ABSTRACT:

Lower extremity soft tissues injuries account for a large proportion of musculoskeletal injuries. In cases where medication, physical therapy and cortisone injections do not provide complete relief, dextrose prolotherapy is a viable treatment option that has been available for many decades. In our clinic, dextrose prolotherapy is particularly effective in patients who are hypermobile or have Ehlers-Danlos syndrome. This review summarizes the published uses of dextrose prolotherapy.

Key phrases/words: dextrose prolotherapy, prolotherapy lower extremity, prolotherapy leg injury

Summary statement:

Dextrose prolotherapy is an effective treatment for lower extremity injuries, and its use should become more readily available and covered by insurance.

Authors

Brent Shaw, Tulane University School of Medicine

Rachel Turner, Tulane University School of Medicine

Catherine Kingry, MD, BA, Tulane University School of Medicine

Jacques Courseault, MD, CAQSM, FAAPMR Tulane University School of Medicine, Fascia Institute and Treatment Center

The authors declare no conflicts of interest and do not have any financial disclosures.

Introduction

Ehlers Danlos Syndrome (EDS) is a connective tissue disorder characterized by joint hypermobility, skin hyperextensibility, and tissue elasticity.1 Scientists have classified thirteen different subtypes of EDS however the 80-90% of these cases are characterized as the hypermobile subtype.1 Hypermobile Ehlers Danlos Syndrome (hEDS) affects 0.19% of the population, yet awareness of hEDS and diagnosis criteria are largely unknown amongst clinicians leading to a predictive higher prevalence.2 The primary physical characteristic of hEDS is the laxity of joint capsules, ligaments, and associated tendons  due to a malfunction in the creation of collagen. Many patients may identify as “double-jointed” allowing them to hyperextend or dislocate many of their joints.  Unlike other EDS subtypes there is no genetic etiology for hEDS and diagnosis must be based on clinical evaluation.

Many confuse hEDS with joint hypermobility syndrome (JMS). In 2017, the International EDS Consortium created new criteria to help solve this discrepancy. The first criteria is the use of the Beighton score to assess joining hypermobility. The tool is a 9-point yes-or-no checklist that grades a patient’s range of motion in four bilateral motions and one unilateral motion to demonstrate hypermobility. This can be seen in Figure 1. A positive sign is a score of greater than 6 for prepubertal children; greater than or equal to 5 for pubertal children and adults up to age 5; and greater than or equal to 4 for those older than 50 years. The second criteria is based on evidence of systemic manifestations, musculoskeletal complications, and/or family history. The third criteria is the exclusion of alternative EDS subtypes, autoimmune disorders, and other pathologies.  

Beighton Fascia Institute

Figure 1. The Beighton criteria includes: (A) forward flexion of the trunk with the knees fully extended so that the palms of the hands rest flat on the floor, (B & C) hyperextension of the right and left elbows beyond 190 degrees, (D & E) hyperextension of the right and left knees beyond 190 degrees, (F & G) opposition of the right and left thumbs to the flexor surface of the forearms, and (H & I) hyperextension and dorsiflexion of the right and left fifth fingers beyond 90 degrees.

Patients diagnosed with hEDS experience negative consequences of living with joint hypermobility. Patients frequently experience recurrent lower extremity joint instability and subluxations at a young age. A 2010 review found that athletes were at an increased risk of knee joint injury during contact activity. Spraining ankles, buckling of the knees and snapping of the hip are all common occurrences that provide patients with physical and psychological discomfort.  When hypermobile patients grow older, these loose and unstable joints become arthritic leading to chronic pain and discomfort. 

The traditional management of hEDS symptoms focuses on a combination of treatment approaches working in unison. These treatments are focused primarily on prevention rather than the reversal of tissue elasticity. A 2014 review found that hypermobile patients experience benefit from physiotherapy exercises however higher quality research is needed to validate these findings. Additionally studies that explored the effect of core and joint stabilization exercises in hypermobile patients showed encouraging results. Lastly hEDS patients are prescribed pain medications however have provided only short-term benefit. Patients may elect to undergo surgery however the degree of pain reduction and patient satisfaction is variable in addition to being worse than a non-hEDS population. These limited treatment options demonstrate a need for an alternative approach that repairs the underlying hEDS pathology.

