Nutrition as a Risk Factor and Predictor of the Outcome of Orthobiological Treatments for Knee Osteoarthritis
Conditions: Musculoskeletal Diseases, Osteoarthritis, Knee, Nutrition, Healthy
Sponsor: I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio

                   
 
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Nutrition as a risk factor and predictor of the outcome of orthobiological treatments for 
knee osteoarthritis 
 
 
 
 
 
 
 
 
 
PI: Paola De Luca 
Laboratorio di Biotecnologie Applicate all’Ortopedia  
Istituto Ortopedico Galeazzi 
Via R. Galeazzi 4 
20161, Milano 
 
 
 
 
 
 

                   
 
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SYNOPSIS 
Title 
Nutrition as a risk factor and predictor of the outcome of orthobiological treatments 
for knee osteoarthritis 
Protocol number 
Nutririsk(L4154)  
Type of study 
Monocentric, observational with additional procedure (extra routine blood 
sampling, questionnaires and measurement  of  Nutritional status), prospective, 
non-controlled. 
Duration 
36 months 
PI 
Paola De Luca 
General Aim 
The general purpose of this study is to evaluate the relation between the nutritional 
status of patients, the features of the orthobiologics products used for patients’ 
treatment and the clinical outcomes after one-step conservative regenerative 
treatment for knee osteoarthritis. 
Primary Outcome: 
The primary outcome of the study will be the identification of the proportion of 
responders and non-responders patients to the orthobiologic treatment (according to 
OMERACT-OARSI [1] criteria) at 6-month follow-up and of their related nutritional 
status. 
Secondary Outcomes 
The secondary outcomes of the study will be: 
- the identification of the proportion of responders and non-responders patients to 
the orthobiologic treatment (according to OMERACT-OARSI criteria [1]) at 2 and 12-
month follow-up and of their related nutritional status; 
- the characterization of the orthobiologic products used for the patient’s treatment. 
Patient enrolment 
Patients affected by knee osteoarthritis undergoing conservative regenerative 
medicine procedures  with autologous material at IRCCS Istituto Ortopedico Galeazzi 
and participating to the observational study “REGAIN”  will be enrolled for this 
study: 
88 patients will be needed: 
1) 22 subjects with body mass index (BMI) considered normal weight (≥18.5 and 
≤25) undergo to Platelet-Rich Plasma (PRP) treatment; 
2) 22 subjects with BMI values that exceed the normal weight range (BMI>25) 
 undergo to PRP treatment; 
3) 22 subjects with BMI within the considered normal weight range (≥18.5 e ≤25) 
and undergo to microfragmented adipose tissue treatment; 
4) 22 subjects with BMI values that exceed the normal weight range undergo to 
microfragmented adipose tissue treatment. (BMI>25) 

                   
 
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Inclusion and exclusion 
criteria 
Inclusion criteria: 
- 
males and females ≥18 and ≤ 65 years; 
- 
presence of knee osteoarthritis; 
- 
indication to regenerative medicine treatments PRP or microfragmented adipose 
treatment; 
- 
participation to the observational study “REGAIN”; 
- 
patients with BMI ≥18.5; 
- 
signature of Informed Consent for the study. 
Exclusion criteria:  
- 
patients with BMI <18.5; 
- 
patients who are not able to comply with the study schedule. 
 
