Proinflammatory reaction to a bisphosphonate infusion in a patient with a reverse shoulder replacement and literature review
- 1 F Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
- 2 Tripler Army Medical Center, Tripler Army Medical Center, Hawaii, USA
- Correspondence to Dr Kyong Min; kyongminmd@gmail.com
Abstract
Bisphosphonates are the first-line pharmacological treatment for osteoporosis due to their efficacy and low rate of self-limited adverse effects. Challenges in adherence to oral treatment has spurred the development of third-generation bisphosphonates that only require single annual infusion due to high potency and binding efficacy. The authors report the case of a woman in her 70s who presented with postoperative shoulder pain after zoledronic acid infusion. Diagnostic work-up revealed stable prosthesis with no signs of fracture, loosening or infection. Administration of oral steroids resulted in resolution of pain and return to baseline function. Acute postoperative joint pain attributed to bisphosphonate infusion has not been previously described in the literature. This case report and literature review suggests consideration of adverse inflammatory reaction due to bisphosphonate infusion in the setting of a patient presenting with joint replacement and acute exacerbation of pain without clear aetiology.
Background
Bisphosphonates are the most commonly prescribed medication for treating osteoporosis. Oral bisphosphonates, alendronate and risedronate have demonstrated efficacy in reducing non-vertebral and hip fractures in patients with osteoporosis, but adherence to treatment is often a challenge. Acute postoperative joint pain, which is attributed to bisphosphonate infusion, has not been reported in the literature. The authors report a case of postoperative shoulder pain in a reverse shoulder replacement attributed to a zoledronic acid infusion.
Case presentation
The patient is a woman in her 70s with a history of osteoporosis and right shoulder rotator cuff tear arthropathy. Her medical history is significant for osteoporosis, hypertension, type 2 diabetes mellitus, hyperlipidaemia and gastro-oesophageal reflux disease. The patient had no reported history of renal disease, and renal function tests were within normal limits. She successfully underwent an uncomplicated reverse total shoulder replacement for her rotator cuff tear arthropathy. The procedure was performed as an outpatient procedure. At her first postoperative visit, the patient reported 5/10 pain on the Visual Analog Score. There were no signs of infections or complications, and radiographs demonstrated a well-positioned reverse shoulder replacement. The patient was instructed to begin early range of motion and start physical therapy.
At the 6-week follow-up, the patient complained of 5/10 pain. The surgical incision was well healed, and there was no evidence or concern for infection. On exam, she was able to actively forward flex to 100°, and she was able to place her hand behind her head.
At her 3-month postoperative visit, the patient’s pain was drastically improved, rated 2/10. She was able to actively forward elevate to 140°, abduct to 120°, externally rotate to 20° and internally rotate to her greater trochanter.
Furthermore, the patient was seen by her primary care physician to discuss her history of osteoporosis and possible initiation of treatment. Prior to surgery, she had previously been taking Fosamax but was unable to tolerate the medication due to stomach pain and exacerbation of her gastroesophageal reflux disease (GERD). Based on this, it was suggested that she undergo zoledronic acid infusion once yearly. The patient did not undergo sensitivity testing prior to her first infusion as this was not standard practice within this institution.
The patient underwent zoledronic acid infusion, and 3 days after the infusion, she experienced acute right shoulder pain. Initially, she attributed the shoulder pain to her physical therapy, but there was no associated trauma, additional exercises or increase in activity. She denied a history of prior similar symptoms to include joint or muscle pain. Her right shoulder pain severity was rated 8/10 and was associated with severe tenderness to palpation over the deltoid and limited range of motion. She also reported global arthralgias and myalgias; however, the majority of the pain was in her right shoulder. She denied any fever, chills, erythema or other constitutional symptoms.
Treatment
Therefore, the patient was started on a 6-day oral course of prednisolone (40 mg). Due to her history of type ii diabetes mellitus, the patient’s blood sugars were closely monitored, and she underwent enhanced bone health surveillance with her primary care physician. Following completion of the oral steroids, the patient reported significant improvement in her pain.
Outcome and follow-up
One week after completing the steroids, she was able to actively forward elevate 130°, abduct 90° and externally rotate 10°. At subsequent follow-up visits, the patient has continued to progress in her range of motion and with no recurrence of pain.
Discussion
Review of bisphosphonates
Mechanism of action
Bisphosphonates are analogues of naturally occurring inorganic pyrophosphate with resistance to chemical and enzymatic hydrolysis. The ability of bisphosphonates to bind strongly to bone mineral is responsible for selective uptake of the target organ. Each bisphosphonate varies in terms of their speed of onset for fracture protection, duration of effect and sites of efficacy.
