Study Protocol Clinical Trial Medicine ®

Clinical trial of manual therapy in the treatment of

chondromalacia patellae
Yan Cai, MSa,b , Ying Deng, MDa, Liang Ou, MDb, Yuxing Guo, MDb, Yanxing Guo, MDa,*
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Abstract
Background: Chondromalacia patellae (CP) is a common and main cause of knee pain, the prevalence of the disease in the
general population is as high as 36.2%, especially in middle-aged patients aged between 30 and 40 years (up to 50%). The use
of manual therapy (MT) to dredge the meridians and muscles around the knee joint and stimulate the relevant acupoints can play
vital roles in relieving pain and improving function. The purpose of this study is to assess the effectiveness, safety and further
comprehensively, completely and multi-dimensionally explain the mechanism and treatment advantages of MT for CP.
Methods: A prospective randomized controlled clinical trial design was used to study the efficacy and safety of MT in the
treatment of CP. One hundred and twenty cases of CP patients will be recruited and randomly divided into experimental group
and control group according to 1:1. The control group: sodium hyaluronate; experimental group: MT added on the basis of the
control group. Both groups will receive standard treatment for 4 weeks and followed up for 3 months. And at the same time, pay
attention to its efficacy and safety indicators. Observation indicators include: the visual analogue scale pain score; the Western
Ontario and McMaster Universities Arthritis Index scores; the Lysholm scores, and Bristol scores, adverse reactions, etc. Data
analysis was performed using SPSS 25.0 software.
Discussion: This study will precisely evaluate the effectiveness and safety of MT in the treatment of CP. The results of this
experiment will provide more reliable clinical basis for the selection of MT for patients with CP.
Abbreviations: CP = chondromalacia patellae, MT = manual therapy.
Keywords: chondromalacia patellae, clinical trial, manual therapy

1. Introduction
Chondromalacia patellae (CP), also known as patellofemoral
pain syndrome, anterior knee pain syndrome, patellofemoral
joint syndrome, etc., was first proposed by Aleman.[1] It is a
degenerative disease of patellar cartilage, which is a common
and main cause of knee pain. Most patients with this disease
have different degrees of poor patellofemoral joint force line
and (or) abnormal patellar motion track, making the lateral
patella perennial high pressure, which can lead to the secretion
of pain-causing inflammatory factors such as interleukin-6,
causing pain and subsequent patellofemoral articular carti-
lage softening until gradual denudation. The prevalence of the
disease in the general population is as high as 36.2%, espe-
cially in middle-aged patients aged between 30 and 40 years
(up to 50%). The prevalence rate in women is higher, about
twice that in men.[2] This disease often occurs after strenuous
exercise, which can lead to soft legs, joint swelling and pain,
restricted movement and other symptoms. The pain is obvi-
ous after going upstairs and downstairs, climbing, squatting,
kneeling and even sitting for a long time, which seriously
affects the quality of life.[3,4] Hence, CP has become a major
global public health problem, and the effective treatment is of
great significance.
CP is generally treated conservatively in the early stage of
the disease, while surgical treatment is suitable for advanced
patients. Through methods including cartilage transplanta-
tion and total knee replacement, the normal tissue structure
around the patella can be restored and reconstructed, and
finally the purpose of treating the disease can be achieved.[5,6]
The consensus released by the International Patellofemoral
Research Center in 2018 believes that the key treatment of
CP is exercise therapy and physical intervention,[7] and its
management should include an individual, multi-modes exer-
cise and treatment method.[8] Among all the treatment meth-
ods, manual therapy (MT) has occupied a certain advantage
in clinical application due to its simple operation, obvious
effect, small side effects, high safety and good economic
effect.

