Bone remodeling associated with CTLA-4
inhibition: an unreported side effect
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important component of the immune checkpoint pathway. CTLA-4 inhibition
causes T-cell activation and proliferation, increases
T-cell responsiveness, and enhances the anti-tumor
immune response. CTLA-4 inhibition also results
in immune-related adverse reactions such as colitis,
hepatitis, and endocrinopathies. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone
remodeling.1,2(p4) Ipilimumab, a recombinant IgG1
kappa antibody against human CTLA-4, has been
approved for use in unresectable or metastatic melanoma. We hypothesize that ipilumumab results in
increase in bone remodeling manifesting as an autoimmune reaction.
We conducted a retrospective case-control study of
patients with stage III/IV melanoma treated at the
University of New Mexico Comprehensive Cancer
Center during April 2009-July 2014. The universi-
ty’s Institutional Review Board approved the study.
Two cohorts were compared: an ipilumimab
cohort receiving ipilumimab at 3 mg/kg every 3
weeks, and a chemotherapy cohort receiving an
investigational chemotherapy regimen: carboplatin
IV at an area under curve of 5 on day 1, paclitaxel
IV at 175 mg/m2 on day 1, and temozolomide orally
at 125 mg/m2 daily on days 2 to 6 every 21 days.
Patients receiving at least 1 cycle of treatment were
included. Those with known hepatic disease or con-
current malignancy were excluded from the study.
Serum ALP level (normal range, 38-150 interna-
tional units per liter [IU/L]) and patient-reported
bone pain measured by the 11-point numeric rat-
ing scale (NRS) for pain assessment were recorded
before treatment initiation, on each cycle, and
upon treatment completion.3 Clinical response was
assessed per RECIST guidelines.4 Bone pain was
Accepted for publication March 22, 2017. †Drs Mansour and Rao contributed equally to the study. Correspondence:
Joshua Mansour, MD; email@example.com. Disclosures: The authors report no disclosures or conflicts of interest. JCSO
2017;15(4):e217-e220. ©2017 Frontline Medical Communications. doi: https://doi.org/10.12788/jcso.0340
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
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
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.
Arpit Rao, MD,a† Joshua Mansour, MD,b† Montaser Shaheen, MD,a Yang Shi, MS,c
Ji-Hyun Lee, DrPH,c Helen Nordquist,d and Olivier Rixe, MD, PhDb
aDivision of Hematology and Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque; bDivision of
Hematology and Oncology, Medical University of South Carolina, Charleston; and cBiostatistics Shared Resource and dClinical
Trials Office, University of New Mexico Comprehensive Cancer Center, Albuquerque