Osteoporotic Fragility Fractures

Each year 1.5 million osteoporotic fragility fractures are diagnosed in the United States alone, the most common being vertebral compression fractures (~750,000 per year), and these numbers are expected to rise with the aging of the baby boom generation. Between 50% and 80% of these fractures are asymptomatic and found incidentally on routine chest radiographs or clinically by progressive height loss. By current estimates, approximately 200,000 vertebral augmentation procedures (vertebroplasty or kyphoplasty) are performed annually, with growth expected due to increases in physician awareness and clinical experience, as well as expansion of the patient population. Over the past 20 years, vertebroplasty has become the standard of care for vertebral compression fractures, providing effective and immediate pain relief for thousands of patients. Until now, polymethylmethacrylate (PMMA) has been established as the only viable material for the treatment of vertebral augmentations. PMMA possesses several significant limitations such as a viscosity that changes with time, toxic monomer release, high exothermic reaction, and bolus-like distribution that may cause stress on adjacent vertebra.

Cortoss Bone Augmentation Material is an injectable, bioactive composite that mimics the mechanical properties of human cortical bone and is the first alternative to PMMA cement that has been evaluated in a large-scale, multi-center, randomized, controlled clinical study and cleared in the United States for the treatment of vertebral compression fractures due to osteoporosis, benign lesions (hemangioma), and malignant lesions (metastatic cancers, myeloma). Cortoss is a blend of cross-linking resins and reinforcing fillers, which include the proprietary bioactive glass found in Orthovita’s Vitoss™ Bioactive foam products. Pre-clinical in vitro and in vivo studies show that, upon injection of Cortoss, a bioactive response occurs at the implant’s surface which promotes the deposition of calcium phosphate, thereby strengthening the implant-bone interface. The pre-polymerized material has a constant, paste-like consistency when being injected and sets quickly to create a load bearing implant with the mechanical properties of human cortical bone.

Cortoss flows and fills into the existing intra-vertebral anatomy rather than displacing it like PMMA. The dispersed fill pattern requires about one-third less material than the bolus fill pattern, potentially decreasing the displacement and embolization of fat and marrow. Compared to PMMA, Cortoss is more hydrophilic, which enables the material to coat and support the existing trabecular structure rather than displacing it.

The unique flow characteristics of Cortoss allow low-pressure, manual delivery through Orthovita’s Aliquot™ Delivery System. The mix-on-demand design of the Cortoss delivery offers a level of control and procedural flexibility not previously possible. The ready-to-use cartridge system allows the physician full control over material delivery timing. The low-pressure, low-inertia delivery provides easy intra-operative handling and stops quickly when the injection pressure is released, minimizing the risk of extravasation.

Inherent radiopacity, lower polymerization temperature, minimal leachate, and optimized mechanical characteristics all reflect that Cortoss has been formulated for safety. The benefits of this composition are:  radiographic visualization without the need for secondary contrast agents, elimination of the risk of thermal necrosis, elimination of toxicity caused by released volatile monomer, and reduced stress on adjacent levels. Engineered specifically for the treatment of VCFs, Cortoss obviates many of the issues inherent with the use of PMMA bone cement.
 
In April 2009, clinical data with 2-year follow-up for patients enrolled in the company-sponsored prospective, randomized, multi-center study comparing the efficacy of PMMA to Cortoss was submitted by Orthovita as part of the FDA approval process. In accordance with the pre-defined statistical analysis plan for this 256-patient pivotal trial conducted under an Investigational Device Exemption (IDE), non-inferiority was determined at the 24-month time point using the primary composite endpoint success rate reflecting improvement in the Visual Analogue Pain Scale (VAS) pain score, maintenance or improvement in Oswestry Disability Index (ODI) function assessment, maintenance of vertebral height and alignment, and no subsequent device-related surgical intervention at the index treatment level. The study hypothesis formulated at the outset was that Cortoss is non-inferior to PMMA at 24 months with a confidence interval of 90% and a δ of 12.5%. The results confirm the hypothesis that Cortoss is non-inferior to PMMA in the vertebral augmentation procedures for VCFs. The study results show that this conclusion can be drawn with a higher degree of certainty than originally anticipated, with a confidence interval of 95%, and a δ of 10%.

At other time points there were no significant differences between Cortoss and PMMA, except as noted below for the individual endpoints of pain and function at 3 and 24 months, respectively. For the composite endpoint, Cortoss and PMMA are not significantly different over time, although there is a trend with a 9.1% difference in favor of Cortoss at 3 months.
  In the pivotal study at 24 months:

•    The composite endpoint success rate was 76.9% for CORTOSS patients and 73.4% for PMMA patients.
•    With an ODI success rate of 96.7%, the CORTOSS patient group experienced a statistically significant benefit in function success over the PMMA group, with an 88.4% ODI success rate, a difference of 8.3% (p<0.05)
•    The difference in function was further confirmed by a significant difference (p<0.05) in the physical functioning ability as measured by the SF-12 questionnaire.

