Poster Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

MET-Call during Zoledronate Infusion: An Unusual Case of Allergy

Clinical Case:

A 54-year-old woman presented post fragility fracture of left distal tibia and fibula sustained in October 2021. Her past medical history is significant for metacarpal fracture after falling from standing height in 2018, recurrent renal calculi, asthma, endometriosis, and multiples allergies including corn, grapes, iodine, maize, oranges, NSAIDs and penicillins. Her medications include Fluticasone/Salmeterol inhaler, Vitamin D3, Calcium carbonate 1200mg daily, and promethazine as required. There was no oral glucocorticoid exposure. She was post-menopausal at age 53, there was no family history of osteoporosis. Bone densitometry revealed generalised osteoporosis (LS: T-score -3.7, FN: -4.3, TH: -4.2). Her secondary osteoporosis screen was remarkable for mild persistent hypercalcaemia. Fractional excretion of calcium has ruled out familial hypocalciuric hypercalcaemia (FHH) (Table). After informed consent, she proceeded to receive zoledronate infusion 5 mg over 30 minutes as per local protocol in October 2022. Seven minutes into the infusion, patient started experiencing shortness of breath, itchy throat and generalised urticarial rash over face, upper back and upper chest. This required a MET response to be initiated. There was no lip or tongue swelling and her observations revealed blood pressure of 165/110mmHg, heart rate 104 beats/minute, oxygen saturation of 98% on room air. There was no wheeze on auscultation.

Zoledronic infusion was promptly ceased. Intravenous hydrocortisone 50mg and oral promethazine 10mg was administered with relief in symptoms. Estimated dose of 1.16mg of zoledronic acid was administered prior to cessation. Patient was subsequently discharged home.

Subsequent pathology revealed a normal Tryptase level of 5.9 ug/L, ruling out possibility of mastocytosis. Her bone turnover markers taken 8 months post partial zoledronate infusion was incompletely suppressed.

She sustained further fragility left distal radius fracture after falling on outstretched hands in March 2023.  At the time of writing, she is being investigated by the Immunology team given potential allergens in other anti-resorptive agents and is being considered for romosozumab.

Table:

Discussion:

Bisphosphonates are widely used for treatment of osteoporosis in postmenopausal women. Zoledronic acid, a Nitrogen- containing bisphosphonate is a potent inhibitor of osteoclasts ¹. Its use has well recognized beneficial effect on bone mineral density and reduction in fracture risk for vertebral and non-vertebral fractures ².Its use is generally well tolerated, acute phase reactions including chills, fever, influenza-like symptoms, night sweats, rigors and shivering, diffuse musculoskeletal pain, gastrointestinal effects, and eye inflammation can occur in up to 40% of patients and are self-limiting  ³.  

Whilst mechanism of acute phase response is not well established, direct activation of γΔT cells, leading to activation of immune system and production of inflammatory cytokines such as TNF-α, INF-γ and IL-6 has been implicated ⁴. Anaphylaxis and acute urticaria post zoledronate is rare and thought to be IgE mediated ⁵ . The IgE level of this patient was 94 kunits/L (N= <114 kunits/L) done in July 2023.

Our case is unique and presents a management dilemma. It is unclear if the reaction is secondary to zoledronic acid, bisphosphonates as a class or its excipients. All preparations of zoledronic acid commonly contain mannitol as an excipient. Mannitol is a naturally occurring sugar in many plants, fruits and vegetables. Common indications include reduction of raised intracranial pressure and as an inhalational irritant in bronchial provocation tests. It is also used widely as an excipient in variety of medications. Mannitol has been implicated in anaphylaxis to intravenous paracetamol via IgE mediated hypersensitivity reaction ⁶.

Unfortunately, most of antiresorptive agents have mannitol as an excipient, which severely limits treatment option for our patient. Denosumab has sorbitol, which due to structural similarity to mannitol also poses a risk of further adverse allergic reactions⁷. Romosozumab would be a suitable alternative in the short term as there are no interfering excipients listed. An alternative would be to co-administer short course of glucocorticoids at the time of zoledronate infusion prophylactically, which has reduced acute phase reactions in cystic fibrosis patients ⁸. Patients with multiple drug allergies present a challenging barrier to patient care. Our patient illustrates a management dilemma with significant limitation in treatment options for her severe osteoporosis exacerbated by patient anxiety and reluctance to trial new therapy.

Take home messages:

• Allergy to excipients in anti-resorptive agents is exceptionally rare. This might be influenced due to under recognition of this effect as most excipients are not listed on drug labels.
• Non-anaphylactic drug reactions can sometimes be mitigated with co-administration of glucocorticoids and anti-histamines with the support of immunology department.
• Subjects with multiple drug allergy/ intolerance syndrome are challenging to manage due to anxiety to accept new therapies, multi-disciplinary approach involving immunologist can assist.