Effects of Bone Marrow Aspirate Concentrate-Platelet-rich Plasma Versus Hyaluronic Acid on Patients with Knee Osteoarthritis: A Randomized Controlled Trial

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https://doi.org/10.35827/cp.2020.19.1.8

접수일: 2020년 3월 20일, 게재승인일: 2020년 6월 5일 책임저자: 김상준, 서울시 서초구 남부순환로 2606

06737, 서울준재활의학과

Tel: 02-576-0100, Fax: 02-577-0035 E-mail: [email protected]

골수 흡인-혈소판 풍부 혈장과 히알루론산의 관절강내 주사의 효과 비교

성균관대학교 의과대학 삼성서울병원 재활의학교실^１, 가톨릭대학교 의과대학 내과학교실 내분비내과²,

이엔셀 바이오, R&D 센터³, 서울준재활의학과⁴

이병찬¹ㆍ김아란¹ㆍ김은경²ㆍ김선정³ㆍ김상준⁴

Effects of Bone Marrow Aspirate Concentrate-Platelet-rich Plasma Versus Hyaluronic Acid on Patients with Knee Osteoarthritis: A Randomized Controlled Trial

Byung Chan Lee, M.D.¹, Ah Ran Kim, M.D.¹, Eun Kyung Kim, M.S.², Sun Jeong Kim, M.S.³ and Sang Jun Kim, M.D., Ph.D.⁴

１Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, ²Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, ³R&D Center, ENCell Co. Ltd, ⁴Seoul Jun Rehabilitation Clinic, Seoul, Korea

Objective: To compare the therapeutic efficacy of the bone marrow aspirate concentrate (BMAC)- platelet-rich plasma (PRP) complex with hyaluronic acid in patients with knee osteoarthritis. Method: Thirty-four patients with knee osteoarthritis participated in this study. Seventeen patients in the study group underwent BMAC and PRP extraction followed by intra-articular injection of BMAC-PRP complex within affected knee. Seventeen patients in the control group underwent intra-articular injection of hyaluronic acid. Knee injury, osteoarthritic outcome score (KOOS), and EuroQol-5D (EQ-5D) questionnaire were evaluated before, one month, three months, and six months after the injection. Results: There were statistically significant temporal differences in total KOOS scores in both BMAC-PRP and HA groups. However, there were no significant group difference in the study period. In the Sports and Recreational Function Scale, there was statistically significant improvement in the BMAC-PRP group compared to the HA group at three months (p=0.041). There were no side effects or complications in both groups. Conclusion: Intra-articular injection of BMAC-PRP showed better functional recovery in the OA at three months and this can be an alternative treatment in terms of functional recovery in the OA in addition to the decrease of pain. (Clinical Pain 2020;19:8-15)

Key Words: Bone marrow aspiration concentrates, Platelet rich plasma, Hyaluronic acid, Osteoarthritis, Knee

INTRODUCTION

Knee osteoarthritis (OA) is the most common joint disease that causes pain and disability. Cartilage loss, sub- chondral bone changes, synovial inflammation, and me- niscus degeneration is common pathologic changes of OA.¹ According to worldwide prevalence estimates, 9.6% of males and 18.0% of females over 60 years have symptomatic OA.² The prevalence rate is increasing with the aging

society, and recent studies predict that it will constitute one-fourth of the causes of disability by 2020.³ OA symptoms are mostly controlled with symptomatic management, including oral medication for relieving pain and intra-articular (IA) injection with steroid or hyaluronic acid (HA).

