Fanconi Syndrome Associated with Long-term Treatment with Zoledronate

Abstract

Intravenous bisphosphonate therapy is used to prevent fractures in the management of bone metastasis. However, it may induce renal damage. We herein report an 81-year-old woman with Fanconi syndrome and osteomalacia who had been diagnosed with metastatic breast cancer and received treatment with zolendronate for over 5 years. Her bone markers normalized after switching zolendronate to denosmab and starting vitamin D and mineral supplementation. This case shows that chronic renal damage induced by zolendronate can cause osteomalacia. In patients with intravenous zolendronate therapy, close monitoring of renal and bone markers is needed, even under long-term therapy.

Introduction

Breast cancer is the most common cancer in the world. In 2020, 2.3 million women were diagnosed with breast cancer, and 685,000 deaths occurred globally (1). The bone is the most common site of breast cancer metastasis. In a retrospective study with extensive follow-up, skeletal complications were found in more than 50% of 718 women who were diagnosed with metastatic breast cancer (2). Bone-modifying agents (e.g. bisphosphonates or denosumab) are recommended for patients with bone metastasis, regardless of symptoms (3,4). Zoledronic acid, a parenteral bisphosphonate, is often used in the management of patients with bone metastatic breast cancer to prevent fracture and spinal cord compression. In patients with breast cancer, adjuvant treatment with zoledronic acid is also reported to reduce the incidence of relapse in bone (5).

Fanconi syndrome is a global dysfunction of the renal proximal tubule characterized by glycosuria, phosphaturia, aminoaciduria and renal tubular acidosis (6). There are many etiologies of Fanconi syndrome. The genetic causes of the syndrome typically present in childhood. However, Fanconi syndrome in adults usually occurs secondary to acquired proximal tubular insults, such as light-chain disease and drug toxicity (7,8). In patients with Fanconi syndrome, bone demineralization through acidosis and hypophosphatemia is a serious complication.

We herein report a woman with bone metastatic breast cancer who developed Fanconi syndrome and osteomalacia after long-term treatment with zoledronate.

Case Report

An 81-year-old woman with a history of breast cancer was referred to the nephrology department of our hospital for the assessment of hypokalemia and renal dysfunction. Seven years before this referral, she was diagnosed with advanced breast cancer with distant metastasis to the lung and bone and was treated by neoadjuvant chemotherapy with pertuzumab, trastuzumab and docetaxel. After neoadjuvant chemotherapy, she received partial mastectomy and postoperative radiation therapy. One month after completing radiation treatment, she received adjuvant therapy with trastuzumab for 11 months. Adjuvant endocrine therapy with letrozole was also started. In addition, 9 months after completing the radiation treatment, zoledronic acid (4 mg/month) was started for bone metastasis. Treatments with letrozole and zoledronic acid had continued until the referral.

Two years after starting treatment with zoledronic acid, her serum potassium level decreased to 2.2 mmol/L, and she received potassium supplementation. Five years after starting the treatment with zoledronic acid, because her renal function had gradually declined, she was referred to the nephrology department for an examination and treatment.

The patient's height was 139 cm, and her weight was 45 kg. Her blood pressure was 162/98 mmHg. Laboratory findings included the following: hemoglobin, 10.8 g/dL; white blood cell count, 3,480 /μL; platelet count, 14×10⁴ /μL ; total serum protein, 6.5 g/dL; serum albumin, 3.5 g/dL; urea nitrogen, 18 mg/dL; serum creatinine, 1.44 mg/dL [estimated glomerular filtration rate (eGFR), 27.3 mL/min/1.73 m²]; serum sodium, 137 mmol/L; serum potassium, 3.9 mmol/L; serum chloride, 112 nmol/L; serum free calcium, 1.0 mmol/L; serum phosphate, 1.8 mg/dL; and serum uric acid, 1.6 mg/dL. A test for antinuclear antibodies was negative, and urinary Bence Jones protein was not detected. An arterial blood gas analysis showed metabolic acidosis with respiratory compensation: pH, 7.31; pO₂, 120 mmHg; pCO₂, 26 mmHg; HCO₃^-, 13.1 mmol/L; and anion gap, 11.9 mmol/L. She also had mild proteinuria (0.37 g/day) and glucosuria (4.3 g/day) with a normal plasma glucose level (95 mg/dL). An elevated urinary beta 2-microglobinuria level (49,000 μg/L) and generalized aminoaciduria were also found. Her uric acid clearance increased to 26.1 mL/min/1.73 m² (reference range: 7.3-14.7 mL/min/1.73 m²), and the maximum tubular transport of phosphate reabsorption relative to glomerular filtration rate transport (TmP/GFR) declined to 0.5 (reference range: 2.3-4.3). In addition, she had vertebral fractures with a reduced hip bone mineral density (T score -2.5). As shown in Table, her laboratory findings at referral revealed hypophosphatemic osteomalacia with relative calcitriol deficiency.

