Abstract

Background

Osteoarthritis (OA) is a slowly progressive chronic disease characterized by pain, loss of function, and deformity of the affected joints. In the past, OA was considered a normal sign of aging and it was described as a degenerative disorder that mainly causes cartilage loss [1]. However, more recent studies have shown that OA occurs and evolves due to the interaction of multiple risk factors affecting the whole joint including the cartilage, subchondral bone, synovium, ligaments, and menisci [2]. Currently, no disease-modifying treatment has been approved, which makes joint replacement the only viable solution for these patients. Non-pharmacological treatments include patient education and self-management, exercises, weight reduction, walking supports (crutches), bracing, shoe and insole modification, local cooling/heating, acupuncture, and electromagnetic therapy [3, 4]. Pharmacological treatments include topical and oral NSAID [5], intra-articular (IA) injections of corticosteroids, visco-supplements, and blood-derived products, including platelet-rich-plasma (PRP) (highly recommended when the use of oral analgesics or anti-inflammatories fails to release disease symptoms) [6]. The intra-articular (IA) infiltration of corticosteroids provides a short-term reduction in OA pain, and it is considered as an adjunct to core treatment for the relief of moderate to severe pain in people with OA [7]. This approach, however, has limited efficacy in delaying disease progression, as well as undesirable potential side effects when administered in high doses and frequency [8, 9]. In this context, PRP is proposed as a potential treatment, capable of improving the clinical condition of patients with osteoarthritis [10–15]. A limited number of publications in PRP, in which PRP has been compared to corticosteroid for the treatment of early knee OA, are available in the literature [16–18]. To address these concerns (what concerns, OA or the side effects, not clear), this study was designed to compare the efficacy of a single intra-articular dose of PRP compared to corticosteroids for the treatment of moderate knee OA. The objective of this study is to evaluate the clinical benefits of PRP when injected into the intra-articular space compared to a corticosteroid (triamcinolone acetonide, Kenalog®), with is a recognized pharmacological treatment in patients with mild to moderate symptomatic knee OA. We hypothesized that intra-articular injection of PRP reduces pain in a very short term (1-week follow-up), similar to triamcinolone acetonide [19], and it leads to an equal or more effective analgesic outcome plus better functional recovery at 1 year follow-up.

Methods

Results

A total of 76 patients were screened from April 2016 to May 2018. Of these screened patients, 33 patients did not meet inclusion criteria and 3 declined to participate (Fig. ​(Fig.1).1). After this, 40 patients were included in either group (per randomization). The mean age of the intention-to-treat patients was 66.5 ± 8.6 and 70.1 ± 9.1 for the PRP and CS group, respectively. Participants were 84% men and 16% women for the PRP group and 71% and 29% for the CS group, respectively. There were no significant differences between the 2 groups across all the baseline parameters (Table ​(Table1):1): age, sex, and K-L grade for OA (except for the basal IKDC index (p = 0.038)). According to the intention-to-treat population, 19 patients were included in the per-protocol evaluation for the PRP group and 17 in the CS group. A total of 4 patients (10%) that were randomized (one from the PRP group and three from the CS group) were not included in the analysis. One randomized patient into the PRP group discontinued the evaluation due to the presentation of an autoimmune disorder after 6 months. This patient presented red spots on the face that was later diagnosed with lupus erythematosus. Three patients that were treated with CS were unable to continue the trial due to an arthroplasty at 6, 7, and 9 months.