Total joint arthroplasty of the knee can be considered when conservative symptomatic management fails.⁴

However, most of these treatments focus on relief of symptoms of OA to increase function and mobility, not on delay or prevention of disease progression to avoid disability. In recent years, new biological treatments using for several orthopedic conditions including focal cartilage injuries, OA, and soft tissue injuries have recently grown in popularity to delay or prevent OA progression. In partic- ular, previous studies demonstrated effects of growth fac-

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tors in cartilage repair both in vitro and in vivo.^5-8 Platelet-rich plasma (PRP), one biological treatment, is concentrated autologous growth factors from a patient's blood. Clinical improvements such as reducing pain and improving quality of life have been reported by intra-articular PRP injections for treatment of focal chondral defects and OA patients.^9-12 In addition, previous studies reported that the effect of IA injection of PRP is equivalent or even superior to IA injection of HA.^11,12 The mechanism of PRP is based on growth factors, including transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), bone morphogenetic proteins (BMPs), and platelet-derived growth factor (PDGF). These factors inhibit inflammation and pain while enhancing biosynthesis of cartilage and bone matrix.¹¹

The use of IA injection of bone marrow aspirate concentrate (BMAC) in various orthopedic conditions has recently become popular. Centrifuged materials from bone marrow aspirates composed of isolated cellular components in dis- tinct layers is called BMAC, which is considered mini- mally manipulated. White blood cells, mesenchymal stem cells (MSCs), hematopoietic stem cells, and platelets are concentrated into one layer and red blood cells into another layer.¹³ IA injection of MSCs contained in BMAC has been reported to treat joint pain. MSCs has tri-lineage potential to hold promise for tissue regeneration, most notably for chondrogenic potential.¹⁴ However, Shapiro et al.¹⁴ demonstrated negative and inconclusive results of IA injection of BMAC in patients with knee osteoarthritis.

Previous studies demonstrated that conjunction with scaffold and BMAC can enhance the viability and differentiation of stem cells.¹⁵ Scaffold materials include HA, collagen, fibrin glue, adipose tissues, and PRP. In partic- ular, PRP may improve the environment for MSC develop- ment and differentiation.¹⁶ PRP can also stimulate MSC proliferation, preserve MSC multipotency, and does not in- terfere with any lineage differentiation.¹⁷ Recent studies reported good regenerative potential in BMAC-PRP complex in diabetic ulcers,¹⁶ osteochondral defects,¹⁸ and spinal cord injury.¹⁹

To the best of our knowledge, the efficacy of IA injection of BMAC-PRP in the knees of patients with OA has not been established. This study compares the clinical outcomes of IA injection of BMAC-PRP and HA in knees of patients with OA.

MATERIALS AND METHODS

This study was conducted as a prospective, open-label, randomized controlled, comparative study in Samsung Medical Center. Patients were enrolled from the outpatient clinic and treated with BMAC-PRP or hyaluronic acid intra-articular knee injections. The following inclusion criteria were used for patient selection: adult older than 19 years, suffered from chronic (at least three months) knee pain or swelling, and radiologically confirmed degenerative changes in the knee joint (simple radiography or MRI).

Exclusion criteria were history of knee arthroplasty or intra-articular steroid injection within three months, suspi- cious for systematic infection or inflammation (ESR over 40 mm/hr, CRP over 10 mg/dl), hematologic disorder (coagulopathies), anticoagulant therapy, immunosuppressant medication, and undergoing chemotherapy for cancer.

After recruitment, patients were randomly assigned to BMAC-PRP and hyaluronic acid (HA) groups. Demographic data including age, sex, involved side, and Kellgren and Lawrence (K-L) grade were collected. The K-L grade de- scribes knee OA on plain radiographs as 0 (no radiologic features of OA), 1 (possible joint space narrowing and osteophyte), 2 (definite osteophyte formation and possible joint space narrowing on weight bearing radiograph), 3 (multiple osteophytes, definite joint space narrowing, sclerosis, and possible bony deformity), and 4 (large osteophytes, marked joint space narrowing, severe sclerosis and definite bony deformity). Knee injury and osteoarthritic outcome score (KOOS) and EuroQol-5D (EQ-5D) ques- tionnaires were administered by one experienced physician who was blinded to group assignment of each patient to evaluate pain and disability. These outcome instruments were recorded before the procedure and at 1 month after, 3 months after, and 6 months after the procedure in both groups. Knee plain radiography was obtained before and 6 months after the procedure.

