Molecular Pathways Involved in Knee Pain

Knee Osteoarthritis Clinical Trial

Official title:

Molecular Pathways Involved in Knee Pain: an Observational Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04443452
• Other study ID #: 19098
• Secondary ID: 22473275727
• Status: Completed
• Start date: November 6, 2020
• Est. completion date: October 31, 2022

Study information

• Verified date: May 2022
• Source: University of Nottingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Knee osteoarthritis (OA) is the most common form of arthritis and the most common cause of knee pain in the world. The rate of knee arthritis is as high as that of cardiac disease and is the most common problem in individuals over the age of 65.

Central Sensitization (CS) is a marker of widespread pain sensitivity that can occur throughout the central nervous system distribution, leading to changes in the spinal cord as well as in the brain. The presence of CS increases the complexity of the clinical picture and can negatively affect treatment outcomes. CS is present in >20% of patients suffering from knee OA indicating that in the majority of individuals suffering with painful knee OA, knee pain should be related to molecular changes in the joint. CS might be also associated with discrete synovial fluid proteomic signatures due to the generation by the joint of chemical mediators (e.g. nerve growth factor) that drive CS, or CS might moderate the relationship between synovial fluid proteomic signatures and symptoms due to alterations in pain processing.

The aim of this study is to explore the potential molecular links between pain and structure on knee pain using synovial fluid proteomics. A secondary purpose is to explore the association of knee pain with biomarkers of stress, metabolism and dietary habits.

In a single session, ultrasound-guided synovial fluid, blood urine and saliva extraction, clinical assessment, completion of a questionnaire booklet and knee x-rays will be conducted. The clinical assessment will measure three features of central sensitisation (sensitivity to blunt pressure on the most painful knee, changes in pain felt during repeated light pricking of the knee skin, and reduction in pain that accompanies inflation of a blood pressure cuff on the non-dominant arm), features of leg strength (dynamometer, time up-and-go test) and features of balance (sway). Participant involvement at each session is expected to last less than 3 hours.

Individuals over 45 having complaints of knee pain for 3-6 months are eligible to participate. The clinical assessments, questionnaire completion and subsequent statistical analysis are expected to be completed within 18 months of study commencement.

The findings can provide more insight into the traits of knee pain, allow the examination of possible correlations to each other, and highlight potential detrimental effects of them on knee joint health.

Description:

Osteoarthritis (OA) is the most common cause of disability in the elderly population and most individuals suffering from osteoarthritis are managed in the primary care setting. Knee OA is the most common form of arthritis and the most common cause of knee pain in the world. The rate of knee arthritis is as high as that of cardiac disease and is the most common problem in individuals over the age of 65. In the United Kingdom, 10% of 65 to 74-year-old individuals consult their general practitioners about OA per year. Out of the entire population, 4% attend their general practitioners as a result of knee OA, and half of them (2%) consult their general practitioner for the first time or with the acute flare of knee arthritis.

There is a considerable body of evidence showing augmented central nervous system (CNS) processing in OA. Central Sensitization (CS) is a marker of widespread and centrally augmented pain that refers to those neurophysiological processes that can occur throughout the CNS distribution, leading to changes in the spinal cord as well as in the brain. The presence of CS increases the complexity of the clinical picture and negatively affects a range of outcomes (e.g. pain, disability, negative affect, quality of life) following treatment. CS is not present within all patients with chronic pain rendering identification of those patients and decision-making for the right management approach even harder. Clinically, CS manifests as hypersensitivity to pain, that sometimes spreads beyond peripheral generators and is a marker for pain chronicity. CS of nociceptive pathways is a mechanism of clinical pain amplification in OA and is present in >20% of patients suffering from knee OA. This means that in the majority of individuals suffering with painful knee OA, knee pain should be related to molecular changes in the joint. CS might be also associated with discrete synovial fluid proteomic signatures due to the generation by the joint of chemical mediators (e.g. nerve growth factor) that drive CS, or CS might moderate the relationship between synovial fluid proteomic signatures and symptoms due to alterations in pain processing. Radiographic knee joint changes and pain levels are associated with knee cartilage loss but whether CS indices are linked to radiographic changes has not been established. High levels of CS might increase the risk of cartilage loss by increasing the levels of pain or might be associated with already existing changes.