Table.

Laboratory Findings at Referral and 6 Months after Hospitalization.

	At referral	6 months after hospitalization	Reference Range
Free Ca (mmol/L)	1.0	1.25	1.15-1.33
P (mg/dL)	1.8	2.8	2.7-4.6
Na (mmol/L)	137	138	138-145
K (mmol/L)	3.9	3.9	3.6-4.8
Cl (mmol/L)	110	103	101-108
HCO3- (mmol/L)	13.1	27.2	21-27.0
UA (mg/dL)	1.6	2.4	3.5-7
iPTH (pg/mL)	126	44	10-65
BAP (μg/L)	32.4	10.3	3.8-22.6
TRACP-5b (mU/dL)	475	98	120-420
eGFR (mL/min/1.73m2)	27.3	27.4	>60

eGFR: estimated glomerular filtration rate

The patient was started on therapy with calcitriol, sodium phosphate, and potassium/sodium citrate. Zoledronic acid was discontinued, and the treatment was switched to denosumab, as zoledronic acid toxicity was suspected. Six months after starting these treatments, her renal function was stable. In addition, her bone markers (BAP and TRACP5b) normalized (Table), which indicated that bone demineralization had been reduced. Her treatment is currently being continued in an outpatient setting.

Discussion

Fanconi syndrome may be an inherited or acquired disease. Acquired Fanconi syndrome has been reported in association with some drugs, heavy alcohol use, and exposure to heavy metals (7,8). Multiple myeloma and solid malignant tumors have also been reported as causes of Fanconi syndrome. In the present case, hypokalemia developed more than three years after the patient stopped neoadjuvant chemotherapy, and Bence Jones protein was not detected.

A number of therapeutic drugs are toxic to the kidney proximal tubule and can cause Fanconi syndrome. The most frequently implicated drugs are cisplatin, ifosfamide, tenofovir, sodium valproate and aminoglycoside antibiotics (8). The patient had not been taking any medications other than zoledronic acid and letrozole for the five years prior to her presentation, and hypokalemia appeared two years after the after start of treatment with zoledronic acid and letrozole. Letrozole is a nonsteroidal inhibitor of aromatase that effectively blocks estrogen synthesis in postmenopausal women and slows the growth of certain types of breast tumors that need estrogen to grow. Letrozole-induced nephrotoxicity is exceedingly rare and occurs within one month after starting the drug (9). In addition, to our knowledge, there have been no reports of the induction of Fanconi syndrome by aromatase inhibitors. In contrast, renal complications from bisphosphonate treatment are well documented, as the drugs are excreted into the urine (10,11). In addition, there have been several reports on Fanconi syndrome after intravenous bisphosphonate treatment. Therefore, the present patient was diagnosed with zoledronic acid-related Fanconi syndrome.

In previous reports, most cases developed Fanconi syndrome within one month after receiving intravenous bisphosphonate treatment (12,13). In one report, Fanconi syndrome was diagnosed after four years of continuous treatment with zolendronate and tratuzumab. In the present case, Fanconi syndrome might have developed three years after the initiation of treatment with zolendronate and letrozole (14). These findings indicate that, in addition to acute damage, chronic damage can induce Fanconi syndrome. In addition, the accumulation of minor acute injuries might also relate to the development of chronic injury in our case.

It is well established that tumor-induced osteomalacia and X-linked hypophosphatemic rickets are associated with elevated levels of serum fibroblast growth factor 23 (FGF-23) (15,16). We measured the serum FGF23 level about our year after the patient's referral to the nephrology department. At that time, her eGFR was 27 mL/min/1.73 m², and her serum FGF23 level was 79 pg/dL [reference range: 9.9-52.9 pg/dL in non-chronic kidney disease (CKD)]. Because the circulating FGF-23 levels gradually increase with a declining renal function, the patient's serum FGF-23 level was therefore not considered to be abnormal for the patients with CKD stage 4 disease (17). Therefore, FGF23 was not considered to have played a key role in our patient. Aside from Fanconi syndrome, cancer treatment-induced bone loss (18) and CKD were also considered possible causes of the vertebral fracture in our patient.

The main goal of treatment of Fanconi syndrome is to prevent complications arising from urinary wasting of solutes. Hypophosphatemia in particular causes bone demineralization and is worsened by vitamin D deficiency. Therefore, we should not neglect basic care, including combinations of calcium, phosphate, and vitamin D supplementation, in cases of Fanconi syndrome, even in patients with bone metastasis.

In conclusion, chronic damage induced by zolendronate can induce Fanconi syndrome. Patients with bone metastasis under long-term treatment with zolendronate should be closely monitored, as renal side effects may occur.

Author's disclosure of potential Conflicts of Interest (COI).

Takashi Uzu: Honoraria, Eli Lilly Japan, AstraZeneca and Kyowa Kirin.