Osteoarthritis (OA) of the knee is a chronic degenerative disorder characterized by progressive disintegration and softening of the articular cartilage in the synovial joints. It is often accompanied by osteophyte development, subchondral sclerosis, and cyst formation.1 Elderly and obese adults are at the highest risk for developing knee OA. Therefore, this disease is one of the most common causes of disability.2 The management of knee OA includes nonoperative therapy, such as analgesic drugs and physiotherapy, and operative treatment including osteotomy and knee arthroplasty.1 Moreover, the risk of falls increases in patients with knee OA because mechanical receptors around the knee joint may be vulnerable because of anatomical changes caused by OA. Hence, impaired sensory input results in the inability to perform normal knee movement and is accompanied by a decline in muscle strength,3 joint proprioception,4 and balance.5 Furthermore, some studies have demonstrated that muscle strength, joint proprioception, and balance could be improved in patients with knee OA after proper intervention.6,7
Platelet-rich plasma (PRP) is an autologous product that mainly contains concentrated platelets and growth factors. It is known to enhance tissue healing at injury sites through modification of the biological microenvironment.8 Given its biochemical and biological nature, PRP treatment has received much attention for its use in the treatment of knee OA.9,10 Recent studies have demonstrated that PRP exerts favorable effects on pain and knee joint function compared with placebo in early stages of the knee OA. However, the effectiveness of PRP in OA is still debatable because previous studies differed in the concentrations of leucocytes used for the preparation of PRP, dosage schedules, and so on.11 Moreover, no study has investigated the effect of PRP in comparison with that of a placebo injection in the same patient with bilateral knee OA. It is of interest to examine the effect of PRP in the same patient with bilateral OA.
Isokinetic testing is frequently used as a diagnostic tool to measure muscle strength and dysbalance and to document therapeutic effect and disease progression in patients with joint or muscle disorders.12 Only two previous studies have used isokinetic testing to evaluate the efficacy of the intra-articular injection of hyaluronic acid (HA) in patients with knee OA, Both studies showed positive results for muscle strength.7,12 However, muscle strength after PRP injection has not been reported.
The goal of the present study was to conduct a prospective, randomized, double-blind, and placebo-controlled study to evaluate the effects of PRP on pain, functional activity, and isokinetic strength in patients with bilateral knee OA. We hypothesized that intra-articular injection of PRP would reduce pain, restore joint function, and increase muscle strength to a greater degree than a placebo injection with normal saline.
This study was conducted at the Tri-Service General Hospital, Taiwan. The study protocol was reviewed and approved by the institutional review board of the Tri-Service General Hospital (Number 2-103-05-075) and all eligible patients provided written informed consent before enrollment. The study conforms to all CONSORT guidelines and reports the required information accordingly (see Checklist, Supplemental Digital Content, http://links.lww.com/PHM/A534). This clinical study was registered at ClinicalTrials.gov (Registration Number NCT02239029). A total of 20 patients were eligible. Their knees (n = 40) were randomized into two groups: PRP group (treated with a single intra-articular PRP injection in the right or left knee via a coin toss) and saline group (the contralateral knee of the same patient, treated via a single 4-mL intra-articular injection of normal saline) (Fig. 1). The coin was tossed 20 times, with heads indicating the right (n = 8) and tails indicating the left (n = 12) knee. All participants were followed up for 6 mos after injection.
Patients with a radiological diagnosis of degenerative joint disease of both knees equivalent to Ahlback Stage I–II were recruited for this study. The stage of degeneration was interpreted by the same radiologist with 8 yrs of experience in orthopedic imaging.13 Eligible participants met the following criteria: age of 50–75 yrs, pain in both knees lasting for a minimum of 6 mos, same OA grade in both knees, and bilateral pain level during walking of at least 4 on visual analog scale. The following exclusion criteria were applied: intra-articular injections (such as HA or steroids) in the knee joint 6 mos before the study, anti-inflammatory medication administered 1 wk before the study, intra-articular tumors, previous knee surgery, any other connective tissue disorder affecting the knee joint, use of anticoagulants, liver disease, cancer history, and inability to undergo muscle strength testing.
