Ketogenic Diet to Reduce Osteoarthritis Pain in MCI (KDROP-MCI)

Osteoarthritis and mild cognitive impairment are common conditions that share underlying biological processes related to metabolism and inflammation. This study will examine whether a well-formulated ketogenic diet influences pain, physical function, and cognitive outcomes in adults with osteoarthritis and mild cognitive impairment. Participants will follow a supervised ketogenic dietary intervention, with assessments conducted before and after the intervention to evaluate changes in symptoms and related biological markers. The goal of this study is to better understand shared mechanisms between joint pain and cognitive health and to explore whether a ketogenic dietary approach may support symptom management in these populations.

Study Overview

• Status: Not yet recruiting
• Conditions: Osteoarthritis; Dementia; Mild Cognitive Impairment (MCI); Mild Cognitive Impairment; MCI; Osteoarthritis (OA) of the Knee; Osteoarthritis (OA) of the Shoulder; Osteoarthritis (OA) of the Hip
• Intervention / Treatment: Other: Well-formulated ketogenic diet

Detailed Description

OA and dementia are two leading contributors to disability worldwide. Although traditionally studied separately, accumulating evidence indicates substantial overlap in their underlying inflammatory, metabolic, and neuroimmune pathways. Chronic OA pain is associated with systemic inflammatory mediators, increased peripheral nociceptor sensitization, impaired descending inhibition, and central neuroinflammation driven by microglia and astrocyte activation. These same mechanisms contribute to cognitive decline, reduced synaptic plasticity, hippocampal vulnerability, and progression from MCI to ADRD.

In aging adults, chronic pain accelerates cognitive decline and increases risk for dementia, and cognitive impairment exacerbates pain-related disability. Neuroinflammation-particularly microglial activation and NLRP3 inflammasome signaling-is a shared mechanistic link between the two conditions. Identifying interventions that target this shared biology is crucial for improving outcomes for older adults with comorbid pain and cognitive decline.

The ketogenic diet has demonstrated therapeutic effects in multiple neurological, metabolic, and inflammatory conditions. Mechanisms include suppression of the NLRP3 inflammasome, improved mitochondrial efficiency, enhanced lipid metabolism via TREM2-associated pathways, reduced oxidative stress, reduced systemic inflammation, glycemic control, and modulation of gut microbiota.

Preclinical data show that ketone bodies improve cognitive function and reduce neuroinflammation in models of AD. Human studies demonstrate the feasibility and potential cognitive benefit of WFKD in ADRD populations and post-concussion syndrome. Additionally, this study team recently investigated the impact of an 8-week WFKD on modifiable risk factors associated with metabolic syndrome, on gut microbiota structure, and RNASeq in healthy, middle-aged adults. However, the application of a WFKD to individuals with OA and early cognitive impairment is unexplored. Our team has conducted two previous clinical trials and is currently analyzing outcomes of an NIA-funded clinical trial using the WFKD. Participants from these trials have successfully adopted the WFKD, evidenced by objective and reported ketone body production and macronutrient profile of dietary intake. The WFKD used in these trials improved micronutrient intake and intake of non-starchy vegetables, and suggests that the WFKD may benefit cognition in patients with AD and symptoms in patients with post-concussion syndrome.

This population is particularly relevant given the aging US population, the high prevalence of OA-associated chronic pain, the presence of early neuroinflammation and neurodegeneration, poor diet quality contributing to systemic inflammation, and heightened vulnerability to cognitive decline, reduced quality of life, and hospitalization/institutionalization.

Understanding how a WFKD influences pain, neuroinflammation, central sensitization, cognitive performance, and biologic indicators from the gut and peripheral nerves will provide critical insight into mechanistic targets for future clinical trials.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jessica Keller, PhD, RDN; Phone Number: 913-609-5915; Email: jkeller8@kumc.edu

Study Locations

• United States
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Medical Center
      • Contact: Jessica Keller, PhD, RDN; Phone Number: 913-609-5915; Email: jkeller8@kumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• English speaking
• Diagnosis of major joint osteoarthritis
• Diagnosis of mild cognitive impairment

Exclusion Criteria:

• Diabetes that requires insulin
• Cancer requiring chemo- or radiation therapy in the last 2 years
• Cardiac event within 1 year
• Recent history of renal stones
• Diagnosis of fibromyalgia
• Already following a ketogenic diet
• Following a dietary pattern that does not allow for a ketogenic approach
• Unable to control one's diet

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Well-formulated ketogenic diet; This is a dietary intervention that is very low carbohydrate, higher healthy fats, and adequate protein.

