Bone remodeling associated with CTLA-4 inhibition: an unreported side effect
Background Ipilimumab is a recombinant IgG1 kappa antibody against human cytotoxic T-lymphocyte antigen 4 (CTLA-4) that augments T-cell activation. It has been approved for treating unresectable or metastatic melanoma. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone remodeling.
Objective To examine whether the use of ipilumumab results in increased bone remodeling that manifests as an autoimmune reaction.
Methods A retrospective case-control study of 51 patients with stage III/IV melanoma was conducted with 2 cohorts: ipilumimab cohort at the standard dose (n = 39) and chemotherapy cohort receiving an investigational chemotherapy regimen (n = 12). Outcome variables were recorded at baseline, with each treatment, and upon treatment completion. The differences in trends of bone pain and mean alkaline phosphatase (ALP) levels were assessed using a generalized linear mixed-effect model.
Results 14 of 39 patients (35.9%) in the ipilimumab cohort reported having bone pain during at least 1 of the treatment cycles, compared with 3 of 12 patients (25%) in the chemotherapy cohort, and that trend was statistically significant over time (P = .023). Trends of mean ALP levels between the 2 cohorts were not statistically significant (P = .653). There was no correlation between bone pain or mean ALP level and response to ipilimumab.
Limitations The patient-reported bone pain was dichotomized; there was a significant variability in perceived pain intensity among patients.
Conclusions Given the increasing use of CTLA-4 inhibitors in the treatment of various malignancies, physicians should be alerted to their bone remodeling effects so that they can appropriately manage the short-term side effects such as bone pain, and monitor patients for possible unknown long-term side effects. In addition, data from postmarketing studies should be evaluated for confirmation of this novel interaction.
Accepted for publication March 22, 2017
†Drs Mansour and Rao contributed equally to the study.
Correspondence Joshua Mansour, MD; mansoour@musc.edu
Disclosures The authors report no disclosures/conflicts of interest.
Citation JCSO 2017;15(4):e217-e220
©2017 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0340
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Discussion
Immune checkpoints are inhibitory pathways that are critical for maintenance of self-tolerance and regulation of appropriate immune response. CTLA-4 is present exclusively on T cells and interacts with its ligands B7.1 and B7.2. CTLA-4 competes with CD28 in binding with B7, leading to dampening of T-cell activation and function.5,6 Development of checkpoint inhibitors such as ipilumimab have heralded a new era of immune targeted therapies for various malignancies including malignant melanoma.
Bone remodeling involves 4 distinct but overlapping phases. The first phase involves detection of loss of bone continuity by osteocytes and activation of osteoclast precursors derived from progenitors of the monocyte-macrophage lineage. The second phase involves osteoclast-medicated bone resorption and concurrent recruitment of mesenchymal stem cells and osteoprogenitors. The third phase involves osteoblast differentiation and osteoid synthesis, and the fourth phase results in mineralization of osteoid and termination of bone remodeling.7,8
The role of T-lymphocytes and cytokines, such as IL-1 and TNF-α, and receptor activator of NF-κB ligand (RANK-L) in osteoclastogenesis is well studied. RANK-L is considered to be the final downstream effector of this process.9 T-lymphocytes have also been shown to promote osteoblast maturation and function.9,10 These findings suggest a significant interaction between immune system activation and bone remodeling.
The search for a reliable biomarker for immune therapy is ongoing. Although ipilumimab-associated immune-related adverse events have been suggested to predict response to therapy,11 there is considerable debate on the subject. Ipilumimab’s impact on bone remodeling could offer a solution.
In the current study, there was a statistically significant difference in proportion of patients with bone pain in the 2 cohorts. This was preserved with stratification based on bone metastasis at inclusion and disease progression on treatment completion making new or worsening skeletal metastasis. Furthermore, the proportion of patients with bone pain increased with each cycle for ipilumimab cohort. However, we were unable to detect an association between bone pain and response to ipilimumab.
We were not able to detect a difference in trend of mean ALP level with treatment in the two cohorts. Although it is possible that no such association exists, we believe our study was not powered to detect it. Finally, we were not able to study markers for osteoblast (bone-specific ALP) and osteoclasts (N- and C-telopeptides of type 1 collagen, deoxypyridinoline, etc) to better assess this interaction because they are not commonly clinically used.
Regarding the limitations of our study, we chose to dichotomize the patient-reported bone pain because it is a subjective measure and there is a significant variability of the perceived pain intensity among patients. We also excluded patients with hepatitis from receiving the ipilumimab therapy and those with known hepatic disease from the study to reduce the impact of hepatic ALP on total serum ALP levels.
In conclusion, as far as we know, this is the first clinical report suggesting a possible relationship between CTLA-4 inhibition and bone remodeling. Supported by a strong preclinical rationale, this side effect remains under-studied and under-recognized by clinicians. A prospective assessment of this interaction using bone specific markers is planned.