Dextrose prolotherapy is an inexpensive, noninvasive treatment that has shown promising results in musculoskeletal pathology research. Hypertonic dextrose is an osmotic irritant that stimulates tissue growth when injected into injured muscles, tendons, ligaments, and joints. Even though dextrose prolotherapy’s mechanism of action it is not fully understood, it believed that it triggers a local inflammation that releases growth factors and cytokines that are involved in the natural healing cascade.13 These mediator molecules cause chemomodulation, leading to the proliferation and strengthening of new connective tissue. Animal histological studies support these findings. Kim and colleagues reported that a single injection of either 5% dextrose (D5W) or 20% dextrose into non-injured rat Achilles tendon resulted in a significant increase in tendon diameter and fibroblast counts compared to saline, suggesting a non-osmolar mechanism of dextrose-induced proliferation.15 

We hypothesize that dextrose prolotherapy can reverse the disease state of hEDS by strengthening the supporting joint tissues to reduce hypermobility and symptomatic discomfort.14 Our aim with this review is to summarize the latest prolotherapy research in lower extremity injuries and draw correlations to hEDS pathology.

Methods

Objective 

The aim of this study was to systematically review dextrose prolotherapy  for treating various lower extremity musculoskeletal injuries in both hypermobile and non-hypermobile patients. 

Data Sources and Selection Criteria

Electronic databases PubMed, Healthline, OmniMedicalSearch, Medscape, and EMBASE were searched from 1990 to November 2021. The search was performed to the similar protocol outlined by a dextrose prolotherapy review performed by Hauser in 2016. Keywords used for search included prolotherapy, dextrose, regenerative injection therapy, and musculoskeletal pain. Inclusion criteria were the injection of human subjects, published in a peer-reviewed journal, and use of dextrose as the sole prolotherapy proliferant. Exclusion criteria included use of treatment of upper extremity injuries, prolotherapy solutions containing P2G, pumice, PRP, bone marrow, lipoaspirate, stem cells, or sodium morrhuate. Non-English studies were included if they provided an abstract in English, and presented sufficient tabular/graphic data for data abstraction.

Outcomes

Studies that investigate the efficacy of injection based therapies to treat musculoskeletal pain assess change in pain intensity from baseline with patient-reported ratings. Rating scales included in this review were the visual analog scale (VAS) or numerical rating scale (NRS). The significance of change in pain score the minimal clinically important change (MCID) criteria which is used to assess clinical relevance.9 A reduction of two points represents the MCID using NRS10 and a decrease of ≤1.5 points with VAS and NRS represents a clinically irrelevant change in pain self-rating.11,12 The studies that assessed the efficacy of dextrose prolotherapy for treatment of OA used the Western Ontario McMaster University Osteoarthritis Index (WOMAC; 100-point scale). This osteoarthritis index measures pain, stiffness, and functional movement. Study heterogeneity and limited RCTs prevented the aggregation of statistical data necessary to perform a meta-analysis. 

Results

Table 1: Reviewed literature that investigated dextrose prolotherapy’s use in Lower Back Pathology

