Authors: Fadi Hassan, BSc (Hons), MBBS,* William D. Murrell, MD, MS,†‡ Andrew Refalo, MS,§ and Nicola Maffulli, MD, MS, PhD, FRCP, FRCS (Orth), FFSEM
Background: Knee osteoarthritis (KOA) is a common condition encountered by physicians. KOA is addressed by a wide array of modalities including a number of nonbiological treatments.
Methods: PubMed, ISI Web of Science, and SPORTDiscus were searched for level 1 to 4 studies published from inception to August 2017.
Results: A total of 18 studies were evaluated and results demonstrated moderate supporting evidence for prolotherapy and limited evidence for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low–molecular weight fraction of 5% human serum albumin. Evidence for local anesthetic agents was conﬂicting.
Conclusion: There is moderate supportive evidence for the effectiveness of prolotherapy in improving pain and function in both, short-term and long-term. Limited supporting evidence found for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low–molecular weight fraction of 5% human serum albumin in improving pain and function. There is conﬂicting evidence for the use of local anesthetic agents in patients with KOA.
Knee osteoarthritis (KOA) is one of the most common musculoskeletal complaints encountered by physicians (1). The most common cause of knee pain is degenerative arthritis (2). Osteoarthritis (OA) is a multifactorial degenerative condition affecting several joints, especially weight- bearing joints (3). KOA places a signiﬁcant burden on societies. In 2005, almost 500,000 total knee replacements were performed, at a cost exceeding $11 billion (4). This burden is expected to grow as the population ages in the coming years, which could lead to signiﬁcant additional ﬁnancial burden on existing and future health care systems (5). Management of KOA starts with conservative man- agement, that includes exercise, lifestyle changes, analgesia, intra-articular injections, and supplements (6-8). In recent years, biologically augmented interventions, such as platelet-rich plasma, mesenchymal stem cells, and growth factors were at the forefront of research and showed initial promising results in modern practice (9,10). Alternatives to biological injectable treatments include prolotherapy, botulinum toxin type A (BoNT/A), sodium bicarbonate and calcium gluconate (SBCG)(11-22).
Prolotherapy (a conjunction for proliferation therapy) involves injecting an irritant substance, usually hyperosmolar dextrose, either intra-articularly or to the attachment of ligaments and tendons (11). Recent data has suggested the beneﬁcial effect in management of KOA (12-14). Mechanisms of action(s) suggest hyperosmolar dextrose hyperpolarizes the nerves by opening the potassium channels, hence, decreasing transmission of pain signals via nociceptive ﬁbers (15), or by producing inﬂammatory response via chemical mediators and growth factors that stimulate local healing of injured tissue (16,17).
It is suggested that botulinum neurotoxins can have antinociceptive effect when applied to painful joints by blocking neurotransmission from nerve terminals of nociceptive ﬁbers (18,19).
SBCG have been investigated for management of KOA (20), and the analgesic effect of bicarbonate is possibly mediated by its alkalinity (21). In addition, calcium gluconate is thought to aid in linkage between chondral and bone proteins. The resulting alkaline environment allows for recovery of homeostatic mechanisms of the cartilage and minimizes the process of apoptosis of chondrocytes. In addition, provides an anti-inﬂammatory effect through COX-2 inhibition (22). Hence, the combination of the 2 is thought to help patients with symptomatic KOA achieve better control of symptoms.
The increasing interest in nonbiological agents is attributed to their high safety proﬁle, low-cost and potential therapeutic effect. Hence, this systematic review aims evaluate the safety proﬁle and effectiveness of alternatives to biological interventions in managing symptomatic KOA.
Strategy for Literature Search
The systematic review was registered with PROSPERO (International Prospective Register of Systematic Reviews) number CRD42017065953. Searches of the electronic databases, PubMed, ISI web of science, and SPORTDiscus, were conducted by F.H. and A.R. for all papers published from inception through to August 2017 (Fig. 1).
The search strategy included a wide range of terms for treatment modalities and different terms for OA, aiming for high sensitivity in order to detect all the appropriate literature.
