Introduction
Aging affects almost all physiological processes and causes changes in body composition. Recently, a triad encompassing simultaneous destruction of bone, muscle, and adipose tissues has been identified and named the osteosarcopenic obesity syndrome.1–3 Osteopenia is the other problem that affects old people, especially in the neck of the femur or lumbar spine. Almost 80% of the American population over age 65 suffers from osteoarthritis (OA). OA is a chronic age-related joint disease that usually occurs in older people and damages articular cartilage and synovial joints. OA causes significant disabilities and functional limitations in daily activities of affected patients. The most important symptoms include joint pain, stiffness, swelling, and decreased range of motion.1–4 Given the high incidence of this disease and costs of medical treatments, OA can be considered an economic burden on society. Available treatments for OA can be classified into three groups: drug, nondrug/nonsurgical (eg, physical and rehabilitation therapy, occupational therapy, massage, exercise) – which are the primary line of treatment – and surgical therapies. The sequence of treatment application begins with drug therapies and ends with surgical therapies.5,6Injectable medications that can cause regenerative changes in tissue structure, manage and alleviate OA symptoms, and help cope with the underlying tissue pathology are very important. This importance is due to the fact that these medicines are not only palliative but also reconstructive and preventive against replacement surgeries. Platelet-rich plasma (PRP) exists in this category. Platelets – besides contributing to the process of hemostasis – play different critical roles in the body. For example, following a tissue injury, platelets attract white blood cells to the site of injury and prevent damaged cells from being infected. Moreover, platelets contain a growth factor (ie, platelet-derived growth factor [PDGF]) that increases the production of stem cells. This characteristic has made platelets attractive in OA treatment. Prolotherapy (PRL) is recommended for chronic musculoskeletal and painful joint conditions, such as knee OA.7–9 PRL involves the injection of an irritant solution into a damaged zone to encourage cell proliferation. Therefore, small amounts of an irritant solution (hypertonic dextrose injection) are injected occasionally into a damaged joint space. The exact mechanism of PRL action is not well understood yet; however, it is probably mediated by stimulation of local healing cells via inflammation induction. The efficacy of PRL and other irritant factors for the treatment of knee OA has been reported in various studies.10–17 In the present study, the effectiveness of PRP therapy and PRL are compared in reducing pain intensity and symptoms of knee OA.
Methodology
This study was undertaken as a double-blind randomized clinical trial after it was approved by the Ethics Committee of Iran University of Medical Sciences. The current study has been registered at the Clinical Trial Center (IRCT) with the code IRCT2014101810599N2. On fulfilling the inclusion criteria and signing the informed consent form, 44 patients with knee OA at the Rasul Akram Hospital were recruited as suitable candidates for intra-articular injection in the present randomized, double-blind clinical trial. Inclusion criteria were age range of 40–70 and stage 1 or 2 OA (based on the Kellgren–Lawrence [KL] scale of the Radiological Society of America); exclusion criteria were rheumatoid arthritis or hemophilia, previous history of knee surgery, drug or alcohol addiction, and use of anticoagulant or nonsteroidal anti-inflammatory drugs (NSAIDs) in the previous 7 days. The primary information, including age, gender, body mass index (BMI), stage of KL, and X-ray scan were recorded for all patients.
Based on a previous study, we calculated the sample size. In that study, the reported percentage of satisfaction in the PRP group at 6 months was equal to 75% (0.75), whereas this percentage was 10.8% (0.108) in the normal saline injection group. When we considered the alpha as 0.05 and beta as 0.1, with power of 95%, we calculated a sample size equal to 13 in each group. We finally enrolled 21 patients in each group.18
We used a block randomization method (block size of four) for determining which patient should be assigned to which group. Randomization remained unbroken during the study.
After admission of patients to the operating theater, the patient’s knee condition was evaluated on the basis of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The WOMAC measures five items for pain (score range 0–20), two for stiffness (score range 0–8), and 17 for functional limitations (score range 0–68). Thus, the possible WOMAC score is between 0 and 96.4
Following routine monitoring processes, such as examining blood pressure, heart rate, and an electrocardiogram, a 20-mL blood sample was drawn under sterile conditions and placed in specialized centrifuge kits for the preparation of PRP (Standard kit, Iran). Then, the blood was centrifuged for 20 minutes at a rotation speed of 3,200 rpm. The plasma was separated and recentrifuged for 5 minutes at a rotation speed of 1,500 rpm. Then, 7 mL of the separated plasma was prepared for intra-articular injection for patients in the PRP therapy group. Patients in the PRL group received 7 mL 25% dextrose.
After administration of local anesthesia and placement of a multi-frequency linear probe of (6–13 MHz with a depth of 6 cm) an ultrasound machine (Sonosite, S-Nerve, South Korea) at the top of the patella, the intra-articular injection was administered under sterile conditions. Then, a 50 mm-long 22-gauge needle (Visioplex needle, Vygon Company, France) was inserted into the knee joint at the upper outer quadrant of the patella under ultrasonographic guidance via the Inplane technique. Then, the prepared solution was injected into the knee joint; this was done with every patient, with neither the patient nor the physician aware of the content of the syringes. Patients remained under medical care for an hour and were then discharged if no complications were detected. The same procedure was repeated 1 month later for all patients. In case of postprocedural pain, paracetamol was prescribed.
Using the WOMAC, levels of pain and knee function were evaluated and recorded for each patient at specified time points – immediately prior to the first injection, 1 month later (immediately prior to the second injection), 2 months later (a month after the second injection), and 6 months later. The investigator and the data analyzer were not aware of patient allocation.
Statistical analyses
Data collected were analyzed using SPSS v. 20. We compared the data and outcome variables (physical activity, pain, stiffness, and WOMAC) between treatment groups (PRP vs PRL) and in successive sessions. Based on the nature of the variables (all are discrete variables) and number of classes, we used parametric tests for analysis of physical activity, pain, and WOMAC between groups and nonparametric tests for stiffness. With regard to physical activity, pain, and WOMAC, we first assessed the normality of data by the Kolmogorov–Smirnov test (K–S test) and determined that all of them were normally distributed – thus, we used parametric tests for analysis. Furthermore, we used mixed-model analysis of variance (ANOVA) for analysis of physical activity, pain, and WOMAC between two groups in successive time sessions. The post hoc test was applied, and Bonferroni correction was considered for interpretation of P-values. For analysis of data from each treatment group in successive sessions separately, we used repeated-measures ANOVA, and all pairwise comparisons (for different time sessions) were accomplished. For comparison of two treatment groups in similar time periods, we used the Student t-test. For stiffness, we used nonparametric tests (Friedman test for comparison of different time sessions in each treatment groups) and Wilcoxon signed rank test for pairwise comparisons. Similar time sessions between two treatment groups were compared by Mann–Whitney U test. P-values were considered significant at <0.05, and they were interpreted on the basis of Bonferroni correction. All baseline data were compared between groups by chi-square, t-, and Mann–Whitney U tests. Normality of data were assessed by the K–S test at first.
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