Author, Date, and Level EvidencePathologyNumber of ParticipantsDextrose Solution and Control GroupNumber of Injections, injection procedure, Follow-up timeResults
Dechow et al.53 (1999) Level 1Lower Back Pain74
  • Active: 5ml 25% dextrose, 25% glycerine, 2.4% phenol made up 100ml with sterile water combined with 5ml of 1% lignocaine 
  • Control: 5ml of saline and 5ml of 1% lignocaine
  • 3 weekly injections
  • All injections were made from a single insertion into the following sites: tip of the spinous process of L4 and L5 and associated supraspinous and interspinous ligaments; apophyseal joint capsules and L4-5 and L5-S1; attachment of the iliolumbar ligaments at the transverse processes of L5; attachment of the iliolumbar and dorsolumbar fascia to the iliac crest; and attachments of the long and short fibers of the posterior sacroiliac ligament and the sacral and iliac
  •  attachments of the interosseous sacroiliac ligaments
  • 6- month follow-up
  • There were no statistical differences in any of Pain or Disability Outcomes
Maniquis-Smigel et al.54 (2017) Level 1Lower Back Pain35
  • Active: 10 mL of 5% dextrose
  • Control: 10 mL 0.9% saline
  • 1 injection
  • A vertical short needle technique was utilized for injection in the caudal epidural space, with needle entry at or below the sacral cornua
  • 1-year follow-up
  • Dextrose participants reported greater NRS pain score change at 15 minutes, 2 hours, 4 hours , and 48 hours, but not at 2 weeks. 
  • Eighty four percent of dextrose recipients and 19% of saline recipients reported ≥ 50% pain reduction at 4 hours (P < 0.001). 
  • These findings suggest a neurogenic effect of 5% dextrose on pain at the dorsal root level; waning pain control at 2 weeks suggests the need to assess the effect of serial dextrose epidural injections in a long-term study with robust outcome assessment.
Hooper et al.56 (2011) Level 3Lower Back Pain147
  • Active: 20% dextrose and 0.75% lidocaine
  • 3 weekly injections, A set of three injections was repeated in 1 month if symptoms persisted and ongoing laxity was identified
  • Lax ligaments were identified by manual examination and injected into Hackett landmarks. Facet capsules of the cervical, thoracic, or lumbar spine. The iliolumbar ligament insertions on the iliac crest and dorsal sacroiliac ligaments were also injected
  • 1-year follow-up
  • Both litigants and non-litigants showed significant improvement from baseline on all disability scales (P<0.001). 
  • There were no differences in the percentage of litigants/non-litigants reporting improvement on impression of change scales for symptoms function, improved ability to work, willingness to repeat treatment, ability to decrease medication, and decreased need for other treatment. 
Köroğlu et al.57 (2019) Level 4Lower Back Pain40
  • Active Group 1: 5% dextrose; 5% dextrose 
  • Active Group 2: 5% dextrose + physical therapy
  • 1 injection
  • Solution injected to iliolumbar and transverse ligament insertion levels and at the facet level.
  • 1- year follow-up
  • A significant reduction in pain was reported in all patients in both groups. The pain and disability scores significantly improved both in two groups at the 3, 12 and 52-week follow-up with no significant difference between the groups.
Solmaz et al.58 (2019) Level 4Lower Back Pain76
  • Active: 5% dextrose
  • 1 injection
  • injected to spinous processes of L1-L2-L3-L4-L5-S1 vertebrae, piriformis
  • 1-year follow-up
  • After 1 year of follow-up, VAS score decreased by 71% and ODI decreased by 68.4%
Kim et al.60 (2011) Level 1SI Joint Pain23
  • Active: 1.25 mL 50% dextrose water with 1.25mL 0.25% levobupivacaine
  • Control: triamcinolone acetonide 40 mg in 0.125% levobupivacaine 2.5 mL
  • Up to 3 biweekly injections
  • Intra-articular SI joint injections
  • 15-month follow-up
  • The cumulative incidence of ≥50% pain relief at 15 months was 58.7% in the prolotherapy group and 10.2% in the steroid group, as determined by Kaplan-Meier analysis 
  • These differences were significant between groups demonstrating superiority to the prolotherapy group
Kim et al.61 (2007) Level 4SI Joint Pain23
  • Active: 25% dextrose + Ongley manipulation
  • 2 weekly injections
  • Injected around the lumbosacral junction, iliolumbar ligament, and sacroiliac joint
  • 3-month follow-up
  • The results showed a decreased lower back and associated leg and buttock’s pain compared to baseline
Lee et al.62 (2009) Level 4SI Joint Pain20
  • Active: 25% dextrose
  • 3 biweekly injections
  • N/A
  • Mean 12.2 month follow-up
  • The NRS and ODI were significantly improved at 1 month after prolotherapy. 
  • The mean duration of pain relief of 50% or more was 12.2 months. 
Hoffman & Agnish.63 (2018) Level 4SI Joint Pain103
  • Active: 15% dextrose in lidocaine
  • 3 monthly injections
  • A 22G 90 mm spinal needle was directed to the lower third of the joint using aseptic technique after locally anesthetizing the area. Position in the SI joint was verified by medial and lateral deflection of the needle hub and observation of a characteristic bend of the needle while the tip
  • 2-year follow-up
  • Of 103 treated patients returning for post-treatment follow-up at a median of 117 days, 23% showed a minimum clinically important improvement.

 

Lower Back

Lumbar Spine

Abnormal radiologic findings should not be used to determine the cause of low back pain.52 Low back discomfort will have various influences including fatigue, poor posture, and loss of proprioception.52 Most cases of low back pain without neurological findings are secondary to myofascial pain generators. Additionally, rates of complication of hEDS patients in lumbar spine surgery have been reported as high as 50%.52 Because of a high complication risk, minimally invasive alternative treatment is needed for this population. 

