Comparing dextrose prolotherapy with other substances in knee osteoarthritis pain relief: A systematic review

CRediT authorship contribution statement

Vitor Santos Cortez: Conceptualization, Methodology, Formal analysis, Writing – original draft, Writing – review & editing, Investigation, Validation. Walter Augusto Moraes: Methodology, Formal analysis, Writing – original draft, Writing – review & editing, Investigation, Validation. João Victor Taba: Methodology, Formal analysis, Writing – original draft, Writing – review & editing, Investigation, Validation. Alberto Condi: Methodology, Formal analysis, Writing – original draft, Writing – review & editing, Investigation, Validation. Milena Oliveira Suzuki: Investigation, Validation. Fernanda Sayuri do Nascimento: Validation, Visualization, Writing — review & editing, Investigation. Leonardo Zumerkorn Pipek: Investigation, Validation. Vitoria Carneiro de Mattos: Validation, Visualization, Writing – review & editing, Investigation. Matheus Belloni Torsani: Supervision, Project administration, Investigation, Validation. Alberto Meyer: Supervision, Project administration, Writing – review & editing, Investigation, Validation. Wu Tu Hsing: Supervision, Project administration, Investigation, Validation. Leandro Ryuchi Iuamoto: Conceptualization, Methodology, Supervision, Project administration, Visualization, Investigation, Validation.

Conflicts of interest

The authors declare no conflicts of interest.

Author (publication year, country)

Initial number of participants

Mean age (years) (SD)

Sex (male/female)

Mean BMI (kg/m²) (SD)

KOA grade^a a Measured by Kellgren-Lawrence scale of the Radiological Society of America.OA, Osteoarthritis; D-PRL, Dextrose Prolotherapy; PRP, Platelet-Rich Plasma; CG, Control-Group; EP, Exercise Program; HA, Hyaluronic Acid; Autologus Conditioned Serum, Autologus Conditioned Serum.

Delgado et al.²²22 Delgado DA, Lambert BS, Boutris N, McCulloch PC, Robbins AB, Moreno MR, et al. Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults. J Am Acad Orthop Surg Glob Res Rev 2018;2(3):e088.

Total: 42

D-PRL: 21

PRP: 21

D-PRL: 64.3 ± 5.31

PRP: 65.6 ± 6.64

p = 0.53

D-PRL: 11/10

PRP: 10/11

p=0.76

D-PRL: 28.3 ± 1.9

PRP: 28.6 ± .8

p =0.68

Grade 1‒2

Boonstra et al.²³23 Boonstra AM, Schiphorst HR, Reneman MF, Posthumus JB, Stewart RE. Reliability and validity of the visual analogue scale for disability in patients with chronic musculoskeletal pain Boonstra, Anne M.; Schiphorst Preuper, Henrica R.; Reneman, Michiel F.; Posthumus, Jitze B.; Stewart, Roy E Int J Rehabil Res 2008;31 (2):165–9.

Total: 66

D-PRL: 22

Saline: 22

CG: 22

D-PRL: 55.7 (6.6)

Saline: 54.4 (7.3)

CG: 52 (6.1)

p = 0.313

D-PRL: 3/18

Saline: 2/20

CG: 2/17

p=0.858

D-PRL: 30 (4.6)

Saline: 32.3 (3.7)

CG: 27.6 (4.0)

p =0.003

Grade 2‒3

Rejeski et al.²⁵25 Rejeski WJ, Ettinger WHJ, Shumaker S, Heuser MD, James P, Monu J, et al. The evaluation of pain in patients with knee osteoarthritis: the knee pain scale. J Rheumatol 1995;22(6):1124–9.

Total: 120

D-PRL: 30

Physical therapy: 30

Botulinum neurotoxin: 30

HA: 30

D-PRL: 64.8 (5.8)

Physical therapy: 70 (6.3)

Botulinum neurotoxin: 67.7 (7.3)

HA: 66.1 (9.1)

D-PRL: 11/19

Physical therapy: 12/18

Botulinum neurotoxin: 8/22

HA: 14/16

D-PRL: 32.4 (4.1)

Physical therapy: 33.2 (3.9)

Botulinum neurotoxin: 31.8 (4.7)

HA: 32.6 (2.5)

Grade 3‒4

Vaishya et al.²⁰20 Vaishya R, Pariyo GB, Agarwal AK, Vijay V. Non-operative management of osteoarthritis of the knee joint. J Clin Orthop Traum 2016;7(3):170–6. [Internet].