Other: Well-formulated ketogenic diet; This is a very low carbohydrate eating pattern that is higher in fat with adequate protein. This approach focuses on a nutrient dense, whole foods approach to a ketogenic diet and recommends 4-6 servings of non-starchy vegetables per day, 1/4 cup of berries per day, daily intake of nuts/seeds, fatty fish 2-3 times per week, and an emphasis on healthy fats like avocado, nuts, and olive oil.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity and pain interference using a Visual Analog Scale	Patient- and caregiver-reported outcome. 0-10 with higher scores reflecting worse pain.	From enrollment to the end of treatment at 8 weeks
Health-related quality of life using a Questionnaire	Patient- and caregiver-reported ouctome.The PROMIS-29+2 Profile is a patient-reported outcome measure with domain scores converted to standardized T-scores (mean = 50, SD = 10), where higher scores indicate worse symptoms for anxiety, depression, fatigue, sleep disturbance, and pain interference, better functioning for physical function, social participation, and cognitive function, and pain intensity is rated separately on a 0-10 scale with higher scores indicating greater pain.	From enrollment to end of treatment at 8 weeks
Physical Function via Functional Activities Questionnaire	Caregiver-reported outcome. FAQ is 0-30 with higher scores indicating worse impairment.	From enrollment to end of treatment at 8 weeks.
Montreal Cognitive Assessment (MoCA) for brief global cognitive screening	Cognitive screener completed by the participant and administered by the study coordinator. The Montreal Cognitive Assessment (MoCA) is a 30-point cognitive screening tool assessing multiple cognitive domains, with total scores ranging from 0 to 30 and higher scores indicating better cognitive function.	From enrollment to end of treatment at 8 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Central sensitization	Physical assessment of the participant. Temporal summation is a quantitative sensory testing measure of central sensitization calculated as the increase in reported pain intensity following repeated identical stimuli, with higher values indicating greater pain facilitation.	From enrollment to end of treatment at 8 weeks.
Ketone levels	We will run a correlational analysis on depth of ketosis and change in pain intensity. We will consider 'nutritional ketosis' as 0.5 mmol/L or higher.	From enrollment to end of treatment at 8 weeks.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: Characterize ketogenic diet-induced changes in the gut	Stool microbiome profiling; Alpha diversity (Observed species, Shannon, Chao1); Beta diversity (Bray-Curtis, UniFrac); Differential abundance of taxa associated with inflammation, SCFA production, bile acid metabolism, metabolic health, and neurodegeneration; Functional pathway analyses (PICRUSt2)	From enrollment to end of treatment at 8 weeks.
Exploratory: Characterize ketogenic diet-induced changes in intraepidermal nerve fiber density	Skin biopsies -Intraepidermal nerve fiber density (IENFD)	From enrollment to end of treatment at 8 weeks.
Exploratory: immunostaining skin sample for ASC, a marker of NLRP3 inflammasome activation	Marker expression will be reported as percent positive cells and/or immunoreactivity intensity quantified by digital image analysis (arbitrary units of optical density or fluorescence intensity) within defined regions of interest.	From enrollment to end of the 8 weeks.

Collaborators and Investigators

• Sponsor: University of Kansas Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: December 17, 2025
• First Submitted That Met QC Criteria: February 13, 2026
• First Posted (Actual): February 18, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: chronic pain; osteoarthritis; ketogenic diet; mild cognitive impairment
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Musculoskeletal Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Arthritis; Joint Diseases; Rheumatic Diseases; Neurocognitive Disorders; Cognition Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cognitive Dysfunction; Osteoarthritis; Chronic Pain; Dementia
• Other Study ID Numbers: KDROPMCI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No