Journal of Bone Metabolism

"Hypercalcemia"

Original Article

Incidence of Hypercalcemia and Vertebral Fractures Following Denosumab Withdrawal in Lung Cancer Patients: A Longitudinal Cohort Study: Marta Villanova, Sharon H. Chou, Le Min; J Bone Metab 2025;32(1):38-48.
Published online February 28, 2025; DOI: https://doi.org/10.11005/jbm.24.803

Background
Bone-target agents (BTAs), including denosumab (DMAb), are one of the bone metastasis treatments that should continue indefinitely. However, BTAs may be interrupted in some cases. In osteoporosis, DMAb withdrawal causes a rebound effect characterized by an increased bone turnover with spine fractures and hypercalcemia; evidence of the DMAb withdrawal effect in oncology is lacking.
Methods
This study aimed to identify the DMAb withdrawal effect amongst lung cancer patients treated with DMAb for bone metastases between January 2020 and December 2021. Patients who discontinued DMAb were included. Encounter notes, radiological and laboratory findings were comprehensively reviewed.
Results
Thirty patients were included with a median follow-up of 21 months (interquartile range [IQR], 10-30) after DMAb discontinuation. Bisphosphonates were administered before starting DMAb in 7 patients (23.3%) and after DMAb withdrawal in 4 cases (13.3%). Three cases of DMAb withdrawal-related hypercalcemia and 3 cases of spine fractures following DMAb cessation were identified in 5 patients (16.7%), all of them were females and the median age was 65 years old (IQR, 65-70). No statistical difference in DMAb duration or number of injections was found in patients developing DMAb withdrawal-related spine fractures or hypercalcemia compared with others (binary logistic regression, p=0.688 and p=0.938, respectively).
Conclusions
Patients with bony-metastatic lung cancer, especially post-menopausal women, are at risk of fractures and calcium abnormalities after DMAb discontinuation, suggesting that DMAb withdrawal effect may also be present in the oncological setting. A close follow-up and careful monitoring during and after discontinuation of DMAb is necessary.

Citations

Citations to this article as recorded by

1. Atypical femoral fracture and jaw osteonecrosis under high doses of denosumab, healed with the aid of low dose of denosumab: a case report
Hanene Lassoued, Olivier Lamy, Cyril Francioli, Elena Gonzalez Rodriguez
Frontiers in Endocrinology.2026;[Epub] CrossRef
2. Hypercalcemia of Malignancy and Medication-Related Osteonecrosis of the Jaw Following Denosumab Discontinuation in Metastatic Breast Cancer: A Case Report
Omar Shazley, Christina Orr
Cureus.2025;[Epub] CrossRef
3. Transient increase in skeletal-related events after discontinuation of high-dose denosumab in cancer patients
Nokitaka Setsu, Nobuhiko Yokoyama, Taito Esaki, Masafumi Yamaguchi, Eriko Tokunaga, Takahito Negishi
Journal of Bone Oncology.2025; 55: 100717. CrossRef
4. Parathyroid Hormone (1–34) Signaling for Bone Health in Breast Cancer Survivorship and Metastasis
Shinyoung Oh, Ha Ram Oh, Chen Shen, Young Ran Park, Ji Hyun Park
Journal of Cellular Physiology.2025;[Epub] CrossRef

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Case Reports

A Rare Case of Hyperfunctioning Lipoadenoma Presenting as a Cystic Pararthyroid Lesion: Jinyoung Kim, Ohjoon Kwon, Tae-Jung Kim, So Lyung Jung, Eun Ji Han, Ki-Ho Song; J Bone Metab 2023;30(2):201-207.
Published online May 31, 2023; DOI: https://doi.org/10.11005/jbm.2023.30.2.201