Total: 90

D-PRL: 30

Saline: 29

EP: 31

D-PRL:56.8 (7.9)

Saline: 56.8 (6.7)

EP: 56.4 (7.0)

p = 0.97

D-PRL: 11/19

Saline: 9/20

EP: 10/21

p=0.82

≤ 25: 10 D-PRL; 8 Saline; 6 EP

25‒30: 6 D-PRL; 11 Saline; 12 EP

≥ 30: 14 D-PRL; 10 Saline; 13 EP

p =0.44

1. Grade 1‒2

D-PRL: 11

Saline: 12

Exercise: 9

2. Grade 3‒4

D-PRL:14

Saline: 9

Exercise: 14

Copsey et al.²¹21 Copsey B, Thompson JY, Vadher K, Ali U, Dutton SJ, Fitzpatrick R, et al. Problems persist in reporting of methods and results for the WOMAC measure in hip and knee osteoarthritis trials. Qual life Res an Int J Qual life Asp Treat Care Rehabil 2019;28 (2):335–43.

Total: 70

D-PRL: 26

Erythropoietin: 20

Pulsed radiofrequency: 24

D-PRL: 60.57 (7.47)

Erythropoietin: 61.15 (7.47)

Pulsed radiofrequency: 56.95 (8.31)

p = 0.45

D-PRL: 10/16

Erythropoietin: 9/11

Pulsed radiofrequency: 11/13

p=0.23

Not reported

Grade 1‒3

Fransen and Edmonds²⁶26 Fransen M, Edmonds J. Reliability and validity of the EuroQol in patients with osteoarthritis of the knee. Rheumatology 1999;38(9):807–13. [Internet].

Total: 104

D-PRL: 52

HA: 52

D-PRL: 61.2 ± 11.5

HA: 63.7 ± 12.2

p = 0.42

D-PRL: 29/25

HA: 33/21

p=0.78

D-PRL: 30.7 ± 1.2

HA: 29.5 ± 1.3

p =0.64

Grade 2‒4

Roos and Lohmander²⁷27 Roos EM, Lohmander LS. The knee injury and osteoarthritis outcome score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64.

Total: 92

D-PRL: 30

PRP: 30

Autologus Conditioned Serum: 32

D-PRL: 57.90 (1.62)

PRP: 58.93 (1.71)

Autologus Conditioned Serum: 61.28 (1.67)

p = 0.338

D-PRL: 15/15

PRP: 16/14

Autologus Conditioned Serum: 12/20

p=0.417

1. D-PRL: Normal (18.50 –25.00): 9; Overweight (25.01–30.00): 14; Obese class I (> 30.01): 7

2. PRP: Normal (18.50 –25.00): 5; Overweight (25.01–30.00): 13; Obese class I (> 30.01): 12

3. Autologus Conditioned Serum: Normal (18.50 –25.00): 4; Overweight (25.01–30.00): 11; Obese class I (> 30.01): 17

p=0.150

1. Grade 2: D-PRL: 7; PRP: 5; Autologus Conditioned Serum: 6

2. Grade 3: D-PRL: 12; PRP: 16; Autologus Conditioned Serum: 9

3. Grade 4: D-PRL: 11; PRP: 9; Autologus Conditioned Serum: 17

Ware²⁴24 Ware JEJ. SF-36 health survey update. Spine 2000;25(24):3130–9. (Phila Pa 1976).

Total 76

D-PRL: 38

Saline: 38

D-PRL: 62.8 (5.8)

Saline: 63.7 (5.2)

D-PRL: 11/27

Saline: 11/27

D-PRL: 24.0 (3.4)

Saline: 25.0 (3.3)

Grade 0-4: 57 were Grade 2‒3

Author (publication year, country)

Group design

Time of interventions

Main parameters (score range)

Time of assessments

Delgado et al.²²22 Delgado DA, Lambert BS, Boutris N, McCulloch PC, Robbins AB, Moreno MR, et al. Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults. J Am Acad Orthop Surg Glob Res Rev 2018;2(3):e088.