The investigators will recruit 140 individuals with OA-related knee pain. They will also use standardised quantitative sensory testing (QST) such as pressure pain detection threshold (PPT), temporal summation (TS) and conditioned pain modulation (CPM). PPT specifically, has been used in past knee pain studies and is considered a valid and reliable method to establish tenderness around the knee joint. Similarly, TS has been used previously to establish whether individuals demonstrate amplified, centrally driven localised knee pain. Conditioned pain paradigms are commonly used to assess the function of endogenous pain inhibitory pathways in humans. In this technique, a painful test stimulus is evaluated in the absence and then in the presence of a second, also painful (conditioning), stimulus applied to a remote region of the body. In a typically functioning nociceptive system, the amount of pain experienced with the primary test stimulus will be reduced during the presentation of the secondary conditioning stimulus. Decreased inhibition of experimental pain is found in many patients with idiopathic pain syndromes. It predicts the tendency to develop future chronic pain. The purpose of using QST is to establish objective and quantifiable data that will allow the stratification of patients into 'sensitised' and 'non-sensitised' and permit further analysis.

Quantitative Sensory Testing is a reliable and valid method to assess for the presence of CS and demonstrates predictive capacity in relation to musculoskeletal (MSK) treatment outcomes. The testing consists of pressure pain threshold (PPT), punctate thresholds, temperature sensitivity, temporal summation (TS) and conditioned pain modulation (CPM) used to quantify noxious or innocuous stimuli within healthy individuals and patients alike. QST has been used, among others, as a screening and assessment tool for sensory abnormalities in patients with pain disorders, as well as to assist in the stratification of patients and evaluate the clinical aspects of peripheral and CS.

Regional pain and symptoms of depression and/or anxiety have been shown to facilitate the development of constant pain therefore, signs of depression or anxiety are important to explore correlation of symptoms at a single time-point. Signs of depression and anxiety can be identified with the use of the Hospital Anxiety and Depression Scale (HADS) that has been shown to be valid in multiple populations. The stress response involves activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Any physical or psychological threat to homeostasis triggers release of corticotrophin-releasing hormone in the hypothalamus, and ultimately raises levels of steroid hormones such as cortisol in the blood stream and saliva. In the short term, cortisol helps to meet the demands of stress by mobilizing energy stores, and assists recovery from stress by inhibiting further release of corticotrophin-releasing hormone. However, continuing stress promotes maladaptive functioning of the HPA axis, which, in turn, may compromise metabolism, impair immune function, and alter cardiovascular control. Cortisol levels in saliva have been implicated in chronic pain presentations (pain severity) and can be considered a useful biological biomarker that can be used to explore psychopathological associations, prognosis and treatment outcomes.

Nutritional information collected via a standardised food frequency questionnaire (FFQ) and metabolic evidence from body secretions can provide significant insight about the course of OA, as the presence of glucosamine and chondroitin sulfate in faecal samples has shown to improve the symptoms of the condition and delay its progression. Nutritional information and metabolic evidence from faecal samples can be used to explore associations of gut microbiota with pain sensitivity and stress levels.

The widely utilised Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) will be also used for the evaluation of knee OA. It is a self-administered questionnaire made of 24 items and consists of three subscales covering pain, stiffness and physical function. It has been used extensively and is considered a valid and reliable tool. For evaluating quality of life, stiffness, generalised well-being, sleeping difficulties and understanding of the diagnosis and treatment, the investigators will use patient-reported outcome measure 'The Versus Arthritis Musculoskeletal Health Questionnaire' (MSK-HQ). MSK-HQ covers a broad aspect of musculoskeletal conditions, and recent studies have shown it to be reliable and valid. Frailty has been also found to be a predictor of disability and a determinant of treatment outcomes and the Simple Frailty Questionnaire (FRAIL) is considered a valid and reliable tool for that purpose.

Both the 30-second sit to stand test (30CST) and the 'time up and go' (TUG) test will be used to see if patients have improved their lower limb fitness levels. 30CST has shown excellent reliability and validity. TUG has been widely used in clinical setups and is a valid tool to assess necessary functional mobility.