- Terms for treatments: Prolotherapy OR Dextrose OR glucose OR sugar OR regenerative OR proliferation OR injection OR botulin OR botox OR Botulinum Toxins OR Botulinum Neurotoxin A OR Clostridium botulinum A OR Clostridium Botulinum Toxin Type A OR Botulinum A OR calcium gluconate OR sodium bicarbonate OR saline AND.
- Terms for conditions: Knee AND menisc* OR tear OR partial tear OR torn OR osteoarthritis OR osteoarthrosis OR arthralgia.
Selecting Studies for Review
Duplicates were removed and relevant titles were selected from the results. This was followed by retrieval of full text of articles to decide whether they meet the inclusion and exclusion criteria or not.
- Study design: level 1 to 4 studies assessing the efﬁcacy of prolotherapy, BoNT/A, saline, calcium gluconate, and sodium bicarbonate.
- Participants: human subjects aged 18 years and older with chronic knee pain/symptoms for at least 6 weeks to ensure true chronicity of symptoms. Studies should also include at least 20 participants to be included and with at least 3-month follow-up.
- Outcome: studies assessing pain and function.
- Language: English, Spanish, Portuguese, French, Italian papers.
- Study design: pilot studies (n < 20), unpublished material (PhD/MSc thesis), letters to the editor, reviews, and conference abstracts.
- Participants: animal, cadaver, and in vitro studies. Studies assessing prolotherapy in other joints/regions, unless knee joint patients were part of the study and results for this subgroup can be extracted separately.
- Outcome: studies assessing outcomes other than pain and function, such as imaging ﬁndings, biomechanical or microcirculatory outcomes.
- Language: nonincluded language papers.
Reference lists were searched further, and Google Scholar was also used to expand the search into cited articles for further relevant articles.
Evaluation of Methodological Quality
As most of the articles were of an experimental nature, the strength and quality of the evidence was determined using the validated Modiﬁed Coleman Methodology Score (23), with a score of > 90 considered to be excellent, 80 to 90 good, 70 to 80 fair, and <70 poor. A modiﬁcation of this score was previously published (24).
Two doctors, W.D.M. and N.M. completed the process of scoring all the articles independently. Disagreements were deﬁned as a difference of more than 2 points from the overall score from each individual article, and disagreements were resolved by consensus.
The overall strength of evidence was then assessed by assigning a level of 1 to 5 according the criteria proposed by van Tulder et al, depending on the number and quality of studies (25).
Cohen d values were used to estimate the effect size of any positive results, which has been shown to be a robust method for assessing magnitude of effects (26,27). Cohen d is used when studies report efﬁcacy in terms of continuous measurement, such as pain scores on a rating scale. A score of zero means that the treatment and control groups have no differences in effect. A score greater than zero indicates the degree to which one treatment is more efﬁcacious than the other. Furthermore, a Cohen d of 0.2 is considered as small,
0.5 as medium, and 0.8 as large effect (27,28). The effect size value is often accompanied by a conﬁdence interval (CI), which gives a reﬂection on the reliability of the comparison.
Figure 1. PRISMA flow diagram of the search results. OA indicates osteoarthritis.
The initial search returned 5115 studies, with 18 articles meeting the inclusion criteria after a process of screening and full-text retrieval. There were no studies that were scored in the excellent range for study methodology, 1 was good quality (29), 7 were scored of fair quality (30–36), and 10 were of poor quality (19,37–45). The mean Coleman Methodology Score modiﬁed for conservative therapy is 68.67 (range: 54.00 to 81.00; SD = 8.51; 95% CI, 64.43-72.90), which falls in the “poor quality” range.
The studies included a total of 1450 patients, of which 953 were females (65.7%) and 497 were males (34.3%). Patients had varying degrees of symptoms and studies reported different outcome measures, such as Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog scale (VAS), knee pain scale, range of motion, patient satisfaction, and radiologic assessment. Data from the 18 studies were extracted and summarized in Table 1. Effect size values and their respective CIs are summarized in Table 2.
