Bone fracture as a novel immune‐related adverse event with immune checkpoint inhibitors: Case series and large‐scale pharmacovigilance analysis

Abstract

Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported.The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines.

Changes in bone turnover markers in patients without bone metastases receiving immune checkpoint inhibitors: An exploratory analysis

“…However, ICIs are correlated with a variety of toxicities as results of an excessively activated immune system and, therefore, considered as immune-related adverse events (irAEs). Despite these toxicities may potentially affect all host tissues [5][6][7][8][9], the effect on the skeleton is poorly investigated due to the few and small case series reported in literature [10,11]. These studies described skeletal adverse effects in patients treated with ICIs including serious vertebral fractures that, in some cases, affected multiple sites [10,11].…”

“…Despite these toxicities may potentially affect all host tissues [5][6][7][8][9], the effect on the skeleton is poorly investigated due to the few and small case series reported in literature [10,11]. These studies described skeletal adverse effects in patients treated with ICIs including serious vertebral fractures that, in some cases, affected multiple sites [10,11].…”

Agonistic and antagonistic targeting of immune checkpoint molecules differentially regulate osteoclastogenesis

“…In conclusion, these results allow for a better understanding of potential bone-related side effects in patients that receive immune checkpoint inhibition as therapy for malignant disease. It seems plausible that adverse events such as bone fractures represent highly efficient or rather ‘too effective’ therapeutic approaches, considering that some patients who showed a complete clinical response to their cancer therapy after treatment with ICIs suffered bone fractures ( 3 ). Hence, the main challenge in cancer therapy is to balance successful anti-malignant therapy while preventing serious, often bone-related, adverse effects.…”

“…The current diagnostic and therapeutical management for diseases such as osteoporosis, aseptic loosening of endoprostheses, and certain cancers is insufficient. However, there is evidence about underlying osteoimmunological mechanisms that are immensely relevant in development of osteoporotic conditions and skeletal fractures (1)(2)(3)(4)(5)(6)(7).…”

Skeletal adverse events in childhood cancer survivors: An Adult Life after Childhood Cancer in Scandinavia cohort study

“…51,52 Some hope is placed on newer, more targeted therapy, but the development of such novel therapies will also introduce a new spectrum of toxicities and we have sparse knowledge at this point how these will affect the future health of childhood cancer survivors. 53…”