YC and YD contributed equally to this work.
This work is supported by Hunan Traditional Chinese Medicine Science and
Technology Plan Project (D2022037), Scientific Research Project Plan of Hunan
Provincial Department of Education (21C0224), and Scientific Research Fund of
Hunan University of Chinese Medicine (2021XJJJ018).
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published
article [and its supplementary information files].
a
Hunan University of Chinese Medicine, Changsha, China, b The Affiliated
Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, China.
*Correspondence: Yanxing Guo, Hunan University of Chinese Medicine, No.
300 Xueshi Road, Yuelu district, Changsha, Hunan 410208, China (e-mail:
dy1990@21cn.com).
Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
How to cite this article: Cai Y, Deng Y, Ou L, Guo Y, Guo Y. Clinical trial
of manual therapy in the treatment of chondromalacia patellae. Medicine
2023;102:24(e33945).
Received: 13 March 2023 / Accepted: 16 May 2023
http://dx.doi.org/10.1097/MD.0000000000033945

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 Cai et al. • Medicine (2023) 102:24Medicine
Based on modern western medical theory, MT techniques
include joint mobilization, manual stretching and trigger point dry
needle. Many studies have found that joint mobilization is effective
in pain reduction, while the most effective joint mobilization is aim
at the knee joint complex directly rather than at the lumbar-pelvic
region or other surrounding joints, although lumbar-pelvic manip-
ulation can also improve patients’ pain and function.[9–11] The use of
traditional Chinese medicine massage to dredge the meridians and
muscles around the knee joint and stimulate the relevant acupoints
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can also play vital roles in relieving pain and improving function.
In recent years, studies on the effect of MT for CP have
increased at home and abroad, but its clinical efficacy is still
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unclear. Therefore, the purpose of our study is to precisely eval-
uate the advantages and disadvantages of MT in the treatment
of CP in this randomized controlled trial.
2. Materials and methods
2.1. Study design
This is a prospective randomized controlled clinical trial study-
ing the effects of MT on CP. This protocol follows the latest
Consolidated Standards of Reporting Trials (2017) (flowchart is
shown in Fig. 1) and Standard Protocol Items: Recommendations
for Interventional Trials 2013 statement.
2.2. Ethics and registration
This research scheme is approved by the Clinical Research Ethics
Committee of our hospital. This experiment has been regis-
tered om Chinese Clinical Trial Registry (registration number:
ChiCTR2300068655). Before randomization, all patients needed
to sign an informed consent form, and only patients who sign
informed consent will be enrolled in the study. During the test,
they are free to choose whether to continue the test at any time.
2.3. Patients
1.2.3. Inclusion criteria. Those who meet the diagnostic criteria
of CP; age: ≥18 and ≤65 years old, regardless of gender; within 3
months before enrollment, they did not receive joint cavity injection
treatment and did not take any drugs to treat CP; those who have
certain communication and understanding ability, and can express
their own will correctly; no other soft tissue and bone diseases
of the knee joint; those who voluntarily accept corresponding
treatment and can cooperate; no other serious nervous or mental
diseases; and those who have signed the informed consent.
2.2.3. Exclusion criteria. Patients who suffer from acute
systemic illness or acute swelling; patients who have severe
impairment of limb function; patients with severe heart, lung,
liver and kidney dysfunction; patients with local skin infection
or ulceration; patients combined with severe mental illness;
patients who are allergic to the drugs used in this study; and
patients who are unable to understand the study protocol or
unwilling after explanation.
3.2.3. Elimination criteria. Patients with serious adverse events
or serious complications, which is not suitable for the next
step; patients with poor compliance, affecting the judgment of
