Introduction
Bisphosphonates are synthetic analogues of inorganic pyrophosphates with a high avidity for bone [ 1 ]. They are known to reduce the incidence of fragility fractures and their associated morbidity and mortality [ 2 ] and are often the first-line therapy of choice in the management of osteoporosis. Zoledronic acid is a routinely prescribed third-generation aminobisphosphonate [ 3 ] administered as an annual intravenous infusion. It is generally well tolerated by most patients, with a common adverse effect being a well-described acute phase response characterized by fever, chills, myalgias, arthralgias, and fatigue, which is normally benign and self-limiting in nature [ 4 ]. However, more severe, debilitating musculoskeletal reactions to intravenous bisphosphonates have been infrequently documented in the literature, with only 4 case reports to date describing reactions manifesting as a substantial bisphosphonate-associated arthritis [ 5-8 ]. Here, we aim to expand upon the current literature regarding adverse musculoskeletal reactions to zoledronic acid, describing the case of a 55-year-old female patient who developed acute bilateral knee effusions in the context of an acute systemic inflammatory response following the first zoledronic acid infusion, necessitating hospital admission.
Case Presentation
We report the case of a 55-year-old female patient who was recently transitioned from 6-monthly denosumab injections to an annual infusion of zoledronic acid with the view to a drug holiday for management of postmenopausal osteoporosis. She otherwise had no significant medical comorbidities, was not on any other regular medications, was functionally independent, and mobilized without any aids. Within 24 hours of receiving her first 5 mg infusion of zoledronic acid over one hour, she developed flu-like symptoms manifesting as generalized myalgias and rigors, treated with a short 3-day course of prednisolone 25 mg daily to good effect. Within 48 hours after prednisone cessation, she awoke from sleep with severe bilateral knee pain and swelling, prompting presentation to the emergency department. There were no other joints involved and a systems review was otherwise negative. Of note, she had no clinical history to suggest the presence of a primary inflammatory arthropathy or connective tissue disease or risk factors for an infectious or postinfectious arthritis.
On examination, her hemodynamics were within normal limits, and she was afebrile. There were large, tense bilateral knee effusions with increased warmth bilaterally. Active range of motion was significantly restricted from 15 to 90 degrees due to significant pain. There was mild tenderness to palpation over the medial and lateral joint margins of both knees. The patient was unable to stand from a seated position or to weight-bear. The remainder of her physical examination was unremarkable.
Diagnostic Assessment
Blood tests ( Table 1 ) demonstrated a normal white cell count of 8.7 × 10 9 /L (4.5-11 × 10 9 /L) [4500–11 000 cells/mm 3 ] with a moderately elevated C-reactive protein (CRP) of 48.3 mg/dL (< 0.3 mg/dL) [3 mg/L]. All other blood tests, including renal function, calcium, magnesium, phosphate, 25-hydroxyvitamin D level, parathyroid hormone (PTH), and ferritin were all within normal limits. Anti-citric citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were negative, and HLA-B*27 allele was not detected. Screening for reactive arthritis, including anti-streptolysin O titer, first void urine chlamydia, and gonorrhea polymerase chain reaction (PCR), was unremarkable. Peripheral blood cultures were negative. Bilateral knee x-rays revealed large bilateral knee joint effusions and mild osteoarthritic changes of bilateral patellofemoral compartments, without any associated fractures. There was no chondrocalcinosis. Diagnostic right-sided knee arthrocentesis performed in the emergency department yielded 35 mL of straw-colored fluid of moderate viscosity. Quantitative cell count revealed 1360 × 10 6 /L white cells (< 2000 × 10 6 /L) [< 2000 cells/mm 3 ] and 30 × 10 6 /L red cells (< 500 × 10 6 /L) [< 500 cells/mm 3 ], in keeping with noninflammatory synovial fluid. No crystals were observed on polarized light microscopy and there was no growth on culture after 7 days.
Table 1.
Summary of laboratory findings
Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI). Abbreviations: CCP, cyclic citrullinated peptide; CRP, C-reactive protein; HLA, human leucocyte antigen; RF, rheumatoid factor; PTH, parathyroid hormone; WCC, white cell count.