Clinical results

Both PRP and CS single injections were effective in reducing pain, and they improved the knee function after the first week of treatment. VAS score changes at 1 year (primary clinical outcome) showed a higher mean change from baseline in the PRP group than the CS group (PRP − 3.1 ± 2.0, − 52%; CS − 0.8 ± 1.8, − 14%). This difference was significant between groups (p = 0.0002). The most surprising effect observed was that PRP induced pain relief just as fast as CS. In fact, a significant reduction of pain from baseline for both groups was found 1 week after treatment (mean VAS change—PRP − 2.8 ± 2.3, − 47%; CS − 3.4 ± 1.2%, − 58%; p < 0.0001). Similarly, significant function improvements from baseline were obtained in the first week for both treatment groups (mean IKDC change—PRP 22.1 ± 16.9, 60%; CS 35.4 ± 10.0, 117%—and mean KSS change—PRP 22.7 ± 12.3, 39%; CS 29.4 ± 12.8, 55%). Interestingly, the pain reduction and the knee functional improvement were not significant between both groups in the very short-term follow-up visit (up to 5 weeks; Table ​Table2).2). The highest change in the VAS score from the baseline was at 3 months for the PRP group (mean − 4.6 ± 1.6; − 77%) and at 1 month in the CS group (− 3.4 ± 1.2; − 58%).

Table 2

Primary outcome and secondary outcomes in per-protocol population during the follow-up of the study

		PRP group (n = 19)		CS group (n = 17)
	Weeks	Mean ± SD	CI (95%)	Mean ± SD	CI (95%)	p value (intergoup)
A
VAS
V1	0	6.1 ± 1.3	5.4–6.6	6.0 ± 1.5	5.2–6.8	0.9855	ns
V2	1	3.2 ± 2.1	2.2–4.2	2.5 ± 1.7	1.6–3.3	0.3675	ns
V3	5	2.3 ± 1.8	1.4–3.2	2.5 ± 1.5	1.7–3.2	0.6525	ns
V4	15	1.4 ± 1.2	0.8–2.0	3.6 ± 2.1	2.5–4.7	0.001	***
V5	30	1.6 ± 1.9	0.7–2.6	4.0 ± 1.6	3.2–4.8	< 0.0001	****
V6	58	2.9 ± 1.5	2.2–3.6	5.1 ± 1.9	4.1–6.0	0.0008	***
B
IKDC
V1	0	36.3 ± 10.7	31.2–41.4	28.9 ± 8.3	24.6–33.1	0.0570	ns
V2	1	61.2 ± 14.4	54.6–67.4	65.9 ± 13.4	59.0–72.8	0.1925	ns
V3	5	68.8 ± 14.8	61.7–75.9	64.1 ± 17.4	55.2–73.0	0.3747	ns
V4	15	78.7 ± 11.4	73.3–84.2	58.2 ± 15.9	50.1–66.4	0.0004	***
V5	30	77.5 ± 14.2	70.6–84.3	56.3 ± 17.4	47.4–65.3	0.0008	***
V6	58	62.0 ± 15.6	54.5–69.6	39.8 ± 16.3	32.8–46.8	0.0002	***
C
KSS
V1	0	57.8 ± 7.1	54.4–62.2	53.2 ± 8.4	48.8–57.5	0.0998	ns
V2	1	81.3 ± 12.6	75.2–87.4	83.2 ± 9.9	78.1–88.4	0.7598	ns
V3	5	85.7 ± 10.5	80.6–90.7	80.9 ± 11.0	75.3–86.6	0.1925	ns
V4	15	88.8 ± 9.4	84.2–93.3	73.2 ± 13.4	66.2–80.0	0.0013	**
V5	30	86.8 ± 11.9	81.1–92.5	71.2 ± 13.7	64.2–78.3	0.0008	***
V6	58	77.3 ± 12	71.6–83.1	60.3 ± 13.7	53.3–67.3	0.0004	***

Data are provided as mean ± SD (range)

p value of Mann-Whitney test

ns not significant, VAS visual analog scale, KSS Knee Society Score, IKDC International Knee Documentation Committee, CI confidence interval

** Statistically significant difference (p ≤ 0.01)

*** Statistically significant difference (p ≤ 0.001)

**** Statistically significant difference (p ≤ 0.0001)

The pharmacological effect of CS seemed to disappear 15 weeks after receiving treatment as all scores tended to worsen after this period. For instance, pain in the CS group improved rapidly but, in general, worsened after 15 weeks of treatment, and the pain steadily increased in each follow-up visit. At the same time, the PRP group resulted in a sustained improvement in pain relief up to 30 weeks, showing a small increase in pain in the 1-year evaluation follow-up (Fig. ​(Fig.2a).2a). For all other outcome scores, there were significant differences between pre-treatment and post-treatment results at any time, evaluated up to 58 weeks of the follow-up (p < 0.05), except for the VAS (p = 0.1537) and KSS (p = 0.1719) indexes for the CS group at 58 weeks (due to worsening of the pain conditions of the patients).