In this study, the sleeping pattern of individuals suffering from degenerative changes of the knee will be assessed with the aim to establish whether sleep disturbance is implicated in the development of CS. Disturbed sleep is a frequent complaint of people experiencing chronic pain such as those with knee osteoarthritis (OA). Changes in sleep architecture can affect health even in the presence of apparently adequate sleep duration. Insufficient amounts of slow wave sleep are associated with hypertension, type 2 diabetes mellitus, poor cognition, and obesity. Sleep disturbances are present in 67-88% of people with chronic pain and ≥50% individuals with insomnia have chronic pain. The investigators will also use the Pittsburgh sleep quality index (PSQI) which has been used in multiple studies and validated to measure sleep disturbances. Poor cognition, as well as sleep, has been found to be a marker of persistent pain and a trait of centrally driven pain in knee pain populations. The Cognitive Failures Questionnaire (CFQ) is a valid and reliable tool to measure self-reported failures in perception, memory, and motor function.

Musculoskeletal Ultrasound scan (MSK-USS) will be also conducted on the knees of participants to establish if they have inflammation of the synovial membrane. There is enough evidence that inflammation is present in all stages of OA. Synovitis or inflammation of synovial fluid is associated with pain, disease severity and, OA progression. Synovitis manifests as synovial membrane thickening, increased vascularity, and/or joint effusion. Synovial hypertrophy, synovitis and knee effusion are linked with arthritis in the knee and associated with knee pain in osteoarthritis. The synovial fluid will be aspirated (subject to participant consent), in order to establish a phenotype which is strongly associated with OA. Studying synovial fluid biomarkers alongside clinical, radiographic and ultra-sonographic characteristics is one strategy to improve resolution and stratification into targetable OA phenotypes. Synovial fluid aspiration will be ultrasound guided as it increases the accuracy of needle placement compared to blind needling (95.8% versus 77.8%, p < 0.001) reduces procedural pain by 43%, improves effusion detection by 200%, and volume of synovial fluid aspirated by 337% compared with blind synovial fluid aspiration. Ultrasound guidance also reduces procedural pain (43% reduction) in knees with no palpable effusion and increases the responder rate and therapeutic duration by 107% and 36% respectively.

Isometric quadriceps strength will be also assessed to establish current strength levels of vastus medialis muscle and see whether muscle strength associates with centrally driven pain or proteomic synovial concentrations. Quadriceps muscles strength deficits are associated with knee osteoarthritis. Isometric testing will be done at 30 and 60 degrees of flexion as per the protocol of a previous study.

Blood samples will be also extracted to assess the biomarkers (including serum levels and gene expression levels of various molecules) and to establish insulin resistance. Urine samples will be collected to identify the existence of collagen degradation markers (e.g. UTXII) and inflammatory regulator markers (e.g. Maresins).

Collection and study of these parameters can provide more insight into the traits of knee pain, allow the examination of possible correlations to each other, and highlight potential detrimental effects of them on knee joint health.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: October 31, 2022
• Est. primary completion date: October 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years and older

Eligibility

Inclusion Criteria:

• have the ability to give informed consent

• be 45 years or over

• have complaints of knee pain for 3-6 months with or without radiographically established OA (K/L scale score = 1)

• have complaints of knee pain for 3-6 months with or without satisfying the non-radiographic American College of Rheumatology criteria for knee OA

• are willing to undertake knee synovial fluid aspiration

• be able to speak, read, and write in English as all instructions and questionnaires are designed in the English language

Exclusion Criteria:

• Inability to give informed consent due to cognitive impairment or otherwise - (capacity levels are already established under General Practitioner care)

• Inability to understand key aspects of the study due to cognitive impairment or otherwise

• Giving history of additional co-morbidities such as cancer, neurological conditions, inflammatory joint diseases including rheumatoid arthritis, diabetic neuropathies, fractures or other conditions causing greater disability than their knee pain

• Acute soft tissue injury to the knee within last 3 months before potential recruitment

Related Conditions & MeSH terms

• Knee Osteoarthritis
• Knee Pain Chronic
• Osteoarthritis
• Osteoarthritis, Knee