Platelet-Rich Plasma Preparation
Platelet-rich plasma was prepared as previously described.14 Briefly, 10 ml of blood was withdrawn from the antecubital vein of each patient and centrifuged at 1500 × g (3400 rpm) for 15 mins at room temperature using the universal centrifuge Regen Lab to that provide 4 ml of PRP (RegenKit-THT-1, Regen Lab, Le Mont-sur-Lausanne, Switzerland), which is a leukocyte- and platelet-rich plasma according to the Dohan Ehrenfest et al. classification.15
The patient was seated with the knee flexed at 70 degrees. The needle was inserted into the intra-articular joint space of the knee 1 cm above the tibial plateau and 1 cm lateral to the patellar tendon toward the femoral notch. This has been demonstrated to be the most accurate injection site for ensuring intra-articular penetration of the drug (93% accuracy rate).16 The physician, who had more than 10 yrs of experience in intra-articular injection of the knee joint, performed the injection in all patients. The injection syringe was covered to prevent patients from being able to identify the contents. In addition, patients turned their heads away from the direction of the syringe when the physician performed the injection. Patients received no analgesics or any other intra-articular injection during the study period. Other treatments, such as physical therapy and therapeutic exercises, were not prescribed. Only acetaminophen (500 mg, up to 4 g/d) was allowed as a rescue medication during the course of the study.
The Western Ontario and McMaster's Universities Osteoarthritis Index (WOMAC) was considered the primary outcome measure. The WOMAC includes 3 subscales with 24 items (5 items for pain, 2 items for joint stiffness, and 17 items for physical function). All items ranged from 0 (mildest) to 10 points (most severe).17 The WOMAC was evaluated at baseline and at 2 wks, 1 mo, 3 mos, and 6 mos after injection. The secondary outcome variable was muscle performance evaluated using isokinetic testing at baseline and at 2 wks, 1 mo, 3 mos, and 6 mos after injection. The evaluation of muscle strength of the knees in both groups was performed with a calibrated isokinetic testing machine (Biodex System 3 Pro, Biodex Corporation, Shirley, NY) according to standard procedures.18 The reproducibility, reliability, and safety of this device and technique are well demonstrated.18–20 The patient was seated with 90-degree hip flexion with the shoulder, wrist, thigh, and tested lower leg fixed with straps. The patient was instructed to perform concentric knee exercises, including flexion and extension, at angular velocities of 60 degree/sec and 180 degree/sec, respectively. A resting interval of 90 secs was allowed between the two velocity tests. Peak torque (Newton meter) was recognized as the maximal force produced by the tested musculature at different angular velocities. The average was calculated using the values obtained from three measurements. The same investigator, with 6 yrs' experience in isokinetic testing and who was blinded to the randomization, documented the clinical assessment and isokinetic testing results. The demographic data of patients were also collected.
To reduce the type II error and increase the power of the study, a preliminary power analysis using G*power 126.96.36.199 statistical software (University of Düsseldorf, Düsseldorf, Germany), based on a power (1-β) of 0.8, α of 0.05, and effect size of 0.45 was performed, indicating that a total sample of 17 patients was necessary in each group.
Statistical analyses were performed using IBM SPSS Statistics Version 22 (Asia Analytics Taiwan Ltd, Taipei, Taiwan). Demographic data were analyzed using the Mann-Whitney U test for continuous data and the χ2 test for categorical data. The differences within the groups were investigated using repeated-measures analysis of variance (ANOVA), followed by post-hoc tests, whereas the difference between the groups was investigated with the Mann-Whitney U test. Statistical significance was set at a P value of less than 0.05.
All 20 participants (5 men and 15 women; mean [SD] age = 63.25 [6.84] yrs) completed the study. Their clinical and demographic characteristics are presented in Table 1. The dominant foot of all patients was on the right foot. Fourteen of 20 knees (70%) were documented as having Ahlback Stage I, and six of 20 knees (30%) as having Ahlback Stage II in both groups. The injection sites for PRP were the left knee in 12 and the right knee in 8 patients. No statistically significant difference in Ahlback Stage, injection site, and duration between the two groups was observed.
As shown in Table 2, no significant differences in baseline WOMAC scores were found between the two groups. The results revealed that both the PRP and placebo groups exhibited improved WOMAC subscales and total scores at all follow-up assessments (P < 0.05). Significant differences in WOMAC pain and total score improvements were found between the two groups at all follow-up assessments (P < 0.05). Interestingly, PRP treatment resulted in significantly lower WOMAC stiffness scores than saline injection at weeks 2 and 4, whereas significant differences in WOMAC function were observed at the third month. A tendency toward decreased differences between groups during a longer follow-up period was observed (Fig. 2).
