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Bone-hard basic research for an ageing society

Osteoporotic bones not only break very easily, they also heal badly when a fracture occurs. A fractured femur neck might mean that elderly patients have to remain bedridden for a long period and maybe even need nursing care. Fractures that heal badly, in combination with other diseases, frequently lead to a fatal outcome. A panregional team of researchers, including researchers from Ulm, has been working together since 2007 on basic research into fracture healing and bone regeneration in osteoporotic patients.

Statistics from highly developed and increasingly ageing societies in the western world show that osteoporosis and osteoporotic bone fractures have considerable consequences on national health budgets. Moreover, according to the director of the Ulm-based Institute of Orthopaedic Research and Biomechanics, Anita Ignatius, a great deal of research is required to improve the situation. 200 million people worldwide suffer from osteoporosis, leading to nine million fragility fractures every year. It is expected that the figures will double by 2050 resulting in healthcare costs of around 77 billion euros.

Bone fractures in one in two women over 50

Osteoporosis mainly affects the vertebrae. The photo on the left shows healthy vertebrae, the photo on the right shows vertebrae with compressed front portions, which leads to a forward bending of the spine (dowager’s hump). © University of Ulm/Institute of Orthopaedic Research and Biomechanics

Osteoporosis is a complex metabolic bone disease in which the biological processes involved in the regulation of bone mass are disturbed. The most important causes of osteoporosis are known, one of which is a lack of physical activity. Risk factors include genes (60 to 80 per cent of the bone mass is genetic), lack of the sex hormone oestrogen in menopausal women and increasing age. All these factors lead to a reduction in bone density, the “bone architecture” is impaired, the mechanical strength of the bone is reduced and the susceptibility to fractures increases. One in two women and one in five men over 50 suffer from osteoporosis-related fractures. Osteoporosis-related fractures occur mainly in the spine, but also in the thigh and forearm. More importantly, the fractures often go undiagnosed due to an absence of symptoms. In addition, osteoporotic fractures often have no mechanical impact.

Orthopaedic surgeons find it difficult to treat osteoporosis-related fractures

The schematic shows the femur of a sheep with a fracture cleft. The DFG-funded group of researchers has unique metaphyseal fracture healing models at its disposal. © University of Ulm/Institute of Orthopaedic Research and Biomechanics

The loss of bone density is associated with two problems. One of the problems is especially challenging for surgeons: it is difficult to stabilise osteoporotic fractures using metal, screws or plates since the bone is very fragile and brittle. Therefore, the surgeons find it difficult to fix the two bone ends firmly together, which in turn prevents fractures from healing effectively. This is a problem in both young and elderly people, explains the Ulm researcher Anita Ignatius. While there is controversial debate in scientific and medical literature as to whether this problem is of any real clinical relevance, practitioners and orthopaedic surgeons confirm this observation. However, large-scale studies relating to this problem are not available, said Ignatius.

While medical practitioners focus on dealing with the consequences of osteoporosis, the panregional DFG-funded (German Research Foundation) 793 group of researchers is working hard to investigate the causes of osteoporosis. Anita Ignatius tells us, that although the healing of healthy bones is well understood, the finer details are not. It is known that bone has a huge capacity for regeneration, which restores the original bone tissue in such a way that no traces of the original fracture are left.

Investigations are no longer descriptive, instead they are focusing on the causes of osteoporosis

Longitudinal histological cut of a mouse femur. The fracture is surrounded by what is known as callus (bone regenerate). A bony bridge between the fracture ends has not yet developed. © University of Ulm/Institute of Orthopaedic Research and Biomechanics

It is (still) unclear why osteoporotic bones only heal with difficulty. Even optimal stabilisation and therapy do not improve the bone's capacity to regenerate. Many animal studies suggest that the process of bone regeneration in osteoporosis sufferers is altered, delayed and less efficient than normal. However, these investigations are descriptive, rather than focusing on the causes of delayed or disturbed bone remodelling of osteoporotic bones, explains Anita Ignatius referring to the current situation faced by the researchers from Hamburg, Würzburg, Munich and Ulm.

"Our immediate goal is to focus in greater detail on the different causes of osteoporosis and delayed bone generation and our ultimate goal is to develop therapeutic options." At present, the researchers are investigating mechanisms that are known to play a role in the bone metabolism and which are also assumed to play a role in the pathogenesis of osteoporosis. Many of these mechanisms are crucial for effective bone healing and together they are responsible for the limited functionality of disturbed bone regeneration in osteoporosis sufferers.