| Laboratory parameter | Result | Normal range |
| WCC | 8.7 × 10 9 /L (8700 cells/mm 3 ) | 4.5-11.0 × 10 9 /L (4500–11 000 cells/mm 3 ) |
| CRP | 48.3 mg/dL (483 mg/L) | <0.3 mg/dL (3 mg/L) |
| Creatinine | 63 μmol/L (0.71 mg/dL) | 45-90 μmol/L (0.51-1.02 mg/dL) |
| Calcium | 2.33 mmol/L (9.34 mg/dL) | 2.10-2.60 mmol/L (8.42-10.42 mg/dL) |
| Magnesium | 0.84 mmol/L (2.04 mg/dL) | 0.70-1.10 mmol/L (1.70-2.67 mg/dL) |
| Phosphate | 0.95 mmol/L (2.31 mg/dL) | 0.75-1.50 mmol/L (1.82 mg/dL – 3.65 mg/dL) |
| 25-hydroxyvitamin D | 66 nmol/L (26.44 ng/mL) | >50 nmol/L (20.03 ng/mL) |
| PTH | 6.9 pmol/L (6.9 ng/L) | 1.6-6.9 pmol/L (1.6-6.9 ng/L) |
| Ferritin | 92 μg/L (92 ng/mL) | 30-300 μg/L (30-300 ng/mL) |
| Anti-CCP antibodies | Negative | N/A |
| RF | <16 IU/mL (16 U/mL) | 0-16 IU/mL (0-16 U/mL) |
| HLA B27 | Not detected | N/A |
Treatment
After exclusion of septic arthritis, crystal arthropathy, and systemic infection, and in the absence of other features to suggest a primary inflammatory arthropathy, a presumptive diagnosis of a severe adverse reaction to intravenous zoledronic acid was made. Symptomatic treatment was initiated with the use of nonsteroidal anti-inflammatory agents (celecoxib 100 mg twice daily). She did not respond to symptomatic treatment, with persistent pain and re-accumulation of the right knee effusion within 24 hours. Bilateral therapeutic knee arthrocentesis was performed, yielding a further 45 mL of fluid from the right knee joint and 100 mL of fluid from the left knee joint. In addition, 2 mL 1% lignocaine and 80 mg of methylprednisolone was also injected into each knee joint. Both knee aspirates again revealed noninflammatory fluid (936 × 10 6 /L white cells from the right knee and 1755 × 10 6 /L white cells from the left knee) with no crystals observed and no growth on culture.
Outcome and Follow-Up
Over the next 48 hours, the patient experienced gradual improvement in her symptoms, with steady improvement in her active range of movement and mobility status. She was able to mobilize independently and was discharged after a 4-day admission. She was followed up in the rheumatology clinic 1 month following discharge with the view to arrange magnetic resonance imaging if the effusions or pain recurred. However, she had complete resolution of symptoms without recurrence; thus, further imaging at this stage has not been indicated.
Discussion
We described the case of a 55-year-old woman with osteoporosis who received her first intravenous infusion of zoledronic acid complicated by an acute phase response requiring systemic corticosteroids and painful bilateral noninflammatory knee effusions. The clinical course, along with the known effect that bisphosphonates can modulate cytokine production [ 9 ], corroborates the theory that this likely represented an adverse drug effect.
Although zoledronic acid is the most potent bisphosphonate in clinical use due to its high affinity for bone [ 1 ] and is known to commonly cause an acute phase response in up to 40% of patients [ 10 ] manifesting as pyrexia, myalgia, arthralgia, and fatigue, these symptoms are usually mild and transient. More serious adverse effects, including osteonecrosis of the jaw and atypical femoral fractures, are also well documented in the literature [ 11 ] but severe musculoskeletal reactions presenting as a bisphosphonate-associated arthritis requiring hospitalization are much rarer, with only 4 case reports to date elaborating on this phenomenon [ 5-8 ] ( Table 2 ).
Table 2.
Summary of case reports of bisphosphonate-associated arthritis following zoledronic acid infusion
Abbreviations: CRP, C-reactive protein; IV, intravenous; WCC, white cell count.
| Reference | Patient characteristics | Clinical presentation | Investigations | Treatment |
| Diaz-Borjon et al (2006) [ 5 ] | 51-year-old woman with metastatic breast carcinoma and malignancy-associated hypercalcemia | Developed diffuse myalgias and bilateral knee pain and swelling within 48 hours of first dose of IV zoledronic acid | Normal WCC and differential Diagnostic arthrocentesis—no crystals, WCC of 300 cells/mm 3 (noninflammatory), no growth on culture and no malignant cells. No imaging performed. | Therapeutic bilateral knee arthrocentesis |
| Werner de Castro et al (2010) [ 6 ] | 64-year-old woman with osteoporosis and no other comorbidities | Developed subjective chills and pain and swelling in interphalangeal and trapezio-metacarpal joints of both hands within 24 hours of receiving first dose of IV zoledronic acid 5 mg | Normal WCC and CRP. No joint aspirate performed. Radiological imaging revealed bilateral osteoarthritis in distal and proximal interphalangeal, metacarpophalangeal, trapezio-metacarpal, patellofemoral, and medial tibiofemoral joints. | Paracetamol and meloxicam |
| White (2015) [ 7 ] | 81-year-old woman with osteoporosis and multiple other medical comorbidities including ischemic heart disease, hypertension, type 2 diabetes mellitus, atrial fibrillation, and recurrent falls | Developed sudden onset severe arthralgia and swelling of both hands, wrists, ankles, and feet, with associated low-grade fevers within 12 hours of receiving first dose of IV zoledronic acid 5 mg | Raised inflammatory markers (WCC 11.5 × 10 9 /L, CRP 16.3 mg/L). No joint aspirate performed. Radiological imaging revealed bilateral osteoarthritis in carpal, distal interphalangeal, metacarpophalangeal and metatarsophalangeal joints. | Codeine phosphate, buprenorphine, and tramadol |