Table 1. Summaries of the studies reviewed
|References||Design||Sample||Primary Outcome||Intervention||Results||MCM Score*|
|Rezasoltani et al (32)||Double-blind RCT||104 participants— 78 F and 26 M||VAS for pain||Group 1: intra-articular prolotherapy. Group 2: periarticular prolotherapy||VAS: sig lower in group 2 at 2, 3, 4, and 5 mo (P = 0.001), but not at 1 mo (P =0.22)||
|Rabago et al (31)||3-arm RCT||90 participants— 60 F and 30 M||WOMAC||Group A: Intra-articular and extra- articular prolotherapy injections Group B: saline injections. Group C: home exercises||50% of dextrose participants exceeded MCIC for WOMAC, compared with 30% and 24% for saline and exercise groups, respectively||78|
|Dumais et al (30)||Crossover RCT (open-labelled)||36 participants— 19 M and 17 F||WOMAC||Group A: exercise program and prolotherapy. Group B: exercise program and prolotherapy||After 36 wk, WOMAC scores improved in both groups by 47.3% and 36.2% in groups A and B, respectively||78|
|Rabago et al (37)||Single-arm uncontrolled study with 1 y follow-up||36 participants— 15 M and 21 F||WOMAC||Extra-articular prolotherapy injections and intra-articular prolotherapy||WOMAC: at 52 wk follow-up, improvement reaching 36.1% (15.9 ± 2.5 points, P < 0.001), which exceeds the MCIC||67|
|Eslamian and Amouzandeh (38)||Single-arm clinical trial||24 female patients—40 knees||VAS for pain||Intra-articular prolotherapy||VAS: decrease of 45.86% (rest) and 44.23% (activity) at 24 wk (P < 0.001)||66|
|Rabago et al (39)||Open-label follow-up study to an RCT and 2 noncontrolled trials||65 participants— 38 F and 27 M||WOMAC||Intra-articular and extra-articular prolotherapy||Sig improvement in WOMAC scores, across the 3 subscales, at all time points in excess of MCIC||65|
|Rahimzadeh et al (40)||RCT||70 patients—30 M and 40 F||VAS for pain||Group A: intra-articular 4000 IU of EPO+local. Group B: intra-articular prolotherapy. Group C: pulsed radiofrequency||VAS: sig different group A as compared with the 2 other groups (P ≤ 0.005)||64|
|Rabago et al (41)||Prospective 3-arm uncontrolled study with 52-week follow- up||38 participants— 21 M and 17||WOMAC||Extra-articular and intra-articular injection prolotherapy||Prior-declined: 75% achieved MCIC. Prior-control: 55.6% participants achieved MCIC. Prior-ineligible: 50% of participants achieved MCIC||62|
|Rabago et al (42)||2-arm controlled trial||37 participants— 16 M and 21 F||WOMAC||Treatment group: intra-articular and extra-articular prolotherapy. Control group: saline injections or gradually increased home-based exercises||WOMAC improvement more sig in the treatment group at 52 wk (17.6 ± 3.2 vs. 8.6 ± 5.0 points, P = 0.05). Both groups MRI-assessed CV (P < 0.05), those that lost the least CV had greatest improvement in symptoms, suggest pain-speciﬁc disease-modifying effect||62|
|Reeves and Hassanein (43)||Double-blind prospective RCT||68 patients (111 knees—25 with ACL laxity)||VAS for pain||Treatment group: prolotherapy. Control: local anesthesia||Sig pain improvement with prolotherapy||58.5|
|Soliman et al (44)||RCT||128 patients—96 F
and 32 M
|VAS for pain||Group A: intra-articular and extra- articular prolotherapy. Group 2: physiotherapy only||Group A: VAS sig improvement 12 mo, compared with their baseline and with group 2 (P ≤ 0.001)||54|
|Hsieh et al (33)||Prospective RCT||41 patients—25 F
and 16 M
