Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 May;14(9):e70901.
doi: 10.1002/cam4.70901.

Inside a Metastatic Fracture: Molecular Bases and New Potential Therapeutic Targets

Alessandro Bruschi  1   2 , Andrea Sambri  1 , Michele Fiore  1   3 , Elisa Bubbico  1 , Cristina Scollo  1 , Andrea Pace  1 , Renato Zunarelli  1 , Andrea Montanari  1 , Alberta Cappelli  4 , Lorenzo Di Prinzio  1 , Massimiliano De Paolis  1
Affiliations
Review

Inside a Metastatic Fracture: Molecular Bases and New Potential Therapeutic Targets

Alessandro Bruschi et al. Cancer Med. 2025 May.

Abstract

Introduction: Bone metastases and pathological fractures significantly impact the prognosis and quality of life in cancer patients. However, clinical and radiological features alone have been shown to fail to predict skeletal related events of a bone metastasis (SREs).

Aim: This study focuses on key molecular players including Matrix Metalloproteinases (MMPs), Integrins, Bone Morphogenetic Proteins (BMPs), Parathormone-related Protein (PTHrP).

Results: The RANK/RANKL/Osteoprotegerin (OPG) pathway, and N-terminal peptide (NTx), involved in the metastatic process and bone integrity disruption. Elevated levels of these molecules have been pointed out as potential biomarkers for predicting SREs, but they have been poorly investigated. Moreover, batimastat, marimastat, tanomastat, andecaliximab, and HIV protease targeting MMPs; Volociximab/M200, cilengitide, abituzumab, and FAK inhibitors targeting integrins; LDN193189, DMH1, and ISLR modulators targeting BMPs; and PTH (7-33)-CBD targeting PTHrP have shown promising results antagonizing these molecules, but no effect on preventing and managing metastatic fractures has been assessed yet.

Conclusions: This paper underscores the importance of advanced molecular biology and transcriptomics in identifying novel therapeutic targets. The integration of these biomarkers with clinical and radiological assessments using artificial intelligence tools could revolutionize the diagnostics and treatment strategies for patients with bone metastases.

Keywords: BMPs; MMPs; NTx; PTHrP; RANK; bone metastasis; integrins; metastatic fracture; skeletal related events.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of molecular interplays inside the bone metastatic niche driving to a metastatic fracture. Matrix Metalloproteinases (MMPs) contribute to extracellular bone matrix (ECM) degradation and to osteoclast activation. The RANK‐RANKL pathway promotes osteoclast activation and it is enhanced by Bone Morphogenetic Proteins (BMPs). BMPs display a dual role, also activating osteoblasts in driving osteoblastic metastasis formation. On the other side, osteoclast activation is also promoted by Parathormone related peptide (PTH‐rP) and Integrins. This pathway drives bone resorption with N‐terminal peptide (NTx) formation and osteolytic metastasis. Both lytic and blastic metastasis are prone to fracture due to lower resistance of the pathological bone.
See this image and copyright information in PMC

References

    1. Anract P., Biau D., and Boudou‐Rouquette P., “Metastatic Fractures of Long Limb Bones,” Orthopaedics & Traumatology, Surgery & Research 103, no. 1 (2017): S41–S51, 10.1016/j.otsr.2016.11.001. - DOI - PubMed
    1. Damron T. A., Morgan H., and Prakash D., “Critical Evaluation of Mirels? Rating System for Impending Pathologic Fractures,” Clinical Orthopaedics and Related Research 415 (2003): S201–S207, 10.1097/01.blo.0000093842.72468.73. - DOI - PubMed
    1. Baek A. E., “Lymph Node Colonization and Metastasis,” Science Signaling 15, no. 734 (2022): eadc9985, 10.1126/scisignal.adc9985. - DOI - PubMed
    1. Borad M. J., Saadati H., and Lakshmipathy A., “Skeletal Metastases in Pancreatic Cancer: A Retrospective Study and Review of the Literature,” Yale Journal of Biology and Medicine 82 (2009): 1–6. - PMC - PubMed
    1. Wilson M. A., Zhong J., and Johannet P., “Preliminary Analysis of Distinct Clinical and Biologic Features of Bone Metastases in Melanoma,” Melanoma Research 30, no. 5 (2020): 492–499, 10.1097/CMR.0000000000000691. - DOI - PMC - PubMed

MeSH terms