Statistical analysis and 
Sample Size 
Statistical analysis will be performed using R Software. Categorical variables will be 
compared between cells and groups using Chi-square or Fisher’s exact test. 
Continuous data distribution will be assessed using Shapiro Wilk test. According to 
the results of the normality test, between groups differences will be assessed by the 
proper Student’s t test (paired or unpaired) or the equivalent non-parametric test 
(Wilcoxon, Mann-Whitney). Two-way ANOVA or general linear regression models will 
be used to assess the effect of two or more variable of the study outcomes. P-values 
<0.05 will be considered statistically significant. 
The sample size has been calculated considering as the primary outcome the 
proportion of patients not responsive (according to OMERACT-OARSI [1] criteria) to 
therapy at the 6-month follow-up in two distinct groups of patients:  subjects with 
body mass index within the reference ranges (Group 1 or 3) and subjects with values 
outside the range (Group 2 or 4).  The proportion of unresponsive patients is expected 
to be 0.45 in Group 1 or 3 and 0.05 in Group 2 or 4. Considering a power of 80% and 
a significance level of 0.05 for a one-tailed Fisher exact test, the sample size is 20 
subjects per group,  and considering 10% of possible dropouts, the number is 
increased to 22 patients per group. The study will be replicated in two classes of 
patients, undergoing PRP or microfragmented adipose tissue treatments.  Then, 44 
patients will be enrolled per class, for a total of 88 patients.  
 
Table of Contents 
SYNOPSIS .......................................................................................................................................................................... 2 
1.0 
Background ........................................................................................................................................................... 6 

                   
 
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2.0 Study aims and flow chart ......................................................................................................................................... 6 
2.1 General aim ............................................................................................................................................................ 6 
2.2 Primary Outcome ................................................................................................................................................... 6 
2.3 Secondary outcomes .............................................................................................................................................. 7 
2.4 Flow-Chart .............................................................................................................................................................. 7 
3.0 Study design ............................................................................................................................................................... 8 
3.1 Study methodology – subjects ............................................................................................................................... 8 
3.2 Study duration ........................................................................................................................................................ 9 
4.0 Patient enrollment ..................................................................................................................................................... 9 
4.1 Inclusion criteria ..................................................................................................................................................... 9 
4.2 Exclusion criteria: ................................................................................................................................................. 10 
4.3 Subject identification ........................................................................................................................................... 10 
5.0 Statistical methodology ........................................................................................................................................... 10 
5.1 Sample size ........................................................................................................................................................... 10 
6.0 Potential risks/benefit ............................................................................................................................................. 10 
6.1 Benefits ..................................................................................................................................................................... 10 
7.0 Ethical Considerations .............................................................................................................................................. 11 
7.1 Ethics Committee ................................................................................................................................................. 11 
7.2 Subject information and informed consent ........................................................................................................ 11 
7.3 Insurance and monitoring .................................................................................................................................... 11 
7.4 Protection of personal data ................................................................................................................................. 11 
8.0 Administrative Procedures ...................................................................................................................................... 11 
8.1 Curriculum vitae ................................................................................................................................................... 11 
8.2 Information about Staff involved ........................................................................................................................ 12 
8.3 Publications .......................................................................................................................................................... 12 
8.4 Funds ..................................................................................................................................................................... 12 

                   
 
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9.0 Bibliography .............................................................................................................................................................. 12 
 
 

                   
 
