused by vitamin D intoxication itself or can be attributable to treatment with alendronate. Sclerosis caused by bisphosphonates tends to disappear after discontinuation of the drug.18
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CONCLUSION
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Short-term oral alendronate sodium treatment effectively corrected hypercalcemia/hypercalcuria, decreased the duration of hospitalization, and was safe in 15 months of observation in this infant with vitamin D intoxication. Brisk response to alendronate sodium treatment may provide further evidence that hypercalcemia in vitamin D intoxication is related to increased bone turnover.
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FOOTNOTES
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Received for publication Mar 18, 2002; Accepted Aug 5, 2002.
Reprint requests to (A.B.) Bozkir Sokak No: 4/7, Selamicesme-Istanbul, 81030, Turkey. E-mail: abereket{at}e-kolay.net
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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ABSTRACT
INTRODUCTION