efficacy and safety; the disease progresses during the treatment
process, and the treatment plan needs to be changed; and for
any reason, the subject asked to withdraw from the trial.
2.4. Sample size calculation
According to the preliminary clinical trial, the total effective rate
of MT combined with sodium hyaluronate was 93.4%, and that
of sodium hyaluronate was 66.6%. Use PASS15.0 to estimate
2
the sample size, adopt a superiority design, in which α = 0.05, β
= 0.2, test power = 0.8, number of cases in experimental group:
number of cases in control group = 1:1, boundary value = –0.4.
According to the software calculation, the total sample size of
the 2 groups was 110 cases. Taking into account the clinical
shedding rate of about 10%, a total of 120 cases will be finally
included. The included patients will be numbered according to
the order of treatment and divided into the treatment group and
the control group by completely random method, with 60 cases
in each group.
2.5. Interventions
This study will select patients who meet the study criteria by
recruiting them at the hospital. A randomized controlled study
will be conducted, in which sodium hyaluronate will be used
in the control group and the experimental group will include
MT exercise on the basis of the control group. If necessary, the
attending doctor may adjust the treatment according to the
patient’s condition, and all interventions will be recorded in
detail for final outcome analysis. Efficacy assessors are not aware
of the study plan, and data statisticians are not involved in study
design and implementation. The health of each patient will be
assessed before and after the treatment, including observational
indicators, and all patients will be followed up by telephone.
2.5.1. Control group. Patients will be placed in the sitting or
supine position, and the knee joint will be kept bent 70° to 90°,
sterilized strictly, with sterile towel laid and aseptic operation
performed. The lower lateral or inner side of the patella will
be used as the conventional puncture point, and the knee joint
cavity will be punctured through a 5 mL syringe. If there is
joint effusion, it will be drained first, and then 25 mg sodium
hyaluronate will be injected (KUNMING BAKER NORTON
PHARMACEUTICAI, SALES CO.LTD. [Kunming City, Yunnan
Province, China], specification 2.5 mL: 25 mg, CFDA approval
number: H20140533); if not, 25 mg sodium hyaluronate can
be directly injected into the joint cavity. After injection, help the
patient to move the knee joint so that sodium hyaluronate can be
evenly coated on the internal surface of the joint. One time/week, 4
times as a course of treatment. Health education should be carried
out for patients to avoid acute jumping, walking up and down
stairs, climbing mountains and other activities that damage joints,
and remind them to pay attention to the warmth of joints as well.
Pay attention to communicate with patients, be aware of their
psychological and emotional changes, avoid or relieve anxiety,
depression, and other adverse emotions of the elderly patients.
2.5.2. Treatment group. The treatment group will be given
MT on the basis of conventional treatment. Manual therapy is
jointly completed by 2 experienced doctors, it lasts for about
20 minutes per time, once a day, and lasts for 4 weeks in total.
2.6. Outcomes
2.6.1. Observation indicator. Improvement in joint pain
and function is the main observation item, and which is
respectively assessed by the visual analogue scale pain score or a
comprehensive evaluation commonly using the Western Ontario
and McMaster Universities Arthritis Index scores, Lysholm
scores, or Bristol scores.
2.6.2. Efficacy indicator. Main efficacy indicators: total
effective rate: (clinical control + significantly effective number
+ effective number)/total number of people × 100%. Clinical
control: pain and other symptoms disappear, joint activity is
normal, integral reduction ≥ 95%; significantly effective: pain
and other symptoms disappear, joint activity is not limited,
70% ≤ integral reduction < 95%; effective: pain and other
 Cai et al. • Medicine (2023) 102:24www.md-journal.com
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Figure 1. Study flow chart.

