Anders Ploug Boesen

Local administration of insulin‐like growth factor‐I (IGF‐I) stimulates tendon collagen synthesis in humans

Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. In animals, injections of insulin‐like growth factor I (IGF‐I) has been shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing, but the effect of local IGF‐I administration on tendon collagen synthesis in human has not been studied. The purpose of this study was to study whether local injections of IGF‐I would have a stimulating effect on tendon collagen synthesis. Twelve healthy nonsmoking men [age 62 ± 1 years (mean ± SEM), BMI 27 ± 1] participated. Two injections of either human recombinant IGF‐I (0.1 mL Increlex©) or saline (control) into each patellar tendon were performed 24‐h apart, respectively. Tendon collagen fractional synthesis rate (FSR) was measured by stable isotope technique in the hours after the second injection. Simultaneously, interstitial peritendinous (IGF‐I) and [procollagen type I N‐terminal propeptide (PINP)], as a marker for type I collagen synthesis, were determined by microdialysis technique. Tendon collagen FSR and PINP were significantly higher in the IGF‐I leg compared with the control leg (P < 0.05). In conclusion, local IGF‐I administration can directly enhance tendon collagen synthesis both within and around the human tendon tissue.

Ultrasonographic Investigation of the Achilles Tendon in Elite Badminton Players Using Color Doppler

Background The most frequent injuries in badminton players are in the lower extremities, especially in the Achilles tendon. Hypothesis The game of badminton may be related to abnormal intratendinous flow in the Achilles tendon as detected by color Doppler ultrasound. To a certain extent, this blood flow might be physiological, especially when examined after match. Study Design Cohort study (prevalence); Level of evidence, 3. Methods Seventy-two elite badminton players were interviewed regarding Achilles tendon pain (achillodynia) in the preceding 3 years. Color Doppler was used to examine the tendons of 64 players before their matches and 46 players after their matches. Intratendinous color Doppler flow was graded from 0 to 4. The Achilles tendon was divided into dominant (eg, right side for right-handed players and vice versa) and nondominant side and classified as midtendon, preinsertional, and calcaneal areas. Results Of 72 players, 26 had experienced achillodynia in 34 tendons, 18 on the dominant side and 16 on the nondominant side. In 62% of the players with achillodynia, the problems had begun slowly, and the median duration of symptoms was 4 months (range, 0-36 months). Thirty-five percent had ongoing pain in their tendons for a median duration of 12 months (range, 0-12 months). Achillodynia was not associated with the self-reported training load or with sex, age, weight, singles or doubles players, or racket side. Forty-six players were scanned before and after match. At baseline, color Doppler flow was present in the majority of players, and only 7 (16%) players had no color Doppler flow in either tendon. After match, all players had some color Doppler flow in 1 or both tendons. Achillodynia and color Doppler flow were related in the nondominant Achilles tendon (chi-square, P =. 008). The grades of Doppler flow also increased significantly after match in the preinsertional area in both the nondominant (P =. 0002) and dominant (P =. 005) side tendons. Conclusion A large proportion of the players had experienced achillodynia and habitually played with a degree of pain that demanded medication. The self-reported pain was associated with increased intratendinous color Doppler flow in the nondominant Achilles tendon. Doppler flow was found in most players before and in all players after the match and therefore may in part be a physiological response to activity.

Associations Between Abnormal Ultrasound Color Doppler Measures and Tendon Pain Symptoms in Badminton Players During a Season: A Prospective Cohort Study

Background: Color Doppler ultrasound is widely used to examine intratendinous flow in individuals with overuse tendon problems, but the association between color Doppler and pain is still unclear. Hypothesis: Intratendinous flow is present and associated with pain in badminton players, and intratendinous flow and pain increase during a badminton season. Study Design: Cohort study (prognosis); Level of evidence, 2. Methods: Ninety-five semiprofessional badminton players were included in the study at a tournament at the start of the badminton season. All players were interviewed regarding pain. The anterior knee tendons and Achilles tendons were studied. Each tendon was scored using a quantitative grading system (grades 0-5) and a qualitative scoring system (color fraction) using color Doppler ultrasound. Eight months later, 86 of the players (91%) were retested by the same investigators during an equivalent badminton tournament (including 1032 tendon regions; 86 players with 4 tendons each with 3 regions), thus forming the study group. Results: At the start of the season, 24 players (28%) experienced pain in 37 tendons (11%), and at the end of the season, 31 players (36%) experienced pain in 51 tendons (15%), which was a statistically significant increase (P = .0002). Abnormal flow was found in 230 tendon regions in 71 players (83%) at the start of the season compared with 78 tendon regions in 41 players (48%) at the follow-up. The decrease in abnormal flow was statistically significant (P < .0001). Of the 37 painful tendons at the start of the season, 25 had abnormal flow (68%). In contrast, 131 tendons (85%) with abnormal flow at the start of the season were pain free. At the end of the season, 18 of the 51 painful tendons (35%) had abnormal flow. Ninety-six of the 131 pain-free tendons (73%) with abnormal flow at the start of the season were normalized (no pain and normal flow) at the end of the season. Conclusion: It was not possible to verify any association between intratendinous flow and pain at the start of the season or at the follow-up (end of the season). Intratendinous flow at the start of the season could not predict symptomatic outcome at the end of the season. The decrease in Doppler flow during the season might suggest that intratendinous flow could be part of a physiological adaptive response to loading and that intratendinous flow as previously believed is not always a sign of pathological changes.