1. D-PRL: 7 mL 25%

2. PRP: 7 mL

One IAI at 0 and 1 months

1. WOMAC

a. Pain level (0‒20)

b. Stiffness (0‒8)

c. Functional limitations (0‒68)

d. Total score (0‒96)

0, 1, 2 and 6 months

Boonstra et al.²³23 Boonstra AM, Schiphorst HR, Reneman MF, Posthumus JB, Stewart RE. Reliability and validity of the visual analogue scale for disability in patients with chronic musculoskeletal pain Boonstra, Anne M.; Schiphorst Preuper, Henrica R.; Reneman, Michiel F.; Posthumus, Jitze B.; Stewart, Roy E Int J Rehabil Res 2008;31 (2):165–9.

1. D-PRL + EP

a. IAI: 5 mL 25% (4 mL 30% dextrose+1 mL 0.9% sodium chloride)

b. EAI: 10 mL 15% (5 mL 30% dextrose+2.5 mL 0.9% sodium chloride + 2.5 mL 0.1% lidocaine)

2. Saline +EP

a. IAI: 2.5 mL 0.9% sodium chloride + 2.5 mL 0.1% lidocaine

b. EAI: 5 mL 0.9% sodium chloride + 5 mL 0.1% lidocaine

3. CG: home-based EP

One IAI and EAI at 0, 3 and 6 weeks

1. WOMAC

a. Pain level (0‒20)

b. Stiffness (0‒8)

c. Functional limitations (0‒68)

d. Total score (0‒96)

2. VAS

a. Pain activity (0‒10)

b. Stiffness (0‒10)

3. SF-36

a. PCS (0‒100)

0, 6 and 18 weeks

Rejeski et al.²⁵25 Rejeski WJ, Ettinger WHJ, Shumaker S, Heuser MD, James P, Monu J, et al. The evaluation of pain in patients with knee osteoarthritis: the knee pain scale. J Rheumatol 1995;22(6):1124–9.

1. D-PRL + EP: 8 mL 20% dextrose+2 mL 2% lidocaine

2. Physical therapy + EP

3. Botulinum neurotoxin A +EP: 100 units+5 mL normal saline

4. HA+EP: 2 mL

1. Three IAI 1 month apart

2. 25 min per exercise session

3. One IAI

4. Three IAI 1 week apart

1. VAS

a. Subjective pain (0‒10)

2. KOOS

a. Patients’ opinion of knee and associated problems (0‒100)

0, 1 and 4 weeks, and 3 months

Vaishya et al.²⁰20 Vaishya R, Pariyo GB, Agarwal AK, Vijay V. Non-operative management of osteoarthritis of the knee joint. J Clin Orthop Traum 2016;7(3):170–6. [Internet].

1. D-PRL

a. IAI: 5 mL 50% dextrose + 5 mL lidocaine + 1% saline

b. EAI: 6.75 mL 50% dextrose + 4.5 mL 1% lidocaine + 1% saline

2. Saline

a. IAI: 5 mL 0.9% sodium chloride + 5 mL 1% lidocaine

b. EAI: 18 mL 0.9% sodium chloride + 4.5 mL 1% lidocaine

3. EP

1. Three IAI at 1, 5 and 9 weeks^a

2. Three IAI at 1, 5 and 9 weeks*

3. 3‒5 sessions per week over 20 weeks

* Optional sessions at 13 and 17 weeks

1. WOMAC

a. Pain level (0‒20)

b. Stiffness (0‒8)

c. Functional limitations (0‒68)

d. Total score (0‒96)

2. KPS

a. Knee pain frequency (0‒4)

b. Severity (0‒5)

0, 5, 9, 12, 26 and 52 weeks

Copsey et al.²¹21 Copsey B, Thompson JY, Vadher K, Ali U, Dutton SJ, Fitzpatrick R, et al. Problems persist in reporting of methods and results for the WOMAC measure in hip and knee osteoarthritis trials. Qual life Res an Int J Qual life Asp Treat Care Rehabil 2019;28 (2):335–43.

