14 March 2022

Medicinal treatment of osteoporosis can sometimes lead to an unusual kind of breakage in the thigh bone. Why do these fractures occur, and how can they be tracked in a national quality register? These are the questions focussed on in two newly published studies in which researchers from Linköping University (LiU) have participated.

image of incomplete atypical fracture next to a complete fracture.A full atypical fractures in the thigh bone (left). In an incomplete fracture the bone tissue has changed, but the thigh bone has not yet broken fully (right).The bones in your skeleton are being constantly rebuilt. One tenth of the bones in an adult skeleton is replaced during the course of a year. This is the result of work done between two types of cells the names of which are misleadingly similar: osteoclasts are “bone eaters” that attach themselves to the skeleton and break down the bone, while osteoblasts create new bone. These are the same cells at work when the body is healing a broken bone. But in that case, the cells work in isolation.Portrait photo Jörg Schilcher, scientist and physician.Jörg Schilcher, scientist and physician.

“The thigh bones are subject to quite significant load from our body weight. Every step puts strain on the bones and, as with all kinds of materials, strain leads to small amounts of damage. But bone tissue is unique in the sense that it can heal itself,” says Jörg Schilcher, associate professor at the Institution for Biomedical and Clinical Sciences, and orthopedist at Linköping University Hospital.

Sometimes, an imbalance can occur between the two types of cells, and the bones wear out faster than they are built up. After a while, osteoporosis disease arises, with cavities in the bone as a typical symptom. Osteoporosis is treated with bisphosphonates, a kind of medicine that mitigates the osteoclast’s breaking down of the bone, and prevents fractures in people with osteoporosis.

Just over ten years ago, researchers at LiU showed that, in unusual cases, bisphosphonates can cause a specific kind of bone breakage in the thigh bone: atypical thigh bone fractures. It starts with small micro-cracks, which occur in the bone due to strain. If the osteoclasts and osteoblasts cannot heal the micro-cracks in time, these cracks can spread, join together and create even larger ruptures. Then, very little force is needed to for the bone to break.

“Take a typical example: an older person cooking food on the stove, with a frying pan in their hand. They turn around and ‘crack!’, the thigh bone has broken, and the person falls down. This kind of breakage has a special appearance, with a straight, transverse fracture. This is why it’s called ‘atypical’, despite being a typical stress fracture”, says Jörg Schilcher.

Finding the fractures is important

One of the first studies by the researchers at Linköping University led to a decline in the use of bisphosphonates.

“Both patients and doctors are nervous about using bisphosphonates, and some are so afraid of these atypical fractures that they are willing to forgo the benefits of bisphosphonates when it comes to preventing osteoporosis fractures. The problem is that we only have evidence for the benefits of treatment with bisphosphonates under a three to five-year period. But doctors have been prescribing this kind of medicine for much longer than that. Ten to fifteen years later, we’re seeing the negative effects – that is to say, these kind of atypical fractures. In recent years, use of this medicine has reduced. The question is then what happens in our population when doctors and patients treat these medicines in a different way, and only use bisphosphonates for short periods, or not at all”, says Jörg Schilcher.

These atypical fractures have been the focus of two scientific articles that Jörg Schilcher has worked on. In the first, a group of researchers looked at the possibility of using the Swedish Fracture Register as a monitoring tool for this kind of unusual fracture. This national quality register covers all kinds of fractures that are treated within the Swedish healthcare system. Since 2015, doctors who register a breakage in thigh bones indicate whether it is an atypical fracture.

“It’s important to find these unusual fractures. They have to be treated in a special way. The doctor must stop the bisphosphonate treatment, otherwise the fracture won’t heal. There’s also quite a high risk that those with atypical fractures also break their other thigh bone, if the bisphosphonate treatment isn’t stopped”, says Jörg Schilcher.

In this new study, published in the journal Acta Orthopaedica, two experts examined X-rays for all the fractures which had been registered as atypical. They found that this categorisation was correct in more than half of the cases. It turned out that a specialist registrar who had received some short training beforehand was much better able to recognise an atypical fracture.

“We concluded that the registration of atypical fractures in the Swedish Fracture Register is pretty good. But it could be made better with just a bit of training. This registration needs to be made better if we are to be able to use the Fracture Register to give feedback to clinics and patients when it comes to atypical thigh bone fractures”, says Jörg Schilcher.

