Lessons Learned From Long-term Side Effects After Zoledronic Acid Infusion Following Denosumab Treatment

A Case Report and Review of the Literature

Ilona Nurmi-Lüthje; Peter Lüthje


J Med Case Reports. 2022;16(473) 

In This Article

Abstract and Introduction


Background: Zoledronic acid is an intravenous, highly potent aminobisphosphonate for use in patients with primary or secondary osteoporosis. Zoledronic acid-induced prolonged side-effects are well known and quite common. However, severe side-effects can be a threat to life. We report a case of severe side-effects induced by zoledronic acid infusion, and its positive effect on long-term back pain.

Case Presentation: In 2012, a 62-year-old white native Finnish woman was operated on for an estrogen and progesterone receptor-positive breast cancer. After radiotherapy, an aromatase inhibitor (letrozole) was started. Nine months after the operation, the patient suffered a low-energy compression fracture of Th XII. She received denosumab to prevent fragility fractures and to improve bone mineral density. Letrozole was discontinued after 5.5 years, and the last denosumab injection was given after 7 years. Six months later, at the age of 71 years, the patient received a single intravenous zoledronic acid infusion. Suddenly, at 10 hours from the infusion, she complained of severe trismus, muscle twitching, spasms, and tingling, matching hypocalcemia and several other symptoms. Her serum 25-hydroxyvitamin D concentration was high (163 nmol/L), the concentration of serum calcium and calcium-ion was normal (2.32 mmol/L and 1.23 mmol/L, respectively). However, the neutrophil to lymphocyte ratio (NLR) was low (1.6). A complete recovery took 2 months. Zoledronic acid infusion also had a positive effect: for many years, the patient had suffered low back pain and strain, which came to an end after this single infusion.

Conclusion: It is important that the potential patients receive sufficient information about the possibility of side-effects following the administration of intravenous zoledronic acid. To ensure that a zoledronic acid infusion is given as safely as possible, the safety information should include that the patient should not be left without monitoring for a minimum 24 hours after the infusion. Being alone and experiencing serious side-effects may lead to acute cardiac problems. Furthermore, the chronic low back pain and strain that our patient suffered for many years has clearly reduced for 16 months after infusion, so far. We conclude that this is a positive effect of zoledronic acid.


We present a case of long-lasting severe acute phase response (APR) following the administration of intravenous zoledronic acid in a 71-year-old white woman. Zoledronic acid is a nitrogen-containing third-generation bisphosphonate. Bisphosphonates bind to hydroxyapatite in bone, particularly at sites of active bone remodeling, and reduce the activity of bone-resorbing osteoclasts.[1] Intravenous or high-dose oral administration of nitrogen-containing bisphosphonates may cause acute-phase reactions in up to 50% of patients receiving their first dose.[2]

Our patient received letrozole medication, an aromatase inhibitor (AI), after the treatment of breast cancer. AIs reduce estrogen levels and are associated with more rapid and greater bone loss compared with normal menopause.[3] Women treated with AIs such as letrozole have higher rates of fractures.[3] According to a recent prospective study, the risk of vertebral fracture during AI therapy was significantly lower for patients receiving denosumab or zolendronic acid therapy compared with oral bisphosphonate therapy.[4] Denosumab and zoledronate can reduce AI-related risk of vertebral fractures already after 24 months of treatment.[4]

In all patients initiating AI treatment, fracture risk should be assessed and an antiresorptive therapy should be started for all patients according to the bone mineral density (BMD), with a T-score < −2.0 or a T-score of < −1.5 standard deviation (SD) with one additional risk factor according to the Fracture Risk Assessment Tool (FRAX algorithm), or with ≥ two risk factors (without BMD) for the duration of AI treatment. Based on current evidence, a denosumab injection biannually for the duration of AI therapy is recommended for the prevention of bone loss in postmenopausal women.[3]

Denosumab reduces bone formation and improves bone mineral density (BMD).[5] Denosumab is a monoclonal antibody against the receptor activator of NF-κB ligand (RANKL) and a potent antiresorptive agent, commonly prescribed for treatment of postmenopausal osteoporosis.[5] In contrast to bisphosphonates, denosumab does not incorporate into bone matrix, and therefore its effects are reversible when therapy is discontinued.[6]

In 2015, Papapoulos et al.[7] reported that denosumab treatment for up to 8 years was associated with persistent reductions of bone turnover markers, continued BMD gains, low fracture incidence, and a consistent safety profile. However, in 2016 the first case report of patients who developed new vertebral fractures after discontinuation of denosumab was published.[8] Yet in the previous decade, osteonecrosis of the jaw[9] and atypical femoral fractures[10] emerged as rare potential complications of bisphosphonates and denosumab.

The last European guidance (2019) for the diagnosis and management of osteoporosis in postmenopausal women recommends the use of bisphosphonate therapy after withdrawal of denosumab therapy because of the possible loss of BMD and the risk of vertebral fracture rate.[11]

A Swiss 8-year observational study showed that a single infusion of 5 mg zoledronate after a 2–5-year denosumab treatment cycle retained more than half of the gained BMD and was not associated with multiple vertebral fractures, as reported in patients who discontinued denosumab without subsequent bisphosphonate treatment.[6]

Unfortunately, the use of a single intravenous zoledronic acid (5 mg/100 mL) treatment has also been associated with mild-to-severe side-effects.[12]

We present a case of prolonged severe side-effects and the spontaneous positive effect of zoledronic acid infusion on long-term back pain.