Early patient outcomes at 3 months include:

•    An 82.8% composite endpoint success rate for patients treated with CORTOSS vs. 73.7% for PMMA patients.
•    With a VAS success rate of 86.6%, the CORTOSS patient group experienced a statistically significant benefit in pain success over the PMMA group, which had a VAS success rate of 75.0%, a difference of 11.6% (p<0.05)

Maintenance of vertebral height and alignment in each group was closely matched at all assessment intervals. On the basis of subsequent surgical interventions, two of the 162 Cortoss patients were considered a failure by requiring surgery at the treated site - one for intercostal neuritis and one for further fracture. Both were treated successfully, the latter with Cortoss.

Pain medication usage dropped steadily and significantly for both groups over time, with 90.7% of Cortoss patients and 86.2% of the PMMA using an analgesic at baseline and declining to 44.1% of Cortoss patients and 40.0% of PMMA patients at the 24-month evaluation.

Physician ease-of-use ratings of both materials was high, with 63% of physicians rating Cortoss as “very easy” vs. 54% who gave PMMA that same designation.

Both Cortoss and PMMA patients exhibited leaks in exactly 63.8% of levels treated. Most of these were asymptomatic and are mentioned only for completeness of the study results, as they are not comparable to leaks that cause symptoms.
The incidence of serious adverse events that were reported as related to the procedure or device was low in both groups—4.3% in each. These events included new fractures, muscle spasm, hypertension, and redness at the incision site.

New fractures at any level occurred more in the PMMA group¬¬ than in the Cortoss group—31.9% vs. 27.8% of patients, respectively. Studies have shown that the presence of multiple existing VCFs at baseline substantially increases the risk of developing a new VCF. Patients with no previous fracture at study outset and with only one level treated comprise a “virgin back” subset of patients, which provide a more homogeneous basis for comparison of the two treatments. In this study there were 112 “virgin back” patients. In this group, 27.3% of the PMMA patients developed a new fracture while for Cortoss patients the rate was 17.6%. This represents a decreased incidence of 35% for the Cortoss group versus the PMMA group. In these patients the incidence of fractures at an adjacent level was also higher in the PMMA group—18.2%—than in the Cortoss group—10.3%—representing a decreased incidence of 43% in Cortoss patients. Because of the relatively small numbers this trend did not reach significance.

John Mathis, M.D. of The Center for Advanced Imaging in Roanoke, Virginia, and editor of the original textbook entitled “Percutaneous Vertebroplasty and Kyphoplasty,” commented: “For over 20 years, the treatment of vertebral fractures relied on the application of a foreign material without much consideration for the mechanical, and none for the biological conditions. Cortoss is a material that was designed to restore mechanical conditions and match the properties of natural bone. I believe that its introduction marks the beginning of the next phase in the treatment of vertebral fractures which will be concentrated on the patients’ physiology.”

With 83% follow-up at the 24-month time point, the study also represents a significant piece of clinical research in this field. The pivotal study, in combination with various clinical trials previously completed in the U.S. and Europe, brings the total number of patients studied for Cortoss in vertebral compression fractures to 527.

“In the evolution of vertebroplasty, development has focused largely on the different tools to deliver PMMA, instead of improving the implant that remains in the patient forever. Years ago, Orthovita had the vision to change this. After investing a tremendous amount of work and effort, the company is now ready to introduce this new and unique implant material. In addition, the exceptional quality of the clinical study that Orthovita designed and executed is an asset to the entire spinal community,” said Pierce D. Nunley, M.D., Director of the Spine Institute of Louisiana, who participated in the trial.

The experience and research to date shows that physicians and their staff are pleased with the innovative handling and biomechanical characteristics that Cortoss offers. These features, supported by the extensive human clinical data demonstrating safety and effectiveness, offer physicians and facilities substantial value and a clear rationale for adopting Cortoss

In the U.S., Cortoss is represented by Orthovita’s orthobiologics and biosurgical sales forces. Commercial success thus far for Orthovita has been grounded in the company’s ability to effectively present the value of basic science and their comprehensive human clinical data throughout a hospital. Vitoss Bone Graft Substitute is now the leading synthetic bone graft for spine surgery and the biosurgery business, led by Vitagel™ Surgical Hemostat, has experienced brisk growth since its inception in 2005. Cortoss will benefit significantly from the commercial infrastructure, core competencies and call patterns that have been established. Further, it is estimated that current coverage addresses roughly 80% of the surgical market for vertebral compression fractures, which establishes a strong position to launch Cortoss while plans to grow the current product lines continues.

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