BMAC extraction was taken from Patients in the BMAC-PRP group. Patients laid on a table in the prone position. Skin sterilization was performed by povidone io- dine and skin and periosteum anesthetic procedure by 1%

lidocaine was followed. The iliac bone was penetrated by a bone marrow aspiration needle and aspiration of bone marrow was performed. To isolate concentrated BMACs, bone marrow aspirates were centrifuged with a BIOMET

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Fig. 1. BIOMET MarrowStim^TM Mini kit was used to acquire bone marrow aspirates. Acquired bone marrow aspirates were centrifuged to isolate the concentrated BMACs. BMAC: bone marrow aspirate concentration.

MarrowStim^TM Mini kit (Biomet Biologics, Inc., Warsaw, IN, USA) (Fig. 1).

To extract PRP, 60 ml autologous whole blood was re- trieved from a patient’s median cubital vein. The whole blood was centrifuged with a BIOMET GPS^TM III kit (Biomet Biologics, Inc.). 6 ml of citrate anticoagulant and 54 ml of autologous whole blood were mixed and then centrifuged at 3,200 RPM for 15 minutes. The platelet-poor plasma (PPP) was then separated. Extraction of remaining PRP contents followed.

After procedure, 2 ml of BMACs and 1 ml of PRP were mixed in a 5 ml syringe. IA injection BMAC-PRP to osteoarthritis knee joint was performed by one experienced physiatrist. IA injection of HA to osteoarthritic knee joint was performed in HA group.

Oral medication including non-steroidal anti-inflammatory drugs and other pain killers was prohibited during the study period. Only acetaminophen was allowed.

Initially, to address clinical improvement, total score, score of subscales of KOOS and EQ-5D from baseline to the final follow-up and between-group differences were evaluated with dependent and independent t tests, respectively. Repeated measures analysis of variance models for total KOOS and all five KOOS subscale, EQ-5D in each group were performed to evaluate within-group changes over time for each follow-up interval. Post-hoc analysis was performed by the Scheffé test to evaluate significant differences between each follow-up time points. SPSS 20.0 software (IBM Corp, Chicago, IL, USA) was used for anal- ysis, and p less than 0.05 were considered statistically significant.

Sample size was calculated based on the literature comparing KOOS between surgical and non-surgical treatment

groups.²⁰ A difference of at least 16.5 in KOOS was considered statistically meaningful. Standard deviation was established as 12.5 based on standard deviation observed between the two groups. Considering a 0.05 two-sided sig- nificance level, power of 90%, and an allocation ratio of 1:1, at least 15 patients were required in each group.

Because the approximate dropout rate was estimated as 10%, 17 patients in each group was the recruitment goal.

The study protocol was approved by the Institutional Review Board of Samsung Medical Center, and patients were registered in the institutional board registry (registry number: SMC 2016-12-061). Written informed consent was acquired from all patients.

RESULTS

A total of 34 knees of 34 patients participated in the study from November 2017 to October 2018. Patients were randomly assigned to two groups: 17 patients (7 men and 10 women) were assigned to the BMAC-PRP group, and 17 patients (7 men and 10 women) were assigned to the HA group. Average age was 66.88 ± 7.39 years in the BMAC PRP group and 69.41 ± 6.54 years in the HA group (p=0.844). Of 34 knees in the BMAC PRP group, 8 were radiographically graded as K-L grade 2 (2 in the BMAC- PRP group, 6 in the HA group), 17 were graded as K-L grade 3 (8 in the BMAC-PRP group, 9 in the HA group), and 9 were graded as K-L grade 4 (7 in the BMAC-PRP group, 2 in the HA group). Initial KOOS score was 241.71

± 93.87 in the BMAC-PRP group and 243.68 ± 83.3 in the HA group (p=0.949). There were no significant differences in initial KOOS score between the two groups (Table 1).

