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

Pantano, Francesco; Tramontana, Flavia; Iuliani, Michele; Leanza, Giulia; Simonetti, Sonia; Piccoli, Alessandra; Paviglianiti, Annalisa; Cortellini, Alessio; Spinelli, Gian Paolo; Longo, Umile Giuseppe; Strollo, Rocky; Vincenzi, Bruno; Tonini, Giuseppe; Napoli, Nicola; Santini, Daniele

doi:10.1016/j.jbo.2022.100459

Cited by 12 publications

(13 citation statements)

References 37 publications

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“…The last study by [ 98 ] evaluated the changes in plasma levels of bone turnover markers (collagen C-terminal telopeptide (CTX-1) and N -terminal propeptide of type I procollagen (PINP)) in 44 patients (median age = 70 years) affected by non-small cell lung cancer ( n = 36) or renal cell cancer ( n = 8) after 3 months of anti-PD-1 monotherapy. The patients had neither prior history of osteoporosis nor preexisting risk factors.…”

Section: Literature Review Resultsmentioning

confidence: 99%

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

Mytareli

Ziogas

Karampela

et al. 2023

Cancers

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Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately.

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Section: Literature Review Resultsmentioning

confidence: 99%

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

Mytareli

Ziogas

Karampela

et al. 2023

Cancers

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“…26 27 38 In contrast, ICIs have been shown to increase bone resorption and thus trigger skeletal adverse events in patients with cancer. [39][40][41] In this study, we investigated the long-term effect of ICIs on levels of bone metabolism biomarkers in patients with cancer and elucidated their impact on bone remodeling using a novel, bioengineered 3D model of the BMU. To the best of our knowledge, our findings highlight for the first time the dual effect of ICIs on bone metabolism through the impaired differentiation of mature OCs, which indirectly leads to increased osteogenesis.…”

Section: Discussionmentioning

confidence: 99%

Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation

Gassner,

Chittilappilly,

Pirich

et al. 2024

J Immunother Cancer

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BackgroundSkeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling.MethodsAn exploratory longitudinal study was conducted to assessserum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model.ResultsDuring the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation.ConclusionOur study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.

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“…Third, in this case, the vertebral biopsy did not detect any active inflammation which indicated imAEs due to durvalumab. A few reports suggested that immune checkpoint inhibitors (ICIs) might cause inflammatory toxicities on bone or bone turnover abnormalities [ 15 , 16 ]. However, none of these reports proved bone toxicities due to ICIs pathophysiologically.…”

Section: Discussionmentioning

confidence: 99%

A Case of Radiation-Associated Vertebral Compression Fracture Mimicking Solitary Bone Metastasis of Lung Cancer

Ikuta,

Shoshihara,

Minami

et al. 2023

J Med Cases

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Radiation therapy plays an important role in the treatment of lung cancer. Although adverse effects of radiation are well known, they are sometimes difficult to be diagnosed. We report a case of a radiation-associated vertebral compression fracture which mimicked bone metastasis of lung cancer. The patient was a 57-year-old man diagnosed with lung squamous cell carcinoma (cT1aN2M0, c-stage IIIA). He received concurrent chemoradiotherapy (CRT) in combination with 6 weeks of weekly carboplatin plus paclitaxel and thoracic radiation of 60 Gy/30 fractions, followed by bi-weekly durvalumab for 12 months. On the last day of the 12-month durvalumab regimen, he complained of backache. Magnetic resonance imaging showed compression fracture of the seventh thoracic vertebra with the spinal cord compressed, and fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography demonstrated weak focal uptake only at the seventh thoracic vertebra. Although the fracture had been suspected to be bone metastasis, surgical biopsy revealed no evidence of malignancy. Since the seventh thoracic vertebra was included in the irradiation area, the patient was diagnosed with a radiation-associated fracture. Dual-energy X-ray absorptiometry of the lumbar vertebrae (L2 - 4) after the surgery revealed osteopenia. In conclusion, we successfully diagnosed the radiation-associated vertebral fracture caused by radical CRT. The fracture mimicked bone metastasis in preoperative imaging tests. Thus, surgical biopsy was useful for diagnosis.

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

Cited by 12 publications

References 37 publications

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation

A Case of Radiation-Associated Vertebral Compression Fracture Mimicking Solitary Bone Metastasis of Lung Cancer

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