1. D-PRL: 5 mL dextrose 25% + 5 mL 0.5% ropivacaine

2. Erythropoietin: 5 mL 0.5% ropivacaine + 4000 IU erythropoietin

3. Pulsed radiofrequency

1. One IAI

2. One IAI

3. One 15 min session

1. VAS

a. Subjective pain (0‒10)

2. ROM

a. Knee joint range of motion values determined through goniometric method were recorded in the pertinent forms

0, 2, 4 6and 12 weeks

Fransen and Edmonds²⁶26 Fransen M, Edmonds J. Reliability and validity of the EuroQol in patients with osteoarthritis of the knee. Rheumatology 1999;38(9):807–13. [Internet].

1. HA: 2.5 mL

2. D-PRL: 10 mL 12.5%

1. Three IAI at 0, 7 and 14 days

2. Three EAI at 0, 7 and 14 days

1. WOMAC

a. Total score (0‒96)

2. VAS

a. Pain activity (0‒10)

0 and 3 months

Roos and Lohmander²⁷27 Roos EM, Lohmander LS. The knee injury and osteoarthritis outcome score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64.

1. D-PRL: 2 mL 50% dextrose +2 mL bacteriostatic water + 1 mL 2% lidocaine

2. PRP: 20 mL

3. Autologus Conditioned Serum: 2 mL derived from 20 mL of blood from each patient

1. IAI once a week for 3 weeks

2. IAI two times every 7 days

3. IAI two times every 7 days

1. WOMAC

a. Total score (0‒96)

2. VAS

a. Pain activity (0‒96)

0, 1 and 6 months

Ware²⁴24 Ware JEJ. SF-36 health survey update. Spine 2000;25(24):3130–9. (Phila Pa 1976).

1. D-PRL: 5 mL 25% (2.5 mL 50% dextrose + 2.5 mL sterile water)

2. Saline: 5 mL

1. IAI at 0, 4, 8, and 16 weeks

2. IAI at 0, 4, 8, and 16 weeks

1. WOMAC

a. Pain level (0‒20)

b. Stiffness (0‒8)

c. Functional limitations (0‒68)

d. Total score (0‒96)

2. VAS

a. Pain intensity (0‒100)

3.EuroQol-5d

a. VAS (0‒100)