The primary mechanism of action is the inhibition of dissolution of hydroxyapatite crystals by attaching directly to bony surfaces, particularly those undergoing active remodelling. When osteoclasts resorb bone bound by bisphosphonate, the bisphosphonate is released and interferes with osteoclasts’ ability to form the ruffled border, adhere to the bony surface and release protons to continue the process of bony resorption. Bisphosphonates further inhibit bone resorption by inhibiting osteoclast progenitor development and promoting apoptosis.1 In addition to the inhibitory effect on osteoclasts, bisphosphonates may have an antiapoptotic effect on osteoblasts and osteocytes via a Conexin 43 signalling pathway.2
Currently, the major bisphosphonate drugs in use are alendronate, risedronate and zoledronate. Risedronate and zoledronate are two of the most potent antiresorptive bisphosphonates due to the nitrogen atom within their heterocyclic ring.1 3 Of all the bisphosphonates, zoledronate, a third-generation bisphosphonate, has the highest binding affinity for hydroxyapatite with strong inhibitory effects on farnesyl pyrophosphate synthase (FPPS) and osteoclasts.1 Zoledronic acid offers the benefit of a single annual infusion that decreases bone turnover, increases bone mineral density and reduces fracture rates.4 5 Standard dosing of zoledronic acid for treatment of osteoporosis is 5 mg intravenous transfused once yearly.4
Adverse reactions
Typically, zoledronic acid is well tolerated; however, there are a few self-limited adverse effects to include chills, nausea and mild myalgias and arthralgias.5 A common adverse effect of oral bisphosphonates is upper gastrointestinal irritation.4 Other rare adverse effects include atrial fibrillation, hypocalcaemia, renal dysfunction and osteonecrosis of the jaw.4 In a double-blind, placebo-controlled trial with 3889 patients receiving either a single 5 mg infusion of zoledronic acid or placebo, the five most reported symptoms that occurred within 3 days of infusion included fever (16.1%), flu-like symptoms (7.8%), myalgias (9.5%), headaches (7.1%) and arthralgias (6.3%). A percentage of 1.3% of patients experienced an increase of >0.5 mg/dL in the serum creatinine level, but this resolved in 85% within 30 days. The study also found a significantly increased risk of arrythmias and severe atrial fibrillation when compared with placebo, 6.9% versuss 5.3% and 1.3% versuss 0.5%, respectively. No patients in the study experienced osteonecrosis of the jaw. However, with subsequent infusions, the rates of the five most common postdose symptoms decreased from 31.6% to 2.8% suggesting improved tolerability as treatment progresses.4
This is the first case report describing acute inflammatory prosthetic joint pain following a zolendronic acid infusion. Reports of adverse reactions following infusion of bisphosphonates have been reported, but not in a patient who recently underwent a joint replacement.
White et al. 6 described the case of an 81-year-old woman with osteoarthritis and osteoporosis who presented with severe polyarthritis in joints with pre-existing osteoarthritis 12 hours following her first intravenous zoledronic acid infusion. After infusion, she awoke with severe joint pain in her hands, wrists, ankles and feet leading to a fall and subsequent admission to the hospital. Initial examination demonstrated diffuse joint erythema and effusions with associated elevation in her CRP.
Werner de Castro et al. 7 described a case 64-year-old woman who presented to an outpatient clinic for treatment of her osteoporosis. She had previously been treated with oral bisphosphonates but had discontinued the treatment, similar to our patient. Initial physical examination revealed Heberden nodes and bilateral knee crepitation. On the day following zoledronic acid infusion, the patient reported diffuse myalgias with subsequent interphalangeal and trapeziometacarpal erythema, warmth and swelling. She was prescribed escalating doses of acetaminophen, aceclofenac and an intramuscular corticosteroid (betamethasone). Her symptoms persisted for two more days and then progressively improved.
Werner de Castro suggests that the release of proinflammatory cytokines is the probable cause of osteoarthritis flares reported in the literature. They postulate that either bisphosphonates themselves or an accumulation of intermediate metabolites in the mevalonate pathway result in the activation and proliferation of gamma-delta T lymphocytes. These gamma-delta T lymphocytes promote acute phase reactions leading to increased levels of interleukin-6 and tumour necrosis factor.7
Learning points
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Bisphosphonates are the first line pharmacological treatment for osteoporosis.
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Each bisphosphonate varies in terms of their speed of onset for fracture protection, duration of effect and sites of efficacy.
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In patients with joint replacements and presenting with acute exacerbation of pain with no clear signs of joint infection, fracture or dislocation and a recent zoledronic acid infusion, the pain may be due an adverse inflammatory reaction to the zoledronic acid.
Ethics statements
Patient consent for publication
Footnotes
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Contributors RM performed literature review, manuscript writing and editing. MC performed manuscript editing. RM developed the study idea and performed manuscript editing.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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