Zoledronic Acid-Induced Acute Renal Failure
in Multiple Myeloma
Salem Bouomrani1,2*, Nesrine Regaïeg1, Marwa Nefoussi1 and Safa Trabelsi1
1 Department of Internal Medicine, Military Hospital of Gabes, Tunisia
2 Department of Medicine, University of Sfax, Tunisia
Submission: October 27, 2018; Published: November 05, 2018
*Corresponding author: Salem Bouomrani, Department of Internal Medicine, Military Hospital of Gabes, Gabes 6000, Tunisia
How to cite this article: Bouomrani S, Regaïeg N, Nefoussi M, Trabelsi S. Zoledronic Acid-Induced Acute Renal Failure in Multiple Myeloma. JOJ Case
Stud. 2018; 9(2): 555757.
Introduction: Despite its potential severity, the renal toxicity induced by zoledronate acid (ZA) is poorly studied and little characterized in current medical practice. Acute renal failure with zoledronate in multiple myeloma (MM) has only been reported by a few authors as sporadic cases. We are reporting an original observation of ZA-induced early nephrotoxicity during MM treatment.
Case report: A 74-year-old female, with no notable pathological history, was explored for recent deterioration of the general condition with diffuse inflammatory rachialgia and bone pain. Investigations concluded to the diagnosis of IgG lambda Durie-Salmon stage IIIA MM. She was treated with six courses of melphalan-prednisolone-thalidomide (MPT) chemotherapy with a favorable initial outcome. The subsequent evolution was marked by the occurrence of two episodes of progression that were treated with two cycles of six MPT courses. Monthly infusions of ZA (Zometa®) at a dose of 4 mg were prescribed for very painful bone metastases. When admitted for the third infusion, the assessment noted acute renal failure with creatinine at 279μmol/l. Stopping Zometa® and adequate hydration allowed gradual normalization of renal function with creatinine at 194μmol/l after one week, 115μmol/l after one month, and 83μmol/l after two months.
Conclusion: ZA should be used with caution in MM, and regular monitoring of renal function is recommended. These measures are particularly useful if frequent administration of this drug, associated risk factors, and pre-existing renal lesions.
Intravenous bisphosphonates are increasingly used in cancerous pathology to prevent acute osteolytic complications and treat hypercalcemia of malignancy. Nephrotoxicity represents a potentially serious and sometimes limiting complication of this use [1,2]. This complication is variable from one molecule to another  and seems to be dose- and duration-dependent [1,2,4,5].
Zoledronic acid (ZA) is a bisphosphonate that has been shown to be effective in preventing, reducing the incidence, and delaying the occurrence of bone events in cancer patients, as well as controlling bone pain [5,6].
It is characterized, moreover, by a widely established tolerance, allowing its long-term admission in a safe way . However, preventive measures are necessary during long-term administration to avoid certain serious but exceptional complications, such as nephrotoxicity and osteonecrosis of the jaw [6,7]. Despite its potential severity, the renal toxicity induced by ZA is little known, poorly studied, and little characterized in current medical practice .
Acute renal failure with Zoledronate in multiple myeloma (MM) has only been reported by a few authors as sporadic cases. We report an original observation of ZA-induced early nephrotoxicity during MM treatment.
A 74-year-old female patient, with no notable pathological history, was explored for recent deterioration of the general condition with diffuse inflammatory rachialgia and bone pain.
The biological assessment showed normochromic normocytic anemia at 8g/dl without thrombocytopenia or leukopenia, erythrocyte sedimentation rate at 140mmH1, C-reactive protein at 52mg/l, hyperprotein at 132g/l with a proteinuria of 24 hours at 0.7g, calcemia at 2.68mmol/l, and hyperuricemia at 740μmol/l. Plasma protein electrophoresis revealed monoclonal hypergammaglobulinemia at 62g/l with suppression of other proteins. Renal function was normal with creatinine at 89μmol/l.
Immunoelectrophoresis of the blood proteins isolated monoclonal IgG gammopathy and urinary immunoelectrophoresis showed free and bound monoclonal
lambda light chains. Standard radiographs of long bones, pelvis,
thoracolumbar spine, and skull showed multiple geodic lytic
lesions. The myelogram confirmed the diagnosis of MM by
showing bone marrow infiltration by 28% of dystrophic plasma
Nuclear magnetic resonance imaging did not objectify
epiduritis or medullary compression. At the end of this
assessment, the diagnosis of IgG lambda Durie-Salmon stage
IIIA MM was retained. She was treated with six courses of
melphalan-prednisolone-thalidomide (MPT) chemotherapy
with a favorable initial outcome (response evaluated at 80%).
