While these results highlight the potential bone-protective effects of semaglutide, the authors recommend that prospective studies be done to confirm the findings.

Semaglutide is part of a group of medicines known as glucagon-like peptide-1 receptor agonists (GLP-1s), which treat type 2 diabetes and obesity. Previous studies had shown that rapid weight loss using GLP-1s can lead to thinner bones and fractures, while more moderate and slower weight loss may preserve bone mass. Scientists at Stanford University knew semaglutide helped people lose more weight than previous generations of anti-obesity medications, but they lacked evidence that compared semaglutide’s effect on bone health to other anti-obesity medications.

Jairo Noreña, M.D., former endocrinology fellow at Stanford University Medical Center in Palo Alto, California, and his colleagues evaluated changes in body mass index (BMI) and fracture incidence in people with type 2 diabetes taking semaglutide, dulaglutide or alternative oral weight-loss therapies phentermine/topiramate and bupropion/naltrexone.

“Bone fractures are painful, expensive and can seriously affect quality of life — especially as people get older,” Noreña said. “We hope this study encourages monitoring of bone health in weight-loss programs.”

The team conducted a retrospective cohort analysis using the Atropos Health Eos electronic health record dataset representing 161 million patients seen in U.S. community hospitals and academic medical centers from January 2016 to December 2023. Participants were adults aged 18 years and older who were diagnosed with type 2 diabetes, with no history of prior fractures or use of osteoporosis medications. The intervention group received semaglutide (n = 26,324), while the control group received dulaglutide, phentermine/topiramate, or bupropion/naltrexone, without prior history of semaglutide use (n = 33,555).

The data indicated semaglutide treatment was associated with greater reduction in BMI compared to the control group. The semaglutide group also had fewer fractures (794) compared to the control group (1045).

“This work is an important early step toward understanding the impact of semaglutide-induced weight loss on bone health in patients with type 2 diabetes,” Noreña said.

Hip dysplasia is the most common cause of hip arthritis for people under 50, according to the International Hip Dysplasia Institute. It occurs when a hip socket is too shallow to support the ball of the thigh bone. In young children, this can cause problems ranging from a mildly wiggly hip to complete dislocation. In adults, it can affect how people walk, lead to early-onset arthritis, and cause pain and mobility issues.

Late diagnosis of DDH remains a public health issue worldwide, leading to problems for adults later in life. More comprehensive ultrasound screening of infants during community-based public health services could help catch these missed cases without requiring hospital resources to conduct the initial screening, researchers said.

The methods used to screen newborns for DDH vary around the world. Most countries, including North America, South Korea, Taiwan and Japan, have a selective screening programme based first on a physical exam or family history. Only a small number of countries, including Austria, Switzerland and Mongolia, provide ultrasound screening for all newborns, which is more accurate.

Associate Professor Kyoko Yoshioka-Maeda from the Graduate School of Medicine at the University of Tokyo wanted to explore ways to catch these missed cases earlier. It was also vital to limit the burden on Japan’s medical system which has a declining number of paediatric orthopaedic surgeons.

‘I wanted to find out if these [ultrasound] devices could be successfully used in a community setting to screen infants for DDH as part of the maternal child and health programme,’ Yoshioka-Maeda explained. ‘Based on our nationwide survey, approximately 2% of municipalities use ultrasound screening because of workforce constraints. There is also a disparity between the availability of paediatric orthopaedic surgeons and hospitals in rural areas compared to urban areas.’

In Japan, about a month or two after a mother has given birth, she is visited by a public health nurse or midwife to check her recovery and the baby’s development. Public health nurses can offer guidance and community-based preventative care but differ from midwives and registered nurses in hospitals, and do not commonly use ultrasound.

Public health nurses and midwives from two rural municipalities in the island prefecture of Okinawa in southern Japan, and one in central Japan’s Aichi Prefecture participated in the study. Participants completed an e-learning module and hands-on seminar for the portable ultrasound device and the Graf method (used to diagnose DDH).

Ultrasound images were remotely reviewed by paediatric orthopaedic surgeons or an experienced senior surgeon. In total, 349 infants were screened out of a target 365, giving an overall coverage of 95.6%. Of these community-based examinations, 85.8% of the images were successfully classified by the surgeons.

Based on the ultrasound findings and other risk factors, 42 infants were referred, and of these, 41 attended hospital visits. Overall, 23 infants (54.8%) required follow-up and 2 (4.8%) treatment. However, only 6 of the 42 children (14.3%) would have previously met the criteria for a referral without ultrasound screening, demonstrating its effectiveness to support early detection of DDH.