|VAS for pain||Group 1: single IA BoNT/A. Group 2: education only||Between group comparison revealed sig difference regarding VAS score at 1 wk (P < 0.001) and at 6 mo (P = 0.001)||74|
|Chou et al (19)||Nonrandomized open-label clinical trial||24 patients (38 knees)—13 M and 11F||WOMAC||All patients received 2 IA injections (100U of BoNT/A + normal saline)||At 3 mo statistically sig change WOMAC||50|
|Sodium bicarbonate and calcium gluconate|
|García-Padilla et al (35)||Double-blind parallel-group RCT||73 participants— 61 F and 12 M (n = 51 completed study)||WOMAC||Both groups IA injection Group 1: sodium bicarbonate and single dose of calcium gluconate. Group 2: sodium bicarbonate and double dose of calcium gluconate||WOMAC: after 12 mo, SBCG1 decreased −14.8 (−14.2 to −17.0) and SBCG2 decreased −14.6 (−16.9 to −12.4). Changes represent 80% and 82% decrease in pain, respectively||78|
|del Carmen Caamano et al (34)||Double-blind parallel-group RCT||97 participants— 74 F and 23 M||WOMAC||Both groups IA injection Group 1: sodium bicarbonate and single dose of calcium gluconate . Group 2: sodium bicarbonate and double dose of calcium gluconate. Group 3: steroid||All treatments sig improved WOMAC a mean changes for groups 1 and 2 were sig greater than group 3 (P < 0.001) at 3 M||77|
|Bar-Or et al (29)||4-arm double-blind RCT (parallel study)||329 participants||WOMAC||Group 1: single IA injection LMWF- 5A. Group 2: single IA injection saline vehicle control. Group 3: single IA injection LMWF-5A Group 4: single IA saline vehicle control||Groups 1 and 3 experienced sig WOMAC improvement in pain scores vs. saline (−0.93 vs. −0.72). Injection volume effect not seen between groups (P = 0.64). The estimated difference vs. control was −0.25 (−0.08 to −0.41, P = 0.004). Reduction in pain with LMWF-5A seen as early as 4 wk (P = 0.03) and persisted to 12 wk (P = 0.004)||81|
|Local anesthetic agents|
|Eker et al (36)||Double-Blind RCT||58 participants – 28F and 24M||Womac||Group 1: IA lidocaine injections. Group 2: IA saline injections||WOMAC: Sig pain improvement noted in both groups at 3 mo (P = 0.006, P = 0.001, respectively). Group 1
continued to improve, no further improvement noted in group 2
|Desmerais (45)||Prospective Study||81 patients||Objective physicians assessment (joint tenderness, ROM, limp presence/ absence, effusion and quadriceps power)||All patients IA injection Group 1: lactic acid solution. Group 2:novocaine solution. Group 3: physiological normal saline. Group 4: hydrocortisone solution. Group 5: mock injection. No injected volume||Physician (objective) assessment: at 6 wk posttreatment 84.7% (50/95) of men and 68% (83/112) of women showed clinical improvement overall with no sig difference between the different interventions||66.5|
*MCM scores are reported as mean scores.
ACL indicates anterior cruciate ligament; ADD, anterior displacement difference; BoNT/A, botulinum toxin A; CV, cartilage volume; EPO, erythropoietin; F, Female; KOA, knee osteoarthritis; KPS, knee pain scale; LMWF-5A, low–molecular weight fraction of 5% human serum albumin; M, male; MCIC, minimal clinically important change; MCM, modiﬁed coleman methodology; MRI, magnetic resonant imaging; NRS, numerical rating scale; QoL, quality of Life; RCT, randomized controlled trial; RIT, regenerative injection therapy; ROM, range of motion; Sig, signiﬁcant/ly; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Arthritis Index.