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1.0 Background  
 
Osteoarthritis (OA) is a multifactorial pathology that includes the synovial fluid inflammation and damage to the 
articular cartilage with consequent loss of it and remodeling of the subchondral bone [2]. Obesity, metabolic syndrome 
and diabetes can directly influence the development of OA [3]. To date, the main treatments of this disease concern 
the control of symptoms or, in the most severe cases, the replacement of the joint [4-5]. Although the Osteoarthritis 
Research Society International guidelines recommend physical exercise and weight loss in overweight and obese 
subjects, this type of solution is often not implemented [6]. Obesity and therefore the high body mass index (BMI), 
represent a risk factor for OA not only for the high load that the joint has to bear, but also for the inflammatory state, 
albeit mild, deriving from it at systemic level, as demonstrated by the presence of OA in obese patient hands [7]. 
Besides to the fact that the high BMI leads to an increase in the OA incidence, it is interesting to investigate the role 
of an incorrect and inadequate nutritional status in the arthrosis pathology, with particular attention to the level of 
the quality of the patient's autologous product (orthobiologic) uses for the treatment.  Orthobiologic is a promising 
nonoperative treatment defined as biological material (including platelet rich plasma (PRP), mesenchymal stem cells, 
microfragmented adipose tissue) used to improve the healing of a musculoskeletal tissue such as cartilage. They 
promote healing process through the release of growth factors and molecules involved in healing and inflammation 
[8]. 
It is easy to understand how the success of a treatment depends on the quality of the product used and it becomes 
essential to find strategies capable of improving the quality of starting material especially in terms of anti-
inflammatory and immunomodulatory potential. It is known that diet directly influences the inflammatory state both 
at the systemic level and at the joint tissue level. Just as an incorrect diet causes an increase in the inflammatory state 
[9], a balanced and controlled diet can modulate the structure of cytokines favoring the anti-inflammatory ones as 
already demonstrated [10]. In this contest, a clear example is represented by Mediterranean diet, resulted associated 
with lower prevalence of OA [11]. Between the conservative treatment for OA, PRP [12] and Microfragmented adipose 
tissue [13] injection represent innovative regenerative approaches more and more widespread. Previous study 
demonstrated that dietary can induced changes in fatty acid composition of human plasma, platelet, and erythrocyte 
lipids [14]. 
The emerging role of extracellular vesicles (EVs) in the cell communication defining them as biomarkers, has become 
a source of interest in the study of different metabolic disease [15-17]. For all these reasons a characterization of 
extracellular vesicles derived from orthobiologics of patients with different nutritional status deserves to be 
investigated. 
2.0 Study aims and flow chart 
2.1 General aim 
The general purpose of this study is to evaluate the relation between the nutritional status of patients, the features 
of the orthobiologics products used for patients’ treatment and the clinical outcomes after one-step conservative 
regenerative treatment for knee osteoarthritis. 
 
2.2 Primary Outcome  
The primary outcome of the study will be the identification of the proportion of responders and non-responders 
patients to the orthobiologic treatment (according to OMERACT-OARSI [1] criteria) at 6-month follow-up and of their 
related nutritional status. 
For this purpose the responder or non-responder patients will be identified based on the results of the VAS, Tegner-
Lysholm Activity Scale and KOOS scores according to the parameters established by Outcome Measures in Rheumatoid 
Arthritis Clinical Trials (OMERACT) and Osteoarthritis Research Society International (OARSI). 

                   
 
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2.3 Secondary outcomes  
The secondary outcomes of the study will be: 
- the identification of the proportion of responders and non-responders patients to the orthobiologic treatment 
(according to OMERACT-OARSI criteria [1]) at 2 and 12-month follow-up and of their related nutritional status; 
- the characterization of the orthobiologic products used for the patient’s treatment. 
 
2.4 Flow-Chart 
 
 
Enrollment 
Surgical 
procedure 
After patients 
discharge 2 
month (+/- 2 
week) 
After patients 
discharge 6 
month (+/- 2 
weeks) 
After patients 
discharge 12 
month (+/- 1 
month) 
Sign of Informed 
Consent 
X 
 
 
 
 
Evaluation of 
inclusion criteria 
X 
 
 
 
 
Evaluation of 
nutritional status 
(anthropometric 
measurements, 
plicometry, 
questionnaires) 
X 
 
 
 
Collection of PRP 
or 
microfragmented 
adipose tissue for 
orthobiologics 
characterization  
X 
 
 
 
Collection of 
blood sample 
(concomitant to 
routine blood 
sample for PRR; 
extra routine 
blood sample for 
X 
 
 
 
 

                   
 
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microfragmented 
adipose tissue) 
Collection of data 
from REGAIN 
questionnaires  
X 
 
X 
X 
X 
Collection of food 
questionnaires 
 
X 
 
 
 
 
3.0 Study design 
Monocentric, observational with additional procedure (extra routine blood sampling, questionnaires and 
measurement  of  Nutritional status), prospective, non-controlled. 
 