In 1999, Dechow and colleagues performed a randomized control trial investigating sclerosing injections of prolotherapy in chronic lower back pain patients.53 The rationale for the methodology was to strengthen the laxity of the spinal ligaments and fascia supporting the lumbar spine which is comparable to the pathology found in hEDS patients. After three weekly injections of a dextrose-glycerine-phenol solution there were no significant differences between treatment and control groups at 6 months.53

In 2016, Maniquis-Smigel and colleagues investigated the effects of 5% dextrose epidural injections for chronic lower back pain in a randomized control trial.54 The study found that dextrose prolotherapy had superior pain improvement at 15 minutes, 2 hours, 4 hours, and 48 hour post procedure compared to the saline group. However, there were no differences between groups at the 2 week follow-up. Given that a recent meta-analysis has produced doubt on the long-term effectiveness of epidural injections, this would not be an advisable injection method for chronic back pain patients.55

There have been several prospective and retrospective case series investigating prolotherapy’s effect in different lower back pain pathology, which can be found in Table 9.56-58 Each of these reports demonstrated increased benefit to dextrose prolotherapy treatment.56-58

Sacroiliac Joint

Sacroiliac (SI) joint instability is common in hEDS patients, and presents as vague low back/ pelvic pain.37 This pathology can be a result of sprained ligaments, systemic conditions, osteoarthritic changes to the sacroiliac surfaces, muscular imbalances, or adaptive pelvic deviation.59 

Kim and colleagues performed the first and only randomized control trial that compared intra-articular SI dextrose prolotherapy injections versus steroid injection for SI joint pain.60 Forty-eight  patients were randomly divided into two groups who received a maximum of three bi-weekly injections. The trial found that intra-articular prolotherapy injections provided significant SI joint relief and its benefit provided a longer lasting benefit compared to steroid injection.60 

There have been three case series investigating the treatment of SI pain with dextrose prolotherapy. Details of these studies can be found in Table 9 and reported increased symptomatic relief after treatment.61-63 

Summary Regarding Lower Back pathology

There is level IV evidence to support the use of dextrose prolotherapy for lower back pain stemming from the lumbar spine. As injection methodology varied across each reviewed study, we suggest that there should be different protocols created based upon the different etiologies of pain. 

There is evidence to support dextrose prolotherapy’s use for lower back pain secondary to SI joint dysfunction. SI dysfunction is a common occurrence in hypermobile patients making dextrose prolotherapy an attractive conservative modality for these patients.

Table 2: Reviewed literature that investigated dextrose prolotherapy’s use in Hip Pathology

Author, Date, and Level EvidencePathologyNumber of ParticipantsDextrose Solution and Control GroupNumber of Injections, injection procedure, Follow-up timeResults
Gül et al.65 (2020) Level 1Hip OA41
  • Active: 7.2 mL 15% dextrose and 0.8 mL lidocaine mixture for supine injection, 10.8 mL 15% dextrose and 1.2 mL lidocaine mixture for lateral injection
  • Control: Exercise
  • 1 to 6 injections every 3 weeks
  • were injected into iliopsoas and adductor, gluteus medius, gluteus minimus, and piriformis insertions
  • 1-year follow-up
  • Dextrose injection out performed exercise controls for VAS pain change score at 6 months and 12 months 
  • The treatment group also outperformed control for HHS at 6 and 12 months
Topol & Reeves.68 (2008) Level 4Groin Pathology75
  • Active: 8mL of 1% preservative- and epinephrine-free lidocaine with 8mL of 25% dextrose solution in a 20mL syringe
  • 1 to 6 monthly injections
  • Injected symphysis pubis, ischiopubic ramus and at 1-cm intervals along a horizontal line 2 cm rostral to the palpated top of the pelvic crest
  • Mean 17 month follow-up
  • Athletes found VAS Pain improvement of 82% ( and Nirschl pain phase scale improvement of 78% 
  • Six athletes did not improve following regenerative injection therapy treatment, and the remaining 66 returned to unrestricted sport. 
Topol et al.69 (2005) Level 4Groin Pathology24
  • Active: 8mL of 1% preservative- and epinephrine-free lidocaine with 8mL of 25% dextrose solution in a 20mL syringe
  • 1 to 6 monthly injections
  • Injected symphysis pubis, ischiopubic ramus, and also along each ischiopubic ramus covering attachments of the adductors
  • Mean 17 month follow-up
  • The mean reduction in pain during sports, as measured by the VAS, improved from 5.3 points, and the mean reduction in NPPS score improved from 4.5 points
  • Twenty of 24 patients had no pain and 22 of 24 were unrestricted with sports at final data collection.