TABLE 2. Effect Size Calculations
Effect Size [Mean SD]*
|Rabago et al (31)||Prolotherapy vs. Saline||Total WOMAC at 12 wk||1.56 (0.06-2.46)|
|Total WOMAC at 52 wk||2.36 (1.46-3.26)|
|Pain subscale of WOMAC at 52 wk||1.9 (0.92-2.88)|
|Prolotherapy vs. excercise||Total WOMAC at 52 wk||2.17 (1.28-3.05)|
|Total WOMAC at 12 wk||1.39 (0.42-2.36)|
|Rabago et al (42)||Combination of techniques vs. prolotherapy alone||VAS for pain at 12 mo||9.5 (9.28-9.72)|
|Hackett technique vs. physiotherapy alone||VAS for pain at 12 mo||0.30 (0.22-0.38)|
|Combination of both techniques vs. Hackett technique only
|WOMAC pain subscale at 5 mo||1.40 (1.26-1.54)
|Soliman et al (44)||BoNT/A vs. education only (control)||VAS for pain at 1 wk||2.26 (1.93-2.59)|
|VAS for pain at 6 mo||1.39 (1.00-1.78)|
|Total WOMAC at 1 wk||1.09 (−1.27 to 3.45)|
|Total WOMAC at 6 mo||1.01 (−2.42 to 4.44)|
|Rezasoltani et al (32)||Periarticular vs. intra-articular prolotherapy injections||WOMAC pain sub-scalet at 5mo||1.40 (1.26-1.54)
|Hsieh et al (33)||BoNT/A vs. education only (control)
|VAS for pain at 1 wk||VAS for pain at 1 wk|
|VAS for pain at 6 mo||1.39 (1.00-1.78)|
|Total WOMAC at 1 wk||1.09 (−1.27 to 3.45)|
|Total WOMAC at 6 mo||1.01 (−2.42 to 4.44)|
|Eker et al (36)||0.5% lidocaine vs. saline injections||NRS at 3 mo post 3rd injection||1.02 (0.49-1.55)|
|Bar-Or et al (29)||LMWF-5A vs. saline (combined arms)||Pain subscale of WOMAC at 6 wk||1.85 (1.84-1.85)|
|Pain subscale of WOMAC at 12 wk||3.23 (3.22-3.24|
|4 ml LMWF-5A vs. 10 mL LMWF-5A||Pain subscale of WOMAC at 6 wk||−0.38 (−0.39 to −0.36)|
|Pain subscale of WOMAC at 12 wk||0.12 (0.10-0.13)|
|LMWF-5A vs. saline (combined arms) in stage III vs. stage IV disease
|Pain subscale of WOMAC at 12 wk in stage III disease||Pain subscale of WOMAC at 12 wk in stage III disease|
|Pain subscale of WOMAC at 12 wk in stage IV disease||Pain subscale of WOMAC at 12 wk in stage IV disease|
|LMWF-5A 4 mL vs. saline||Pain subscale of WOMAC at 6 wk||2.01 (1.996-2.02) Pain subscale of WOMAC at 12 wk|
|Pain subscale of WOMAC at 6 wk||2.01 (1.996-2.02) Pain subscale of WOMAC at 12 wk|
|LMWF-5A 10 mL vs. saline||Pain subscale of WOMAC at 6 wk||0.94 (0.93-0.96) Pain subscale of WOMAC at 12 wk|
|Pain subscale of WOMAC at 6 wk||0.94 (0.93-0.96) Pain subscale of WOMAC at 12 wk|
*Values are rounded to 2 decimal places.
BoNT/A indicates botulinum toxin A; LMWF-5A, low–molecular weight fraction of 5% human serum albumin; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Arthritis Index.
Following the van Tulder criteria for levels of evidence, our results show moderate supporting evidence for the use of prolotherapy in symptomatic KOA (25). In the studies included, prolotherapy was found to have both short-term and long-term beneﬁts in improving WOMAC, VAS scores, and patient satisfaction (37–39). Positive results were seen as early as 9 weeks and were maintained at the 3.5 years follow-up point (31,39,42). Furthermore, additional beneﬁt was demonstrated when prolotherapy was added to home exercises (30).
One study compared erythropoietin injections to dextrose injections and pulsed radiofrequency. Results showed erythropoietin to be superior in improving VAS scores, range of motion, and patient satisfaction. Dextrose injections were found to be as efﬁcient as pulsed radiofrequency at 4 and 12 weeks (40).
A recent study compared the 2 techniques against physiotherapy. The treatment group was subdivided into Hackett technique injections only and another one following a combination of Hackett and Lyftogt’s techniques (44). Both injection groups showed signiﬁcant improvement in VAS, WOMAC and radiologic ﬁndings at 12 months compared with the control group (P ≤ 0.001). However, the combination group required fewer injections and the effect size calculations supported that by showing a small positive effect favoring the combination group.