| Kiyumi et al (2023) [ 8 ] | 62-year-old woman with osteoarthritis, osteoporosis, and peptic ulcer disease | Developed generalized myalgias, fevers, and bilateral knee and wrist pain and swelling within 12 hours of receiving first dose of IV zoledronic acid 5 mg | Normal WCC, mildly elevated CRP (10 mg/L) Diagnostic arthrocentesis—noninflammatory fluid with negative culture and crystals. Radiological imaging revealed bilateral osteoarthritis in distal and proximal interphalangeal, trapezio-metacarpal, and medial tibiofemoral joints. | Paracetamol and codeine |
In each case, the patient had received a zoledronic acid infusion within 48 hours prior to the onset of symptoms, whereas the relative delay in onset of bilateral knee pain and swelling in our patient's case may have been due to the use of systemic glucocorticoids following the zoledronic acid infusion. Interestingly, in 3 of the 4 cases, the patient was documented to have clinical or radiographic evidence of pre-existing osteoarthritis in the affected joints and the adverse effect was interpreted by the authors as a “flare-up” of osteoarthritis. Our patient was similarly noted to have radiographic evidence of mild osteoarthritis affecting both knee joints, and we, too, elected to approach treatment of her case as a severe bisphosphonate-induced flare of osteoarthritis. Whereas in all 4 previously reported cases, the patients’ symptoms resolved reliably with cessation of the drug and symptomatic management in the form of oral analgesia, our patient demonstrated a poor response to oral nonsteroidal anti-inflammatory agents, with a persistently severe and debilitating symptom burden. As there were no apparent contraindications to local corticosteroid use, and in line with the conditional recommendations from the Osteoarthritis Research Society International (OARSI) guidelines [ 12 ] on the nonsurgical management of osteoarthritis, we decided to administer corticosteroid injections to both knees, with good subsequent therapeutic benefit.
Overall, it is challenging to draw any definitive conclusions from the limited data, and it remains unclear which patient characteristics (including pre-existing osteoarthritis) predict susceptibility to this specific type of reaction to zoledronic acid. It may be hypothesized that this adverse drug effect represents a unique musculoskeletal manifestation on the severe end of the spectrum of acute phase reactions which are known to occur with zoledronic acid infusion. Although inflammatory pathways causing activation of the T-cell and subsequent release of cytokines, such as tumor necrosis factor-α (TNF-α), interferon-gamma (IFN γ ), interleukin 1 (IL-1) and interleukin 6 (IL-6) have been implicated in these acute phase reactions in molecular studies [ 13 ], a curious discrepancy which remains unexplained is the fact that all synovial fluid analyses in our and previous case reports were noninflammatory in nature despite elevated systemic inflammatory markers and preceding acute phase reactions. The apparent link between this systemic inflammatory response and these now recognized flares of noninflammatory arthropathy, therefore, remains elusive. Whether or not this adverse effect strictly precludes further doses of zoledronic acid also remains unclear, especially as there are currently no reported cases describing the effects of re-administration of intravenous bisphosphonates. Gerster et al (2004) [ 14 ] did describe the immediate recurrence of a case of acute polyarthritis following the re-administration of oral bisphosphonates (weekly alendronate), suggesting that clinicians may prefer to adopt a more cautious approach when considering a re-trial of bisphosphonates, particularly if there exist other feasible treatment options for the patient's osteoporosis. Overall, further research is required to elucidate the specific mechanism behind this adverse reaction and what risk factors may be potentially modifiable to minimize the risk of its occurrence.
Learning Points
Intravenous zoledronic acid is routinely prescribed for postmenopausal osteoporosis, malignancy-associated hypercalcemia, multiple myeloma, secondary bone metastases, and Paget disease.
This case represents the fifth documented report of a rare reaction to first dose zoledronic acid infusion presenting with severe joint pain and swelling.
In patients presenting with severe joint pain following bisphosphonate exposure, clinicians should initially evaluate for and exclude other etiologies of arthropathy including septic arthritis, primary inflammatory arthropathy, and crystal arthropathy.
Prescribing physicians starting intravenous bisphosphonate treatment should be aware of this rare serious adverse reaction to zoledronic acid such that they can appropriately counsel patients on the risk during the consent process.
Contributors
All authors made individual contributions to authorship. C.C. was involved in the diagnosis and management of this patient; J.W. and C.C were involved in manuscript submission. All authors reviewed and approved the final draft.
Contributor Information
Jenny Wei, Rheumatology Department, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
Catherine Soo Ihn Cho, Rheumatology Department, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
Funding
No public or commercial funding
Disclosures
None declared
Informed Patient Consent for Publication
Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.
Data Availability Statement
Original data generated and analyzed during this study are included in this published article.
References
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Associated Data
Data Availability Statement
Original data generated and analyzed during this study are included in this published article.