Open in a separate window

Fig. 2

Evaluation of the subjective state according to VAS (a), IKDC (b), and KSS (c) over time. Values are the average of each score at any one time. VAS, visual analog scale; KSS, Knee Society Score; IKDC, International Knee Documentation Committee

Knee function improvement was observed in both groups up to 5–15 weeks with no significant differences between groups (p > 0.05) (Table ​(Table2).2). At V4 (15 weeks), the PRP group presented a better significant improvement in the IKDC and KSS scores compared to the CS group, which decreased in effectiveness up to 1 year (Fig. ​(Fig.2b,2b, c). Maximum functional improvement and better patient expectation, satisfaction, and activity levels were observed after 15 weeks for the PRP group (mean change from baseline of 41.1 ± 13.6, 112% and 30.2 ± 11.7, 51% for IKDC) and after 5 weeks for the CS group (mean change from baseline of 33.7 ± 13.5, 111% and 29.4 ± 12.8, 55% for KSS).

Discussion

This single-center prospective randomized controlled study showed that a single intra-articular injection of PRP was more efficient than CS for treating moderate OA (Kellgren-Lawrence grades II–III) compared to triamcinolone acetonide. The effectiveness of PRP has been questioned by some authors because the evidence of its efficacy has been highly variable depending on the specific indication [21–24]. Other studies have shown that PRP has been effective for knee OA when compared to placebo, ozone, or HA in several high-quality, randomized, controlled trials [25–29]. Some of these studies suggested that intra-articular infiltrations of PRP provide quantifiable benefits for pain relief and functional improvement within a limited time period (up to 1 year) [25, 28, 29]. For instance, Filardo et al. [30] performed three consecutive intra-articular infiltrations of PRP in a group of 91 patients with chronic degenerative knee conditions with improvement in the IKDC and EQ-VAS indexes up to 1 year. However, this condition deteriorated 24 months after 1 year of clinical improvements (especially for younger patients with a low to mild degree of cartilage degeneration). Similar results were reported by Fukawa et at [31]., who performed three consecutive injections of PRP with a VAS reduction up to 1 year with a deterioration of the improvement after 24 months. In this study, a single intra-articular injection of PRP resulted in significant pain relief for up to 12 months, with a maximum pain decrease after 3 months. This difference suggested that the number of PRP injections could be critical for the maintenance of the beneficial effect. In contrast to this, Patel et al. [32] did not find significant differences in WOMAC scores between single and double PRP injections for early OA at 6 weeks and 3 and 6 months.