A 58-year-old woman visited the hospital complaining of fatigue and indigestion lasting for more than 3 months. She had no medical history other than taking a calcium plus vitamin D supplement for osteopenia. The initial blood test showed a high calcium level of 14.0 mg/dL. Additional tests were performed to differentially diagnose hypercalcemia. The blood test results were as follows: serum parathyroid hormone (PTH)=247.0 pg/mL, PTH-related peptide <1.0 pg/mL, phosphorous=2.6 mg/dL, 25-hydroxy-vitamin D=14.5 pg/mL, creatinine=1.09 mg/dL, and 24 hr urine calcium=215 mg/dL. A 4.5 cm sized cystic lesion on the intra-thyroidal space was confirmed on neck sonography and 4-dimensional parathyroid computed tomography, but technetium-99m methoxyisobutylisonitrile parathyroid scintigraphy showed equivocal results. After removal of the cystic lesion, serum calcium and PTH were normalized, and parathyroid lipoadenoma was confirmed in the postoperative pathology. Clinical features of parathyroid lipoadenoma are known to be similar to common parathyroid adenoma, but imaging studies often report negative findings. Therefore, it is necessary to better understand this rare disease for the differential diagnosis. For the final diagnosis and treatment of this disease, parathyroidectomy with intraoperative PTH measurement may be required.

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Parathyroid Crisis as Presentation of Atypical Parathyroid Adenoma: Two Diagnostically Challenging Cases: Galo Andrés Salvador Landeta, Alexis Trejo Montes, Tania Islem Gamboa Jimenéz, Vargas-Ortega Guadalupe, González-Virla Baldomero, Balcázar-Hernández Lourdes; J Bone Metab 2022;29(2):133-140.
Published online May 31, 2022; DOI: https://doi.org/10.11005/jbm.2022.29.2.133

Atypical parathyroid adenoma (APA) is a rare cause of primary hyperparathyroidism (PHPT) and represents a diagnostic challenge since it is an intermediate form of parathyroid neoplasm of uncertain malignant potential with atypical histological features that require differential diagnosis of parathyroid carcinoma (PC). We present 2 cases of parathyroid crisis as a presentation of APA. The first case was that of a 56-year-old man with parathyroid crisis, constitutional syndrome, and anemia, with evidence of APA after en bloc resection, evolving with hungry bone syndrome after surgery and curation criteria at 6 months after parathyroidectomy (PTX). The second case was a 64-year-old woman with acute chronic kidney disease and parathyroid crisis, with evidence of APA after selective PTX and >50% reduction in parathyroid hormone levels after surgery; however, persistent PHPT at 6 months post-surgery was observed. These cases represented a diagnostic challenge due to their rare clinical presentation (parathyroid crisis), with a heterogeneous spectrum of target organ damage and infrequent symptoms (constitutional syndrome and acute chronic renal disease), in turn caused by a rare pathology (APA). The presentation of these patients may be indicative of PC; however, histopathological diagnosis is a key to the diagnosis of APA. The differential diagnosis of APA vs. PC in clinical practice is indispensable.

Citations

Citations to this article as recorded by

1. Exceedingly Hyper‐Secreting Parathyroid Adenoma: A Literature Review and Case Series
Delaney E. S. Clark, Arati Bendapudi, Connor B. Haines, Nicholas Rossi, Hasanain Hasan, Orly Coblens
Head & Neck.2026;[Epub] CrossRef
2. Extended parathyroidectomy with reconstruction of the recurrent laryngeal nerve for an atypical tumor of the parathyroid gland: clinical observation
E. A. Ilyicheva, G. A. Bersenev
Endocrine Surgery.2026; 19(3): 63. CrossRef
3. Multiple fractures due to hungry bone syndrome following parathyroidectomy: a clinical case report and review of literature
Farnaz Tavakoli, Fatemeh Yaghoubi, Davood Dalil, Mahdi Rezaei
Clinical Diabetes and Endocrinology.2024;[Epub] CrossRef
4. Severe Hypercalcemia as Presentation of Atypical Cystic Parathyroid Adenoma: A Case Report
Paola G. Donoso Naranjo, Macarena Naranjo Arellano, Esteban Castillo Sánchez-Heredero, Isabel Martín Garrido
Annals of Internal Medicine: Clinical Cases.2024;[Epub] CrossRef
5. Forestalling Hungry Bone Syndrome after Parathyroidectomy in Patients with Primary and Renal Hyperparathyroidism
Mara Carsote, Claudiu Nistor
Diagnostics.2023; 13(11): 1953. CrossRef