‘We received strong support from caregivers, municipal administrators, hospitals, public health centres and paediatric orthopaedic surgeons, which was key for the success of this study,’ said Yoshioka-Maeda. ‘In order to roll this out across Japan, the first hurdle is the budget to purchase the equipment and train and support the staff. The other bottleneck is image interpretation, as there is a very limited number of paediatric orthopaedic surgeons in Japan. Developing an AI-based system could help us with that.’

The study, titled “Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Frailty Progression in Older Adults With Type 2 Diabetes,” and published in Diabetes Care, looked at older adults who had just started different types of diabetes medications and followed them for one year. They found that people taking SGLT-2 inhibitors or GLP-1 drugs were less likely to show signs of frailty, such as weakness, slowed movement, or fatigue, compared with those starting other diabetes medications. In other words, these treatments appeared to help patients with diabetes maintain strength and function as they aged. The benefit could not be fully explained by heart benefits, suggesting the medications may directly help protect against frailty.

Analyzing a national 7% sample of U.S. Medicare claims, researchers tracked one-year changes in a validated claims-based frailty index (CFI; range 0–1, with higher scores indicating greater frailty). Compared with new users of DPP-4 inhibitors, those starting GLP-1 receptor agonists saw a mean CFI change of –0.007 (95% CI: –0.011 to –0.004) and those starting SGLT-2 inhibitors saw a mean change of –0.005 (95% CI: –0.008 to –0.002), indicating slower frailty progression. Users of sulfonylureas showed no significant difference. Additional analyses found that cardiovascular or other safety events accounted for only a small portion of the effect, suggesting a potential direct benefit of these medications on frailty itself.

According to prior research, roughly 10–15% of adults over age 65 experience frailty, with higher rates in those with type 2 diabetes. People with diabetes are particularly at risk due to chronic inflammation, muscle loss, cardiovascular disease, and the cumulative burden of managing a complex condition. Frailty is associated with falls, disability, hospitalization, and reduced lifespan. Because it is difficult to reverse once established, slowing frailty progression has emerged as an important goal in geriatric care, making the findings of this study especially significant for older adults with diabetes.

“While SGLT-2 inhibitors and GLP-1 receptor agonists are primarily prescribed for blood sugar control and heart protection, our findings show they may also help older adults with diabetes stay stronger and less vulnerable to health setbacks,” said lead author of the study, Chanmi Park, MD, MPH, Assistant Scientist I, Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife. “Because frailty is common, serious, and hard to reverse, this could meaningfully change how clinicians think about medication choices for aging patients.”

In addition to Park, the other researchers were Saran Thanapluetiwong, MD, Visiting Research Fellow, Marcus Institute for Aging Research, Hebrew SeniorLife; Xiecheng Chen, PhD, Data Scientist I, Marcus Institute for Aging Research, Hebrew SeniorLife; Gahee Oh, MD, MPH, Daa Scientist II, Marcus Institute for Aging Research, Hebrew SeniorLife; Darae Ko, MD, MSc, Associate Scientist, Marcus Institute for Aging Research, Hebrew SeniorLife; and Dae Hyun Kim, MD, MOH, ScD, Associate Director & Senior Scientist, Marcus Institute for Aging Research, Hebrew SeniorLife.

The study, led by Feinuo Sun, UT Arlington assistant professor of kinesiology and the senior author of the paper in The Journal of Pain, investigated how state-level policies— including minimum wage laws, Medicaid coverage, other welfare programs and education levels—affect pain outcomes.

“For the first time, we examined the development of arthritis pain over 10 years and how state welfare policies shape these trends,” Dr. Sun said.

Arthritis pain has become more common over the last decade, now affecting an estimated 58.5 million Americans, according to the Centers for Disease Control and Prevention. Between 2011 and 2021, an additional 4.6 million people reported moderate to severe joint pain.

The study analyzed data from the Behavioral Risk Factor Surveillance System from 2011 to 2021, tracking arthritis-related pain over a full decade. This approach differs from previous research, which typically relied on cross-sectional data capturing only a single year.

Texas is among the states showing a significant increase in overall joint pain. Colorado saw the largest rise, with an average increase of 26.2%, followed by Hawaii, Nebraska, Kansas, North Dakota and Texas. Only four states—Montana, Wyoming, South Dakota and New York—showed a decreasing trend.

However, among the states with a significant increase in overall joint pain, Texas was the only one to see a decrease in the educational gap—meaning the difference in pain prevalence between adults with high and low education levels narrowed, Sun said.

“In Colorado, both the education gap and overall pain prevalence have risen, indicating that pain has been increasing most rapidly among adults with the lowest education levels,” she said. “In contrast, in Texas, the education gap narrowed while overall pain prevalence still increased, suggesting that the rise was primarily driven by growing pain prevalence among higher-educated adults.”

Identifying states with both rising pain prevalence and widening education gaps, Sun said, is a key takeaway from the study, as it highlights where interventions may be most needed.