In both groups, mean total KOOS score improved after

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Table 3. Within-Group Difference in Patient-Reported Outcome Scores Across All Time Points Among the BMAC-PRP Group

Measurement: subscale Initial assessment One month Three months Six months KOOS: Total 241.71 ± 93.87^†,‡,§ 283.75 ± 73.99* 321.03 ± 101.48* 320.99 ± 83.35*

KOOS: Pain 56.37 ± 15.92^†,‡,§ 65.66 ± 13.96* 71.21 ± 17.80* 71.97 ± 13.40*

KOOS: Symptom 59.45 ± 17.67^†,‡,§ 66.24 ± 14.41* 72.73 ± 16.54* 75.00 ± 15.32*

KOOS: ADL 58.82 ± 24.90^†,‡,§ 67.51 ± 15.17* 73.80 ± 18.27* 76.07 ± 15.97*

KOOS: Sports 28.82 ± 23.62^§ 35.45 ± 19.81 43.64 ± 32.57 42.27 ± 28.14*

KOOS: QOL 38.24 ± 21.52^†,‡,§ 48.86 ± 20.69* 59.66 ± 23.78* 55.68 ± 21.19*

EQ-5D 8.65 ± 1.69 7.70 ± 0.95 7.80 ± 1.69 7.4 ± 1.84

BMAC: bone marrow aspirate concentration, PRP: platelet rich plasma, HA: hyaluronic acid, KOOS: Knee injury and osteoarthritic outcome score, ADL: Activities of Daily Living, QOL: Quality of Life, EQ-5D: EuroQol-5D.

*Significantly different from the initial assessment. ^†Significantly different from one month follow-up. ^‡Significantly different from three month follow up. ^§Significantly different from six month follow up.

Table 2. Within-Group Difference in Patient-Reported Outcome Scores from BMAC-PRP Group and HA Group

Measurement:

subscale

BMAC-PRP HA

Initial measurement 6 months after

injection p Initial measurement 6 months after

injection p

KOOS: Total 241.71 ± 93.87 320.99 ± 83.35 0.004 243.68 ± 83.33 317.24 ± 96.96 0.021 KOOS: Pain 56.37 ± 15.92 71.97 ± 13.40 0.001 56.70 ± 18.38 71.79 ± 20.90 0.021 KOOS: Symptom 59.45 ± 17.67 75.00 ± 15.32 0.003 65.34 ± 18.41 79.95 ± 16.01 0.014 KOOS: ADL 58.82 ± 24.90 76.07 ± 15.97 0.005 59.43 ± 20.33 73.87 ± 21.62 0.013 KOOS: Sports 28.82 ± 23.62 42.27 ± 28.14 0.041 26.18 ± 17.81 35.38 ± 20.56 0.190 KOOS: QOL 38.24 ± 21.52 55.68 ± 21.19 0.042 36.03 ± 21.48 56.25 ± 27.00 0.009

EQ-5D 8.65 ± 1.69 7.40 ± 1.84 0.333 8.94 ± 1.98 7.69 ± 1.84 0.069

Table 1. Age, Initial KOOS, Kellgren-Lawrence Grade between BMAC-PRP and HA Groups

BMAC-PRP HA p

Age 66.88 ± 7.39 69.41 ± 6.54 0.84

Initial KOOS 235.86 ± 68.91 234.97 ± 82.67 0.95

K-L grade 0.10

K-L grade 2 2 6

K-L grade 3 8 9

K-L grade 4 7 2

Values are mean ± standard deviation.

BMAC: bone marrow aspirate concentration, PRP: platelet rich plasma, HA: Hyaluronic Acid, KOOS: Knee injury and osteoarthritic outcome score, K-L grade: Kellgren and Lawrence grade.

treatment (Table 2). Follow up KOOS score at one month was 283.75 ± 73.99 in the BMAC-PRP group and 281.74

± 67.59 in the HA group. Follow up KOOS score at 3 months and 6 months was 321.03 ± 101.48 and 320.99 ± 83.35 in the BMAC-PRP group, and 318.92 ± 84.98 and 317.24 ± 96.96 in the HA group, respectively (Table 3, 4).

However, there is no group difference noted at final 6 month follow up (Table 5).