b. Total score

4. Timed up and go

5. 30 s chair stand

6. 40 m fast-paced walk

0, 16*, 26 and 52 weeks

* EuroQol-5D was not assessed

Author (publication year, country)	Baseline assessment main results (score range) (SD)	Post-intervention last assessment main results (score range) (SD)	Study conclusions	Funding
Delgado et al.²²22 Delgado DA, Lambert BS, Boutris N, McCulloch PC, Robbins AB, Moreno MR, et al. Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults. J Am Acad Orthop Surg Glob Res Rev 2018;2(3):e088.	1. WOMAC Pain level (0‒20) (p=0.76) a. D-PRL: 14.6 ± 1.4 b. PRP: 14.8 ± 1.5 2. WOMAC Stiffness (0‒8) (p= 0.73) a. D-PRL: 5.2 ± 1.3 b. PRP: 5.4 ± 1.2 3. WOMAC Functional limitations (0‒68) (p=0.81) a. D-PRL: 43.3 ± 6.7 b. PRP: 47.8 ± 4.7 4. Total WOMAC (0‒96) (p=0.75) a. D-PRL: 67.1 ± 7.9 b. PRP: 67.9 ± 7.3	6 months: a. D-PRL: 14.6 ± 1.4 b. PRP: 14.8 ± 1.5 2. WOMAC Stiffness (0‒8) (p =0.73) a. D-PRL: 5.2 ± 1.3 b. PRP: 5.4 ± 1.2 3. WOMAC Functional limitations (0‒68) (p=0.81) a. D-PRL: 43.3 ± 6.7 b. PRP: 47.8 ± 4.7 4. Total WOMAC (0‒96) (p= 0.75) a. D-PRL: 67.1 ± 7.9 b. PRP: 67.9 ± 7.3	PRP was more effective when compared to D-PRL and no significant side effects was observed	Not reported
Boonstra et al.²³23 Boonstra AM, Schiphorst HR, Reneman MF, Posthumus JB, Stewart RE. Reliability and validity of the visual analogue scale for disability in patients with chronic musculoskeletal pain Boonstra, Anne M.; Schiphorst Preuper, Henrica R.; Reneman, Michiel F.; Posthumus, Jitze B.; Stewart, Roy E Int J Rehabil Res 2008;31 (2):165–9.	1. Total WOMAC (0‒96) (p=0.761) a. D-PRL: 68.7 (11.4) b. Saline: 69.2 (17.6) c. CG: 68.9 (11.9) 2. VAS Pain activity (0‒10) (p=0.045) a. D-PRL: 7.2 (1.0) b. Saline: 7.4 (2.0) c. CG: 7.0 (0.9) 3. SF-36 PCS (0‒100) (p=0.159) a. D-PRL: 34.1 (8.9) b. Saline: 30 (7.4) c. CG: 35 (9.3)	18 weeks: 1. Total WOMAC (0‒96) a. D-PRL: 32.7 (11.6) b. Saline: 46.7 (13.5) c. CG: 59.8 (10.7) 2. VAS Pain activity (0‒10) a. D-PRL: 1.1 (1.9) b. Saline: 4.6 (1.8) c. CG: 4.5 (2.0) 3. SF-36 PCS (0‒100) a. D-PRL: 48.5 (7.5) b. Saline: 39.6 (8.5) c. CG: 41.1 (11.7)	D-PRL may become a promising method for KOA treatment	Scientific Research Projects Unit of the Istanbul University (ID: 41877)
Rejeski et al.²⁵25 Rejeski WJ, Ettinger WHJ, Shumaker S, Heuser MD, James P, Monu J, et al. The evaluation of pain in patients with knee osteoarthritis: the knee pain scale. J Rheumatol 1995;22(6):1124–9.	1. VAS Subjective pain (0‒10) (p=0.125) a. D-PRL: 6.5 (1.3) b. Physical therapy: 7.2 (1.1) c. Botulinum neurotoxin: 6.6 (1.6) d. HA: 6.7 (0.7) 2. KOOS (0-100) (p=0.111) a. D-PRL: 99.4 (13.7) b. Physical therapy: 94 (15.1) c. Botulinum neurotoxin: 93.3 (16.8) d. HA: 89.9 (14.3)	3 months: 1. VAS Subjective pain: Botulinum neurotoxin and D-PRL were better pain management therapies, while HA was the least efficient method 2. KOOS: Botulinum neurotoxin and D-PRL scores were reduced more than physical therapy (non-statistically significant difference), while HA was the least efficient method	D-PRL or botulinum neurotoxin type A could be effective first-line treatments. Physical therapy can be useful if patient is not willing to continue regular therapeutic programs	None