symptoms basically disappear, joint activity is slightly limited,
30% ≤ integral reduction < 70%; and ineffective: no significant
improvement in symptoms such as pain and joint activity,
integral reduction < 30%.
2.6.3. Adverse events rate. Including the number of patients
who experience any uncomfortable symptoms during treatment
(such as dizziness, nausea, etc).
2.7. Data collection and management
Data will be collected according to the evaluation criteria before
and 4 weeks after the treatment, and each patient was followed
up by telephone for 3 months after the end of treatment. It was
impossible to collect follow-up information and record the rea-
sons for loss to follow-up. Access to the database is limited to
the researchers in this research group.

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 Cai et al. • Medicine (2023) 102:24Medicine
2.8. Study quality control
Throughout the trial, each participant will be monitored for
safety. All adverse event occurrences will be referred to the office
of the Clinical Research Ethics Committee, which will review
the events and determine causal relationship.
2.9. Statistical analysis
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In this study, SPSS25.0 statistical analysis software (IBM,
Amenk, NY) will be used for data analysis. If the measurement
data meet the normal distribution, independent-sample t test
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will be used between groups and paired-sample t test will be
used within groups; if not, non-parametric test will be used and
the results will be expressed in quartiles; the count data were
tested by chi-square. The incidence of adverse events is com-
pared by chi-square test. P < .05 is statistically significant.
3. Discussion
CP is one of the common diseases of knee joint. Pain and dys-
function caused by CP severely decreases the quality of life of
patients. Currently, the diagnostic standard of CP has not yet
formed a unified consensus. There is no effective cure for the
treatment of CP, and the effects of surgical treatment which are
widely used in clinic, such as cartilage transplantation and total
knee replacement, is not superior o non-surgical treatment.[12,13]
Moreover, doctors and patients concern constantly about the
potential adverse effects of these operation.
At present, MT is one widely used conservative treatment for
patients with CP. Manipulative therapy can promote blood cir-
culation and accelerate metabolism, mainly through the follow-
ing mechanisms to achieve the purpose of treatment: increase
the local nutrient supply, and strengthen the “pumping effect”
of cartilage tissue itself, which is conducive to the self-repair of
the articular cartilage. Eliminate local intra osseous venous sta-
sis, reduce intra ossseous hypertension, and promote absorption
of local inflammatory tissue. Exogenous cold pathogen is one
of the causes of CP, manipulative treatment can generate heat
and disperse cold, and promote local Qi and blood circulation.
Promote the mechanical balance of the knee joint, release the
adhesion, and improve the stability and functional state of the
knee joint.
As far as we know, there has been no standard large-sample
clinical study on MT in the treatment of CP, although increasing
studies have found that MT has a statistically significant effect
on alleviating symptoms of CP with a well-established safety
profile. We intend to evaluate its efficacy and safety in a prospec-
tive randomized controlled study.
Author contributions
Conceptualization: Yan Cai, Ying Deng.
Data curation: Yan Cai, Yanxing Guo.
Formal analysis: Yan Cai, Yuxing Guo.
Software: Yan Cai, Yuxing Guo.
Writing – original draft: Liang Ou, Yanxing Guo.
Writing – review & editing: Yan Cai, Ying Deng.
References
[1] Aleman O. Chondromalacia post-traumatica patellae. Eta Chir Scand.
1928;63:149.
[2] Smith BE, Selfe J, Thacker D, et al. Incidence and prevalence of
patellofemoral pain: a systematic review and meta-analysis. PLoS One.
2018;13:e0190892.
[3] Coburn SL, Barton CJ, Filbay SR, et al. Quality of life in individuals
with patellofemoral pain: a systematic review including meta-analysis.
Phys Ther Sport. 2018;33:96–108.
[4] Mcclinton SM, Cobian DG, Heiderscheit BC. Physical therapist
management of anterior knee pain. Curr Rev Musculoskelet Med.
2020;13:776–87.
[5] Grevenstein D, Mamilos A, Schmitt VH, et al. Excellent histological
results in terms of articular cartilage regeneration after spheroid-based
autologous chondrocyte implantation (ACI). Knee Surg Sports
Traumatol Arthrosc. 2021;29:417–21.
[6] Woon CYL, Christ AB, Goto R, et al. Return to the operating room
after patellofemoral arthroplasty versus total knee arthroplasty for
isolated patellofemoral arthritis – a systematic review. Int Orthop.
2019;43:1611–20.
[7] Collins NJ, Barton CJ, Van Middelkoop M, et al. 2018 Consensus state-
ment on exercise therapy and physical interventions (orthoses, taping
and manual therapy) to treat patellofemoral pain: recommendations
from the 5th International Patellofemoral Pain Research Retreat, Gold
Coast, Australia, 2017. Br J Sports Med. 2018;52:1170–8.
[8] Saltychev M, Dutton RA, Laimi K, et al. Effectiveness of conservative
treatment for patellofemoral pain syndrome: a systematic review and
meta-analysis. J Rehabil Med. 2018;50:393–401.
[9] Jayaseelan DJ, Scalzitti DA, Palmer G, et al. The effects of joint mobi-
lization on individuals with patellofemoral pain: a systematic review.
Clin Rehabil. 2018;32:722–33.
[10] Eckenrode BJ, Kietrys DM, Parrott JS. Effectiveness of manual therapy
for pain and self-reported function in individuals with patellofemoral
pain: systematic review and meta-analysis. J Orthop Sports Phys Ther.
2018;48:358–71.
[11] Rahou-El-Bachiri Y, Navarro-Santana MJ, Gomez-Chiguano GF, et
al. Effects of trigger point dry needling for the management of knee
pain syndromes: a systematic review and meta-analysis. J Clin Med.
2020;9:2044.
[12] Siemieniuk RAC, Harris IA, Agoritsas T, et al. Arthroscopic surgery
for degenerative knee arthritis and meniscal tears: a clinical practice
guideline. Br J Sports Med. 2018;52:313.
[13] Mellinger S, Neurohr GA. Evidence based treatment options for com-
mon knee injuries in runners. Ann Transl Med. 2019;7(Suppl 7):S249.