In five KOOS subscales (Pain, Symptoms, Activities of Daily Living, Sports and Recreational Function, and Knee-Related Quality of Life), there were no statistically significant differences between groups (Fig. 2). However, only in Sports and Recreational Function Scale, Initial Score was 28.82 ± 23.62, and follow up score at 6 months was 42.27 ± 28.14 which was statistically significant in BMAC-PRP group (p=0.041). Initial Score was 26.18 ± 17.81 and follow up score at 6 months was 35.38 ± 20.56 in HA group (p=0.190) (Table 2).

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Table 5. Between-Group Difference in Patient-Reported Outcome Scores from BMAC-PRP Group and HA Group Measurement:

subscale

Initial measurement Final Follow up (6 months after injection)

BMAC-PRP HA p BMAC-PRP HA p

KOOS: Total 241.71 ± 93.87 243.68 ± 83.33 0.949 320.99 ± 83.35 317.24 ± 96.96 0.921 KOOS: Pain 56.37 ± 15.92 56.70 ± 18.38 0.956 71.97 ± 13.40 71.79 ± 20.90 0.981 KOOS: Symptom 59.45 ± 17.67 65.34 ± 18.41 0.349 75.00 ± 15.32 79.95 ± 16.01 0.450 KOOS: ADL 58.82 ± 24.90 59.43 ± 20.33 0.939 76.07 ± 15.97 73.87 ± 21.62 0.783 KOOS: Sports 28.82 ± 23.62 26.18 ± 17.81 0.715 42.27 ± 28.14 35.38 ± 20.56 0.496 KOOS: QOL 38.24 ± 21.52 36.03 ± 21.48 0.767 55.68 ± 21.19 56.25 ± 27.60 0.956

EQ-5D 8.65 ± 1.69 8.94 ± 1.98 0.645 7.40 ± 1.84 7.69 ± 1.84 0.710

Table 4. Within-Group Difference in Patient-Reported Outcome Scores Across All Time Points Among the HA Group

Measurement: subscale Initial assessment One month Three months Six months KOOS: Total 243.68 ± 83.33^‡,§ 281.74 ± 67.59^§ 318.92 ± 84.98* 317.24 ± 96.96*^,†

KOOS: Pain 56.70 ± 18.38^‡,§ 67.74 ± 13.11 71.79 ± 16.47* 71.79 ± 20.90*

KOOS: Symptom 65.34 ± 18.41^‡,§ 75.55 ± 16.23 77.47 ± 16.78* 79.95 ± 16.01*

KOOS: ADL 59.43 ± 20.33^‡,§ 66.40 ± 14.18 72.17 ± 16.89* 73.87 ± 21.62*

KOOS: Sports 26.18 ± 17.81 31.15 ± 15.16 28.08 ± 20.47 35.38 ± 20.56

KOOS: QOL 36.03 ± 21.48^‡,§ 42.79 ± 20.39 56.25 ± 21.50* 56.25 ± 27.60*

EQ-5D 8.94 ± 1.98 8.92 ± 1.71 8.54 ± 1.61 7.69 ± 1.84

*Significantly different from the initial assessment. ^†Significantly different from one month follow-up. ^‡Significantly different from three month follow up. ^§Significantly different from six month follow up.

Initial EQ-5D was 8.65 ± 1.69 in the BMAC-PRP group and 8.94 ± 1.98 in the HA group. Final EQ-5D was 7.40

± 1.84 in the BMAC-PRP group and 7.69 ± 1.84 in the HA group. There were no differences between groups (Table 5) and all time point (Table 3, 4). There were no side effects in either group.

DISCUSSION

This study showed that intra-articular BMAC-PRP injection improved clinical symptoms in patients with knee OA equivalently to intra-articular HA injection. At 3 months, BMAC-PRP injection group showed statistically significant improvement of scores in sports and recreational function subscales of KOOS which is not demonstrated in HA injection group.