Vaishya et al.²⁰20 Vaishya R, Pariyo GB, Agarwal AK, Vijay V. Non-operative management of osteoarthritis of the knee joint. J Clin Orthop Traum 2016;7(3):170–6. [Internet].	1. WOMAC Pain level (p =0.73) a. D-PRL: 66.8 (14.9) b. Saline: 62.7 (14.3) c. EP: 63.2 (13.1) 2. WOMAC Stiffness (p=0.49) a. D-PRL: 57.1 (19.9) b. Saline: 53.9 (14.2) c. EP: 55.3 (18.0) 3. WOMAC Functional limitations (p=0.73) a. D-PRL: 65.2 (15.8) b. Saline: 67.6 (17.5) c. EP: 61.9 (12.7) 4. Total WOMAC (p =0.73) a. D-PRL: 63.1 (15.0) b. Saline: 62.7 (14.3) c. EP: 60.5 (11.3)	52 weeks: 1. WOMAC Pain level mean score change a. D-PRL: 14.18 (SE 3.62) b. Saline: 7.38 (SE 3.67) c. EP: 9.24 (SE 3.63) 2. WOMAC Stiffness mean score change a. D-PRL: 15.55 (SE 4.66) b. Saline: 9.97 (SE 3.67) c. EP: 8.31 (SE 4.68) 3. WOMAC Functional limitations mean score change (p < 0.001) a. D-PRL: 16.25 (SE 3.39) b. Saline: 5.46 (SE 3.44) c. EP: 7.31 (SE 3.4) 4. Total WOMAC mean score change (p= 0.022) a. D-PRL: 15.32 (SE 3.32) b. Saline: 7.59 (SE 3.36) c. EP: 8.24 (SE 3.33)	D-PRL was more effective when compared to Saline and EP	National Institutes of Health: National Center for Complementary and Alternative Medicine (5K23AT001879-02)
Copsey et al.²¹21 Copsey B, Thompson JY, Vadher K, Ali U, Dutton SJ, Fitzpatrick R, et al. Problems persist in reporting of methods and results for the WOMAC measure in hip and knee osteoarthritis trials. Qual life Res an Int J Qual life Asp Treat Care Rehabil 2019;28 (2):335–43.	1. VAS Subjective pain (0‒10) (p=0.349) a. D-PRL: 7.11 (1.03) b. Erythropoietin: 6.65 (0.96) c. Pulsed radiofrequency: 7.08 (1.08) 2. ROM (p=0.339) a. D-PRL: 101 (1.36) b. Erythropoietin: 98.08 (1.60) c. Pulsed radiofrequency: 95 (1.97)	12 weeks: 1. VAS Subjective pain (0‒10) (p= 0.002) a. D-PRL: 5.53 (1.60) b. Erythropoietin: 3.50 (1.23) c. Pulsed radiofrequency: 5.50 (1.93) 2. ROM (p=0.039) a. D-PRL: 113 (2.16) b. Erythropoietin: 123 (1.53) c. Pulsed radiofrequency: 113 (2.16)	Erythropoietin was more effective than D-PRL or pulsed radiofrequency	Not reported
Fransen and Edmonds²⁶26 Fransen M, Edmonds J. Reliability and validity of the EuroQol in patients with osteoarthritis of the knee. Rheumatology 1999;38(9):807–13. [Internet].	1. VAS Pain instensity (0‒10) a. D-PRL: 7.8 ± 1.4 b. HA: 8.2 ± 1.7 2. Total WOMAC (0‒96) a. D-PRL: 52.7 ± 9.8 b. HA: 55.9 ± 10.4	1. VAS Pain intensity (0‒10) (p= 0.02) a. D-PRL: 2.5 ± 1.1 b. HA: 2.1 ± 0.6 2. Total WOMAC (0‒96) (p < 0.001) a. D-PRL: 83.7 ± 12.7 b. HA: 88.5 ± 15.6	Both methods had positive results, but HA was more effective than D-PRL in pain and symptoms control	Not reported
Roos and Lohmander²⁷27 Roos EM, Lohmander LS. The knee injury and osteoarthritis outcome score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64.	1. VAS Pain activity (0‒96) (p=0.120) a. D-PRL: 67.00 (2.50) b. PRP: 61.10 (1.21) c. Autologus Conditioned Serum: 61.25 (3.44) 2. Total WOMAC (0‒96) (p=0.103) a. D-PRL: 65.93 (1.67) b. PRP: 60.33 (3.70) c. Autologus Conditioned Serum: 56.28 (3.13)	6 months: 1. VAS Pain activity (0‒96) a. D-PRL: 63.30 (2.92) b. PRP: 55.00 (2.27) c. Autologus Conditioned Serum: 35.00 (3.51) 2. Total WOMAC (0‒96) a. D-PRL: 72.33 (2.57) b. PRP: 45.67 (3.82) c. Autologus Conditioned Serum: 34.88 (3.35)	Autologus conditioned serum and PRP are more effective than D-PRL	Physical Medicine and rehabilitation Reseach center, Tabriz University of Medical Sciences (Grant no. 63138)
5. VAS Pain intensity: Difference between groups: -10.98 (-21.36 to -0.61)*	1. WOMAC Pain a. D-PRL: 49.9 (23.1) b. Saline: 44.0 (20.4) 2. WOMAC Stiffness a. D-PRL:48.0 (26.3) b. Saline: 46.8 (27.0) 3. WOMAC Function a. D-PRL: 49.0 (21.8) b. Saline: 45.9 (22.1) 4. Total WOMAC a. D-PRL: 49.1 (21.8) b. Saline: 45.6 (21.2) 5. VAS Pain intensity a. D-PRL: 63.1 (21.2) b. Saline: 60.1 (19.2)	52 weeks: 1. WOMAC Pain level Difference between groups: -10.34 (-19.20 to -1.49)* 2. WOMAC Stiffness Difference between groups: -8.01 (-18.56 to 2.54) 3. WOMAC Function limitations Difference between groups: -9.55 (-17.72 to -1.39)* 4. Total WOMAC Difference between groups: -9.65 (-17.77 to -1.53)* *p < 0.05	D-PRL may be appropriate care for patients with KOA refractory to more conservative care	Chinese University of Hong Kong Direct Grant for Research 2013-14 (HKD 40,000)

