Opinion
EDITORIAL
Platelet-Rich Plasma for Osteoarthritis and Achilles Tendinitis
Jeffrey N. Katz, MD, MSc
Symptomatic, radiographically documented knee osteoar-
thritis (OA) affects more than 14 million adults in the US and
approximately 240 million worldwide, 1,2 while sympto-
matic, radiographically documented ankle OA has been esti-
mated to affect 3.4% of per-
sons older than 50 years
Related article page 2021
(approximately 3 million to
4 million adults older than 50 years in the US).3 Ankle OA de-
velops typically in response to trauma (eg, fracture) and there-
fore often affects people in their active working years. Achil-
les tendinitis has an incidence estimated of approximately 2
per 1000 in the Netherlands4 and is associated with Achilles
tendon rupture, an extremely disabling condition. These 3 con-
ditions: knee OA, ankle OA, and Achilles tendinopathy, are
costly and disabling, yet few effective therapies are available
that relieve pain and also reverse underlying tissue damage.
In this issue of JAMA and over the past several months, 3
randomized clinical trials (RCTs) have been published that
tested platelet-rich plasma (PRP) therapy for knee OA,5 ankle
OA,6 and Achilles tendinopathy.7 Platelets are rich in growth
factors such as platelet-derived growth factor, epidermal
growth factor, insulin-like growth factor, transforming growth
factor β1, vascular endothelial growth factor, and basic fibro-
blast growth factor. These substances have protean anabolic
properties including the capacity to remodel bone and blood
vessels and promote angiogenesis, chondrogenesis, and col-
lagen synthesis. These processes collectively are involved in
healing following musculoskeletal injury.8,9 Platelet-rich
plasma is a particularly appealing therapy because it is de-
rived from a patient’s own cells, averting the risk of immune-
mediated rejection, and because it can be delivered at the point
of care. Commercially available kits permit clinicians to draw
a patient’s blood, centrifuge the blood to isolate platelets and
plasma, and inject the PRP into affected tissues (joint or ten-
don), all within a 30-minute period.
Injections of PRP have most commonly been used for dis-
orders involving the knee and shoulder, followed by foot and
ankle and lateral epicondyle. The disease processes thought
to be most amenable to PRP are soft tissue pathology of ten-
dons, ligaments, the labrum, and meniscus, followed by car-
tilage pathology.10 Some RCTs of PRP have been encouraging.
For example, trials of PRP to treat lateral epicondylitis have
yielded promising results.8,11 However, PRP trials for OA and
Achilles tendinitis have been mixed, with some studies sup-
porting efficacy and others finding PRP no more effective
than placebo.12-14
Clinical trials of OA have generally compared PRP with
hyaluronic acid injections, and few trials have compared PRP
with intra-articular placebo injections.13 While some prior
2012 JAMA November 23/30, 2021 Volume 326, Number 20 (Reprinted)
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trials that compared PRP with saline or hyaluronic acid prod-
ucts for treatment of knee OA were of high quality, others
had important limitations, particularly failure to blind par-
ticipants and outcome assessors.15 Given the heterogeneity in
results of RCTs, the American College of Rheumatology and
the Osteoarthritis Research Society International recommend
against use of PRP for OA whereas the American Academy of
Orthopaedic Surgeons provide a “limited” recommendation
because of the paucity of high-quality studies and the mixed
results of these trials.16-18
With this background, the rigorous RCT of PRP for knee
OA reported in this issue of JAMA,5 along with the RCTs of PRP
for ankle OA and for midportion Achilles tendinopathy re-
ported in recent issues, represent important new evidence.6,7
These 3 clinical trials were randomized and placebo con-
trolled and included blinding of patients, assessors, and treat-
ing clinicians. The studies used validated outcome measures,
had adequate statistical power, and reported excellent fol-
low-up rates. While no study is perfect, these RCTs appeared
free of obvious biases.
In each study, both the participants randomized to the ac-
tive treatment and those randomized to the placebo im-
proved substantially, and there was no significantly greater ben-
efit in the active treatment group, compared with placebo. For
example, in the trial of 288 adults aged 50 years or older with
knee OA, Bennell et al5 reported that participants who were
randomized to receive 3 PRP injections improved by 2.1 points
on a 1- to 10-point pain scale over 12 months, whereas partici-
pants randomized to placebo improved by 1.8 points. Thus,
mean improvement in participants randomized to the inter-
vention and placebo, respectively, was at least as great as the
minimum clinically important difference of 1.8 points, but the
mean difference in pain relief between the PRP and placebo
groups of 0.4 points was neither clinically meaningful nor sta-
tistically significant.5
Similarly, in the RCTs of ankle OA (100 patients with ankle
OA) and Achilles tendinopathy (240 patients with chronic
midportion Achilles tendinopathy), participants randomized
to PRP improved substantially, but not meaningfully more than
those randomized to placebo.6,7 These findings emphasize the
importance of comparing interventions with placebos in trials
of injection therapies. The placebo effect of intra-articular in-
jection on a 0- to 10-point visual analog scale for pain was es-
timated previously at 1.8 points,19 consistent with the find-
ings documented in the trial by Bennell et al5 for knee OA.
Bennell et al5 also assessed knee cartilage volume on mag-
netic resonance imaging at baseline and at 12 months and re-
ported that both the PRP and placebo groups lost approxi-
mately 1% of cartilage volume over 12 months of follow-up, with
jama.com
 Editorial Opinion