Intervention

Diagnostic Test:
• Quantitative Sensory Testing
PPT: An electronic data collection unit will be used featuring an electronic algometer connected with a laptop where the amount of pressure will be displayed on the screen. When the pressure pain detection threshold is reached (the point where the pressure sensation starts to be experienced as pain), the individual will press a button at a handheld device, that will automatically store the pressure value in the system and serve as an indication, for the examiner, to stop the testing. TS: A pinprick stimulator (Weight: 256mNewton) will be used. The examiner will apply the pen that features a retractable blunt needle in a repetitive manner (once per second for ten seconds). The individual will be asked for the intensity of pain (NRS) at the first and at the last time and the given score will be noted. CPM: A manual blood pressure sphygmomanometer will be used in conjunction with the electronic algometer described above (PPT).

Radiation:
• Radiographic Evaluation
Tibiofemoral and patellofemoral radiographs of the most painful knee will be taken using a standardised protocol (standing posterior-anterior (PA) and skyline views) and will be scored by a single experienced observer in order to generate data for correlation analyses with the primary and secondary outcomes. A Perspex Rosenberg template with lead beads is used for the standing PA view to standardising the degree of knee flexion, foot rotation and magnification. PA radiographs are taken with the participant facing the x-ray tube while standing on the Rosenberg jig and leaning forwards with their thighs touching the anterior aspect of the jig, the x-ray beams passing from the posterior aspect through to the anterior aspect of the knee. Variable jigs are used for the skyline view to obtaining 300 of knee flexion with the participant lying in a reclined supine position on a couch. Grading of radiographs for changes of OA will be based on the Kellgren and Lawrence (K/L) score.

Procedure:
• Ultrasound-guided Aspiration
Ultrasound scanning will be conducted on the most painful knee to identify synovial effusion. During the ultrasound scan, the supra-patellar pouch, medial and lateral recess of the knees will be assessed for synovial thickening, synovial fluid/effusion and for positive power Doppler. An ultrasonic probe will be used to direct ultrasonic waves onto the knee joint during sonography, and a computer converts the signals received so that they can be presented on the screen. During skin application, a sterile probe cover and sterile acoustic gel will be used. Once the best aspiration location is identified and the location of the needle insertion marked, the skin will be prepared with a cleansing agent such as iodine or chlorhexidine. The needle may be introduced into the skin either parallel to the probe or perpendicular to the probe. Once the aspiration is completed, the needle will be removed, the skin cleansed, and a bandage will be applied.

Diagnostic Test:
• Muscle Strength Assessment
Isometric testing will be done at 30 and 60 degrees of flexion as done in the previous study and the participant will be in sitting position with hips and knees strapped to keep the position standardised.
• Function Assessment (A)
The participant will start in a seated position. The participant will stand up upon therapist's command, walk 3 meters, turn around, walk back to the chair and sit down. The time will stop when the participant is seated. The subject can use an assistive device. If the assistive device is used, it will be documented. Important Note: A practice trial will be completed before the timed trial.
• Function Assessment (B)
The 30-Second Chair Test is administered using a chair. The participant is seated in the middle of the chair with arms crossed at the wrists and held against the chest. The participant will practice a repetition or 2 before completing the test. If a participant must use their arms to complete the test, they are scored 0. The participant is encouraged to complete as many full stands as possible within 30 seconds. The participant is instructed to fully sit between each stand. While monitoring the participant's performance to ensure proper form, the tester silently counts the completion of each correct stand. The score is the total number of stands within 30 seconds (more than halfway up at the end of 30 seconds counts as a full stand). Incorrectly executed stands are not counted. The 30-second chair stand involves recording the number of stands a person can complete in 30 seconds rather than the amount of time it takes to complete a pre-determined number of repetitions.
• Balance Assessment
Static balance and postural sway either in the medial-lateral or antero-posterior direction will be assessed using the RS Scan force plate. The participant will be asked to stand on the plate looking straight forward for 30 seconds in two conditions: first with their eyes open and then with eyes closed. Medial-lateral, antero-posterior and total sway will be recorded.