Another important finding is the impact of Medicaid generosity in reducing both overall pain and disparities across education levels. The study found that states with more generous Medicaid programs not only have lower joint pain prevalence but also smaller education gaps in pain. The score for Medicaid generosity was measured across four dimensions: income eligibility, immigrant benefits, administrative burden and benefit levels.

“Medicaid generosity is a comprehensive measure of how accessible and beneficial the program is,” Sun said. “And we found that more generous Medicaid programs help reduce arthritis-related pain, particularly among adults with lower levels of education.”

Next steps for the research include exploring how individuals’ experiences with pain are influenced by changes in state-level policies, helping researchers better understand how geography and governance shape public health.

Participants within the study who took part in the weekly cycling and education sessions reported better recovery outcomes compared to participants who undertook regular physiotherapy. The results reveal that better outcomes for patients can be achieved in a group setting using the cycling and education classes, and that less clinical time is needed to deliver this compared to one-to-one standard physiotherapy treatment.

Tom Wainwright, Professor of Orthopaedics at BU and a physiotherapist at UHD, was the chief investigator of the study. He said: “For the time it takes to treat one patient using standard physiotherapy, we can treat multiple patients in a group session and provide them with better outcomes. This has proved to be more cost-effective than standard treatment and so we hope this will contribute to reducing NHS waiting times for physiotherapy treatment in the future.”

The “CHAIN” intervention used in this study was first launched in 2013 and is a weekly education session and static cycling class that takes place over 8 weeks for patients suffering from hip osteoarthritis (OA). OA is a leading cause of disability in older people. In the UK, 10 million people have OA, with 3.2 million suffering from hip OA.

A five-year follow-up reported a significant improvement in hip function after treatment compared to usual physiotherapy care. The majority of participants were still using self-management strategies to manage their hip pain, and 57 percent had not pursued surgical intervention.

BU’s Professor Rob Middleton and orthopaedic surgeon at UHD said: “Hip replacements cost the NHS over £6,000 per patient, so avoiding surgery for hip problems reduces the burden on the NHS, saves money, and provides better outcomes for patients. Now with this new study we can also see the potential for static cycling to save further money for the NHS by bringing down waiting lists for physiotherapy.”

Dr Peter Wilson, Chief Medical Officer at UHD said: “We are an ageing population and increasingly we are seeing more patients with osteoarthritis that need either surgery or physiotherapy. Finding alternative ways to treat these patients could help reduce waiting times and the financial demand on NHS services.”

Professor Wainwright continued: “We previously knew that CHAIN worked and benefitted patients. What this latest study has shown is that it improves clinical outcomes and is far more cost-effective when compared to usual physiotherapy care.”

Patients taking advantage of CHAIN are referred to the UHD Physio Team via their GP. They are then registered on the eight-week programme.

The researchers have teamed up with BH Live, a local registered charity and a leading leisure centre operator, to deliver the group sessions at BH Live Active, Littledown in Bournemouth.

Viv Galpin, BH Live’s Health & Wellbeing Manager, said: “Studio cycling is a fantastic form of low-impact exercise. Among many other advantages, it helps to improve muscles around joints, maintain bone strength, improve balance, and reduce joint pain and stiffness. It’s great to see so many participants are already benefitting from our programme.”

One of the participants, Sue, was originally referred to her local hospital.  She had to give up her two favourite hobbies, walking and dancing, because of painful hip problems. Speaking about her experiences, she said: “My leg would give way and suddenly I couldn’t walk. The first week of the spinning class I could barely manage to get on the bike. By the third week I had already noticed a positive difference in my hip. After the programme I was walking and dancing and grateful to have a good night’s sleep again.”

To help roll out CHAIN on a national level, the BU team have developed a virtual course on their education app. Individuals are able to follow the programme from their home or gym using a static bike.

The future aim of CHAIN is to roll it out nationally by providing other clinical teams across the UK with the knowledge and skills to set up their own interventions.

Professor Wainwright concluded: “By providing an app to help people manage their hip pain virtually and by supporting other clinicians with a toolkit to set up their own CHAIN programmes, the outcomes in the future could change the way we treat hip pain on a national and international level, helping to benefit our patients and improve lives for thousands of people.”

For further information about the CHAIN programme, please visit the BU website.

Image: Group CHAIN Spinning Class at BH Live Littledown Centre, Bournemouth

View more Credit: BH Live

Principal investigator Queran Lin, MPH, WHO Collaborating Centre for Public Health Education and Training, Faculty of Medicine, Imperial College London; and Clinical Research Design Division, Clinical Research Centre, Sun Yat-Sen Memorial Hospital, Guangzhou, explains, “While previous Global Burden of Disease (GBD) studies have provided important insights, they have largely focused on high-level descriptions and visualizations at global and national scales, failing to capture local disparities or the dynamic interactions between socioeconomic development and disease trends. With access to sufficient computational resources and advanced analytical capabilities, our Global-to-Local Burden of Disease Collaboration aims to unlock the full potential of the GBD dataset (pioneered by the Institute for Health Metrics and Evaluation, University of Washington). By employing cutting-edge approaches such as transformer-based deep learning models, we were able to generate the most granular disease burden estimates to date, offering a new framework for guiding precision public health across diverse populations.”

