Authors: Fadi Hassan, BSc (Hons), MBBS,* William D. Murrell, MD, MS,†‡ Andrew Refalo, MS,§ and Nicola Maffulli, MD, MS, PhD, FRCP, FRCS (Orth), FFSEM

Abstract 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.

 

INTRODUCTION

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.

METHODS

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.

Inclusion Criteria

• 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.

Exclusion Criteria

• 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).

Statistical Analysis

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.

RESULTS

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*
Prolotherapy
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)	79
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
BoNT/A
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
Human albumine
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	76
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

References	Comparison	Outcome Measure	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.

DISCUSSION

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).

LIMITATIONS

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.

CONCLUSIONS

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.

 

 

REFERENCES

1. Cherry DK, Woodwell DA, Rechtsteiner EA, et al. National Ambulatory Medical Care survey: 2005 summary. Adv Data from Vital Heal Stat. 2007;387:1–40.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26–35.
3. Creamer PHM. Osteoarthritis. Lancet. 1997;350:503–508.
4. Losina E, Walensky RP, Kessler CL, et al. Cost-effectiveness of total knee arthroplasty in the United States: patient risk and hospital volume. Arch Intern Med. 2009;169:1113–1122.
5. Herndon JH, Davidson SM, Apazidis A. Recent socioeconomic trends in orthopaedic practice. J Bone Joint Surg Am. 2001;83: 1097–1105.
6. Barron MC, Rubin BR. Managing osteoarthritic knee pain.
J Am Osteopath Assoc. 2007;107:ES21–ES27.
7. Percope de Andrade MA, de Oliveira Campos TV, de Abreu-e- Silva M. Supplementary methods in the nonsurgical treatment of osteoarthritis. Arthroscopy. 2015;31:785–792.
8. da Costa BR, Nuesch E, Kasteler R, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2014:CD003115.
9. Anitua E. Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. Int J Oral Maxillofac Implants. 1999;14:529–535.
10. Murrell WD, Anz AW, Badsha H, et al. Regenerative treatments to enhance orthopedic surgical outcome. PMR. 2015; 7:S41–S52.
11. Rabago D, Best TM, Zgierska AE, et al. A systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and platelet-rich plasma. Br J Sports Med. 2009;43:471–481.
12. Rabago D, Best TM, Beamsley M, et al. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med. 2005;15:376–380.
13. Hassan F, Trebinjac S, Murrell WD, et al. The effectiveness of prolotherapy in treating knee osteoarthritis in adults: a systematic review. Br Med Bull. 2017;122:91–108.
14. Burdakov D, Jensen LT, Alexopoulos H, et al. Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron. 2006;50:711–722.
15. Jensen KT, Rabago DP, Best TM, et al. Early inflammatory response of knee ligaments to prolotherapy in a rat model. J Orthop Res. 2008;26:816–823.
16. Banks AR. A rationale for prolotherapy. J Orthop Med. 1991;13: 54–59.
17. Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res. 2006;9:179–188.
18. Boon AJ, Smith J, Dahm DL, et al. Efficacy of intra-articular botulinum toxin type A in painful knee osteoarthritis: a pilot study. PMR. 2010;2:268–276.
19. Chou CL, Lee SH, Lu SY, et al. Therapeutic effects of intra- articular botulinum neurotoxin in advanced knee osteoarthritis. J Chinese Med Assoc. 2010;73:573–580.
20. García-Padilla S, Duarte-Vázquez MA, Gonzalez-Romero KE, et al. Effectiveness of intra-articular injections of sodium bicarbonate and calcium gluconate in the treatment of osteo- arthritis of the knee: a randomized double-blind clinical trial. BMC Musculoskelet Disord. 2015;16:114–123.
21. Schweiz KR. Die intra-artikuläre alkali-therapie [Intra-articular alkali therapy]. Med Wschr. 1948;78:80.
22. Kang S-J, Kim J-W, Kim K-Y, et al. Protective effects of calcium gluconate on osteoarthritis induced by anterior cruciate ligament transection and partial medial meniscectomy in Sprague-Dawley rats. J Orthop Surg Res. 2014;9:14–21.
23. Coleman BD, Khan KM, Maffulli N, et al. Studies of surgical outcome after patellar tendinopathy: clinical significance of methodological deficiencies and guidelines for future studies. Victorian Institute of Sport Tendon Study Group. Scand J Med Sci Sports. 2000;10:2–11.