Our study demonstrated that intra-articular BMAC-PRP injection improved KOOS and EQ-5D without any side effects. This might be due to the known regenerative and anti-inflammatory activities of BMAC and PRP, which were demonstrated in previous studies.10,18,21,22

However, radiographic, histologic, and cytokine studies were not conducted in this research.

It is difficult to know that the BMAC-PRP complex is more effective than the BMAC or PRP alone in this study because we did not assign any groups to receive BMAC or PRP alone. We had to focus on the optimal protocols to improve the functional recovery in the OA rather than to investigate the therapeutic mechanism of BMAC or PRP because extraction of BMAC was an invasive procedure.

We hypothesized that PRP plays a role as a cell scaffold for BMAC components, and BMAC might play a role as

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Fig. 2. Changes in mean total KOOS scales and five subscales (Pain, Symptoms, Activities of Daily Living, Sports and Recreational Function, and Knee-Related Quality of Life) in BMAC-PRP group and HA group are presented. All subscales were significantly increased after the procedure except Sports and Recreational Function scale in HA group (p=0.190). BMAC: bone marrow aspirate concentration, PRP: platelet rich plasma, HA: Hyaluronic Acid, KOOS: Knee injury and osteoarthritic outcome score.

a regenerative and anti-inflammatory activator by secreting growth factors and cytokines,²³ so we determined BMAC- PRP injection as a study group rather than BMAC injection alone. Previous study suggests that BMAC injection without PRP would be insufficient because BMAC contains less than 0.001% mononucleated cells, and the regeneration potential of those cells may not be optimal.²³ However, several previous studies suggest that un-cultured BMAC causes lesion coverage and tissue repair.^22,24

Although we did not find superiority of BMAC-PRP over HA in the total scores of KOOS and EQ-5D, clinical superiority of BMAC-PRP over HA was observed in sports and recreational function subscales of KOOS. These results indicate that BMAC-PRP groups have better performance than HA groups and suggest that BMAC-PRP reduces pain and increases functional recovery more than HA. This would be important in terms of functional recovery in OA because most treatments in the OA have shown decrease

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of pain and few treatments showed improvement of functional recovery. Our results were similar with a Kim’s study,²⁵ which showed improvement of Lysholm score after BMAC injection with adipose tissue. While the improvement of KOOS was similar between one and six months after BMAC-PRP injection in our study, continuous improvement of Lysholm score was observed in the Kim’s study. We thought that this difference might be due to the difference of characteristics of BMAC scaffold. PRP is flu- id material while adipose tissue is solid one, which could stay longer in the joint cavity than PRP. However, we think that adipose tissue does not play an important role as an enhancing factor for BMAC because Centeno’s study showed there was no significant difference between with and without adipose graft in the efficacy of BMAC.²⁶ During or after injection, there were no side effects or complications.

There are several limitations of this study. One is that the study was designed as an open label study. To perform a double-blind study, BMAC-PRP must be discarded after bone marrow aspiration and blood sampling in the control group. This is ethically challenging because bone marrow aspiration is an invasive procedure. The relatively small sample size for comparative study is also a limitation.

Longer follow up duration is also needed to prove the sus- tained efficacy of BMAC-PRP. The last limitation is that the cell count and number of anti-inflammatory mediators in aspirates was not analyzed. Further studies with a larger sample size and double-blind design are necessary to clarify the therapeutic effects of BMAC-PRP on knee OA.

CONCLUSION

This study demonstrated that BMAC-PRP improved pain and function in patients with knee OA. BMAC-PRP has equal effects as HA, which had proven efficacy in previous studies. There was greater improvement on sports activity and recreational sub-scores in BMAC-PRP group than HA group. This indicates that BMAC-PRP is a more appro- priate alternative option in patients with relatively active lifestyles. A double-blind, randomized controlled study with a larger sample size is necessary to clarify the therapeutic effects of BMAC-PRP on knee OA.

DECLARATION OF CONFLICTING INTERESTS

There was no commercial conflict of interest in this study.

FUNDING

This work was supported by the National Research Fund (2018R1D1A1B07047084).

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