Hip Pain

hEDS patients present with capsuloligamentous laxity that can lead to instability and recurrent subluxations and repeated dislocations of the hip joint.64 If left undertreated, these patients may develop recurrent soft tissue injuries and chronic pain, leading to premature arthritis and capsular degeneration.64 The only randomized control trial for hip pathology studied the treatment of osteoarthritis secondary to developmental dysplasia of the hip,65 which has been shown to present in 4% of EDS patients compared to 0.1% in the general population.66-67 

Gul and colleagues studied 41 patients who were split into two groups. The first group received a maximum of six 15% dextrose injections, while the second group performed exercise therapy. The study results showed the dextrose group demonstrated superior pain relief compared to the control group with respect to VAS at 6 months and the Harris Hip Score at 6 and 12 months.65

Dextrose prolotherapy may be beneficial for treating groin pain. Two case series studied the effect of dextrose prolotherapy in patients who presented with groin pain both of which showed improvement through 17 month follow up.68-69

Summary Regarding Hip Pathology

The current literature supports dextrose prolotherapy’s benefit in patients presenting with hip or groin tendon pathology. Additional trials to validate these preliminary results are needed. Gul and colleagues’ injection procedure65 could be repurposed to an hEDS population as these patients tend to have lax hip tendons. Studies investigating the use of dextrose prolotherapy in treating hip osteoarthritis would also be beneficial to broaden the scope of treatment. 

Table 3: Reviewed literature that investigated dextrose prolotherapy’s use in Knee Pathology

Author, Date, and Level EvidencePathologyNumber of ParticipantsDextrose Solution and Control GroupNumber of Injections, injection procedure, Follow-up timeResults
Ryan et al.71 (2011) Level 4Patellar Tendinopathy47
  • Active: 1 ml 2% lidocaine and 1 ml 50% dextrose
  • 1 to 7 injections mean 6.4 weeks a part
  • Abnormal hypoechoic areas and anechoic clefts/foci in the thickened portion of the patellar tendon were the primary target of the intratendinous injection given under ultrasound guidance
  • Mean 45 week follow-up
  • At mean 45 weeks post-enrollment, subjects reported a reduction in pain across the three VAS items (rest 38.4±25–18.7±18.4; ADL 51.1±22.9–25.8±20.1; sport 78.1±15.7–38.8±26.1; p<0.01).
Reeves & Hassanein.72 (2000) Level 1Knee OA25
  • Active: 9cc of 10% dextrose and .075% lidocaine in bacteriostatic water
  • Control: 9cc of .075% lidocaine in bacteriostatic water
  • 6 bimonthly injections
  • Injection was conducted an inferomedial approach, for a tibiofemoral injection
  • 1-year follow-up
  • At 12 months the dextrose-treated knees experienced a 44% decrease, 63% decrease in swelling, 85% decrease in knee buckling, and a 14 degree increase in knee flexion
  • Analysis of blinded radiographic readings of 0- and 12-month films revealed stability of all radiographic variables except for 2 variables which improved with statistical significance.
Rabago et al.73 (2013) Level 1Knee OA90
  • Active: Intra: 5 mL 50% dextrose, 5 mL lidocaine, 1% saline, Extra: 6.75 mL 50% dextrose, 4.5 mL 1% lidocaine 11.25 mL 0.9% saline
  • Control: Intra: 5 mL 0.9% sodium chloride,5 mL 1% lidocaine; Extra: 18 mL 0.9% sodium chloride 4.5 mL 1% lidocaine
  • Up to 5 monthly injections
  • Intra-articular: Injection was performed using the inferomedial approach. 
  • Extra-articular: Up to 15 subdermal injections were placed, and injected using a peppering technique with a 25-gauge needle at each ligament-bone insertion. Each puncture site allowed for placement of solution at up to 3 ligament-bone insertions using a skin-sliding technique.
  • 1 year follow-up
  • WOMAC scores for patients receiving dextrose prolotherapy improved more at 52 weeks than did scores for patients receiving saline and exercise 
  • The treatment group exceeded the WOMAC-based minimal clinically important difference
  • Individual knee pain scores also improved more in the prolotherapy group 
Rabagoet et al.74 (2013) Level 1Knee OA37
  • Active: Intra: 5 mL 50% dextrose, 5 mL lidocaine, 1% saline, 
  • Active Extra: 6.75 mL 50% dextrose, 4.5 mL 1% lidocaine 11.25 mL 0.9% saline
  • Control: Intra: 5 mL 0.9% sodium chloride,5 mL 1% lidocaine;
  • Control: Extra: 18 mL 0.9% sodium chloride 4.5 mL 1% lidocaine
  • 5 monthly injections
  • Intra-articular: Injection was performed using the inferomedial approach. 
  • Extra-articular: Up to 15 subdermal injections were placed, and injected using a peppering technique with a 25-gauge needle at each ligament-bone insertion. Each puncture site allowed for placement of solution at up to 3 ligament-bone insertions using a skin-sliding technique.
  • 1 year follow-up
  • Prolotherapy participants exceeded that of Controls in VAS points, at 52 weeks. 
  • Both groups lost CV yet no differences were noted
Farpour & Fereydooni.75 (2017) Level 1Knee OA52
  • Active: 6 mL of the dextrose 25%
  • 2 injections biweekly
  • Periarticular: physiatrist examined the knee and marked tender points around the knee up to three points. 
  • Intra-articular: injection was performed via the inferolateral approach
  • 8 week follow-up
  • Dextrose prolotherapy’s VAS, OKS, and WOMAC scores improved from baseline through the fourth and eighth weeks in both groups without any superiority between intra-articular and extra-articular injection methods
Rezasoltani et al.76 (2017) Level 1Knee OA104
  • Intra: 8 mL of 10% dextrose and 2 mL of 2% lidocaine; 
  • Extra: 5 mL of 20% dextrose and 5 mL of 1% lidocaine
  • 3 weekly injections
  • Periarticular: 4 points around the knee capsule where periarticular nerves exit. Two points were located at upper lateral and medial parts of knee joint, one point at a line medial to knee and one point located at the head of fibula
  • Intra-articular: injected through an infra-patellar approach
  • 5-month follow-up
  • Pain, joint locking, and limitation scores were all improved in both groups. 
  • Difficulty in walking on flat surfaces or climbing stairs, and sitting and standing pain, were all improved in both groups from 1 to 5 months after treatment