Next, we determined the effects of PRP on muscle strength in patients with knee OA. As shown in Table 3, both groups exhibited significant improvements in knee strength at each time point compared with baseline (P < 0.05), whereas changes in extensors at angular velocities of 180 degrees/sec were insignificant at each time point compared with baseline (P > 0.05) in the placebo knees. The data also indicated a greater percentage of knee strength improvement (extensor > flexor) and the strength differences between the two knees became more obvious when the follow-up period was longer. Unexpectedly, PRP treatment resulted in insignificant differences in muscle strength compared with saline, whereas the only significant improvements in flexor at angular velocities of 60 degrees/sec were observed at the sixth month (P = 0.04). Neither obvious complications nor adverse effects related to the injections were observed during the treatment and follow-up period in both groups.
We conducted a prospective, randomized, double-blind, and placebo-controlled study to simultaneously evaluate the effects of intra-articular PRP on pain, functional activity, and isokinetic strength in the same patient with bilateral knee OA. We found that intra-articular injections of PRP or normal saline improved pain, stiffness, disability, and knee strength in patients with mild to moderate knee OA. We showed that PRP treatment resulted in significantly better improvement in pain, stiffness, and disability than normal saline.
Increasing evidence has highlighted the efficacy of intra-articular injections of PRP for OA with promising clinical outcomes. Montañez-Heredia et al.21 reported a double-blind randomized controlled trial to assess the efficacy of PRP versus HA in knee OA with three intra-articular injections at 15-day intervals. Pain and functional improvements were evaluated before and after treatment (3- and 6-mo follow-up) using visual analog scale, the Knee and Osteoarthritis Outcome System scale, and the European Quality of Life scale. The authors concluded that PRP treatment effectively improved pain at 3 mos after injection compared with HA in patients with early OA grades.21 Kavadar et al.22 reported 102 patients with grade 3 OA knee randomized into three groups and who received PRP injected with once, twice, or three times. Each injection was separated by a 2-wk interval. The result was recorded before treatment and at 1, 3 and 6 mos after the treatment via the visual analog scale, WOMAC, and Timed Up and Go test. The authors concluded that PRP is effective for the treatment of pain and functional status in moderate knee OA.22 A recent study revealed that intra-articular PRP significantly decreased symptoms compared with HA or placebo in patients with knee OA.23 However, a recent trial with a large number of 192 patients reported that the efficacy of PRP was comparable with that of HA treatment.24 It was suggested that the study design can have a crucial influence on outcome measurements, with a faulty design leading to the misinterpretation of results.
Few studies with placebo-controlled, double-blind, and randomized designs have been published.25,26 In these studies, patients with bilateral knee OA received either PRP or placebo injection in one knee; the injection of a placebo might interfere with the results because patients may tend to feel improvement in the injected knee. It was suggested that the intra-articular injection of PRP and a placebo in the same patient is a relatively ideal study model as long as the grade of OA is the same in both knees (as per the inclusion criteria of the current study). Besides, previous studies established that PRP injection into only one OA knee instead of both knees could also be measured by WOMAC individually.27 Although a crossover study would also be a suitable design, we did not consider it because such studies require long follow-up periods. The same grade of OA in both knees of the same patient also diminished the impact of model selection in this study. In the present study, we found that concurrent intra-articular injection with PRP and normal saline in the same patient could significantly improve pain, stiffness, strength, and disability. Furthermore, obvious differences between the two knees were observed during initial follow-up and progressively declined over time, suggesting that PRP has immediate effects comparable with those of saline alone. We found a tendency toward decreased differences between the knees with a longer follow-up period. A possible explanation is that saline is associated with a placebo effect, leading to improvement in symptoms. In addition, it was postulated that the pain relief effect of PRP on one knee with OA might contribute to improving pain in the other knee injected with normal saline through a compensatory mechanism, because both limbs were constantly used during the course of the study.