Another way to classify injections is either periarticular or intra-articular. A recent study comparing periarticular and intra-articular prolotherapy injections showed periarticular injections to be superior in improving VAS (P = 0.001) and WOMAC (P < 0.05) scores at 5 months, as well as yielding a large positive effect as per effect size analysis (32).
One fair quality randomized controlled trial (RCT) and 1 poor quality prospective study for BoNT/A were included in this review (19,33). The ﬁrst RCT showed BoNT/A to yield signiﬁcant improvement in outcomes assessing pain and function at 1 week and 6 months, with a large positive effect (P < 0.001 and P = 0.001, respectively) (33). CIs for VAS were narrow and the lower range was higher than the threshold for large effect; however, intervals for WOMAC effect sizes were wide, which may affect the validity of conclusions drawn from them. Another nonrandomized study showed BoNT/A to be beneﬁcial in patients with advanced KOA but not patients with mild symptoms (19). The dose of BoNT/A is not yet established; however, previous studies suggested 100 IU to be a safe dose in large joints and 50 IU in smaller joints (33).
The literature is sparse on the use of BoNT/A injections to manage OA in humans. Animal studies previously suggested BoNT/A injections have the potential for reducing chronic OA pain; however, they were found ineffective for the management of acute pain (46,47). A previous study showed promise in BoNT/A in managing chronic arthritis pain and improving function in upper and lower extremities (17). Furthermore, the control group in the studies we included did not have a saline injection or a form of controlled injectable treatment, hence, their experience was signiﬁcantly different and the possibility of placebo effect and bias cannot be eliminated (19,33). Furthermore, due to the high cost and lack of high-quality evidence with large sample size, BoNT/A is not considered as ﬁrst-line treatment; however, it has the potential in helping refractory cases.
Limited supporting evidence suggests SBCG is beneﬁcial in improving pain and function associated with KOA. Two fair quality studies comparing the effect of sodium bicarbonate with either single (7.5%) or double dose (15%) calcium gluconate found both regimes to be effective in improving WOMAC scores, with the effect lasting 6 months after treatment suspension (34,35). One study suggested the double dose of calcium gluconate can prevent further narrowing of joint space at 3 and 18 months(35). However, in terms of pain and function, the difference between the group is minimal. Both studies did not have a control group with no active treatment, as one study compared the 2 doses directly (35) and the other study compared both groups with methylprednisolone (34).
Low–molecular weight fraction of 5% human serum albumin (LMWF-5A) has been proposed for managing arthritic pain due to its anti-inﬂammatory and immuno-modulatory properties. One fair quality RCT demonstrated the effectiveness of 10 and 4 mL dosing of 5% human albumin (LMWF-5A) in improving pain as early as 4 weeks and until the 12 weeks follow-up (29). Effect size was shown to be large for both concentrations at 6 and 12 weeks, suggesting short-term and medium-term beneﬁts. The difference between the 2 concentrations was very small and the treatments were shown to be more effective in patients with advanced grade OA (stage IV). The authors suggested this could be due to a pronounced saline effect in those with minimal OA, hence, making the LMWF-5A effect less signiﬁcant. The level of evidence remains limited.
One RCT investigating local anesthetics for treatment KOA showed continuous improvement in WOMAC in lignocaine group with every assessment point until the 3 months follow-up, which was not observed in the control group, as well as a signiﬁcantly larger decrease in numerical rating scale score in the treatment group (60.39% vs. 25.49%) (36). Another 5-arm RCT showed lignocaine to be as effective as placebo in objective and subjective measures (45).
The main limitations relate to the lack of robust literature available. The average quality of included studies falls in the “poor” range, which limits the validity of any conclusions drawn. Furthermore, the number of studies included is considered to be small, which inﬂuences the overall strength of evidence. There is large heterogeneity among the studies in patient characteristics, study design, interventions, and length of follow-up.
There is moderate supportive evidence for the effectiveness of prolotherapy in improving pain and function in both, short-term and long-term. Limited supporting evidence found for BoNT/A, SBCG, and LMWF-5A in improving pain and function. There is conﬂicting evidence for the use of local anesthetic agents in patients with KOA.
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