Author (publication year, country)	Reported limitations
Delgado et al.²²22 Delgado DA, Lambert BS, Boutris N, McCulloch PC, Robbins AB, Moreno MR, et al. Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults. J Am Acad Orthop Surg Glob Res Rev 2018;2(3):e088.	1. Lack of CG. 2. Lack of morphological assessment of structures in and around the knee joint. 3. Small sample size. 4. Limited timeframe for patient assessment.
Boonstra et al.²³23 Boonstra AM, Schiphorst HR, Reneman MF, Posthumus JB, Stewart RE. Reliability and validity of the visual analogue scale for disability in patients with chronic musculoskeletal pain Boonstra, Anne M.; Schiphorst Preuper, Henrica R.; Reneman, Michiel F.; Posthumus, Jitze B.; Stewart, Roy E Int J Rehabil Res 2008;31 (2):165–9.	1. Small sample size. 2. Limited timeframe for patient assessment. 3. Higher number of female patients. 4. Participants with moderate-to-severe pain level and refractory to conservative therapy.
Rejeski et al.²⁵25 Rejeski WJ, Ettinger WHJ, Shumaker S, Heuser MD, James P, Monu J, et al. The evaluation of pain in patients with knee osteoarthritis: the knee pain scale. J Rheumatol 1995;22(6):1124–9.	1. Limited timeframe for patient assessment. 2. Did not evaluate combined therapy.
Vaishya et al.²⁰20 Vaishya R, Pariyo GB, Agarwal AK, Vijay V. Non-operative management of osteoarthritis of the knee joint. J Clin Orthop Traum 2016;7(3):170–6. [Internet].	1. Small sample size. 2. Lack of very severe baseline WOMAC scores. 3. Relative youth of the participants. 4. Indirect assessment of participant satisfaction. 5. Radiographs were not avaliable for all participants. 6. Exclusion of patients taking chronic opioids.
Copsey et al.²¹21 Copsey B, Thompson JY, Vadher K, Ali U, Dutton SJ, Fitzpatrick R, et al. Problems persist in reporting of methods and results for the WOMAC measure in hip and knee osteoarthritis trials. Qual life Res an Int J Qual life Asp Treat Care Rehabil 2019;28 (2):335–43.	1. Limited follow up time. 2. Lack of literature on intra-articular prescription of erythropoietin.
Fransen and Edmonds²⁶26 Fransen M, Edmonds J. Reliability and validity of the EuroQol in patients with osteoarthritis of the knee. Rheumatology 1999;38(9):807–13. [Internet].	None reported
Roos and Lohmander²⁷27 Roos EM, Lohmander LS. The knee injury and osteoarthritis outcome score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64.	1. Limited budget making long-term follow up of 12 or 24 months impossible. 2. Due to the different characteristics of injected materials (color and viscosity), it was not possible to design a double-blinded study.
Ware²⁴24 Ware JEJ. SF-36 health survey update. Spine 2000;25(24):3130–9. (Phila Pa 1976).	1. Lack of a usual care group may limit the external validity. 2. Exclusion of morbidly obese patients may limit the generalizability of the data. 3. Treatment of only one painful knee may not reflect the overall efficacy of D-PRL. 4. Failure to track the amount of exercise and weight loss in each group. 5. Language and culture differences also limited direct comparisons to other work.

[1] *Corresponding author. E-mail address: leandro.iuamoto@fm.usp.br (L.R. Iuamoto).

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Comparing dextrose prolotherapy with other substances in knee osteoarthritis pain relief: A systematic review

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