Thursday September 22 2011
We cannot tell if the drug can treat arthritis in humans
A jab that “can repair damaged joints could benefit millions crippled by osteoarthritis”, reported the Daily Express. The newspaper said that scientists have found that an existing drug called Forsteo, which is used to treat brittle bones, could thicken the cartilage that pads the joints.
In new research the scientists tested Forsteo, also known as teriparatide, on the injured knee joints of mice, looking at whether it prevented cartilage degeneration after knee injury. They found that, depending on the length of time since the injury occurred, the drug could prevent degeneration of cartilage and even cause cartilage to regrow.
As this was animal research, its application to people is limited without further follow-up. Forsteo already has a licence for treating certain individuals with osteoporosis and thinning bones. It combats these conditions by building up bone mass. However, it is still unclear whether it would be a suitable treatment to prevent cartilage loss in people whose joint injuries put them at risk of developing future osteoarthritis. Further studies in humans, including dosing studies, would be needed to see if this drug could benefit people beyond its existing clinical uses.
Where did the story come from?
The study was carried out by researchers from the University of Rochester Medical Centre and was funded by the Arthritis Foundation and the US National Institute of Arthritis and Musculoskeletal Research. The study was published in the peer-reviewed medical journal Science Translational Medicine.
The research was covered well by the Daily Mail and the Daily Express. The Daily Mail did include an apt quote from Arthritis Research UK, which cautioned about making assumptions based on animal research: “We need to sound a big note of caution, as animal models of osteoarthritis are not like humans with osteoarthritis, and many agents that have worked and looked very promising in animals have not worked in human trials.”
What kind of research was this?
In this animal study researchers created a mouse model of osteoarthritis caused by a past injury and tested whether a hormone treatment could repair the mice’s injured joint tissue.
The researchers said that osteoarthritis of the knee is often caused by trauma that damages the knee’s ligaments or meniscus, the fibrous cartilage pad found in the space between the shin and thigh bones. They surgically recreated this injury in order to make their mouse model of osteoarthritis.
The researchers said that in the degenerative joint disease osteoarthritis, cartilage cells called chondrocytes develop inappropriately, and that a type of hormone called a parathyroid hormone is thought to play a role in regulating the development of chondrocytes. The hormone treatment used in this research was a synthetic form of parathyroid hormone called teriparatide (brand name Forsteo).
This was animal research and, as such, the implications that we can draw for humans from this study are unclear. The research made a mouse model of osteoarthritis which may not capture all the biological and mechanical aspects of human osteoarthritis, and it is also possible that mice may respond differently to this treatment from humans.
What did the research involve?
To make the mouse model the researchers surgically caused the injury to the meniscus and the ligaments in the right knee of ten-week-old mice. They also performed a ‘sham operation’ on the left knees of these mice, making an incision but leaving the ligaments and cartilage uninjured. This sham surgery would allow the researchers to compare the processes that occurred in a knee that had undergone all the same surgical processes as the injured knee, bar the joint injury itself. They gave the mice painkillers while they recovered from this surgery over three days.
Cells in the body use special proteins called receptors to detect substances such as hormones, so the researchers looked at the activity of the gene used to create receptors for parathyroid hormone (PTHR1). The activity of this gene was examined in normal human cartilage samples, samples from people who had had the meniscus injury to their knee, cartilage from people with progressive osteoarthritis, control mice and mice with surgically injured knees.
They divided the mice into two groups, the ‘immediate group’ who would receive treatment immediately after their injury and the ‘delayed group’, who started their treatment eight weeks after surgery. The mice were given an injection of teriparatide every day or a salt solution as a control treatment. Teriparatide was given at a dose of 40 micrograms per kg of body weight.
Four, 8 or 12 weeks after injury the researchers examined the knee joints of the mice. They looked at bone volume, cartilage degeneration, maturation of the chondrocytes and proteins called proteoglycans, which are important for maintaining the structure of the knee.
What were the basic results?
The researchers found that they could not detect expression of the PTHR1 gene in normal human cartilage, but that it was possible to detect in cartilage from humans who had the meniscal injury and from people who had progressive osteoarthritis. They found that this pattern was the same in the mice, as cartilage from the injured knee had greater PTHR1 expression than in the sham knee.
They found that teriparatide increased the bone volume of joints compared with the control salt solution treatment. If teriparatide was given immediately after injury it also increased the amount of proteoglycans and inhibited the degeneration of cartilage. If teriparatide was given eight weeks after injury it instead caused regeneration of the cartilage.
How did the researchers interpret the results?
The researchers said that their preclinical findings provide proof of concept that teriparatide may be useful in slowing down cartilage degeneration and inducing regeneration of the matrix (scaffolding structure of the knee) in patients with osteoarthritis.
This animal model of osteoarthritis has shown that treatment with parathyroid hormone could protect against cartilage damage and promote cartilage regeneration after a surgically induced injury in mice.
However, as a piece of animal research the application to humans is currently limited as the model may not fully represent all aspects of osteoarthritis in humans. For example, as well as the biological differences between humans and mice there are mechanical considerations that cannot be explored through mouse models, particularly in regard to human knee joints, which must bear a great deal of strain due to the size and weight of humans.
Also, many people who experience knee problems due to trauma will experience problems several years after their knee damage was sustained, rather than in the period immediately after it occurred. This model does not tell us about how old injuries might respond as treatment was given only after a recent injury.
The drug is currently licensed for the treatment of osteoporosis in postmenopausal women, men at increased risk of fractures and for the treatment of corticosteroid-induced osteoporosis. It was already known to stimulate bone formation in osteoporosis where the bones become thin and fragile and prone to fractures. The recommended dose is 20 micrograms daily, with a maximum duration of treatment of 24 months. It is unclear how the 40 micrograms per kg that the mice received relates to a dose proposed for humans, and safety at this dose will need to be assessed. As with all drugs used in humans there are side effects that need consideration, for example, for this drug, stomach upsets, allergies and abnormally high levels of calcium. Also, the response mice displayed to the dose of teriparatide used may be different in humans.
Osteoarthritis can be both painful and debilitating, and this study has shown some promising effects on cartilage cells. However, it should be seen as an initial exploration paving the way for further work testing whether teriparatide has the same effect in humans.