Pain and low muscle strength are associated with limited knee function in patients with knee OA. It has been suggested that patients with chronic pain exhibit pain avoidance behavior leading to muscle wasting. A recent study has demonstrated that the reduction of pain is associated with improved joint and muscle strength in patients with OA receiving intra-articular injections of HA.11 Isokinetic muscle strength has been shown to improve in response to the injection of HA in patients with OA.7 In those two studies, the effect of HA on the muscle strength of the knee was determined 5 wks after injection. In the present study, we reported the long-term follow-up of muscle strength after intra-articular injection of PRP and saline in patients with knee OA, showing improvements in the maximum peak torque in extension and flexion at both low (60 degree/sec) and high angular velocities (180 degree/sec) after the injections in both groups. The tendency toward increased differences between the knees at longer follow-up periods was observed in the PRP knees compared with the saline knees. This may have resulted from pain reduction (PRP > saline) as measured by WOMAC, which tends to make patients more willing to use their knee joints and ensures that muscle strength continues to improve. The muscles of the knee, the quadriceps, and hamstrings are known to work together to stabilize the knee joint. Quadriceps strength is important for the protection of the articular structures. Thus, decreased quadriceps strength might be a primary risk factor for knee OA.28 It has been reported that elderly patients with pain related to knee OA usually have weak quadriceps muscles because of disuse atrophy. Disuse due to pain was defined as one of the major reasons for this muscle weakness.13 The present results are in agreement with those of previous studies, showing greater percentages of improved knee strength in the extensors than in the flexors. However, none of the participants received additional strength exercises, and a follow-up duration of 6 mos is insufficient to observe the expected differences. The only significant improvements in the flexors at angular velocities of 60 degree/sec are observed at the sixth month (P < 0.05) (Table 3). This may due to the small size of the study population. Because most patients with chronic pain may avoid using the affected joints during daily activities and inactivity may cause muscle wasting, the failure of significant long-term maintenance of strength improvement may be predictable regardless of pain improvement. It has been suggested that these patients should be instructed to perform adequate concurrent strength exercises to augment their strength recovery. All types of strength exercise (isometric, isotonic, and isokinetic) have a similar important impact on knee OA. However, the optimal dosage (intensity, frequency, and duration) has not yet been established.29 Further studies are necessary in the future.
The present study has some limitations. First, the size of the study population was relatively small. Second, concurrent injection with PRP and normal saline in the same patient may overestimate the impact of the placebo effect and further mask the differences between the groups. Further studies with a larger sample size, more conscientious design, and longer follow-up duration are required to elucidate the effects of PRP on isokinetic muscle strength. Third, because of cost and ethical issues, we used only a single injection of PRP or saline instead of multiple injections and were unable to measure PRP composition, including the concentrations of platelets, white blood cells, and growth factors. Most previous studies used one PRP injection in their study design. Moreover, Patel et al.30 showed that a single dose of PRP is as effective as a double dose in early knee OA. This finding supports the validity of our study design and our aim was to design a placebo-controlled study rather than a dose-dependent or concentration-dependent one. Further studies implementing these design elements may be necessary in the future.
In conclusion, this prospective, randomized, double-blind, placebo-controlled study revealed that both intra-articular PRP and normal saline injected into a patient with bilateral knee OA could improve long-term pain, functional activity, and knee strength. Furthermore, PRP treatment significantly improves pain, stiffness, and disability in patients with knee OA compared with normal saline treatment. Additional strengthening training is recommended to enhance muscle strength recovery.
The authors thank Miss Jenifert Hsu who provided technical assistance for the completion of this study.