Knee

Patellar Tendinopathy

Knee instability is common in hEDS patients, particularly patellar subluxation and dislocation.70 In 2011, Ryan et al performed a pilot study investigating dextrose prolotherapy’s benefit in patients with patellar tendinopathy.71 Forty-seven patients were injected with an average of four injections of 25% dextrose into the patella tendon. At 45 week follow-up patients experienced an improvement in function, in addition to improvements in tendon integrity under ultrasound.71 This pilot study warrants further investigation of dextrose prolotherapy in randomized control trials.

Knee Osteoarthritis

Patellar subluxation and dislocation creates an unstable knee joint which eventually leads to a higher incidence of meniscal tears and premature patellofemoral arthritis.37 One-hundred percent of hEDS patients experience arthritis before the age of 40.37 Fortunately there are numerous randomized control trials to support the use of dextrose prolotherapy in knee osteoarthritis.

Reeves & Hassanien were the first to publish an investigation regarding the efficacy of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity.72 Patients received three bimonthly tibiofemoral injections of 10% dextrose or control. The results demonstrate that prolotherapy treated patients experienced improvements in pain, swelling, knee buckling, and range of motion. Blinded radiograph measurements were also taken and the treatment group demonstrated superiority in lateral patellofemoral cartilage thickness and distal femur width.72 

In 2011, Rabago and colleagues investigated the association between quality of life and MRI measures in patients who were treated with knee OA.73 Patients were injected with five monthly dextrose prolotherapy or saline injections and were tracked for 52 weeks. The study concluded that dextrose prolotherapy is a safe and effective therapy for patients with knee OA compared to control. Patients in the dextrose group showed an increase of cartilage growth shown by MRI imaging.73 These same researchers performed a randomized control trial two years later in 90 patients with knee OA and came to similar conclusions of dextrose prolotherapy’s benefit in knee OA patients.74 

Finally, two studies were published that investigated whether peri-articular or intra-articular dextrose prolotherapy injection would provide patients the most benefit.75,76 The first 2017 study concluded both procedures were effective in improving pain, function and range of motion in knee OA patients with no significant differences between them.75 The second study performed that same year found that the peri-articular group experienced superior improvements in VAS compared to the intra-articular group.76 

Summary Regarding Knee Pathology

There is evidence supporting efficacy of dextrose prolotherapy in treating knee osteoarthritis. Standardizing a pre and post treatment protocol would be the next step in making dextrose prolotherapy more widely available for knee OA patients. Since the hEDS population lacks knee joint integrity in addition to patellar pathology, we would recommend that prolotherapy would be injected both in an intra and periarticular manner. Additional research building on these preliminary results are needed. 