Using GBD data, the study integrates the largest spatiotemporal rheumatoid arthritis dataset spanning 953 global to local locations from 1980 to 2021 with a novel deep learning framework to reveal how demographic ageing, population growth, and uneven healthcare infrastructure exacerbate rheumatoid arthritis burdens differently across regions. It also enabled investigators to analyze the prevalence, incidence, mortality, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) of rheumatoid arthritis, as well as their socioeconomic inequalities and achievable disease control based on socioeconomic development level (frontiers) and forecast long-term burdens until 2040 with scenario simulations.

The study observed that globally there were significant absolute and relative sociodemographic index (SDI)-related inequalities, with a disproportionately higher burden shouldered by countries with high and high-middle SDI. Among the key findings of the study are:

• Global rheumatoid arthritis burden increased: From 1980 to 2021, the global rheumatoid arthritis burden kept rising, showing an increase among younger age groups and a wider range of geographic locations worldwide, with hotspots like the UK’s West Berkshire (incidence rate: 35.1/100,000) and Mexico’s Zacatecas (DALY rate: 112.6/100,000) bearing the highest burdens in 2021 among 652 subnational regions.
• Widening inequalities: DALY-related inequality surged 62.55% from 1990, with Finland, Ireland, and New Zealand as the most unequal countries in 2021.
• Failure to meet frontiers: As SDI increased over time, frontier deviations worsened, which indicated the burden of rheumatoid arthritis has been severely neglected.
• Noneconomic disparities persisted: Economic factors alone are not the sole determinants of rheumatoid arthritis disease burden. High SDI regions such as Japan and the UK exhibited contrasting patterns in disease burden. Japan’s declining DALY rates despite high SDI may reflect nationwide early diagnosis programs, widespread use of biologic therapies, and a diet rich in anti-inflammatory components.
• Forecasted increases and need for positive policy: By 2040, low-middle SDI regions may see increasing DALYs due to ageing/population growth, while DALYs in high SDI areas may decrease. Controlling smoking may reduce rheumatoid arthritis deaths by 16.8% and DALYs by 20.6% in high-smoking regions (e.g., China), offering significant benefits for medium/high SDI areas.

Co-lead author Baozhen Huang, PhD, Department of Biomedical Sciences, City University of Hong Kong, says, “Japan’s sustained decline in DALYs despite a high SDI proves that socioeconomic status alone doesn’t dictate outcomes; proactive healthcare policies such as early diagnosis programs can reverse trends.”

Many regions around the world still lack the necessary evidence base to inform precision health policy and targeted interventions. These data are intended to support more informed clinical decisions and health policy planning, especially in settings where reliable subnational evidence has historically been scarce.

Co-lead author Wenyi Jin, MD, PhD, Department of Orthopedics, Renmin Hospital of Wuhan University; and Department of Biomedical Sciences, City University of Hong Kong, concludes, “The adoption of this advanced framework quantifies the expected impact of feasible intervention scenarios in public health, supplying policymakers at global, national, and local levels with more reliable, dynamic evidence, redefining the very paradigm of health surveillance.”

The condition in question is so-called osteonecrosis of the jaw, in which the jawbone weakens and deteriorates as a result of the medication. The incidence of osteonecrosis was 0.3% among low-dose antiresorptive drug (AR) users and as high as 9% among those receiving high doses. Antiresorptive drugs are commonly used in Finland, particularly in the treatment of osteoporosis and in the prevention of bone metastases in patients with breast or prostate cancer. The most commonly used AR drugs are denosumab and bisphosphonates.

According to the study, the risk of jaw osteonecrosis was significantly higher in patients using denosumab. These users were up to five times more likely to suffer serious jaw damage than those taking bisphosphonates. When corticosteroids were also involved, the risk increased further: simultaneous use of corticosteroids in addition to AR drug increased the risk of developing osteonecrosis of the jaw by 2 times in high-dose AR recipients and 6 times in low-dose AR recipients. Other significant risk factors for jaw osteonecrosis included male sex and a cancer diagnosis.

This is the first population-level study conducted in Finland on the incidence and risk factors of medication-related jaw osteonecrosis. The analysis covered data from nearly 60,000 Finnish patients.