The subsequent evolution was marked by the occurrence
of two episodes of progression after two and three years that
were treated with two cycles of six MPT courses, followed by
maintenance treatment with thalidomide. Monthly infusions of
zoledronic acid (Zometa®) at a dose of 4mg were prescribed
for very painful bone metastases. When admitted for the third
infusion, the assessment noted a blood creatinine at 279μmol/l
without evidence of dehydration, urinary tract infection,
associated hypercalcemia, or rhabdomyolysis. Renal ultrasound
and Doppler examination of renal vessels were without
abnormalities. Stopping Zometa® and adequate hydration
allowed gradual normalization of renal function with creatinine
at 194μmol/l after one week, 115μmol/l after one month, and
83μmol/l after two months.
Nephrotoxicity does not complicate oral bisphosphonates
used in the treatment of osteoporosis; it complicates only
intravenous bisphosphonates used in the treatment of bone
metastases and severe hypercalcemia [1,9].
Regardless of the intravenous bisphosphonate used, the
clinical and simple laboratory evaluation (based only in serum
creatinine assay) largely underestimates the frequency of this
complication; Systematic screening in Phase III large clinical
trials estimated the incidence of bisphosphonate-induced
kidney damage at 7.7 to 15.2% depending on the dose of the drug
used for infusion (4 or 8mg) and depending on the underlying
neoplasia (7.7% for breast cancer, 10.7% for multiple myeloma
and breast cancer, and 15.2% for prostate cancer) .
Conversely, in the experimental animal study, 100% of
rats presented histological renal lesions after intravenous
bisphosphonate therapy . These lesions were basal
membrane thickness, cytoplasmic vacuolization, loss of brush
border, tubular epithelial smoothness, tubular lumen obstruction
and cell necrosis .
In humans, similar lesions such as loss of brush border,
tubular degeneration with luminal ectasia, tubular atrophy,
interstitial fibrosis, hypereosinophilia, and inflammation were
also observed on histological examination of renal biopsies in
patients with acute tubular necrosis under zoledronate .
This nephrotoxicity remains exceptional with ZA in large
series: only 0.02% in the American series of Chang JT et al of
430,000 cancer patients receiving zoledronate . Similarly, the
French Adverse Event Reporting System database reported only
seven cases over a period of four years following the introduction
of this drug in the country , and no case was noted in Sabry
NA et al series of 40 cancer patients receiving this treatment at
usual doses and monitored over three months .
The clinical spectrum of this nephrotoxicity includes
acute renal tubular necrosis, collapsing focal segmental
glomerulosclerosis, acute renal failure, deterioration of preexisting
chronic renal failure, interstitial nephritis, nephrotic
syndrome, tubulopathies, and Fanconi syndrome [1,5,8,12].
The risk factors for ZA-induced nephrotoxicity are:
advanced cancer, MM, pre-existing renal insufficiency, diabetes,
hypertension, severe dehydration, rapid infusion of the drug
(<15 minutes), and concomitant use of other nephrotoxic drugs
This nephrotoxicity occurs at variable intervals compared
with the start of treatment with bisphosphonates (1-120 days)
. It appears to be dose- and infusion duration-dependent (1.5)
but may also occur early and even after a single infusion of the
drug, and without any risk factors favoring it .
MM seems to be particularly predisposing to zoledronateinduced
nephrotoxicity; in fact, five out of six patients who
developed renal insufficiency (related to acute tubular necrosis)
caused by zoledronate in the Markowitz CS et al.  series
were myelomatous. Similarly, in American cases of ZA-induced
nephrotoxicity reported by the Food and Drug Administration
(FDA), 42 patients/72 were myelomatous (58.3%) .
However, it seems that other factors, particularly genetic/
ethnic, intervene in this nephrotioxicity; indeed, no case of renal
damage has been reported in the Teoh G et al series of 44 Asian
patients with MM receiving ZA intravenously and at usual doses
The mechanisms evoked for this nephrotoxicity are: the
aggregation of bisphosphonates and calcium complexes in
renal cells, and even more the induction by bisphosphonates
of renal tubular cell death (similar to their apoptotic effect on
osteoclasts) . This is particularly due to the renal uptake and
elimination of bisphosphonates . Acute renal failure with
zoledronate in MM has only been reported by a few authors as
sporadic cases [16-18].
Usually zoledronate-induced renal damage is reversible
when the bisphosphonate is stopped (100% reversibility in
the Markowitz GS et al.  series) [5,8]. However, recovery of
renal function after stopping treatment may not be complete
, and even fatal outcomes of this nephrotoxicity have been
reported : of the 72 American cases, 27 required dialysis and
18 decided .
Concomitant administration of vitamin E (15mg/week
intramuscularly) significantly reduces the nephrotoxicity of ZA
as demonstrated by the experimental animal study of Serti IU
et al. .
ZA should be used with caution in MM, and regular
monitoring of renal function, especially tubular function, is
recommended in any patient receiving zoledronate. These
measures are particularly useful if frequent administration of
this drug, associated risk factors, and pre-existing renal lesions.
The monitoring of creatinine before each infusion, the good
hydration, the temporary suspension of infusions in case of
occurrence of nephropathy, and the adjustment of the doses of
the bisphosphonate in case of pre-existing nephropathy are the
only guarantors to avoid this potentially fatal complication of