Locations

Country	Name	City	State
United Kingdom	The University of Nottingham, City Hospital Campus	Nottingham	Nottinghamshire

Sponsors (2)

Lead Sponsor	Collaborator
University of Nottingham	Versus Arthritis

Country where clinical trial is conducted

United Kingdom, 

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* Note: There are 83 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Dietary Habits (OPTIONAL)	Dietary habits will be assessed with the Food Frequency Questionnaire (FFQ) where participants are asked to indicate the consumption frequency of different types of food materials with a 0-9 scale (0 indicates 'never or less than once a month' and 9 'more than 6 times per day') on 150 distinct foods divided into dairy, fruits, vegetables, meat and fish, soups, bread, sweets, potatoes, and beverages. A total score is calculated for each category with the maximum depending on the amount of items in each category. The larger the total value the more frequent the consumption of a food category per day is.	18 months
Other	Biosamples (Synovial fluid A)	Concentration of inflammatory markers (cytokines) identified in extracted synovial fluid.	18 months
Other	Biosamples (Synovial fluid B)	Concentration of proteomic concentrations (fibronectin) identified in extracted synovial fluid.	18 months
Other	Biosamples (Synovial fluid C)	Concentration of gene expression molecules (RNA polymerase II) identified in extracted synovial fluid.	18 months
Other	Biosamples (Blood A)	Concentration of stress markers (cortisol) identified in participants' blood samples.	18 months
Other	Biosamples (Blood B)	Concentration of insulin resistance markers (fasting blood glucose) identified in participants' blood samples.	18 months
Other	Biosamples (Blood C)	Concentration of metabolic rate markers (triglycerides) identified in participants' blood samples.	18 months
Other	Biosamples (Urine A)	Concentration of metabolic rate markers (UTXII collagen degradation marker) identified in participants' urine samples.	18 months
Other	Biosamples (Urine B)	Concentration of inflammatory regulator markers (maresins) identified in participants' urine samples.	18 months
Other	Biosamples (Saliva)	Concentration of stress markers (cortisol) in participants' saliva samples.	18 months
Other	Biosamples (Faeces A) [OPTIONAL]	Concentration of metabolic rate markers (glucosamine) in participants' faecal samples.	18 months
Other	Biosamples (Faeces B) [OPTIONAL]	Concentration of metabolic rate markers (chondroitin sulfate) in participants' faecal samples.	18 months
Primary	Pain Sensitivity: Pressure Pain Detection Threshold (PPT)	PPT is a non-invasive test during which the sensitivity of the nerves is assessed by recording the amount of pressure applied to the skin. Pressure is applied through a probe. The pressure probe used is mounted in a handheld device connected to a computer. Pressure applied to the skin is gradually increased until the participant indicates (by pressing a button) that the sensation has changed from pressure to pain. The probe will be used on 3 sites at the knee area (2cm above the medial and lateral edge of the patella and laterally on the joint line), proximal shin (tibialis anterior muscle - 5cm inferior to the tibial tuberosity) and over the contralateral forearm (brachioradialis muscle) using a standardised protocol used in other studies within the Pain Centre. Each region will be tested one time with short rest periods between each. The participants will be familiarised with the test before it is administered so that they know what to expect and how to respond.	18 months
Primary	Pain Sensitivity: Temporal Summation Pain (TS)	TS is a non-invasive test during which repetitive mechanical stimulation is applied over a short period to get their augmented response. A 256mN weighted pinprick stimulator will be used and applied perpendicular to the skin of suprapatellar region of the painful knee (5cm proximal from the centre of patella). The participant will be asked to rate the pain or sharpness they experience from 0-10 where 0 indicates no pain or sharpness and 10 indicates the most intense pain or sharpness imaginable. The response of the participant will be recorded. The same stimulator at the same site will be applied ten times repeatedly at a rate of 1/second. At the end of the series of 10 pinpricks, the participant will be asked to rate the average pain or sharpness they experienced out of the 10 stimuli using the same scale. The TS value will be calculated as the difference between the two ratings (single stimulus minus the average of the 10 stimuli).	18 months