“Our study confirms that denosumab is associated with a significantly higher risk of jaw osteonecrosis compared to bisphosphonates, but the difference in risk between the two was surprisingly large. It was also particularly surprising how strongly the simultaneous use of corticosteroids increased the risk in patients on low-dose bone medication,” says Miika Kujanpää, doctoral researcher at the University of Oulu and dentist.

The researchers recommend that patient treatment plans be reviewed more carefully when multiple medications are in use, particularly denosumab and corticosteroids together. They also emphasise the role of oral health care in reducing risks – for example, the condition of teeth and gums should be checked both before and during bone medication treatment.

The study was published in Scientific Reports in May. It was funded in part by the Finnish Dental Society Apollonia.
Kujanpää, M., Vuollo, V., Tiisanoja, A. et al. Incidence of medication-related osteonecrosis of the jaw and associated antiresorptive drugs in adult Finnish population. Sci Rep 15, 17377 (2025). https://doi.org/10.1038/s41598-025-02225-2

In rheumatology, treatment often begins with disease-modifying anti-rheumatic drugs (DMARDs)5. When patients do not respond adequately or their disease progresses, treatment is escalated to biologics or advanced therapies, explains Ms Flora. The introduction of biologics has “revolutionised” treatment for patients, she says. They have been described by patients as life-transforming, fast-acting, controlling disease, and getting patients into remission quickly.

The rapid development of biosimilars over the past five years has had a significant impact. Unlike simple generics such as paracetamol or aspirin, biologics and biosimilars are large, complex molecules that require complex manufacturing processes. They are not direct copies of the originator molecules and for this reason they are called “similar”. However, their clinical effects are the same as the originator drugs’. Indeed, biosimilars are clinically equivalent and now considered interchangeable with their originator biologic medicines, says Ms Flora. Biosimilars have widened access to treatment for patients; for example, NICE guidelines have allowed patients with moderate rheumatoid arthritis to access these medicines earlier than was previously possible. Furthermore, biosimilars cost less than the originators, enabling the NHS to provide more cost-effective services, she explains.

Optimising treatment is a key aspect of the specialist pharmacist role, particularly once patients are stable or in remission on a biological DMARD (bDMARD). Guidance suggests that, at this stage, the dosage of bDMARDs can be reduced either by lengthening the interval between doses or reducing the dose. For tablets, reducing the dosage is typically easier, while for prefilled injections (many biologics), the dosage is fixed. Therefore, in clinical practice, dose optimisation for injectable biologics often involves extending the dosing intervals. For example, a monthly injection could be extended to every second month.

Dose reduction or interval extension can be driven by both clinicians identifying stable patients and patients proactively seeking to take less medication. Patients may wish to reduce their medication burden and potential long-term risks. Feedback from patients indicates that they often feel empowered and listened to when involved in these decisions, and many are happy to inject less frequently, explains Ms Flora. While dose optimisation is encouraged in remission, stopping treatment abruptly is generally not recommended. Clinical evidence shows that simply stopping biologics is likely to cause a patient’s disease to flare. Slowly tapering the dose or extending the interval reduces this risk, helping to keep patients well.

Homecare

Homecare services ensure that medicines, including injections and even tablets, are delivered directly to the patient’s doorstep, eliminating the need for frequent hospital visits to collect medications. For new injectable treatments, a trained professional, often a nurse, visits the patient’s home to provide counselling, instructions on how to take the medicine, things to look out for, and training on administration. Homecare also frees up hospital resources for patients who require in-hospital care, says Ms Flora. Medicines delivered via homecare can sometimes be cheaper due to VAT regulations. Moreover, homecare also indirectly supports sustainability efforts by reducing patient travel to hospitals and potentially using less plastic over the long term if dose intervals are extended, she adds.

Rheumatology pharmacy

A rheumatology specialist pharmacist’s work is very varied. About 80% of the role is clinical or patient-focused, involving activities like overseeing biologic services to ensure safety and access, managing prior approval for funding from Integrated Care Boards (ICBs), and supporting patients from different areas. Ms Flora is also heavily involved in shared care, supporting access to medicines across the interface between hospitals and GPs. She also works closely with the multidisciplinary team (MDT), supporting nurses, allied health professionals, junior doctors, and consultants and participating in MDT meetings to review patients, discuss funding issues, and address barriers to treatment. In addition, the role includes supporting and training junior pharmacy colleagues and contributing to service improvement and audit.

For pharmacists considering a career in rheumatology or high-cost drugs, Ms Flora offers several tips: be inquisitive about complex cases, be visible, and form strong professional relationships within the MDT. Networking is highly valued, as “your network is your net worth”. To young pharmacists contemplating this path, the advice is simple: “just try it”, she says. The field is varied, with many different conditions and constant changes, making it a rewarding career choice.