Successful outcome may lead to a pharmacological target

Anita Ignatius explains the overall goal of the group of researchers, which is to gain further insights into these processes. They hope that, by the end of the funding period in 2012, their investigations will identify a pharmacological target to improve the healing of osteoporotic fractures. They are also hoping to come up with approaches for a mechanical intervention for bone healing. The Ulm researchers led by Anita Ignatius have already found out in previous investigations that mechanotransduction is also disturbed in osteoporotic bones.

During the first funding period (up to 2010), the Ulm researchers developed standardised fracture-healing models on small (mice) and large (sheep and pigs) animals. The findings gained in in vitro and animal experiments are now being tested on human cells. It was previously impossible to develop fracture-healing models of this kind under standardised conditions. “This is the unique selling point of our group of researchers,” said Anita Ignatius.

World-first investigation of fracture healing using animal models

With the sheep model, the German researchers have the first model for metaphyseal fractures, which is the specific area of osteoporotic bones described by Anita Ignatius as “foam-like structure at the end of the bones”. One of the Munich group of researchers is working on a transgenic pig model as model organism. This model produces larger quantities of Rank ligands, which leads to the activation of osteoclasts and, as hypothesised by the researchers, to the development of osteoporosis due to the equilibrium of osteoblasts and osteoclasts being severely disturbed.

However, small and large animal experiments are only suitable for the investigation of individual aspects. The researchers are able to phenotypically simulate the complex osteoroporosis processes in experimental animals by removing the animals’ ovaries, which in turn delays the regeneration of bone due to the lack of sex hormone. Initial fracture-healing studies on osteoporotic animals confirm this finding and additional investigations will be undertaken to provide further evidence.

The findings gained in animal experiments, which are being tested in vitro using human bone cells, are based on only one of many aspects. In addition to elucidating the complex pathogenesis of osteoporosis, the complex process of fracture healing is also being looked at. In fracture healing, stem cells and their precursor cells as well as the principles of angiogenesis or mechanosensitivity need to be taken into account in order to obtain a picture of the healing of osteoporotic bone fractures that is as complete as possible. Moreover, osteoporosis symptoms and those associated with the old age of people might be similar.

In the spotlight: Wnt signalling

Since neither a pathogenic master gene, nor a diagnosable cell biological disorder of the bone metabolism are known, the researchers need to investigate a large number of signalling pathways in the hope of finding a biomolecule that has a key function in these processes. The researchers are currently very much focused on the Wnt signalling pathway, a highly complex mechanism that appears to be of crucial importance for the bone metabolism as well as the pathogenesis of osteoporosis. Additional investigations focus on the central regulation of bone formation and stem cell dysfunction.

The researchers are now interested in finding the sites of the Wnt signalling pathway that allow them to effectively intervene in order to increase the activity of the osteoblasts and potentially improve the healing of the osteoporotic fracture. If they succeed in increasing the activity of osteoblasts, this might open up the possibility of developing a bone anabolic drug to promote bone formation rather than simply inhibiting bone degradation. It appears that the Ulm researchers have already achieved an initial success. Anita Ignatius reports that her group is currently focusing on receptors and co-receptors involved in these processes.

The five research groups from Hamburg, Würzburg, Ulm and Munich know that, in a disorder as complex as osteoporosis, hormones, cytokines and growth factors are all involved in the bone metabolism and that potential pharmacological targets always have to be considered with some reservation. “A lot of research is still required,” said Anita Ignatius, who possibly already has future projects in mind. The DFG reviewers were highly impressed with the work of the cooperation partners and decided to fund all the projects for another financing round.

The DFG-funded 793 research group involves five research groups, including the Centre of Biomechanics, the Department of Experimental Trauma Surgery and Skeletal Biology at the University Hospital Hamburg-Eppendorf, the Institute of Molecular Animal Breeding and Biotechnology at the Gene Centre of the University of Munich (LMU), the Surgical Hospital and Polyclinic of the LMU Hospital, the Orthopaedic Centre for Musculoskeletal Research at the University of Würzburg and the Institute of Orthopaedic Research and Biomechanics at the University of Ulm.

F. Jakob et al.: Frakturheilung bei Osteoporose, in: Osteologie, Bern 2007; 16, S. 71-84 (DOI: 10.1024/1019-1291.16.2.71).

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