General Objectives
Fractures in the elderly lead to a great and often irreversible loss of quality of life, and are associated with an increase in mortality. It is not only the fracture itself that has these detrimental effects, but the associated events and complications that appear during the long time it takes for the fracture to heal. Pain and immobility after osteoporotic fractures lead to severe loss of quality of life and, partly in consequence, increasing general frailty. This may be irreversible. The longer healing time, the more of these problems will occur. Many patients with osteoporotic fractures cannot tolerate load bearing even after surgery. In these cases, even a moderate reduction in the time to load bearing would be of benefit.
The rate of secondary interventions after fracture is between 6 and 10%, which is a significant burden for the national health insurances, since annual costs exceed 10 billion €. The prevalence of bone fractures in the EU, in particular in osteoporotic patients, is around 6 million. In addition, 8 million osteoporotic fractures occur in the U.S. and another 30 million fractures are registered elsewhere. As the population ages, it is predicted that in the EU more than 12 million bone fractures will occur yearly by 2050. Developing novel therapies to enhance bone formation, to shorten the healing time and prevent non-unions is an urgent medical need.
Standard therapy to treat bone fractures includes mechanical support either by plaster and /or mechanical devices (e.g. nails, plates and screws). Attempts to biologically support fracture healing are based on the use of either bone morphogenetic protein-2 (BMP2) or bone morphogenetic protein-7 (BMP7). These signaling molecules initiate and accelerate bone formation. However, they need to be combined with bovine collagen carrier. Bovine collagen is immunogenic and inflammatory, and when used with large amounts of recombinant BMPs, causes major side effects. In addition, although BMP2 and BMP7 may be efficacious in long bone fractures, such as the broken lower leg, they do not promote bone formation inside cancellous bone, i.e. in the type of bone broken in the most common cases, such as hip or wrist fractures.
Experimental and clinical data obtained by project partners support a new concept, elucidating the importance of another BMP, BMP6, which appears efficacious in cancellous bone. BMP6 has 2 orders of magnitude stronger effects that the “older” BMPs. It also has more specific effects in its ability to convert stem cells to bone forming cells. This suggests that the relation between desired effects and side effects will be more advantageous than for BMP2 or BMP7. Furthemore, the OSTEOGROW project consortium members discovered that a patient’s peripheral blood coagulum could be used as a carrier for BMP6. This result could lead to a successful delivery of growth factors to broken bone ends. Therefore, we propose to test in clinics the OSTEOGROW device, as a safe, effective and affordable new therapeutic solution for the enhancement of bone healing and prevention of bone non-unions.
The proposed new model for ensuring and accelerating bone healing is the core of the research and technological activities of the collaborative project OSTEOGROW. So far, development of such a novel approach has been impeded by the lack of coordinated attempts aiming to identify the cellular and molecular mediators of bone fracture repair. Other obstacles to the development of novel approaches and strategies for modern fracture treatment are limitations in the methods for radiological and clinical follow-up of patients in randomized controlled phase II and III clinical studies on bone regeneration.
In parallel, our unforeseen discovery that BMP6, contrary to BMP2 and BMP7, accelerates repair also in cancellous bone, led us to propose additional testing and to perform clinical trials on bone regeneration. The aim is to prove that the OSTEOGROW device is superior to currently used biological bone regeneration procedures. The consortium members have already optimized and scaled-up the production of BMP6 from the developed working cell bank. The bone conditions that will be treated locally with OSTEOGROW in a first phase include acute radial fractures and tibial osteotomies.
Members of the OSTEOGROW consortium have made pioneering contributions to the field of BMPs with special reference to the discovery of novel family members, their receptors, signal transduction pathways, function in bone regeneration, and have participated in clinical trials on fracture repair. Moreover, consortium members have already collaborated in scientific projects, published manuscripts in distinguished journals, edited international books on BMPs, and organized international conferences on BMPs in the EU and the USA.
Apart from acceleration of the healing of common cancellous bone fractures, the OSTEOGROW device is likely to become the safest, most affordable and effective, easy-to-use solution for treating bone defects in patients at risk to develop, or those with already diagnosed, long bone non-unions.
To achieve its objectives and milestones, the OSTEOGROW consortium will develop 3 inter-connected and complementary thematic areas (Work-blocks) which will address the GMP production of clinical grade of BMP6 (WB1), the final formulation, safety and toxicology of BMP6 and novel approach to reproductive toxicology (WB2), regulatory work, clinical studies, management and dissemination (WB3).