DISKO: Effect of Denosumab on pain and BMLs in knee osteoarthritis

• Research type

  Research Study

• Full title

  The effect of Denosumab on Pain and bone Marrow Lesions in symptomatic Knee Osteo-arthritis: A Randomised Double Blind Placebo controlled Clinical Trial

• IRAS ID

  191262

• Contact name

  Terence O'Neill

• Contact email

  terence.ONeill@manchester.ac.uk

• Sponsor organisation

  The University of Manchester

• Eudract number

  2016-000754-35

• Duration of Study in the UK

  3 years, 6 months, 31 days

• Research summary

  Summary of Research
  Knee osteoarthritis (OA) is the commonest cause of knee pain in older adults. Despite this there are no effective treatments which reduce knee pain and also the rate at which the disease progresses. Furthermore current treatments are limited because of their side effects and the fact that many are not particularly effective. Recent research, however, suggests that treatments which prevent bone loss may be effective at reducing pain and joint damage in people with knee osteoarthritis. \n\nOur aim is to determine whether a one off administration of a drug treatment which prevents bone loss called ‘denosumab’, and given as an injection under the skin, is effective at relieving pain in people with painful knee OA and reducing structural damage at the knee. \n\nOver 160 men and women aged 50 years and over with painful knee OA will be randomised to receive either the active treatment or placebo given as an injection under the skin on a one-off basis. Those who take part will receive also calcium and vitamin D supplements if they are not already taking them. Participants will be followed for a 6 month period with magnetic resonance imaging (MRI) scans of their knee at the start and end of the study. \n\nThe analysis will focus on whether or not treatment with denosumab reduces structural damage at the knee and also knee pain.\n

  Summary of Results
  STUDY TITLE:
  The effect of Denosumab on Pain and Bone Marrow Lesions in Symptomatic Knee Osteo-arthritis: A Randomised Double-Blind Placebo controlled Clinical Trial (DISKO)

  ISRCTN REGISTRATION NUMBER:
  ISRCTN96920058

  EudraCT REGISTRATION NUMBER:
  2016-000754-35

  SPONSOR ORGANISATION:
  The University of Manchester

  FUNDING:
  Versus Arthritis (formerly Arthritis Research UK; financial support) AMGEN (supplied study drug and placebo)

  COMPETING INTERESTS:
  None declared

  WHAT PUBLIC INVOLVEMENT WAS THERE IN THE STUDY?:
  The trial lay summary and patient information sheet have been reviewed by people with arthritis who were members of the Versus Arthritis Centre for Epidemiology Research User Group (RUG), at the University of Manchester.

  WHERE AND WHEN THE STUDY TOOK PLACE:
  The recruitment and trial management of the DISKO trial were based at the University of Manchester (Manchester, UK). The trial visits (where participants met with research staff) took place either at Salford Royal NHS Foundation Trust (Manchester, UK) or The Wellcome Trust/NIHR Manchester Clinical Research Facility. Trial visits took place between December 2017 and October 2020. The study recruited participants from outpatient clinics at local hospitals, and from the community through advertisement in local newspapers.

  The study stopped recruiting new patients early, during March 2020, in part due to the COVID-19 pandemic.

  WHY WAS THE RESEARCH NEEDED?:
  Knee osteoarthritis (OA) is a common, painful condition with very few treatment options available to patients. Currently there are no licensed treatments which reduce knee pain and/or slow the physical (structural) worsening of knee osteoarthritis. Denosumab is a drug treatment which is currently used for osteoporosis, but is appealing as a potential treatment for knee OA, because of the way the drug acts to prevent bone damage. A recent small study found that a treatment which acts in a similar way to Denosumab (zoledronic acid) may help with knee pain and also reduce the size of ‘bone marrow lesions’. These lesions are an indicator of damage to the knee thought to be part of knee OA that can be seen with a magnetic resonance image (MRI scan). Denosumab is thought to have a similar effect to zoledronic acid, and might also be safer; however, no clinical trials using Denosumab have been undertaken in this setting.

