EULAR 2022—Zoledronic acid is an injectable bisphosphonate approved for use in the U.S. to treat hypercalcemia of malignancy, multiple myeloma and patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy.1 Often, oral bisphosphonates, such as alendronate, ibandronate and risedronate, are used to treat osteoporosis.2 The use of bisphosphonates to treat osteoporosis has come under scrutiny due to reports of patients developing osteonecrosis of the jaw.
Claire Amigues from the Hospital Pasteur, Rheumatology, Nice, France, presented a study during EULAR 2022 that characterized zoledronate-related osteonecrosis of the jaw in patients with osteoporosis compared with the incidence of osteonecrosis of the jaw in patients treated with oral bisphosphonates.3,4
Methods
All reports of bisphosphonate adverse events from the French Pharmacovigilance Database from 1985 to 2020 were evaluated.3 For zoledronic acid, cases were separated by rheumatic or oncologic indications. For patients who developed osteonecrosis of the jaw, the potential risk factors analyzed included age, gender, smoking, having diabetes, having an alcohol use disorder, corticosteroid therapy, cancer, previous chemotherapy or immunotherapy, recent dental care and the time of bisphosphonate exposure.
Researchers assessed the association between the occurrence of osteonecrosis of the jaw and the bisphosphonate by calculating the reporting odds ratio in a case/non-case study. A stratification of assumed risk factors was performed to assess their effect on the patient risk of osteonecrosis of the jaw. The incidence of osteonecrosis of the jaw while receiving bisphosphonate therapy between 2011 and 2020 was estimated by relating the number of osteonecrosis of the jaw cases while receiving bisphosphonate therapy reported to the French Pharmacovigilance Database to the estimated number of patients treated with zoledronic acid, alendronate and risedronate over the same period according to health insurance reimbursement data. Incidence rate calculations, confidence interval calculations and comparison of incidence rates were performed.
Results
For patients treated with zoledronic acid, 2,254 adverse events were reported. Of these, 1,103 adverse events were reported in patients receiving zoledronic acid for oncologic indications, of which 568 cases were osteonecrosis of the jaw. For patients with rheumatologic indications receiving zoledronic acid, 1,151 adverse events were reported, of which 70 cases were osteonecrosis of the jaw.
In the patients with rheumatologic indications, 30 had recently undergone dental care and had a mean time of bisphosphonate exposure of 48.7 months. Risk factors for developing osteonecrosis of the jaw were smoking and a history of cancer and chemotherapy.
For patients treated with alendronate, 1,010 adverse events were reported in the study period. Of these, 188 cases were osteonecrosis of the jaw, 91 of which had recent dental care and a mean time of bisphosphonate exposure of 70.9 months. In this group of patients, the risk factors for developing osteonecrosis of the jaw were being 65 years old, having diabetes, corticosteroid therapy and having a history of cancer.
In patients treated with risedronate, 711 adverse events were reported. Of these, 68 cases were osteonecrosis of the jaw, with 28 patients having had recent dental care and a mean time of bisphosphonate exposure of 53.6 months. In these patients, risk factors for developing osteonecrosis of the jaw were being at least 65 years old, smoking, corticosteroid therapy and having a history of cancer and chemotherapy.
The reporting odds ratio calculation showed that corticosteroid therapy was more frequently associated with patients treated with risedronate (2.10 [1.64–2.69]) and alendronate (1.33 [1.04–1.70]) than zoledronic acid in patients with rheumatologic conditions, with no other significant differences. Additionally, the incidence of osteonecrosis of the jaw was significantly higher in patients with rheumatic conditions treated with zoledronic acid than those treated with either alendronate or risedronate (P<0.001, for both).
Between 2011 and 2020, 614,932 patients were treated with zoledronic acid for rheumatic conditions, with 59 cases of osteonecrosis of the jaw, yielding an incidence of 9.6/100,000 person-years. During this period, 2,233,536 patients were treated with risedronate, with 44 cases of osteonecrosis of the jaw, yielding an incidence of 2.0/100,000 person-years, and 2,432,373 patients were treated with alendronate, with 125 cases of osteonecrosis of the jaw, yielding an incidence of 5.1/100,000 person-years.
Conclusion
The data from this study confirm that in a large population of patients with osteoporosis, bisphosphonate-associated osteonecrosis of the jaw rarely occurs and can occur more often in patients treated with injectable zoledronic acid than in those treated with the oral bisphosphonates alendronate and risedronate.
Additionally, the risk of bisphosphonate-related osteonecrosis of the jaw appears related to the bone resorption inhibition potency of the particular bisphosphonate, with risedronate having the lowest bone resorption potency and zoledronic acid in rheumatic conditions having the highest bone resorption potency. Being an active smoker seems to be a consistent risk factor for developing osteonecrosis of the jaw, as does having had recent dental care.
The pharmacovigilance study limitations include that this study was retrospective in nature, the under-reporting of adverse events often occurs and researchers only examined claims from one database.
Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.
References
- Highlights of prescribing information: Zometa (zoledronic acid). U.S. Food & Drug Administration. 2019 Dec 12.
- Rosen HN. Bisphosphonate therapy for the treatment of osteoporosis. Up-To-Date. 2022 Jul 21.
- Moore N, Noblet C, Kreft-Jais C, et al. La banque de cas du système français de pharmacovigilance: quelques exemples d’exploitation [French pharmacovigilance database system: examples of utilisation]. Therapie. 1995 Nov–Dec;50(6):557–562. French. PMID: 8745956.
- Amigues C, Fresse A, Roux C, et al. Zoledronate-related osteonecrosis of the jaw in osteoporosis: Incidence, risk factors and comparison to oral bisphosphonates [OP0240]. Ann Rheum Dis. 2022;81 (suppl 1):158.