The role of the rheumatology specialist pharmacist is integral to optimising the use of advanced therapies, improving patient outcomes, enhancing access to care, and contributing to the sustainable delivery of rheumatology services.

About Kalveer Flora

Kalveer Flora leads the rheumatology specialist pharmacy service at London Northwest University Healthcare Trust. She also serves as the lead pharmacist for the Clinical Reference Group (CRG) for NHS England.  She chairs Rheumatology Pharmacists UK which is a group of specialist pharmacists and pharmacy staff working within the space of rheumatology and biologics and she is co-chair of the Sustainability Special Interest Group (SIG) of the British Society of Rheumatology.  Kalveer Flora’s work embraces a variety of different aspects “but essentially it’s overseeing the rheumatology services to patients and that can be a wide range of inflammatory conditions”, she says.

ESCP Workshop

In October 2024 Hilary McKee and Kalveer Flora ran a workshop at the ESCP Symposium in Krakow, Poland, at which they described their work as independent prescribers and invited the audience to think about how they might tackle some of the common problems that arise in rheumatology clinics.

Metformin, which is commonly prescribed to treat type 2 diabetes, reduced knee arthritis pain over six months in a clinical trial published in JAMA.

The randomised clinical trial looked at whether metformin, compared to a placebo, reduced knee pain in patients with symptomatic knee osteoarthritis (knee OA) and overweight or obesity.

The research was performed entirely as a community-based study using telehealth. Some of the 107 participants with pain from knee osteoarthritis (73 women and 34 men), who had a mean age of 60, took up to 2000 mg of metformin daily for six months. Others took the placebo. None had diabetes.

Knee pain was measured on a 0-100 scale, with 100 being the worst. The metformin group reported a 31.3 point reduction in pain after six months, compared to 18.9 for the placebo group. This was considered a moderate effect on pain.

“These results support use of metformin for treatment of symptomatic knee osteoarthritis in people with overweight or obesity,” the researchers found. “Because of the modest sample size, confirmation in a larger clinical trial is warranted.”

Lead researcher Professor Flavia Cicuttini, who heads Monash University’s Musculoskeletal Unit and is The Alfred’s Head of Rheumatology, said the results showed that metformin was a potentially new and affordable way to improve knee pain in those with knee OA and overweight or obesity.

Knee OA treatments include lifestyle approaches such as exercise and weight loss, which patients often find difficult, and medications such as paracetamol, topical anti-inflammatory creams and oral anti-inflammatory medications which have small benefits and may be unsuitable for some patients for safety reasons.

No new OA drugs have been approved in Australia since Celebrex (celecoxib) and Vioxx (rofecoxib) in the late 1990s.

Professor Cicuttini said effective treatments that improved knee pain in osteoarthritis were limited. She said this led some patients and their doctors to seek alternative treatments including surgery.

This resulted in major problems managing knee OA in Australia and internationally, including an increase in the rate of knee replacements performed for earlier stages of OA. This was based on the idea that effective treatments for knee OA were limited and that knee replacements lasted a long time

“At first glance this may seem reasonable, but it is a major problem because patient dissatisfaction with knee replacements is already high at between 20-30 per cent, even when the operation is technically perfect*,” Professor Cicuttini said. “Dissatisfaction rates are highest when the operation is done for early knee OA.

“To go through the effort and cost of a big operation like a knee replacement, only to be unhappy with the results because of ongoing pain and symptoms, is definitely low-quality care. Doing a knee replacement earlier also increases the potential need for the procedure to be redone.

“This costs about 3.5 times as much, so about $70,000 compared to $20,000, and the results tend not to be as good as the first time. The best outcome for patients is to delay the knee replacements until it is absolutely needed.”

Professor Cicuttini said metformin now provided GPs an alternative they could offer patients in addition to managing weight and increasing activity. “Metformin works in a number of ways on the knee, including affecting low grade inflammation and other metabolic pathways that are important in knee OA,” she said. “It is a different way to treat knee OA pain.

“GPs are very familiar with metformin, which is a low-cost, safe medication. It could be provided to patients in addition to other treatments they use and has the potential to delay people having knee replacements before they are absolutely needed. If people on metformin have less knee pain and are able to do more physical activity, then knee replacements can wait.”

Professor Cicuttini and her colleagues are now working with consumers, GPs, orthopaedic surgeons and other healthcare professionals to introduce metformin into the knee OA management pathway in order to improve patient outcomes and potentially better target knee replacements. Metformin could be used ‘off label’ after discussions between patients and their doctor.

“Metformin is safe and well tolerated,” she said. “It is used safely in other non-diabetes conditions such as polycystic ovarian syndrome. Metformin could be provided simply and safely using a telehealth approach, as we did in our study, meaning that it could be provided across the community, including in regional and remote areas.”