Table 4: Reviewed literature that investigated dextrose prolotherapy’s use in Foot/Ankle Pathology

Author, Date, and Level EvidencePathologyNumber of ParticipantsDextrose Solution and Control GroupNumber of Injections, injection procedure, Follow-up timeResults
Ersen et al.78 (2018) Level 1Plantar Fasciitis60
  • Active: 3.6 mL dextrose [15% solution] and 0.4 mL lidocaine
  • Control: plantar fascia and Achilles tendon stretching exercises three times a week for three months
  • 3 injections every 3 weeks
  • The needle was inserted from the medial side of the heel, perpendicular to the long axis of the ultrasound transducer, and advanced under continuous ultrasound guidance into the proximal plantar fascia
  • 1 year follow-up
  • The VAS, FAOS, and FFI scores were significantly improved in both groups (p<0.001)
  • The VAS and FAOS scores were higher in the prolotherapy group than the control group at 42, 90, and 360 days of treatment. 
  • The FFI scores were also higher in the prolotherapy group than the controls at 42 and 90 days of treatment; however, both groups had similar scores at 360 days.
Uğurlar et al.79 (2018) Level 1Plantar Fasciitis158
  • Active: 1 mL of bupivacaine 5 mg/mL, 3 mL of 5% dextrose, and 6 mL of 0.9% physiologic sodium chloride solution
  • Control: 1 mL of betamethasone 40 mg/mL and 2 mL of bupivacaine 5 mg/ mL 
  • 3 weekly injections
  • Under ultrasound guidance patients were injected with dextrose, PRP, or steroid into the site of maximum tenderness
  • 36 month follow-up
  • The effect of prolotherapy and platelet-rich plasma was seen within 3 to 12 months; however, at the 36-month follow-up point, no differences were found among the 4 treatments.
Asheghan et al.80 (2020) Level 1Plantar Fasciitis62
  • Active: 2 cc dextrose 20% 
  • Shock Wave: 2000 shocks at a pressure of 2 Bars and a frequency of 10 Hz
  • 2 injections a week a part
  • The needle was inserted on the medial side of the heel and it was visualized as it was approaching from the medial to lateral aspect of the field, targeting the hypoechogenic and mixed echogenic region of the plantar fascia
  • 12 week follow-up
  • The VAS and FAAM scales showed significant improvements of pain and function in both study groups 6 weeks and 12 weeks after the treatments. 
  • A significant reduction was noted for plantar fascia thickness. 
  • Shockwave therapy was superior in respect to the FAAM-sport subscale however no other differences between groups were found.
Raissi et al.81 (2021) Level 2Plantar Fasciitis44
  • Active: 20% dextrose 
  • Control: 40 mg methylprednisolone
  • 1 injection
  • 12 week follow-up
  • Initially after  2 weeks, the corticosteroid group had significantly lower daytime and morning NRS scores, higher FAAM-S, and lower plantar fascia thickness at insertion and 1 cm distal to the insertion zone compared to the dextrose group
  • After 12 weeks, all study variables were statistically similar between corticosteroid and dextrose prolotherapy groups. No injection-related side effects were recorded in either group.
Yelland et al.83 (2011) Level 1Achilles Tendinopathy40
  • Active: glucose 20%, algnocaine 0.1%, ropivacaine 0.1%
  • Active 2: glucose 20%, algnocaine 0.1%, ropivacaine 0.1% + eccentric exercises
  • Control: eccentric exercises
  • 4 to 12 weekly injections until pain-free
  • Injected tender points which were  most commonly the anterolateral and anteromedial margins of the tendon and on the most posterior aspect of the tendon 2–7 cm from the calcaneus attachment
  • 12 month follow-up
  • Compared with control, reductions in stiffness and limitation of activity occurred earlier with prolotherapy and reductions in pain, stiffness and limitation of activity occurred earlier with combined treatment.
Chan et al.84 (2017) Level 4Achilles Tendinopathy30
  • Active: 2 ml syringe was filled with 1 ml 50% dextrose and 1 ml 0.5% Marcaine to produce a 25% dextrose solution
  • 1 injection
  • Injections were given to abnormal hypoechoic areas under US guidance
  • Average 12.6 month follow-up
  • 70% of patients responded with VISA-A scores increasing by 31 points after 3 months and by 40 points after 12.60 months 
  • After 5.2 \weeks, echogenicity was significantly reduced and 27% of tears were no longer detectable. 
Akpancar et al.85 (2019) Level 4Ankle OA49
  • Active: 2 mL 25% dextrose for intra-articular, 1.8 mL 15% dextrose in combination with 0.2 mL
  • PRP group: 4mL of PRP
  • 3 injections every 3 weeks
  • 1 mL to painful areas at the tibial edge and 1 mL to talar dome adjacent to ankle joint and 2 mL intra-articularly 
  • 1-year follow-up
  • Both PRP and dextrose treatments resulted in greater improvement in pain and ankle functions at follow-up periods up to 1 year
  • There was no difference between the groups for the outcomes at follow-up periods.