As far as we know, only a few trials have been published that compare clinical outcomes after PRP and corticosteroid (CS) injections for treating mild OA [16–18]. In general, those studies concluded that a single dose of PRP is comparable to 1 dose of CS (none of them analyzed the very short-term effects—1 week). Most of the studies of PRP commonly perform the first assessment of patients 1 month after treatment, making impossible the determination of the evolution in the first few days [33]. Based on this remark and based on our personal experience that we have from our routine care activity, we evaluated the clinical outcome of the patients in the very short term (1 week). From our knowledge, this is the first PRP clinical study for early-stage knee OA that incorporated outcome assessment by means of this approach. We found that the analgesic effect of PRP in the very short term was comparable to CS, and the same was noticed for the knee function (Table ​(Table2;2; 1 to 5 weeks; ns). The rapid reduction in pain observed upon treatment with PRP might be attributed to a combined effect, mainly due to the induction of endogenous cell endocannabinoids [34] together with the anti-inflammatory activity effect of PRP on chondrocytes [35, 36]. The variation in pain and knee function in the PRP group contributed to the sustained duration of the overall beneficial effects for up to 30 weeks, whereas in the CS group, a tendency to worsen after 5 weeks was registered. A recent meta-analysis reported the limitation of the beneficial effect of the CS 15 weeks after the end of treatment [37]. We hypothesized that the improvement of both parameters (pain and function) were mainly due to control of the inflammation of the knee rather than the trophic effect of PRP on cartilage. This rationale is due to the fact that it has not yet been demonstrated that the improvement of knee function after PRP treatment correlates with a volume increase of the articular cartilage [38–40], even when has been demonstrated that in vitro, TGF-β1/3 can induce chondrogenesis of mesenchymal stem cells [41]. However, there is evidence that suggests that PRP has other effects on the joints other than the anti-inflammatory and this may probably explain why the group that received PRP had better results than the CS group. Even though the mechanism of action on improving cartilage repair remains unclear, it has been reported in the literature that PRP can induce tissue maturation characterized by increased cell proliferation and tissue stiffness [42]. These cells, in turn, produce more superficial zone protein that functions as a boundary lubricant that helps reduce friction and wear [43, 44]. Moreover, it has been reported that PRP can enhance HA secretion from synovial fibroblasts in arthritic patients, producing a lubricating effect that could reduce the shear stress of the joint [45].

Administration of CS for treating OA has been controversial because these injections can reduce pain in the short term, but they may not be helpful in the treatment of the underlying arthritic lesion [46]. CS administrations have been reported to have deleterious effects on musculoskeletal tissues such as reduction of collagen synthesis, suppression of cell proliferation, induction of oxidative stress, and impact on cell viability [47–50]. This harmful effect could also influence the difference in long-term results between treatment groups in detriment of the CS group.

Intra-articular PRP infiltrations have been widely used for the treatment of knee OA with many beneficial results [28, 32, 51]. In this study, intra-articular PRP injections were well tolerated. The most common side effect being mild synovitis tended to resolve within the first week after treatment. Treatment with PRP injections can be considered safe since no severe adverse events or complications have been reported. We consider that the safety of PRP is mainly due to two factors: the administration of the PRP done through minimally invasive procedures and non-existent risk of transmission of infectious diseases (because it is an autologous procedure). In addition, in this study, we used pure PRP (the leukocyte layer fraction was not recovered per manufacturer’s instructions) to prevent possible inflammatory reactions [52, 53] in spite of the reported safety of using leucocyte-rich PRP [54]. Another relevant aspect of this study was that we plotted our results on a numerical scale (Fig. ​(Fig.2).2). Curiously, most of the studies represent the time variable on non-numerical plots which masked the real trends. This makes it difficult to appreciate the rate of the clinical improvement or worsening. For instance, outcome evolution graphs with ordinate axes (X) with equidistant values of 1, 3, and 6 months are frequently found in the literature [38, 55, 56].

Conclusion

This study shows that one intra-articular PRP injection is safe, it can reduce pain, and it can improve the knee function of patients with mild/moderate knee OA. The PRP intra-articular injection improves short-term scores of pain and knee function with no significant difference when compared to corticosteroids. However, PRP treatment resulted in a longer sustained effect than triamcinolone up to 12 months after administration. PRP can also produce a mild synovitis in the first week after administration without risk for the patient. It is recommended that a larger, randomized clinical trial should be performed to further assess the efficacy of PRP treatment in patients with mild/moderate OA.

Acknowledgements

Abbreviations

Authors’ contributions

AF and AP conceived, designed, and performed the trial. AF and AP analyzed the data. LV performed the statistical analysis. AF wrote the paper. The authors read and approved the final version of the manuscript.

Funding

No funding was received for this study.

Availability of data and materials

Data is available via the corresponding author under a reasonable request.

Ethics approval and consent to participate

The Medical Ethics Committee of Rigas Stradins University (RSU) and Ethics Committee of Medical and Biomedical Research Foundation of Riga Eastern Clinical University Hospital Support Foundation (Ref E-9(2))

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests. LV is the scientific affairs manager from FDIA Spain and gave support to the statistical analysis.

Footnotes

References