Researchers ignite hope for new osteoporosis treatments

It is estimated that 924,000 Australians have osteoporosis, with osteoporotic fractures costing the nation’s healthcare system upwards of $3 billion each year.
 
With an increasingly ageing population, both the physical and financial burden are expected to increase. But there is hope.
 
Researchers at the Garvan Institute of Medical Research have discovered a new type of bone cell – termed ‘osteomorphs’ – that provide greater understanding of bone biology and, as a result, present significant potential in-roads for osteoporosis therapy.
 
Professor Tri Phan, senior co-author and Head of the Intravital Microscopy and Gene Expression Lab at the Garvan Institute, says the discovery is a ‘game-changer’.
 
‘This new cell type may be very important in bone disease and in osteoporosis,’ he told newsGP.
 
‘These cells were hiding in the bone all this time. The difficulty is that because bone is so hard and opaque and inaccessible, for a long-time people were mostly studying static images, tissue sections, or in vitro, in test tubes.’
 
Each day, specialised cells known as osteoclasts, break down old bone tissue and build it back up to support the skeleton’s growth and repair any damage. However, as people get older, new formation can fall behind bone loss, resulting in osteoporosis.
 
To better understand this process, researchers used intravital imaging technology to look inside the bone tissue of live mice. What it revealed was that osteoclasts do not necessarily die off, but rather are recycled, with the ability to travel to other parts of the body, such as into the bloodstream and bone marrow.
 
‘The dogma was that osteoclast cells die off,’ Professor Phan said.
 
‘But rather than dying, they’re reborn. What it does allow is osteoclasts – which are very massive cells, not very motile – to break apart into smaller cells [and] allows it to move from one bone to another bone. That’s why we called them morphs – [they] resembled Mighty Morphin Power Rangers.
 
‘It’s cellular recycling and something we’ve never seen before.’
 
The researchers deleted 40 of the genes switched on in osteomorphs in experimental models, and found that for 17 of these genes the deletion impacted on the amount of bone and bone strength.
 
‘When we further investigated human genomic data in publicly available databases, we found that genes switched on in osteomorphs were linked to human gene variants that lead to skeletal dysplasia and control bone mineral density,’ Professor Peter Croucher, senior co-author and Head of the Bone Biology Lab at the Garvan Institute, said.
 
‘Together, these findings revealed just how crucial osteomorphs are in bone maintenance, and that understanding these cells and the genes that control them may reveal new therapeutic targets for skeletal disease.’
 
While it is not entirely clear why cellular recycling takes place, Professor Phan says there a number of possibilities.
 
‘Osteoclasts, because they break down bone, are very metabolically active. That places lots of stress on the cell,’ he explained.
 
‘So, breaking down might be a way of coping with [the] stress of all that work they have to do.
 
‘The other possibility is that it takes lots of energy and resources to make these cells in the first place. So rather than discarding once finished, recycling may allow for more efficient use of resources. We don’t know.’
 
The research also provides insight into why some people experience ‘rebound vertebral fractures’ – a known side effect of the osteoporosis drug denosumab, which works as a RANK ligand inhibitor to prevent bone loss.
 
‘When we give the mice the equivalent, the osteoclasts break up [into osteomorphs], but couldn’t recycle. They just accumulated these morphs,’ Professor Phan said.
 
‘Once you stop the drug and it washes out, the morphs are poised to rebound [and] they can degrade the bone very rapidly. We’ve seen this clinically – once people are taken off the drug, they can develop rebound fractures.
 
‘Taking patients off it needs to be done cautiously, this suggests. Doctors may need to consider giving another drug to prevent this.’
 
By studying the effects of denosumab and other osteoporosis medication on osteomorphs, the research team hopes to inform how these treatments can be improved and how their withdrawal effects can be prevented.
 
So what’s the next step? Professor Phan says the team are now turning their attention from mice to humans – a task not without its challenges.
 
‘While in mice we can make genetic reports and put them under the microscope, it’s very hard to do in humans,’ he said.
 
‘But we can get the gene expression profile. So, we’re using that to find if the cells are in humans.’

Interview conducted by Doug Hendrie.
 
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osteomorphs osteoporosis skeletal diseases