Foot/Ankle

Ankle instability is a common problem with hEDS patients. This lack of stability in the ankle often causes falling.79 A misaligned hindfoot can also result in imbalance that exacerbates any underlying knee, hip or back instability or malalignment.79 

Plantar Fasciitis

Pathology in the plantar fascia can also lead to significant pain and decreased quality of life for hEDS patients.79 There are a number of RCTs supporting the use of dextrose prolotherapy in plantar fasciitis. In 2017 Ersen and colleagues injected 50 patients with 3 serial injections of dextrose prolotherapy into the plantar fascia.80 The results of the study found that patients in the treatment group reported superior improvements in VAS and FOAS at follow-up one year later, supporting the use of dextrose prolotherapy in treating plantar fasciitis.80 The second study investigated the effect of prolotherapy, platelet-rich plasma (PRP), and corticosteroid injections in plantar fasciitis.81 One-hundred and fifty eight patients were enrolled in this RCT, who found that PRP and dextrose prolotherapy provide significant improvements at 3 and 12 months; however, at 3 year follow-up there were no differences among the three groups versus control. This study supports dextrose prolotherapy’s use up to a year for plantar fasciitis, where additional follow-up injections might be needed.81 The two most recent clinical trials investigated the benefit of dextrose prolotherapy for chronic plantar fasciitis against radial extracorporeal therapy (RET) and corticosteroid injection.82,83 Both trials did not find significant differences between treatment groups at 12 weeks.82,83

Achilles Tendinopathy

Patients with hEDS sometimes exhibit reduction in passive plantar flexor muscle tension, as well as Achilles tendon stiffness, which leaves them prone to tendon injury.84 To date, there have only been two studies investigating dextrose prolotherapy’s effect on Achilles tendinopathy. Yelland and colleagues performed the first randomized control trial in 2009 that investigated 43 patients with painful Achilles tendinosis.85 These patients were divided into three groups, the first only performing eccentric loading exercises, the second receiving prolotherapy, and the third receiving a combined treatment. The results found that the combined treatment group demonstrated superiority in reductions in pain, stiffness and limitations of activity compared to the control group.85 In 2017, Chan and colleagues performed a case series showing patients responding favorably to dextrose injections.86 

Ankle Osteoarthritis

hEDS patients are increasingly prone to arthritic changes in the foot and ankle due to the laxity of the connective tissue surrounding the ankle joint.37 There is limited research on dextrose prolotherapy’s effect in this type of osteoarthritis. The first study was performed in 2019 where Akpancar & Gul compared PRP or dextrose prolotherapy’s effect in the management of osteochondral lesions of the Talus.87 The retrospective study of 49 patients found that both PRP and dextrose prolotherapy provided similar benefits in ankle pain and function as dextrose prolotherapy offers advantages of less cost and minimal invasiveness.87

Summary Regarding Foot/Ankle Pathology

There is encouraging evidence supporting the use of dextrose prolotherapy in healing various foot and ankle pathology. Further research on the injection protocols are necessary to investigate dextrose prolotherapy’s effectiveness in foot and ankle pathology in patients with hEDS.

Discussion 

There is encouraging evidence for the use of dextrose prolotherapy in lower extremity injuries. The most considerable amount of evidence is using dextrose prolotherapy to treat knee OA with a number of Level I studies finding positive results. In the reviewed studies, it was found that dextrose was inexpensive, minimally invasive, and provided no adverse side-effects other than local inflammation upon injection. Even though there is great potential in the orthopedic use of dextrose prolotherapy, most insurances do not provide coverage for it, which significantly reduces the access to this therapy. Since hEDS patients have limited treatment options to begin with, our hope is that further research will legitimize prolotherapy viability for treating hEDS pathology and eventually be covered by insurance.

To date, there are no randomized control trials or retrospective case series investigating dextrose prolotherapy’s effect in a population of solely hEDS patients. However this blank slate can be used to create a standardized protocol to treat these patients. In this paper’s reviewed studies there were various dextrose concentrations, local anesthetics, volume of solutions, and injection procedures spread across the different pathologies. Differing protocols make it increasingly difficult to create consistency amongst the research and standardization could provide a gateward toward acceptability of dextrose prolotherapy’s efficacy amongst the scientific community. 

Research is lacking across the board in hEDS patients but the studies reviewed in this paper are fairly recent and there is a shift in awareness and research into hypermobility across the board. Some limitations of this review include publication bias, where manuscripts containing negative results or results that did not benefit the authors were not published. Additionally most studies had different prolotherapy protocols, injection intervals, and follow-up times which leads to heterogeneity in summarizing results.