Prevention of breast cancer skeletal metastases with parathyroid hormone

Swami, Srilatha; Johnson, Joshua; Bettinson, Lance A; Kimura, Takaharu; Zhu, Hui; Albertelli, Megan A.; Johnson, Rachelle W.; Wu, Joy Y.

doi:10.1172/jci.insight.90874

Cited by 40 publications

(31 citation statements)

References 77 publications

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“…At least in the preclinical setting, further agents are being explored with this purpose, including anabolic agents such as the parathyroid hormone analogue (teriparatide) whose administration in murine models of BC was found able to counteract the onset of spontaneous BM [90]. However, safety concerns regarding this agent have limited, to date, its use in cancer patients [91] and may hamper further clinical investigation.…”

Section: Discussionmentioning

confidence: 99%

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

D’Oronzo

Silvestris

Paradiso

et al. 2020

IJMS

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Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This condition implies a severe disability and deterioration of the quality of life, with consequent additional social costs. In recent decades, several studies explored the role of agents acting within the bone microenvironment to counteract BM development, and several bone-targeting agents (BTAs) have been introduced in the clinical practice to manage bone lesions and reduce the risk of skeletal complications. However, long-term exposure to these agents is not free from potential toxicities and needs careful monitoring. In this context, the potential capability to prevent BM onset in selected BC patients, through the early administration of BTAs, has been explored by several researchers, with the belief that “prevention is better than cure” and that, ultimately, metastatic BC is an incurable condition. Here, we revised the mechanisms of BM development in BC as well as the strategies for selecting high-risk patients suitable for early BTA treatment.

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Section: Discussionmentioning

confidence: 99%

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

D’Oronzo

Silvestris

Paradiso

et al. 2020

IJMS

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“…However, tumor burden was increased in other skeletal sites suggesting that PTH-mediated alteration of the endosteal niche renders different skeletal sites to cancer cell colonization (50). In contrast, an anabolic (4 weeks, daily) treatment of mice with PTH was demonstrated to prevent skeletal metastases and preserve bone architecture in orthotopic and intratibial breast cancer models (51). Despite different experimental design, which is likely to explain the different results, both studies demonstrate that alteration of the bone microenvironment and osteoblast function by PTH affect breast cancer bone colonization.…”

Section: Osteoblasts As Novel Target To Treat Bone Metastases-bone Anmentioning

confidence: 99%

“…Nevertheless, recently published studies highlight their potential as novel cellular targets to prevent and/or treat breast cancer bone metastasis (7,8,29,34,38,39,75). In addition, the therapeutic importance of osteoblasts has been acknowledged with novel therapeutics including bone anabolic agents such as PTH and anti-sclerostin antibody (51,55). However, a detailed characterization of how bone anabolic agents modify the composition and/or location of the endosteal niche as well as potential consequences on tumor cell colonization and metastatic outgrowth remains to be performed.…”

Section: Conclusion/perspectivementioning

confidence: 99%

The Endosteal Niche in Breast Cancer Bone Metastasis

2020

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The establishment of bone metastasis remains one of the most frequent complications of patients suffering from advanced breast cancer. Patients with bone metastases experience high morbidity and mortality caused by excessive, tumor-induced and osteoclast-mediated bone resorption. Anti-resorptive treatments, such as bisphosphonates, are available to ease skeletal related events including pain, increased fracture risk, and hypercalcemia. However, the disease remains incurable and 5-year survival rates for these patients are below 25%. Within the bone, disseminated breast cancer cells localize in "metastatic niches," special microenvironments that are thought to regulate cancer cell colonization and dormancy as well as tumor progression and subsequent development into overt metastases. Precise location and composition of this "metastatic niche" remain poorly defined. However, it is thought to include an "endosteal niche" that is composed of key bone cells that are derived from both, hematopoietic stem cells (osteoclasts), and mesenchymal stromal cells (osteoblasts, fibroblasts, adipocytes). Our knowledge of how osteoclasts drive the late stage of the disease is well-established. In contrast, much less is known about the interaction between osteogenic cells and disseminated tumor cells prior to the initiation of the osteolytic phase. Recent studies suggest that mesenchymal-derived cells, including osteoblasts and fibroblasts, play a key role during the early stages of breast cancer bone metastasis such as tumor cell homing, bone marrow colonization, and tumor cell dormancy. Hence, elucidating the interactions between breast cancer cells and mesenchymal-derived cells that drive metastasis progression could provide novel therapeutic approaches and targets to treat breast cancer bone metastasis. In this review we discuss evidences reporting the interaction between tumor cells and endosteal niche cells during the early stages of breast cancer bone metastasis, with a particular focus on mesenchymal-derived osteoblasts and fibroblasts.

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“…Die Relevanz dieser in vitro-Befunde für den Menschen in vivo muss überprüft werden. Fragen nach der Beeinflussung von manifesten Knochenmetastasen unterschiedlicher Tumore durch Teriparatid sowie die Auswirkungen auf die (Tumor-) Stammzellmobilisierung aus Knochenmarksnischen wären dringlich zu klären [10,11,14]. ▶Tab.…”

Section: Klärungsbedürftige Caveatsunclassified

“…Für die Anwendung nach Radiatio von Skelettanteilen, bei erhöhtem Osteosarkom-Risiko wie beim M. Paget und bei aktivem Tumorleiden bestehen bis heute Kontraindikationen. Für letztere Situation gibt es jedoch präklinische Hinweise dafür, dass die Anwendung von Teriparatid bei Knochenmetastasen Anti-Tumor-Wirkung aufweisen könnte[14]. Entsprechende Studien im Menschen müssten aber noch auf den Weg gebracht werden.…”

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Teriparatid – Das molekulare und klinische Profil bei der Therapie der Osteoporose

Jakob¹,

Müller-Deubert²,

Ebert³

2019

Osteologie

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ZusammenfassungPTH und PTHrP fördern situationsabhängig Knochenformation, -umbau und -abbau. Sie binden an den PTH Rezeptor Typ 1 (PTH1R) auf Osteoblasten, Osteozyten und T-Zellen und vermitteln Genregulation. Kurze Pulse wirken anabol, chronische Stimulation wirkt stark katabol. Teriparatid ist von PTH abgeleitet (Aminosäuren 1–34) und induziert Knochenformation, die durch mechanische Belastung auch an instabilen Stellen verstärkt wird. Klinische Endpunkte sind Zunahme an Knochenmasse und -struktur und deutliche Reduktion der Frakturrate der Wirbelkörper und – mit geringerer Effizienz – der non-vertebralen Frakturen. Die Wirkung ist in einem umfangreichen Studienprogramm in randomisierten kontrollierten und „Real-Life“-Studien evidenzbasiert belegt. Teriparatid wirkt bei Frauen und Männern, unter Glukokortikoid-Therapie und nach Bisphosphonat-Vorbehandlung. Es kann nur einmalig über 24 Monate verabreicht werden, nachfolgende Gabe von Antiresorptiva verbessert den Outcome. Gesundheitspolitische Vorgaben beschränken seine Anwendung in Deutschland auf die Situation neuer Frakturen unter Antiresorptiva. Teriparatid ist sicher, hat ein sehr gutes Nebenwirkungsprofil und ist das erste Beispiel einer Regenerativen Therapie in der Osteologie.

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Prevention of breast cancer skeletal metastases with parathyroid hormone

Cited by 40 publications

References 77 publications

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

The Endosteal Niche in Breast Cancer Bone Metastasis

Teriparatid – Das molekulare und klinische Profil bei der Therapie der Osteoporose

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