Objectives and Rationale: Reconstruction of large bone defects resulting from bone tumors, sports injuries, trauma such as that caused by car accidents, gunshot wounds, or high-energy blast injuries seen in military conflicts, have long been a challenge for orthopaedic surgeons. Failure to heal these bone injuries may result in multiple returns to the operating room, significant pain and problems, increased risk of infection and complications, and loss of leg or arm function or even amputation. Therefore, finding new ways to treat bone healing problems is important. We found that romiplostim, a drug known to increase platelet numbers (clot blood), can enhance bone healing in mice and rats. Here we will prepare for human studies by conducting studies in a larger animal model that is more representative of humans, the pig.

One of the advantages of romiplostim is that it has already been proven to be safe for use in humans for a blood disease (FDA approved); therefore, we think it will likely prove safe in these studies, but this must be tested. A related advantage is that, based on the current safety of romiplostim, we believe it will be safer than the current FDA proteins that can heal bone (bone morphogenetic proteins), especially in light of recent findings showing increased cancer with use of these bone morphogenetic proteins.

Applicability of the Clinical Research: This research is potentially applicable to any orthopaedic surgery where bone morphogenetic proteins are used to treat bone problems. These are used primarily in spine surgery and in treating any bony defect or fractures that are difficult to heal. In the U.S., there are more than 13.5 million fractures each year. The area we will be testing is specific to the fracture of lower leg bones. This is a significant problem, as in 2001 the National Center for Health Statistics reported 5,038,000 fractures of the lower leg bones per year in the U.S. resulting in 569,000 hospital days and 825,000 physician visits. Each year more than 600,000 fractures and 100,000 spine surgeries require additional treatment for the bones to heal, such as treatment with the bone morphogenetic proteins.

A benefit of showing that romiplostim can safely heal bones is that it may offer fewer side effects than that observed with using bone morphogenetic proteins. In addition to likely being safer with respect to cancer risk, our animal data in mice and rats show that the bone formed by romiplostim looks more normal than the bone formed by bone morphogenetic proteins. Indeed, with bone morphogenetic proteins at the fracture site, a large mass of bone forms (callus) which can irritate the muscle, ligaments, and tendons in the area and can cause other problems. With romiplostim the healed bone looks more like it did before the fracture. The risk is that we do not know whether what works in mice and rats will work in humans. This is why we need to conduct this study. Another risk is that platelet numbers could increase in the blood rather than just at the fracture site. While we do not think this will happen, if it does we do not think this will cause a health hazard, as this protein was given to humans to increase platelet levels and hazardous side effects were not observed in healthy people. Overall, we believe that if our animal data can be confirmed in larger animals and then in humans this would offer a new treatment option for healing bones that might be safer than what is currently available.

Most drugs take 15+ years to move from the animal data we have into being able to treat humans. Since this drug is currently approved to use in humans for a different problem, the process to have it tested and approved will be shorter. We anticipate an accelerated timeline, and that romiplostim could be moved into clinical practice to treat patients suffering from high-risk fractures/bone loss from motor vehicle accidents, gunshot wounds, or blast injuries in approximately 5-10 years. With respect to a timeline for individual patients, we expect that bone healing times will be similar to those observed with bone morphogenetic proteins (it varies for each specific bone problem and is based on the patient, for example, whether they smoke or have other health issues).

Military Benefit: Ongoing military conflicts have increased the number of military personnel who suffer from high-energy or blast injuries with bone loss. Over 75% of modern war injuries involve the arms or legs, predominantly caused by fragments from explosive devices, which commonly cause open (exposed bone) fractures with difficulty staying clean and preventing tissue loss. Injured soldiers have dramatic needs for methods to improve bone healing. Therefore, the successful results of our research would demonstrate the safety of using romiplostim for bone regeneration under difficult conditions such as blast injuries.