About knee osteoarthritis (OA)
Effective therapy for knee OA is limited, with a growing international trend toward knee replacements on patients with even milder cases*, despite recommendations that surgery be reserved for symptomatic end-stage OA**. This trend has been partly explained by the lack of effective treatments for knee OA and improved longevity of knee replacements*. Other research has found pain is an ‘omni- present’ feature of knee osteoarthritis and perceived to interrupt and deter daily activities such as walking, making people less confident in their bodies***. Current guidelines leave the timing and patient appropriateness for surgery to the discretion of the treating clinicians****. However, a systematic review and meta-analysis provided consistent evidence that mild radiological OA was a major contributor to the 20-30% patient dissatisfaction with knee replacements, including persisting pain*****.

About metformin
Metformin is a safe, inexpensive, well-tolerated oral medication that has been first-line therapy for type 2 diabetes for more than 60 years. Metformin reduces the production of glucose produced and released by the liver, insulin resistance, and low blood-sugar levels. It causes modest weight loss and reduces inflammation in people with and without diabetes. Other effects of metformin, such as anti-inflammatory properties, and improved glucose and lipid metabolism, such as reduced insulin resistance, may reduce knee pain in osteoarthritis******.

This research was supported by the National Health and Medical Research Council (NHMRC).

*Shohat N, Heller S, Sudya D, Small I, Khawalde K, Khatib M, Yassin M. Mild radiographic osteoarthritis is associated with increased pain and dissatisfaction following total knee arthroplasty when compared with severe osteoarthritis: a systematic review and meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2022;30:965-81.
**Kloppenburg M, Namane M, Cicuttini F Osteoarthritis. Lancet. 405:71-85, 2025 Jan 04.59.
***Reference: Wallis JA, Taylor NF, Bunzli S, Shields N. Experience of living with knee osteoarthritis: a systematic review of qualitative studies. BMJ Open. 2019 Sep 24;9(9):e030060. doi: 10.1136/bmjopen-2019-030060. PMID: 31551381; PMCID: PMC6773287
****Usiskin I. Surgical Treatments for Osteoarthritis. Eur J Rheumatol. 2023;11:S41-7.
*****Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open. 2012;2:e000435.
******Lim YZ, Wang Y, Estee M, Abidi J, Udaya Kumar M, Hussain SM, Wluka AE, Little CB, Cicuttini FM. [Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies.  Osteoarthritis Cartilage.2022 11];30(11):1434-1442

Ms McKee’s rheumatology work started when she joined a rheumatology consultant’s ward round where she answered medicines-related queries. Soon after she was asked to manage the supply of the newly-launched leflunomide and later developed a service for training people to self-inject methotrexate. By the time independent prescribing for pharmacists became a reality, the foundations for a fully-fledged clinic role were in place. She now holds four clinic sessions each week.

The key points from this interview are summarised below:

Challenges of polypharmacy in rheumatology

Polypharmacy – the use of multiple medicines – can be a problem in rheumatology as additional medications are prescribed to deal with side-effects from disease-modifying anti-inflammatory drugs (DMARDs).  This situation is often described as a ‘prescribing cascade’. “Actually, the most drugs I ever saw a patient on were 42 medications …. and that was just because things had kept being added, and nobody had looked to stop anything”, says Ms McKee. Another important aspect of polypharmacy is the potential for wastage. As medications account for about 25% of the NHS’s carbon footprint, reducing unnecessary medication use could have an important environmental impact and contribute to the ‘greener NHS’.

Methotrexate treatment

People can be hesitant about the use of methotrexate because of its potential for toxicity, in particular, immunosuppression. However, the doses used in rheumatology are lower than those used in cancer treatment and patients are carefully monitored “The aim, as we tell our patients, is to spot a problem before it becomes a problem”, says Ms McKee.

Cannabis derivatives in rheumatology

Many rheumatology patients purchase cannabis derivatives on the internet and they frequently mention this during consultations. The benefits of cannabis in rheumatology are not yet clinically proven.

Medication Adherence

Adherence can be an issue – and it might be suspected if a patient does not get the expected results with a prescribed treatment. Sometimes patients are misinformed about side-effects by neighbours or information in the press or internet and do not take their treatment as a result.

Role of Biological DMARDs

The introduction of biological DMARDs, starting with infliximab in about 2000, has revolutionised the treatment of inflammatory arthritis. “The biologics are very powerful drugs; they aim to stop the disease in its tracks and with that we prevent joint damage on down the line”, says Ms McKee. Many of the joint deformities that used to be common are now rarely seen.

Once a patient’s disease is stable the dose can be reduced and this is usually done by ‘dose extension’ i.e. lengthening the gaps between doses rather than reducing the dose amount. Some patients can be hesitant about dose extension out of fear of a flare. Simply stopping the treatment will usually result in a flare up of the disease.  Dose adjustment always requires individual assessment and sometimes off-label prescribing is necessary.