no meaningful difference between PRP and placebo. These
findings do not support the hypothesis that PRP arrests or re-
verses structural joint damage. It is possible, however, that a
1-year follow-up period may be too short to observe a benefi-
cial effect. Consistent with other studies of PRP, the PRP in-
jections did not have increased toxicity, compared with pla-
cebo, in each of these studies.
Analyses of secondary outcomes in the trial by Bennell
et al5 of knee OA offer a more nuanced interpretation of trial
findings. For example, 46% of patients randomized to re-
ceive PRP rated their pain as moderately better or much bet-
ter at 12 months than before treatment, compared with 36%
of patients randomized to placebo injections (P = .05). The au-
thors reported similar results for self-reported improvement
in function and improvement overall. It is unclear why self-
reported pain scores and self-reported ratings of improve-
ment portray contrasting profiles of the success of PRP.
How should these 3 high-quality RCTs influence clinical
practice? The findings of Kearney et al7 regarding PRP for Achil-
les tendinitis are consistent with several prior trials, suggest-
ing that PRP may simply be ineffective for Achilles tendinitis.8
Paget et al6 reported that among patients with ankle OA, intra-
articular PRP injections, compared with placebo injections, did
not significantly improve ankle symptoms and function over
26 weeks, and suggested that their findings “do not support
the use of PRP injections for ankle osteoarthritis.” Bennell et al5
reported that PRP treatment, compared with saline injection,
did not significantly improve the 2 primary outcomes, changes
in knee pain and joint structure (ie, medial tibial cartilage vol-
ume). However, the suggestion of possible benefit for some of
the secondary outcomes (self-reported improvement in pain
and function), as well as the mixed results of prior studies, sup-
port caution before dismissing PRP entirely for knee OA.
One potential explanation for the differences in findings
across PRP trials for knee OA is that Bennell and colleagues con-
ducted a more rigorous trial, especially with respect to blind-
ing of patients and assessors. However, protocols for prepar-
ing and administering PRP differ among studies and could also
explain why PRP in some RCTs may appear more effective than
in other trials. In typical clinical trials of medications, the com-
position of tablets is standardized. In contrast, PRP prepara-
tion and delivery may vary with respect to duration of cen-
trifugation, inclusion of leukocytes in the preparation, volume
of PRP administered, number of injections administered, and
other details. The concentrations of platelets and specific
growth factors in PRP preparations also vary widely.20 It is pos-
sible that these differences may influence the efficacy of a spe-
cific PRP intervention. Until these protocols are standard-
ized, comparisons of findings across trials will be challenging.
Platelet-rich plasma is an example of a promising labora-
tory discovery that was subsequently applied in human
RCTs. However, the 3 RCTs published recently in JAMA sug-
gest that translation of PRP from bench to beside has not
yielded a successful new therapy for knee and ankle OA and
Achilles tendinitis. Until a new generation of trials using stan-
dardized approaches to PRP therapy provides evidence of
efficacy, it would be prudent to pause the use of PRP for OA
and Achilles tendinitis.

ARTICLE INFORMATION REFERENCES a randomized clinical trial. JAMA. 2021;326(16):

Author Affiliations: Orthopedic and Arthritis
Center for Outcomes Research, Division of
Rheumatology, Inflammation and Immunity,
Department of Orthopedic Surgery, Brigham and
Women’s Hospital, Harvard Medical School, Boston,
Massachusetts; Department of Epidemiology,
Harvard T.H. Chan School of Public Health, Boston,
Massachusetts.
Corresponding Author: Jeffrey N. Katz, MD, MSc,
Orthopedic and Arthritis Center for Outcomes
Research, Brigham and Women’s Hospital,
75 Francis St, BTM-5016, Boston, MA 02115
(jnkatz@bwh.harvard.edu).
Conflict of Interest Disclosures: Dr Katz reported
receiving support from Biosplice as principal
investigator of an observational study of
osteoarthritis outcomes.
Funding/Support: Dr Katz is supported by grants
from the National Institute of Arthritis and
Musculoskeletal and Skin Diseases and the
National Institutes of Health and a research grant
from Biosplice.
Role of the Funder/Sponsor: The supporters had
no role in the preparation, review, or approval of
the manuscript or the decision to submit the
manuscript for publication.
Additional Contributions: I thank Maame
Opare-Addo, BA, Brigham and Women’s Hospital,
for assistance in the preparation of the manuscript.
She received no payment for her contributions.
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