  WHAT WERE THE MAIN QUESTIONS STUDIED?:
  The main aim of DISKO was to establish whether a one-off injection of Denosumab under the skin is effective at reducing the size of knee bone marrow lesions, and also relieving pain, in people with painful knee OA. We compared Denosumab to a one-off injection that looked exactly the same, but had no biological effect (a placebo).

  WHO PARTICIPATED IN THE STUDY?:
  The study originally intended to recruit 167 people, but due to the trial’s early closure, 58 were recruited. The 58 people were men and women aged 40 and over with painful knee OA. They were recruited from primary care, from outpatient clinics at local hospitals, and from the community through advertisement in local newspapers.

  WHAT TREATMENTS OR INTERVENTIONS DID THE PARTICIPANTS RECEIVE?:
  Participants had a screening visit which included questionnaires, a knee assessment and a blood test. After this, they also had a magnetic resonance image (MRI) scan of their knee. If they were then eligible for the study, they attended a baseline visit about two weeks after the scan. At this visit, they were randomly chosen to receive either a single injection (under the skin) of 60mg Denosumab or a placebo injection. All participants also received calcium and vitamin D supplements. Participants were seen 3 and 6 months later and given repeat questionnaires. A second MRI scan was also obtained at the 6 month (final) visit.

  WHAT MEDICAL PROBLEMS (ADVERSE REACTIONS) DID THE PARTICIPANTS HAVE?:
  At the end of the study, 59 adverse events had been recorded, 30 in one group and 28 in the other. One of these was thought to be related to the calcium supplementation during the study, but no other adverse events were felt to be related to any part of the study procedure. Most (23 of the 59) events were musculoskeletal in nature.

  Two serious adverse events were recorded. Neither of them were deemed to be related to any part of the intervention (the vitamin supplements, MRI scan, or injection), and only one of the two serious adverse events occurred after the injection was given.

  WHAT WERE THE RESULTS OF THE STUDY?:
  At 6 months, there was a small difference in bone marrow lesion size between both groups (in terms of area and volume); this difference could have occurred simply by chance. On the other hand, some of the measures of pain seemed to show a difference between the groups at 3 months, but this difference became smaller after 6 months. Like the bone marrow lesions, this difference was so small that we could not rule out that this difference simply occurred by chance. Because the study was stopped early, the research team had fewer participants than planned, making it difficult to interpret these findings.

  Because this study was analysed in a ‘blinded’ way, the study staff do not currently know which of the two groups received a placebo, and which one received Denosumab. Once the study analyses have been completed, we will reveal this information.

  HOW HAS THIS STUDY HELPED PATIENTS AND RESEARCHERS?:
  Even though this study had fewer participants with knee OA than planned, the data provide interesting findings relating to changes in knee symptoms following an injection of Denosumab and may be of help in planning future studies of therapy in this setting.

  Some of the data collected from the MRI scans might also help us better understand the biological changes that happened in knee OA, and so could help us find future treatments for knee OA.

  DETAILS OF ANY FURTHER RESEARCH PLANNED:
  We plan to write more about this study’s results once the blinding has been ended. The MRI data we collected is very complex, and so there is more to analyse there too. The findings will be written up and published in academic journals.

  WHERE CAN I LEARN MORE ABOUT THIS STUDY?:
  More information about the DISKO trial is available at the University of Manchester’s website: https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbbNi8hDaI-2FrHZLB3SZV1A8-2F4xsYEo7yYLdHztiuvek-2F5vQSN_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YI7-2B7uB9uoT8RRp-2FioqNFU4q2Qg4V5h567J8m5AFEoggDokrdE0IkxXaziU03YjIuKZhknu26sfu1F6DiUEOMim9dEwJArbJpnG-2FSzTIAiXinqK0CbZ3eO8P-2ByT0tD3xF7Qfa9j3tou-2BfGBpIK8PdCDoEfW5jt-2Bpex47UqY83v1ag-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7Cce477135c7bb46d53ce108d9c602124c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637758534458803275%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=pMIuDfFPUbbvPKEbNn%2Bn4GdlfDYIBn%2FO%2FUBOf410PVQ%3D&reserved=0

• REC name

  North West - Greater Manchester South Research Ethics Committee

• REC reference

  17/NW/0262

• Date of REC Opinion

  22 May 2017

• REC opinion

  Favourable Opinion