Working in the clinic

Working in the clinic calls for a capacity to ‘think on your feet’ says Ms McKee, because you can be faced with the unexpected. For example, a patient whose disease was stable on biologics mentioned in passing that she had developed night sweats. “Well, that’s a red flag immediately. You can’t let that patient go out of the door without investigating”, says Ms McKee.  Investigations were required to exclude tuberculosis and cancer.  Another example was a clergyman whose disease was well-controlled on methotrexate. He was planning to go to Africa for missionary work and asked about getting a yellow fever vaccine. As this is a live vaccine, methotrexate has to be discontinued for three months before it is given. When this was explained he decided that the risk of a flare was too great and he decided against going to Africa.

It is important to be willing to evaluate the response to treatment critically and standard treatment guidelines are useful but guidelines are black and white, whereas patients are not. “They’re grey, they’re complicated and you need to think outside the box”, she says.

Tips for success

Two key tips are – “be aware of your own limitations” and “know your drugs inside out”. Prescribing in rheumatology is complex and patients have many comorbidities; it is a specialty with many opportunities for pharmacists.  “Get in there and just do it” advises Ms McKee.

ESCP Workshop

In October 2024 Hilary McKee and Kalveer Flora ran a workshop at the ESCP Symposium in Krakow, Poland, at which they described their work as independent prescribers and invited the audience to think about how they might tackle some of the common problems that arise in rheumatology clinics.

The study, by researchers at the University of York, builds on work conducted by Harvard Medical School that compared more than 450,000 users of a class of drugs, called bisphosphonates, with non-users during the months leading up to the pandemic in 2020.

The Harvard study showed that those who used drugs, such as alendronate and zoledronate, had lower odds of testing for SARS-CoV-2 infection, Covid-19 diagnosis and Covid-19-related hospitalization, but the study didn’t explain why this was the case.

To understand why this might be the case, researchers at York and India’s Birla Institute of Technology and Science, Pilani, explored all bisphosphonates listed in a drug candidate database that could potentially bind to a specific enzyme domain found in nidoviruses, which are a group of viruses that includes coronaviruses.

The researchers applied this technique to the top candidates in a drug repurposing database, called ‘CoviRx’, and after analysing the data, the researchers narrowed down their selection to seven promising bisphosphonates. Among these, two compounds were found to be similar to already approved drugs, minodronate and zoledronate.

They showed that alendronate is also similarly promising, suggesting all three could be potential candidates for further research and clinical trials.

Honorary Professor Seshadri Vasan from the University of York’s Department of Health Sciences, said: “Although vaccines have proved effective against Covid-19 and its variants, they are not able to prevent their transmission, and so new drugs are being sought to keep pace with the continuously mutating virus.

“One approach to this challenge is to use drugs already in-use for other conditions, and so in 2023 we released a database of drugs that allows scientists to narrow their search from a list of 7,817 potential candidates to a ‘top 214’. We also screened 1,992 bisphosphonates in another public database.

“Using this approach we were able to provide a molecular explanation for osteoporosis drugs such as alendronate and zoledronate protecting against Covid-19, and predict that other molecules like minodronate, a drug used in Japan, may also be beneficial.”

Researchers are now calling for further studies that build on the work of Harvard, and others that have shown the potential of osteoporosis drugs, and extend to human clinical studies to explore their potential in Covid-19 and other coronaviruses.

The research is published in the Journal of Molecular Graphics and Modelling.

The new study, which is published in Arthritis Care and Research, shows that care must be taken when repeated doses are required for chronic painful conditions such as osteoarthritis in older people.

The study was led by Professor Weiya Zhang, from the NIHR Biomedical Research Centre in the School of Medicine at the University of Nottingham.

Professor Zhang said: “Due to its perceived safety, paracetamol has long been recommended as the first line drug treatment for osteoarthritis by many treatment guidelines, especially in older people who are at higher risk of drug-related complications.”

The study analysed data from the Clinical Practice Research Datalink-Gold. Participants were aged 65 and over with an average age of 75,  and had been registered with a UK GP practice for at least a year between 1998 and 2018.

Researchers looked at the health records of 180,483 people who had been prescribed paracetamol repeatedly (≥2 prescriptions within six months) during the study. Their health outcomes were then compared to 402,478 people of the same age who had never been prescribed paracetamol repeatedly.

The findings showed that prolonged paracetamol use was associated with an increased risk of peptic ulcers, heart failure, hypertension and chronic kidney disease.

Professor Zhang adds: “Whilst further research is now needed to confirm our findings, given its minimal pain-relief effect, the use of paracetamol as a first line pain killer for long-term conditions such as osteoarthritis in older people needs to be carefully considered.”
The full study can be found here.