 
3.1 Study methodology – subjects 
After the ethics committee approval, patients meeting the inclusion criteria undergoing conservative knee 
regenerative medicine treatments with orthobiologics and participating to the observational study “REGAIN”   will be 
enrolled into the study. The PROMs will be completed by patients based on their clinical condition and on the specific 
treatment they will receive at the REGAIN Center. The aforementioned PROMs include but are not limited to:  
- VAS, Tegner-Lysholm Activity Scale, KOOS. 
Patients will be asked to filled the PROMs at the time of the enrollment (before the treatment) and then at 2, 6 and 
12 months after the treatment.  
Blood and nutritional information will be collected only the day of the treatment to allow for evaluation of the possible 
association between patients’ characteristics and treatment outcomes. Blood sampling will be performed to carry out 
the following laboratory analysis, in detail: complete blood count, blood glucose, hemoglobin A1C (HbA1c), creatinine, 
GOT and GPT transaminases, C reactive protein, triglycerides, total cholesterol, HDL.  
In particular, for patients undergoing a PRP treatment, a blood sample is already routinely harvested and therefore 
only an extra test tube will be added to test blood glucose, hemoglobin A1C (HbA1c), creatinine, GOT and GPT 
transaminases, C reactive protein, triglycerides, total cholesterol, HDL. For patients undergoing a treatment with 
microfragmented adipose tissue, an ad hoc blood collection will be carried out by filling two test tubes. 
 
Nutritional information include anthropometric measurements, diet history and food consumption questionnaire (24h 
recall, “Quanto mangio veramente”, Italian Mediterranea Index, anamnesi). Anthropometric measurements include 
weight and height, waist circumference, arm circumference measurements, biceps, triceps, subscapular and suprailiac 
folds measurement (plicometry) through the use of the skinfolder. It should be noted that the skinfolder is only one 
of the tools used to evaluate the patient's nutritional status, without diagnostic purposes and without the will to 
investigate anything about the device.  
 
Concerning the orthobiologics characterization, PRP and microfragmented adipose tissue will undergo to different 
evaluations as per the observational study protocol “Utilizzo dei Patient-Reported Outcome Measures (PROMs), delle 
valutazioni cliniche oggettive e biomolecolari per il monitoraggio dei pazienti sottoposti a trattamenti di medicina 
rigenerativa”.  
 

                   
 
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In addition, for the purpose of this study, isolation and characterization of extracellular vesicles derived from PRP and 
micro fragmented adipose tissue will be performed, in order to deepen the orthobiologic characterization.  The 
following techniques will be applied, where appropriate: 
- 
Count and identification of cells from PRP and microfragmented adipose tissue (hemacytometer, 
nucleocounter, flow cytometry); 
- 
Extracellular vesicle isolation, count and dimensional analysis (ultracentrifuge, Nanosights); 
- 
Extracellular vesicle marker identification (flow cytometry). 
 
These data will be analyzed for their possible association with nutritional status of the patient and clinical outcomes.  
Regardless the specific protocol or investigation, the analysis will not include genomic DNA or diagnostic analysis. All 
samples (blood and tissues) will be analyzed at Istituto Ortopedico Galeazzi and destroyed at the end of the study.  
3.2 Study duration 
 
Total duration of study: 36 months 
Starting: after approval of Ethical Committee 
Time for sample collection/enrollments:  22 months  
Time for data collection at the last follow-up: 12-34 months 
Data analysis: 30- 36 months 
4.0 Patient enrollment 
Will be included patients affected by knee osteoarthritis undergoing conservative regenerative medicine procedures  
with autologous material at IRCCS Istituto Ortopedico Galeazzi and participating to the observational study [REGAIN]  
 
