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Wednesday, March 10, 2004

Award honors research on predicting fracture risk

By Carolyn Rogers

The 2004 Ann Doner Vaughan award was presented yesterday to Brian D. Snyder, MD, PhD; John A. Hipp, PhD, and Ara Nazarian, MSc, for their manuscript, "Non-invasive prediction of fracture risk due to benign and metastatic skeletal defects."

The paper outlines a series of basic science studies and subsequent clinical trials that led investigators to conclude that computed tomography (CT)-based structural rigidity analysis is just as sensitive, and significantly more specific, than the best radiographic guidelines in estimating metastatic cancer vertebral fracture risk.

"While much has been learned about the mechanisms of metastatic spread of cancer to bone, little headway has been made in establishing reliable guidelines for estimating fracture risk associated with skeletal metastases, or monitoring the response of a specific bone lesion to treatment," said Dr. Snyder, the project's principal investigator.

The skeleton is the third most common site of metastatic cancer (after the liver and the lung), and one-third to half of all cancer cases metastasize to bone. Although cancer patients are living longer due to new and aggressive treatments, skeletal metastasis continues to be a feared complication because fractures can occur at sites of bone involvement after minimal trauma.

"Although guidelines have been described, most clinicians make subjective assessments regarding fracture risk and treatment response based on plain radiographs using methods now recognized to be inaccurate," Dr. Snyder said. "The prevention of fractures due to skeletal metastasis depends on objective criteria for evaluating changes in the bone structural properties that reflect the interaction of the tumor with the host bone."

Systemic treatment with cytotoxic agents, hormone manipulation, bisphosphonates or local treatment with radiation and/or surgical stabilization constitute the range of therapies available to cancer patients with skeletal metastases. Identifying which treatment is optimal for a particular patient is controversial in part because there are no proven objective methods for evaluating a patient's response to treatment.

Tumor-induced osteolysis determines fracture risk

"Our hypothesis is that a change in bone structural properties as a result of tumor-induced osteolysis determines the fracture risk in patients with skeletal metastases," explained Dr. Snyder.

"Our goal was to develop an imaged-based clinical tool to monitor the fracture risk associated with individual lesions in patients with skeletal metastases and to use this tool to optimize treatment and monitor a patient's response to treatment."

In a series of laboratory experiments, the researchers demonstrated that the reduction in the load-carrying capacity of a bone with simulated defects could be predicted accurately and non-invasively using common imaging modalities.

They also demonstrated that bone material properties from tissue excised from normal, osteoporotic and metastatic cancer bone specimens could be modeled analytically using a bivariate function of bone tissue density and bone volume fraction.

These basic science studies validated the basic hypothesis and led to the application of the methods in two clinical trials-one with benign bone defects in children and the other with metastatic defects in patients with breast cancer.

Clinical trials

"We applied our methods for predicting fracture risk to analyze bones from children with benign bone defects," Dr. Synder said. "These studies showed that our relatively simple methods were much better at predicting fracture then common clinical methods."

In the second trial, researchers used CT-based data to calculate the load-bearing capacity of vertebrae infiltrated with metastatic breast carcinoma. They were able to predict the occurrence of a new vertebral fracture in women with metastatic breast cancer with 100 percent sensitivity and 69 percent specificity.

These results contrasted with the best available fracture risk criteria based on the size and location of the lesion on CT images of the spine, which were only 22 percent specific.

"These results support the hypothesis that bone can be considered a rigid material undergoing remodeling by osteoblasts and osteoclasts in response to local and/or systemic modulators of their activity, and that changes in bone material properties reflect the net effect of this remodeling activity," Dr. Snyder said.

These non-invasive, image-based methods that measure both bone mineral density and whole bone geometry also may be used to monitor the response of skeletal metastases to anticancer treatment and to predict whether a specific lesion has weakened the bone sufficiently such that pathological fracture is imminent, he added.

"We have introduced CT-based structural analysis as a clinical tool to monitor the fracture risk associated with skeletal metastases in individual patients, and expect that this tool can be used to optimize treatment based on fracture risk and to continuously monitor the response of the metastasis to treatment," he concluded.

The investigators

Dr. Snyder is assistant professor of orthopaedic surgery at Harvard Medical School, and director of the Orthopaedic Biomechanics Laboratory at Beth Israel Deaconess Medical Center in Boston.

 Dr. Hipp is director of the Spine Research Laboratory at Baylor College of Medicine in Houston.
 Mr. Nazarian is a graduate student, co-advised by Dr. Snyder, who has been working on the project as part of his PhD dissertation.

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Last modified 19/February/2004