Immune checkpoint inhibitors: friend or foe for osteoporosis

Dear Editor,

Immune checkpoint inhibitors (ICIs) are enabling long-term survival in patients with cancer, as well as new therapeutic indications in the early stages of cancer, ¹ but the potential effect on skeletal disease, especially osteoporosis, remains unclear.

Researchers found that osteoclast hyperactivity was associated with activation of the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) pathway. ² It was found by Xiu-Ping Cai et al. that PD-1 levels were significantly higher in the peripheral blood mononuclear cells (PBMCs) of postmenopausal osteoporosis (PMOP) patients compared with healthy controls. They suggested PD-1/PD-L1 signaling is involved in osteoporosis pathogenesis by regulating inflammation, stimulating osteoclasts, and inhibiting osteoblasts, ³ indicated that PD-1 may be involved in the pathogenesis and development of PMOP. ³ Nagahama et al. ⁴ found that osteoclast formation was inhibited in mice with PD-1 deficiency, leading to mild osteopetrosis. According to Kaiyuan Wang et al., mice lacking Pdcd1 were found to be protected against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Deficit of PD-1 or treatment with nivolumab-inhibited osteoclastogenesis without affecting tumor burden. As a result of suppressing osteoclastogenesis by anti-PD-1 immunotherapy, they concluded that long-term benefits could be obtained in preventing bone destruction. ⁵ These studies indicates that the anti-PD-1 might be the potential therapy for the osteoporosis.

However, several clinical studies have reported that the ICIs have potential skeletal adverse effects. Data from the United States Food and Drug Administration Adverse Event Reporting System showed compression fractures, fractures at various skeletal sites (rib, thoracic vertebral, and humerus) were recorded after the treatment of ICIs, ⁶ but the effect of other systemic treatments like glucocorticoids should be considered. One of the retrospective case series examined clinical, laboratory, and imaging data collected from patients who developed new fractures or resorption of bone lesions while taking drugs targeting PD-1, CTLA-4, or both. Vertebral compression was present in all patients, and two of the three fractured at multiple locations. Resorbtive lesions were found in the shoulder, hand, and clavicle. Five of the six patients had elevated or high-normal biochemical markers of bone resorption. ⁷ According to Filippini et al., ⁸ four patients received systemic treatment with ICIs in combination or alone and ended up with new osteoporotic fractures. The potential mechanism is that ICI therapy triggers cytokine-secreting T-cells, which are responsible for bone remodeling in proinflammatory states. When activated T-cells produce proinflammatory cytokines and upregulate the nuclear factor-κB ligand, osteoclast differentiation and maturation are favored over osteoblastogenesis, resulting in bone loss and fracture risks.^8–10 Based on these analyses, adverse skeletal events such as fractures may be precipitated by ICIs.

Additional research is required to clarify the potential effect of ICIs on osteoporosis.

It is important to risk stratify patients who begin treatment with ICIs, monitor them for skeletal lesions, and perform laboratory tests (calcium/phosphorus metabolism, PTH and biochemical markers of bone turnover) and imaging tests.