1. Vaishya R, Pariyo GB, Agarwal AK, et al: Non-operative management of osteoarthritis
of the knee
joint. J Clin Orthop Trauma
2. Van Manen MD, Nace J, Mont MA: Management of primary knee osteoarthritis
and indications for total knee
arthroplasty for general practitioners. J Am Osteopath Assoc
3. Kirkley A, Webster-Bogaert S, Litchfield R, et al: The effect of bracing on varus gonarthrosis. J Bone Joint Surg Am
4. Barrett DS, Cobb AG, Bentley G: Joint proprioception in normal, osteoarthritic and replaced knees. J Bone Joint Surg Br
5. Khalaj N, Abu Osman NA, Mokhtar AH, et al: Balance and risk of fall in individuals with bilateral mild and moderate knee osteoarthritis
. PLoS One
6. Sun SF, Hsu CW, Hwang CW, et al: Hyaluronate improves pain, physical function and balance in the geriatric osteoarthritic knee
: a 6-month follow-up study using clinical tests. Osteoarthritis Cartilage
7. Tang SF, Chen CP, Chen MJ, et al: Improvement of muscle strength in osteoarthritic knee
patients after intraarticular knee
injection of hyaluronan. Am J Phys Med Rehabil
8. Zhou Y, Wang JH: PRP treatment efficacy for tendinopathy: a review of basic science studies. Biomed Res Int
9. Campbell KA, Erickson BJ, Saltzman BM, et al: Is local viscosupplementation injection clinically superior to other therapies in the treatment of osteoarthritis
of the knee
: a systematic review of overlapping meta-analyses. Arthroscopy
10. Lubowitz JH: Editorial commentary: autologous platelet-rich plasma
11. Dhillon MS, Patel S, John R: PRP in OA knee
- update, current confusions and future options. SICOT J
12. Miltner O, Schneider U, Siebert CH, et al: Efficacy of intraarticular hyaluronic acid in patients with osteoarthritis
—a prospective clinical trial. Osteoarthritis Cartilage
13. Ahlback S: Osteoarthrosis of the knee
. A radiographic investigation. Acta Radiol Diagn (Stockh) Suppl
14. Napolitano M, Matera S, Bossio M, et al: Autologous platelet gel for tissue regeneration in degenerative disorders of the knee
. Blood Transfus
15. Dohan Ehrenfest DM, Rasmusson L, Albrektssson T, et al: Classification of platelet concentrates: from pure platelet-rich plasma
(P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF). Trends Biotechnol
16. Jackson DW, Evans NA, Thomas BM: Accuracy of needle placement into the intra-articular space of the knee
. J Bone Joint Surg Am
17. Barr S, Bellamy N, Buchanan WW, et al: A comparative study of signal versus aggregate methods of outcome measurement based on the WOMAC Osteoarthritis
Index. Western Ontario and McMaster Universities Osteoarthritis
Index. J Rheumatol
18. Ho CW, Chen LC, Hsu HH, et al: Isokinetic muscle strength of the trunk and bilateral knees in young subjects with lumbar disc herniation. Spine (Phila Pa 1976)
19. Chen LC, Kuo CW, Hsu HH, et al: Concurrent measurement of isokinetic muscle strength of the trunk, knees, and ankles in patients with lumbar disc herniation with sciatica. Spine (Phila Pa 1976)
20. Drouin JM, Valovich-mcLeod TC, Shultz SJ, et al: Reliability and validity of the Biodex system 3 pro isokinetic dynamometer velocity, torque and position measurements. Eur J Appl Physiol
21. Montañez-Heredia E, Irízar S, Huertas PJ, et al: Intra-articular injections of platelet-rich plasma
versus hyaluronic acid in the treatment of osteoarthritic knee
pain: a randomized clinical trial in the context of the Spanish National Health Care System. Int J Mol Sci
22. Kavadar G, Demircioglu DT, Celik MY, et al: Effectiveness of platelet-rich plasma
in the treatment of moderate knee osteoarthritis
: a randomized prospective study. J Phys Ther Sci
23. Meheux CJ, McCulloch PC, Lintner DM, et al: Efficacy of intra-articular platelet-rich plasma
injections in knee osteoarthritis
: a systematic review. Arthroscopy
24. Filardo G, Di Matteo B, Di Martino A, et al: Platelet-rich plasma
injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med
25. Smith PA: Intra-articular autologous conditioned plasma injections provide safe and efficacious treatment for knee osteoarthritis
: an FDA-sanctioned, randomized, double-blind, placebo-controlled clinical trial. Am J Sports Med
26. Paterson KL, Nicholls M, Bennell KL, et al: Intra-articular injection of photo-activated platelet-rich plasma
in patients with knee osteoarthritis
: a double-blind, randomized controlled pilot study. BMC Musculoskelet Disord
27. Cerza F, Carnì S, Carcangiu A, et al: Comparison between hyaluronic acid and platelet-rich plasma
, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med
28. Tok F, Aydemir K, Peker F, et al: The effects of electrical stimulation combined with continuous passive motion versus isometric exercise on symptoms, functional capacity, quality of life and balance in knee osteoarthritis
: randomized clinical trial. Rheumatol Int
29. Filardo G, Kon E, Longo UG, et al: Non-surgical treatments for the management of early osteoarthritis
. Knee Surg Sports Traumatol Arthrosc
30. Patel S, Dhillon MS, Aggarwal S, et al: Treatment with platelet-rich plasma
is more effective than placebo for knee osteoarthritis
: a prospective, double-blind, randomized trial. Am J Sports Med
Platelet-Rich Plasma; Osteoarthritis; Knee
Supplemental Digital Content
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.