AI, artificial intelligence, might be able to help doctors find the atypical fractures in the future.

“We know that only around seven percent of atypical thigh bone fractures are correctly identified if the Fracture Register is not used. We believe that AI might be the perfect solution here, to help the radiologists be extra attentive when there’s even the slightest reason to suspect an atypical fracture.”

Jörg Schilcher’s research group collaborates with other research groups in California, Melbourne and Berlin to improve preventive measures against atypical thigh bone fractures. Improvements include better diagnosis and better results after surgical treatment. The group works with, among others, Anders Eklund’s research group at LiU’s Faculty of Science and Engineering, to develop AI-based support for software that’s used in analysing X-ray pictures.

Magnesium as a possible treatment

In the other study, led by researchers in Hong Kong, the researchers give a possible explanation as to why these atypical fractures have difficulty healing. Jörg Schilcher works with tissue analyses of bone biopsies in cases where a breakage has almost occurred, but the thigh bone has not yet broken fully – this is called an “incomplete fracture”. These histological analyses have been the basis for the collaborative project with the research group in Hong Kong. But Jörg Schilcher believes that it is important to distinguish between this condition (where the bone tissue has changed, but the thigh bone has not yet broken fully), and full atypical fractures, which heal in a different way.image of incomplete atypical fracture next to a complete fracture.A full atypical fractures in the thigh bone (left). In an incomplete fracture the bone tissue has changed, but the thigh bone has not yet broken fully (right).

“For me, this study provides an explanation as to why an incomplete, atypical fracture doesn’t heal and instead continues to grow, leading eventually to a complete fracture”, says Jörg Schilcher.

The researchers noted that there was lots of connective tissue in the incomplete fractures in humans. Connective tissue is well-known to impede healing. The research team in Hong Kong was able to use rats to investigate the same problem, and discovered, using several different methods, where the connective tissue comes from, which cellular mechanisms are behind the appearance of connective tissue, and how the negative effects of bisphosphonates on bone healing could be stopped in the rats.

“The study shows that we can stop the negative effects of bisphosphonates by giving the rats magnesium. The whole line of reasoning behind this is very good. It could well be an effective solution for clinical treatment”, says Jörg Schilcher, who is a co-author on the study, which has been published in the journal Materials Today.

The study has also been mentioned in an article in the magazine Science.

The research has been funded by ALF funding, Region Östergötland, the Swedish Society of Medicine and the Wallenberg Center for Molecular and Translational Medicine, WCMM, at Linköping University.

The article: Surveillance of atypical femoral fractures in a nationwide fracture register, Hans Peter Bögl, Georg Zdolsek, Lukas Barnisin, Michael Möller and Jörg Schilcher, Acta Orthopaedica 2022; 93: 229–233, published online 11 January 2022, DOI: 10.2340/17453674.2022.1380

The article: Magnesium facilitates the healing of atypical femoral fractures: A single-cell transcriptomic study, Nianye Zheng, Jiankun Xu, Ye Chun Ruan, Liang Chang, Xinluan Wang, Hao Yao, Jiali Wang, Ri Zhang, Qingyun Xue, Ning Tang, Tim-yun Ong, Jörg Schilcher, Regis J. O'Keefe and Ling Qin, Materials Today, published online 19 January 2022, https://doi.org/10.1016/j.mattod.2021.11.028

More about the research

Latest news from LiU

Nerve damage from cancer treatment can be predicted

Many women treated for breast cancer using taxanes, a type of cytostatic drug, often experience side effects in the nervous system. Researchers at LiU have developed a tool that can predict the risk level for each individual.

Woman in safety helmet.

Her mission is difficult – but fun and achievable

We are in the midst of a tough transition towards more sustainable development. This requires innovation and knowledge, says Marie Trogstam, a LiU alumna who is now head of sustainability and infrastructure at the Confederation of Swedish Enterprise.

Closeup of small pieces of liver in a petri dish.

A liver biopsy may predict spread of pancreatic cancer

Microscopic changes in the liver can be used to predict spread of pancreatic cancer. The discovery may provide new ways of predicting the course of the disease and preventing pancreatic cancer from spreading to other organs.