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Original Article

Clinical Characteristics, Causes and Survival in 115 Cancer Patients with Parathyroid Hormone Related Protein-mediated Hypercalcemia: Joon Jin, Jin Ook Chung, Min Young Chung, Dong Hyeok Cho, Dong Jin Chung; J Bone Metab 2017;24(4):249-255.
Published online November 30, 2017; DOI: https://doi.org/10.11005/jbm.2017.24.4.249

Background

The aim of this study is to determine the proportion of cancers presenting with parathyroid hormone (PTH) related protein (PTHrP)-mediated hypercalcemia, examine the clinical and biochemical characteristics, identify predictive factors for survival. And we also compared those characteristics between solid organ and hematologic malignancy groups.

Methods

Cancer patients with PTHrP-mediated hypercalcemia who were treated at Chonnam National University Hospital in Korea from January 2005 to January 2015 were retrospectively reviewed.

Results

Of all 115 patients, solid organ malignancies were the most common etiology (98 cases, 85.2%), with squamous cell carcinoma (50 cases, 43.4%), adenocarcinoma (27 cases, 23.4%). Interestingly, hepatocellular carcinoma (HCC; 18 cases, 15.7%) and cholangiocarcinoma (11 cases, 9.6%) were much more common causes than other previous reports. Hematologic malignancy was less common (17 cases, 14.8%), with multiple myeloma (9 cases, 7.8%) and non-Hodgkin's lymphoma (5 cases, 4.3%). Overall median survival was only 37 days. There was significant difference in median survival between two groups (35 days for solid organ malignancy and 72 days for hematologic malignancy; P=0.015). Cox regression analysis identified age, the type of malignancy and the time interval of developing hypercalcemia after cancer diagnosis as independent predictive factors for survival time.

Conclusions

PTHrP-mediated hypercalcemia was most frequently caused by solid organ malignancy. However, HCC and cholangiocarcinoma were important causes of PTHrP-mediated hypercalcemia may be due to geographic differences in cancer incidence in Korean population. Age, the type of malignancy and the time interval of developing hypercalcemia after cancer diagnosis were independent poor predictive factors for survival time.