Primary	Pain Sensitivity: Conditioned Pain Modulation (CPM)	CPM is the application of PPT before and while a pressure cuff is inflated. A 7.5cm wide tourniquet cuff will be wrapped around the arm contra-laterally to the most painful knee. The lower rim of tourniquet cuff will be kept 3cm proximal to cubital fossa. The cuff will be inflated with the aim to reach above-systolic pressure with a maximum of 270mm/Hg. After target pressure is achieved, the participant will be asked to repeatedly make a handgrip or squeeze a foam ball until they develop ischemic pain =4 out of 10 on a 0-10 scale. Once NRS of 4/10 will be achieved, the probe of algometer will be applied in the same manner as during PPT testing. Once the participant presses the button, the probe will be withdrawn, and the cuff will be deflated released from the participants arm. The difference in PPT score (PPT with conditioning minus PPT without conditioning) will be considered the CPM value. A positive value indicates efficient CPM whereas a negative value indicates impaired CPM.	18 months
Secondary	Central aspects of knee pain (CAP-Knee)	Central augmented pain assessed on a 8-item CAP-Knee questionnaire, where items 1-7 are scored from 0-3, 0 indicating "never" and 3 indicating "often" or "always". Item 8 (pain distribution manikin) was allocated a score of 0 if at most 1 knee is shades, and no other regions below the waist, or a score of 3 if both knees were shaded, or one knee plus any additional shaded areas below the waist. A total sum score ranging from 0-24 will be calculated.	18 months
Secondary	Anxiety	Anxiety will be assessed with the Anxiety part of the Hospital Anxiety and Depression Scale (HADS) where patients are asked to indicate their levels of emotion frequency with a 4-level scale (0-3: 0 indicates never and 3 all the time) at 7 questions. A sum of all responses is calculated (21 being the maximum) for analysis. The higher the value the higher the levels of anxiety.	18 months
Secondary	Depression	Depression will be assessed with the Depression part of the Hospital Anxiety and Depression Scale (HADS) where patients are asked to indicate their levels of emotion frequency with a 4-level scale (0-3: 0 indicates all the time and 3 never) at 7 questions. A sum of all responses is calculated (21 being the maximum) for analysis. The higher the value the higher the levels of depression.	18 months
Secondary	Cognitive function	Cognitive function will be assessed with the Cognitive Failures Questionnaire (CFQ) where participants are asked to indicate symptom frequency with a 0-4 scale (0 indicates never and 4 very often) on 25 statements. A sum of all responses is calculated (100 being the maximum) for analysis. The higher the value the more impaired cognitive function is.	18 months
Secondary	Sleep Quality	Sleep quality will be assessed with the Pittsburgh Sleep Quality Index (PSQI) where participants are asked to respond to 18 statements indicating their: 1) sleep duration in minutes/hours on 4 questions, 2) symptom frequency with 4 possible answers spreading from 'not during the past month' to 'three or more times a week' on 12 statements, 3) symptom severity with 4 possible answers spreading from 'no problem at all' to 'very big problem' on 1 statement and 4) sleep quality with 4 possible answers spreading from 'very good' to 'very bad' on 1 statement. Responses are coded from 0-4 (0 indicating no sleeping issues and 4 frequent and severe sleeping problems). A sum of all 18 responses is calculated (72 being the maximum) for analysis. The higher the value the less sleep quality there is.	18 months
Secondary	Knee Pain, Stiffness, and Physical Functioning	Knee pain, stiffness and physical functioning will be assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) where participants are asked to rate their symptom severity with a 0-4 scale (0 indicates never and 4 extreme) five items for pain (score range 0-20), two for stiffness (score range 0-8), and 17 for functional limitation (score range 0-68). The higher the value in each domain the more pain, stiffness and physical dysfunction there is.	18 months
Secondary	General Musculoskeletal Health	General health will be assessed with the Musculoskeletal Health Questionnaire (MSK-HQ) where participants are asked to indicate symptom frequency with a 0-4 scale (0 indicates very severe and 4 not at all severe) on 14 statements. A sum of all responses is calculated (56 being the maximum) for analysis. The lower the value the more reduced general musculoskeletal health is.	18 months
Secondary	Frailty	Frailty will be measured with a modified questionnaire where participants will be asked to respond to 8 Yes/No questions (Yes is marked with 1 and No with 0) about inability to walk, using aids, weight loss, co-morbidities and levels of physical activity. A total out of all responses (8 being the maximum) is calculated for analysis. The higher the score, the higher the levels of frailty	18 months