88 patients will be needed: 
1) 22 subjects with body mass index (BMI) considered normal weight (≥18.5 and ≤25) undergo to Platelet-Rich 
Plasma (PRP) treatment; 
2) 22 subjects with BMI values that exceed the normal weight range (BMI>25) 
 undergo to PRP treatment; 
3) 22 subjects with BMI within the considered normal weight range (≥18.5 e ≤25) and undergo to microfragmented 
adipose tissue treatment; 
4) 22 subjects with BMI values that exceed the normal weight range undergo to microfragmented adipose tissue 
treatment. (BMI>25) 
 
4.1 Inclusion criteria 
- 
males and females ≥18 and ≤ 65 years; 
- 
diagnosis of knee osteoarthritis (any Kellgren-Lawrence grade); 
- 
indication to regenerative medicine treatments with PRP or microfragmented adipose treatment; 

                   
 
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- 
participation to the observational study “REGAIN” ; 
- 
patients with BMI ≥18.5; 
- 
signature of Informed Consent for the study. 
 
4.2 Exclusion criteria: 
- 
Patients with BMI <18.5; 
- 
patients who are not able to comply with the study schedule. 
 
 
4.3 Subject identification 
Researchers will prepare an identification list in chronological order of all the subjects recruited for the study to 
correlate an ID number with the personal information of the subjects preserving the subject anonymity, according to 
the D.Lgs. 196/2003 and ssm and EU Regulation 679/2016 and Guidelines of the Privacy Authority 24/07/2008. 
5.0 Statistical methodology 
5.1 Sample size 
The sample size was calculated considering as primary outcome the proportion of patients not responder  to treatment 
(according to OMERACT-OARSI [1] criteria) at the 12-month follow-up in two distinct groups of patients:  subjects with 
body mass index within the reference ranges (Group 1 and 3) and subjects with values outside the range (Group 2 and 
4).  The proportion of unresponsive patients is expected to be 0.45 in Group 1 and 0.05 in Group 2. Considering a 
power of 80% and a significance level of 0.05 for a one-tailed Fisher exact test, the sample size is 20 subjects per group 
and considering 10% of possible dropouts, this number is increased to 22 patients. The study will be replicated in two 
classes of patients, undergoing PRP or microfragmented adipose tissue treatments.  Then, 44 patients will be enrolled 
per class, for a total of 88 patients.  
 
5.2 Analysis methodology 
Statistical analysis will be performed using R Software. Categorical variables will be compared between cells and 
groups using Chi-square or Fisher’s exact test. Continuous data distribution will be assessed using Shapiro Wilk test. 
According to the results of the normality test, between groups differences will be assessed by the proper Student’s t 
test (paired or unpaired) or the equivalent non-parametric test (Wilcoxon, Mann-Whitney). Two-way ANOVA or 
general linear regression models will be used to assess the effect of two or more variable of the study outcomes.  
P-values <0.05 will be considered statistically significant. 
6.0 Potential risks/benefit  
6.1 Benefits 
Patients will not have direct benefits by participating in this study. Compared to the enlarged scientific community, 
the study may indirectly contribute to an extension of knowledge in the direction of potential clinical applications of 
the results obtained.   
The identification of new associations between the evaluation of nutritional status (including anthropometric 
measurements of body composition, biochemical analysis, evaluation of food consumption and energy expenditure), 
quality of orthobiologics and clinical outcome of patients will allow to predict which or how nutritional aspects has an 
impact on clinical result. In this scenario, the results of this study will allow to identify the need of possible modification 
of patients’ food habits to favor better results of the regenerative treatment, improving their life quality and reducing 
the societal economic burden.  
 