24. Abdul-Wahab TA, Betancourt JP, Hassan F, et al. Initial treatment of complete rotator cuff tear and transition to surgical treatment: systematic review of the evidence. Muscles Ligaments Tendons J. 2016;6:35–47.
25. van Tulder M, Furlan A, Bombardier C, et al. Updated method guidelines for systematic reviews in the cochrane collaboration back review group. Spine (Phila Pa 1976). 2003;28:1290–1299.
26. McGough JJ, Faraone SV. Estimating the size of treatment effects: moving beyond p values. Psychiatry (Edgmont). 2009;6: 21–29.
27. Cohen J. Statistical Power Analysis for the Behavioral Sciences, 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.
28. Faraone SV. Understanding the effect size of ADHD medi- cations: implications for clinical care. 2003. Available at: www. medscape.com/viewarticle/461543. Accessed November 24, 2017.
29. Bar-Or D, Salottolo KM, Loose H, et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee.
PLoS One. 2014;9:e87910.
30. Dumais R, Benoit C, Dumais A, et al. Effect of regenerative injection therapy on function and pain in patients with knee osteoarthritis: a randomized crossover study. Pain Med. 2012;13: 990–999.
31. Rabago D, Patterson JJ, Mundt M, et al. Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2013;11:229–237.
32. Rezasoltani Z, Taheri M, Mofrad MK, et al. Periarticular dextrose prolotherapy instead of intra-articular injection for pain and functional improvement in knee osteoarthritis. J Pain Res. 2017;10:1179–1187.
33. Hsieh L-F, Wu C-W, Chou C-C, et al. Effects of botulinum toxin landmark-guided intra-articular injection in subjects with knee osteoarthritis. PMR. 2016;8:1127–1135.
34. del Carmen Caamano M, Garcia-Padilla S, Angel Duarte- Vazquez M, et al. A double-blind, active-controlled clinical trial of sodium bicarbonate and calcium gluconate in the treatment of bilateral osteoarthritis of the knee. Clin Med Insights Arthritis Musculoskelet Disord. 2017;10:1–7.
35. García-Padilla S, Duarte-Vazquez MA, Gonzalez-Romero KE, et al. Effectiveness of intra-articular injections of sodium bicarbonate and calcium gluconate in the treatment of osteo- arthritis of the knee: a randomized double-blind clinical trial. BMC Musculoskelet Disord. 2015;16:114–123.
36. Eker HE, Cok OY, Aribogan A, et al. The efficacy of intra- articular lidocaine administration in chronic knee pain due to osteoarthritis: a randomized, double-blind, controlled study. Anaesth Crit Care Pain Med. 2017;36:109–114.
37. Rabago D, Zgierska A, Fortney L, et al. Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: results of a single-arm uncontrolled study with 1-year follow-up. J Altern Complement Med. 2012;18:408–414.
38. Eslamian F, Amouzandeh B. Therapeutic effects of prolother- apy with intra-articular dextrose injection in patients with moderate knee osteoarthritis: a single-arm study with 6 months follow up. Ther Adv Musculoskelet Dis. 2015;7:35–44.
39. Rabago D, Mundt M, Zgierska A, et al. Hypertonic dextrose injection (prolotherapy) for knee osteoarthritis: Long term outcomes. Complement Ther Med. 2015;23:388–395.
40. Rahimzadeh P, Imani F, Faiz SHR, et al. Investigation the efficacy of intra-articular prolotherapy with erythropoietin and dextrose and intra-articular pulsed radiofrequency on pain level reduction and range of motion improvement in primary osteoarthritis of knee. J Res Med Sci. 2014;19:696–702.
41. Rabago D, Patterson JJ, Mundt M, et al. Dextrose and morrhuate sodium injections (prolotherapy) for knee osteoarthritis: a prospec- tive open-label trial. J Altern Complement Med. 2014;20:383–391.
42. Rabago D, Kijowski R, Woods M, et al. Association between disease-specific quality of life and magnetic resonance imaging outcomes in a clinical trial of prolotherapy for knee osteo- arthritis. Arch Phys Med Rehabil. 2013;94:2075–2082.
43. Reeves KD, Hassanein K. Randomized prospective double- blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Altern Ther Health Med. 2000;6:68–74-80.
44. Soliman DMI, Sherif N, Omar O, et al. Healing effects of prolotherapy in treatment of knee osteoarthritis healing effects of prolotherapy in treatment of knee osteoarthritis. Egypt Rheumatol Rehabil. 2016;43:47–52.
45. Desmarais MHL. Value of intra-articular injections in osteo- arthritis. A controlled series. Ann Rheum Dis. 1952;11:277–281.
46. Krug HE, Frizelle S, McGarraugh P, et al. Pain behavior measures to quantitate joint pain and response to neurotoxin treatment in murine models of arthritis. Pain Med. 2009;10:1218–1228.
47. Anderson JJ, Baron G, Van Der Heijde D, et al. Ankylosing spondylitis assessment group preliminary definition of short- term improvement in ankylosing spondylitis. Arthritis Rheum. 2001;44:1876–1886.