Background/Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer. Despite their efficacy on tumor outcomes they can cause severe and sometimes long-standing immune-related adverse events (irAE). Enhanced immune activation from ICI can conceivably induce expression of the receptor activator of nuclear factor kappa-Β ligand (RANK-L) resulting in osteoclast activation, bone loss and fracture. Our objective was to determine the incidence rates of major osteoporotic fractures (MOF) in patients with melanoma treated with ICI, before and after initiation of ICI treatment.

Methods: We analyzed 2011-2022 data from the Optum’s de-identified Clinformatics® Data Mart Database (a large commercial healthcare claims dataset from the United States). We identified patients who received one or more ICI currently approved by the Food and Drug Administration (FDA), on at least one occasion. We excluded off-label drug regimens (e.g. non approved combinations). We required that patients have a minimum of 12 months of observable data before receiving the ICI therapy. We used International Classification of Diseases (ICD 9/10) diagnostic codes to identify a diagnosis of melanoma, and we also required a minimum of 90 days follow-up after ICI initiation. We identified MOF which included fractures of the hip, forearm, humerus or vertebrae using ICD 9/10 diagnostic codes. To define a fracture event, we required at least 2 codes for a fracture in the same anatomical site within 90 days. We compared MOF rates in the year before ICI initiation with rates in the year after initiation of ICI, using proportional hazard models with robust sandwich estimate of the covariance matrix to account for correlated outcomes between the pre- and post- ICI treatment periods in the same patient. Patients were censored at last follow-up or death.

Results: We identified 34,864 patients who had received ICI and had continuous enrollment of at least 12 months prior to ICI initiation. Of these, 3,362 had a diagnosis of melanoma and had a minimum of 90 days follow-up after treatment initiation. Of the 3,362 patients with melanoma, 2,143 (64%) were male, mean age was 67 years (SD:14), 2,315 received monotherapy, 176 received combination therapy, and 871 received both therapeutic regimens in sequence. Forty-eight (1.4%) patients had a fracture in the year before ICI initiation, and 57 (1.7%) had a fracture in the year after initiation of treatment. The hazard ratio (HR) for fracture over the year after versus the year before the first ICI dose was 1.69 [95% CI 1.14 – 2.41].

Conclusion: Our findings suggest that patients who receive ICI are at increased risk of MOF during the first year after receiving therapy. Further research is needed to determine whether there are additional risk modifiers, such as concomitant treatment with steroids for irAE or metastatic bone disease, and to develop strategies for risk reduction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increase-in-major-osteoporotic-fractures-after-therapy-with-immune-checkpoint-inhibitors/