6.2 Potential risks 

                   
 
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One risk could be related to blood sampling for biochemical assays: possible complications could be lipotimia, slight 
pain or irritation at the sampling site. Another risk could be related to the detection of anthropometric 
measurements such as redness at the landmark with skinfolder. 
7.0 Ethical Considerations 
The protocol is compliant with current Declaration of Helsinki, with EN ISO 14155: 1 and EN ISO 14155: 2 and the        
Good Clinical Practice (GCP) and all the staff involved in the study is committed to acting in accordance with the 
principles contained therein. 
7.1 Ethics Committee 
All documentation relating to this study must be submitted to the Ethics Committee, for the necessary approvals.     
The beginning of the study and the inclusion of individuals is subordinate to the favorable opinion expressed by Ethics 
Committee.  
Any amendment to the protocol, information to the patient and the informed consent form must be submitted to the 
Ethics Committee. 
It is the responsibility of the principal investigator of the study to inform the ethics committee of complications or 
adverse events that may be of interest to the subjects included in the study and any problems that may present a risk 
to the subject, according to current regulations. 
7.2 Subject information and informed consent 
Before being included in the study, subjects who meet all the criteria for inclusion and exclusion of the study, should 
be informed in detail by persons authorized by the principal investigator and be placed in a position to understand 
objective, meaning, duration of the study. All the risks / benefits, advantages / disadvantages must be discussed with 
the subject. Before admission to the study, the subject must give their written informed consent by signing and dating 
the form, of which will receive a copy. The subject is guaranteed that participation in the study is voluntary and that 
at any moment can withdraw from the study without suffering any consequences. 
7.3 Insurance and monitoring 
The only additional procedure that implies a minimal risk is blood sample collection. Then, the Sponsor assume that a 
specific insurance policy is not necessary. For the same reason no monitoring activities will be performed. 
7.4 Protection of personal data 
The researcher conforms to the principle of the right of the subject to the protection of privacy under Legislative 
Decree no. 196/2003 and ssm and UE regulation 679/2016 and guidelines of the privacy authority 24/07/2008. All 
clinical data recorded on the CRF and used for further evaluation are anonymous. Patient’s clinical data and are coded 
by number of subject, date of birth and identification is restricted to authorized personnel involved in the study and 
under the responsibility of the researcher. Clinical data of the subject are stored and processed electronically for 
purposes of scientific evaluation, but any discussion or analysis of the data will always be done anonymously. 
8.0 Administrative Procedures 
8.1 Curriculum vitae 
The PI of the project can provide an updated CV demonstrating her experience in research projects in the field of 
nutrition and regenerative medicine for musculoskeletal disorders. She has a special research interest in the 
characterization of orthobiologics products such as PRP and microfragmented adipose tissue. In particular, she has 
been involved in several in vitro and clinical studies including the investigation of the importance of the nutritional 

                   
 
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role in post-operative recovery of orthopaedic patients, as well as the role of mesenchymal stem cells and tissue 
resident progenitor cells for the treatment of musculoskeletal disorders.  
8.2 Information about Staff involved  
The researcher has the responsibility to inform all personnel involved in the study of all the relevant aspects of the 
study. A list of personnel designated by the principal investigator to be involved directly or indirectly in the study in 
question should be set up, updated and stored. 
8.3 Publications 
All data collected in this study are property of the IRCCS Galeazzi Orthopaedic Institute.  
It is foreseeable the production of manuscripts and abstract. The principal investigator is committed to the publication 
of results and will be responsible for publishing the results of this study. The principal researcher can publish or present 
the study results in accordance with this section of the protocol. 
The principal investigator is entitled to use the results of all the work produced according to this protocol, including, 
but not limited to, test results and statistical data obtained. The principal institute/researcher agrees that, apart from 
his or her employees, executives, collaborators, and representatives, the data will not be disclosed except after written 
consent. 
It is the responsibility of the principal investigator to send the study report to the competent authorities. 
 
8.4 Funds 
Funds for lab analysis and for preliminary activities of the Ethical Committee will be covered with funds of the Ministry 
of Health and research funds. 
 
 
 
9.0 Bibliography 
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T, Underwood M, McAlindon TE. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular 
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Jan 3. PMID: 31917095. 
 
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