Possible Fanconi Syndrome associated with zoledronic acid

In August 2015, HSA received its first local ADR report of possible Fanconi Syndrome (FS) associated with zoledronic acid. The patient presented with multiple electrolyte imbalances, together with low uric acid levels and mild proteinuria approximately 10 days after receiving a single intravenous (IV) infusion of zoledronic acid 4mg for bone metastases secondary to prostate cancer. At the time of reporting, the outcome was unresolved, with the patient still requiring oral calcium replacement therapy.

Zoledronic acid (Zometa®, Novartis (Singapore) Pte Ltd) has been registered locally as a 4mg infusion since February 2005 for the treatment of osteolytic, osteoblastic, and mixed bone metastases of solid tumours and osteolytic lesions of multiple myeloma in conjunction with standard antineoplastic therapy, as well as for the treatment of hypercalcaemia of malignancy. There are also two other generic brands.

Another strength (5mg infusion) of zoledronic acid (Aclasta®, Novartis (Singapore) Pte Ltd) has been registered locally since March 2006 for the treatment of osteoporosis in post-menopausal women and in men at increased risk of fracture, prevention of glucocorticoid-induced bone mineral density loss, prevention of osteoporosis in post-menopausal women with increased risk of osteoporosis, and treatment of Paget’s disease of the bone.

Local case report

The patient, a male in his fifties, had no past medical history of note and was not on long-term medication. He was admitted to hospital for right lower limb weakness and was subsequently diagnosed with prostate cancer with metastatic bone disease. A single dose of IV zoledronic acid 4mg was hence administered four days into admission. Other concomitant medications started during his hospital admission included gabapentin, tramadol, paracetamol/orphenadrine, ketoprofen, metoclopramide, lactulose, omeprazole, dexamethasone, bicalutamide, dopamine and several antibiotics.

Approximately 10 days later, the patient developed multiple acute electrolyte abnormalities including hypocalcaemia, hypophosphataemia, hypokalaemia and low uric acid levels. Paired urine sample analyses revealed high fractional excretion of uric acid and high urinary losses of phosphate, potassium and uric acid, indicating renal wasting of these electrolytes (Table 1). In addition, mild proteinuria (0.2g/L) was also detected. His other laboratory results were unremarkable. He did not have glucosuria.

Table 1. Relevant laboratory test results and subsequent change in therapy*

	Baseline (Day -20)	Day 1 (Onset of ADR)	Day 2	Day 3	Day 4	Day 5	Day 6	Day 29
Calcium, Adjusted (mmol/L)	2.54	1.67   Started 6 cycles of IV calcium gluconate	1.98   Started 2 cycles of IV calcium gluconate	2.03   Started 2 cycles of IV calcium gluconate	1.88   Started IV calcium gluconate and calcium carbonate tablets	2.32	2.32   Stopped IV calcium gluconate. Patient kept on calcium carbonate tablets	2.30   Continued calcium carbonate tablets
Phosphate (mmol/L)	1.2	0.6	0.7	0.5	0.9	0.8	0.9	1.1
Potassium (mmol/L)		4.0		3.5	3.0   Started potassium citrate	3.9	4.2   Stopped potassium citrate	4.2
Magnesium (mmol/L)		0.8			0.6   Started magnesium supplements	0.7	0.9	0.9
Sodium (mmol/L)		138		139	137	133		137
Bicarbonate (mmol/L)					26
Vitamin D (ng/ml)				<9   Started Cholecalciferol
Parathyroid hormone (pmol/L)			7.1

*Values in red are out of the normal reference range

FS was suspected to be induced by zoledronic acid based on the onset and clinical course of the patient. However, this patient did not present with all the classical and florid constellations of electrolyte abnormalities as expected with typical FS. Certain features that were lacking to support the diagnosis of FS included glucosuria and acidosis. In addition, the patient had severe vitamin D deficiency (<9ng/ml), which is a risk factor for hypocalcemia¹ and could have potentiated the persistent hypocalcaemia observed.

Literature reports

Several cases of zoledronic acid-induced FS have been reported in the literature.^2-4 The patients were administered zoledronic acid either for bone metastasis or malignancy-associated hypercalcaemia. The diagnosis of FS was established by the characteristic electrolyte abnormalities of blood and urine. In one of the cases, the diagnosis was further confirmed via renal biopsy, which showed scattered formation of cylinders inside the proximal renal tubules, infiltration of inflammatory cells around the proximal tubules and stroma of the same region, and interstitial oedema with lack of glomerular changes.² All three patients reported an improvement of renal tubular function after discontinuation of zoledronic acid treatment. Close monitoring of proximal tubular function during therapy with zoledronic acid was recommended by the authors of all the case reports.

Discussion

The diagnosis of drug-induced FS is usually suggested by a temporal relationship with exposure to a drug known to be toxic to the renal proximal tubule. However, it is worthwhile to note that with certain drugs such as tenofovir, toxicity can occur months or even years after establishing patients on treatment.⁵

This is the first report of zoledronic acid-induced FS reported locally. Healthcare professionals are advised to closely monitor the renal function of patients prescribed zoledronic acid so as to avoid the potential nephrotoxicity of the drug. Although some risk factors (i.e. elderly or very young population, pre-existing renal impairment and volume depletion) for drug-induced FS have been identified, in many cases it is unclear why patients develop toxicity while others do not. Pharmacogenomics has also been postulated to play a role in the development of drug-induced FS, although more research is required to establish this role.⁵

Healthcare professionals are encouraged to report any adverse drug reactions suspected to be associated with the use of IV zoledronic acid to the Vigilance and Compliance Branch of HSA.

HSA would like to take this opportunity to thank Dr Yeo Pei Shan, Senior Resident, Department of Endocrinology,Tan Tock Seng Hospital for her contribution to this article and partnering with us in our vigilance efforts to safeguard public health.

References

1. Ann Oncol 2006; 17: 897-907
2. Endocr J 2012; 59: 1051-6
3. Intern Med 2011; 50: 1075-9
4. Gan To Kagaku Ryoho 2015; 42: 867-70
5. Q J Med 2014; 107: 261-9
6. Pediatr Nephrol 2015; 30: 1407-23 

About Fanconi Syndrome^5,6

Fanconi Syndrome is a generalised dysfunction of the renal proximal tubules and can be inherited (i.e. Wilson’s disease, Dent’s disease) or acquired (i.e. drug-induced). The characteristic clinical features of Fanconi Syndrome include amino aciduria, organic aciduria, low molecular weight proteinuria, hypophosphataemia, normoglycemic glycosuria, metabolic acidosis, hypouricaemia, hypokalaemia and polyuria. However, some patients may only exhibit some of these features. These symptoms are a result of urinary wasting of solutes normally reabsorbed by the proximal tubule.

Drugs implicated in causing Fanconi Syndrome include ifosfamide, oxaliplatin, cisplatin, acetazolamide, tenofovir, valproic acid and antibiotics such as aminoglycosides and tetracyclines. Substantial recovery of proximal tubular function can occur after withdrawal of therapy but chronic damage may persist in some cases.

Published: 30 Dec 2015

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