NEPHROCALCINOSIS: A POTENTIAL COMPLICATION OF BISPHOSPHONATE THERAPY IN CHILDREN

Abstract

12 September 2011 Dear Editor, Although bisphosphonate therapy is effective in severe childhood osteoporosis, both short and long term side effects occur.1 We have treated a total of 124 children including those with severe Osteogenesis Imperfecta (OI) since 1998, and more recently, patients with other forms of osteoporosis (e.g. juvenile idiopathic osteoporosis or steroid induced) with serious fractures (e.g. vertebral crush fractures). All patients received intravenous pamidronate therapy. The protocols (Table 1) were those used at the Children's Hospital at Westmead at that time. Our protocol included a dietary calcium assessment to ensure a dietary calcium intake of ≥1200 mg/day for at least 1 week after the initial infusion to prevent hypocalcaemia, a known complication of bisphosphonate therapy. Patients were prescribed calcitriol 0.25 mcg twice daily at the time of each pamidronate infusion and for 7 days post-infusion. We present four patients who developed nephrocalcinosis during intravenous pamidronate therapy. None of these patients had nephrocalcinosis prior to commencement of therapy. An 8-year-old boy with severe OI Type 1B and multiple long-bone fractures was treated with intravenous pamidronate and vitamin D as per protocol. His dietary intake of calcium was adequate and baseline vitamin D levels were normal. Early medullary nephrocalcinosis was noted on ultrasound after 3.5 years of pamidronate therapy. Calcitriol therapy was ceased and pamidronate continued. Repeat renal ultrasound after 6 months showed complete resolution of the nephrocalcinosis. A 7-year-old boy with Juvenile Idiopathic Osteoporosis and multiple vertebral compression fractures was referred for continuation of bisphosphonate therapy. He was treated with calcitriol 0.25 mcg (as per protocol) and given supplemental calcium. Mild medullary nephrocalcinosis was identified on renal ultrasound after 2 years of pamidronate therapy. Vitamin D therapy was ceased. Pamidronate therapy was ceased after 3 years of treatment. Renal ultrasound showed complete resolution of nephrocalcinosis after 6 years. A 2-year-old girl with OI Type 1A was commenced on IV pamidronate therapy (total duration 2.5 years) following a history of multiple, atraumatic hip and vertebral fractures. Dietary calcium intake was adequate and baseline vitamin D levels were normal. She was commenced on pamidronate and calcitriol, as per protocol. After 12 months of therapy, she was advised to cease Calcitriol because of concerns arising from Cases 1 and 2 above. Early nephrocalcinosis was noted after 22 months of intravenous bisphosphonate therapy. Follow-up ultrasound after 3 years was normal. A 15-year-old boy with severe ulcerative colitis and steroid induced osteoporosis presented with painful crush fractures of the thoracic spine. Calcium supplementation was commenced. Baseline vitamin D level was normal and vitamin D supplementation was not prescribed. After 12 months of pamidronate therapy ultrasound demonstrated a small area of nephrocalcinosis of the mid pole of the left kidney. The patient admitted taking a natural supplement which contained 320 IU (8 mcg) vitamin D3 per day. Advice was given to cease this supplement and pamidronate therapy was continued. An ultrasound 12 months later was normal. Serum calcium and alkaline phosphatase levels remained normal in all four patients whilst on bisphosphonate therapy. Urinary calcium: creatinine ratio was normal in the four cases presented. Bone turnover markers (urinary pyridinoline and deoxypyridinoline) were measured yearly in all patients on bisphosphonate therapy and remained within the normal range in the four cases. Nephrocalcinosis is defined as a generalised increased solute content (in particular, calcium) within the kidney. Medullary nephrocalcinosis is the typical pattern seen in 98% of cases in humans.2 The diagnosis of nephrocalcinosis is usually made radiologically, using ultrasound, computed tomography or intravenous pyelogram. Risk factors for the development of nephrocalcinosis include; hypercalciuria, vitamin D intoxication, distal renal tubular acidosis, hyperparathyroidism, hyperoxaluria and prematurity.3 The mechanism of development of nephrocalcinosis is likely related to hypercalcaemia and subsequent hypercalciuria. Nephrocalcinosis has not been previously reported following bisphosphonate therapy in children, but has been seen in pamidronate-treated rabbits.4 Vitamin D excess or intoxication can cause severe hypercalcaemia resulting in calcium deposition in the tissues, including nephrocalcinosis.3,5 All of the cases described above were taking vitamin D supplementation in addition to bisphosphonate therapy, either as part of a treatment protocol to prevent hypocalcaemia (Cases 1–3) or as self medication (Case 4). Interestingly, three of the four cases presented were treated with bisphosphonate prior to 2001, when vitamin D supplementation was routine. Since cessation of routine supplementation, only one case has developed nephrocalcinosis and he was found to be inadvertently taking a supplement containing vitamin D. Nephrocalcinosis has been observed in four children treated with both intravenous pamidronate and vitamin D supplementation. Excess Vitamin D has been shown to be a cause of nephrocalcinosis. We suggest that vitamin D supplementation during bisphosphonate therapy may have contributed to the development of nephrocalcinosis. In the presence of normal vitamin D levels, vitamin D supplementation on bisphosphonate therapy may be unnecessary and may be associated with the development of nephrocalcinosis.