Citations

Citations to this article as recorded by

1. Functional pancreatic neuroendocrine tumors predominantly presenting with hypercalcemia: a case report
Jieting Duan, Yanping Zhu, Yan Wang, Xiang Kui, Yingmei Tang
Frontiers in Oncology.2026;[Epub] CrossRef
2. Chapter 4: Differential diagnosis of primary hyperparathyroidism
Peter Kamenický, Pascal Houillier, Marie-Christine Vantyghem
Annales d'Endocrinologie.2025; 86(1): 101693. CrossRef
3. Parathyroid hormone-related protein levels and treatment outcomes in hypercalcemia of malignancy: a retrospective cohort study
Kazuhiko Kato, Akio Nakashima, Ai Kimura, Yukio Maruyama, Ichiro Ohkido, Yoichi Miyazaki, Takashi Yokoo
JBMR Plus.2025;[Epub] CrossRef
4. Parathyroid Hormone-Related Protein-Producing Adenocarcinoma Suspicious of Lung Cancer: A Case Report
Masahiro Hirabayashi, Tomonobu Koizumi, Daichi Nakajima, Shuko Azegami, Hajime Midorikawa, Nami Kitagawa, Hideaki Hamano, Tatsunori Chino, Maki Ohya
Case Reports in Oncology.2024; 17(1): 900. CrossRef
5. Association between parathyroid hormone-related peptide levels and mortality in patients with malignancy
Ai Kimura, Kazuhiko Kato, Akio Nakashima, Yukio Maruyama, Ichiro Ohkido, Yoichi Miyazaki, Takashi Yokoo
Endocrine Practice.2024;[Epub] CrossRef
6. Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway
Zhenyu Guo, Tingqin Huang, Yingfei Liu, Chongxiao Liu
International Journal of Stem Cells.2023; 16(3): 315. CrossRef
7. Case 16: A 75-Year-Old Man With Macroglossia and Hypercalcemia
Jinyoung Kim, Nanyeong Kim, Youngwoo Jeon, Tong-Yoon Kim, Tae-Jung Kim, Hyuk-Sang Kwon, Chul Soo Park, Ki-Hyun Baek
Journal of Korean Medical Science.2023;[Epub] CrossRef
8. A Case of Parathyroid Hormone-related Protein Producing Tumor in Simultaneous Multiple Cancers of the Breast and Lung
Tomomi KON, Saki NAKAGAWA, Keiri OH, Ryuichi YOSHIDA, Akira SUGIURA, Shinji TANIUCHI
Nihon Rinsho Geka Gakkai Zasshi (Journal of Japan Surgical Association).2023; 84(8): 1170. CrossRef
9. Cancer-Associated Hypercalcemia
Caren G. Solomon, Theresa A. Guise, John J. Wysolmerski
New England Journal of Medicine.2022; 386(15): 1443. CrossRef
10. Emerging Perspectives of Bone Metastasis in Hepatocellular Carcinoma
Xiaofeng Yuan, Ming Zhuang, Xi Zhu, Dong Cheng, Jie Liu, Donglin Sun, Xubin Qiu, Yunjie Lu, Kurt Sartorius
Frontiers in Oncology.2022;[Epub] CrossRef
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Valery G. Zaitsev, Anastasia A. Zheltova, Svetlana A. Martynova, Elena V. Tibirkova
Russian Open Medical Journal.2021;[Epub] CrossRef
12. Hypercalcemia is associated with a poor prognosis in lymphoma a retrospective monocentric matched-control study and extensive review of published reported cases
Nicolas Vallet, Marjan Ertault, Jean-Baptiste Delaye, Thomas Chalopin, Alban Villate, Laurianne Drieu La Rochelle, Julien Lejeune, Amélie Foucault, Martin Eloit, Chantal Barin-Le Guellec, Olivier Hérault, Philippe Colombat, Emmanuel Gyan
Annals of Hematology.2020; 99(2): 229. CrossRef
13. Hypercalcemia Associated with Extramammary Paget’s Disease
Tetsuko Sato, Yoshihisa Wada, Nobuhiko Kamitani, Takenobu Yamamoto, Yumi Aoyama, Wataru Fujimoto, Ryo Tanaka
Case Reports in Oncology.2020; 13(3): 1209. CrossRef
14. An Unusual Case of Severe Hypercalcemia
Shahanaze Javath Hussain, Deepak Amalnath, Mukta Wyawahare, D. K. S. Subhrahmanyam
Indian Journal of Gynecologic Oncology.2019;[Epub] CrossRef
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Julie E. Kim, Dorothy Martinez
Endocrinología, Diabetes y Nutrición (English ed.).2019; 66(1): 69. CrossRef
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Julie E. Kim, Dorothy Martinez
Endocrinología, Diabetes y Nutrición.2019; 66(1): 69. CrossRef
17. Cholangiocarcinoma in a Child with Progressive Abdominal Distension and Secondary Hypercalcemia
Chalinee Monsereenusorn, Kantang Satayasoontorn, Piya Rujkijyanont, Chanchai Traivaree, Ozgur Cogulu
Case Reports in Pediatrics.2018;[Epub] CrossRef
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Christoph Henzen
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