Tendon and skeletal muscle matrix gene expression and functional responses to immobilisation and rehabilitation in young males: effect of growth hormone administration

•  Loss of muscle and tendon function during periods of immobilisation and rehabilitation represents a challenge in clinical medicine. •  It is not known to what extent growth hormone (GH) supplementation is able to counteract the absence of mechanical loading during immobilisation in musculo‐tendinous connective tissue. •  This study examines the effect of GH in musculo‐tendinous connective tissue in humans during immobilisation and subsequent rehabilitation. •  The main study findings were the observation that GH supplementation stimulates collagen expression in musculo‐tendinous tissue and abolishes the normal decline in tendon stiffness and lysyl oxidase during immobilisation. Furthermore, GH supplementation results in an increased tendon size and stiffness during rehabilitation. •  GH supplementation has a matrix‐stabilising effect during periods of inactivity and rehabilitation in humans.

Human Achilles tendon glycation and function in diabetes

Diabetic patients have an increased risk of foot ulcers, and glycation of collagen may increase tissue stiffness. We hypothesized that the level of glycemic control (glycation) may affect Achilles tendon stiffness, which can influence gait pattern. We therefore investigated the relationship between collagen glycation, Achilles tendon stiffness parameters, and plantar pressure in poorly (n = 22) and well (n = 22) controlled diabetic patients, including healthy age-matched (45-70 yr) controls (n = 11). There were no differences in any of the outcome parameters (collagen cross-linking or tendon stiffness) between patients with well-controlled and poorly controlled diabetes. The overall effect of diabetes was explored by collapsing the diabetes groups (DB) compared with the controls. Skin collagen cross-linking lysylpyridinoline, hydroxylysylpyridinoline (136%, 80%, P < 0.01) and pentosidine concentrations (55%, P < 0.05) were markedly greater in DB. Furthermore, Achilles tendon material stiffness was higher in DB (54%, P < 0.01). Notably, DB also demonstrated higher forefoot/rearfoot peak-plantar-pressure ratio (33%, P < 0.01). Overall, Achilles tendon material stiffness and skin connective tissue cross-linking were greater in diabetic patients compared with controls. The higher foot pressure indicates that material stiffness of tendon and other tissue (e.g., skin and joint capsule) may influence foot gait. The difference in foot pressure distribution may contribute to the development of foot ulcers in diabetic patients.

Effect of growth hormone on aging connective tissue in muscle and tendon: gene expression, morphology, and function following immobilization and rehabilitation

It is unknown whether loss in musculotendinous tissue during inactivity can be counteracted by growth hormone (GH), and whether GH accelerate rehabilitation in aging individuals. Elderly men (65-75 yr; n = 12) had one leg immobilized 2 wk followed by 6 wk of retraining and were randomly assigned to daily injections of recombinant GH (rhGH; n = 6) or placebo (Plc; n = 6). Cross-sectional area (CSA), muscle strength (MVC), and biomechanical properties of m. quadriceps and patellar tendon were determined. Muscle and tendon biopsies were analyzed for gene expressions (mRNA) of collagen (COL1A1/3A1) and insulin-like growth factors (IGF-1Ea/Ec). Fibril morphology was analyzed by transmission electron microscope (TEM). In tendon, CSA and biomechanical properties did not change following immobilization, but an increase in CSA was found after 6 wk of rehabilitation in both groups. The changes were more pronounced when GH was injected. Furthermore, tendon stiffness increased in the GH group. Muscle CSA declined after immobilization in the Plc but not in the GH group. Muscle CSA increased during retraining, with a significantly larger increase in the GH group compared with the Plc group. Both a time and a group effect were seen for IGF-1Ea/Ec and COL1A1/3A1 mRNA expression in muscle, with a difference between GH and Plc. IGF-1Ea/Ec and COL-1A1/3A1 mRNA expression increased in muscle following immobilization and retraining in subjects receiving GH, whereas an increase in IGF-1Ec mRNA expression was seen in the Plc group only after retraining. In conclusion, in elderly humans, GH seems to have a matrix stabilizing effect during inactivity and rehabilitation by stimulating collagen expression in the musculotendinous tissue and increasing tendon CSA and stiffness.

Effect of High-Volume Injection, Platelet-Rich Plasma, and Sham Treatment in Chronic Midportion Achilles Tendinopathy: A Randomized Double-Blinded Prospective Study

Background: Injection therapies are often considered alongside exercise for chronic midportion Achilles tendinopathy (AT), although evidence of their efficacy is sparse. Purpose: To determine whether eccentric training in combination with high-volume injection (HVI) or platelet-rich plasma (PRP) injections improves outcomes in AT. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 60 men (age, 18-59 years) with chronic (>3 months) AT were included and followed for 6 months (n = 57). All participants performed eccentric training combined with either (1) one HVI (steroid, saline, and local anesthetic), (2) four PRP injections each 14 days apart, or (3) placebo (a few drops of saline under the skin). Randomization was stratified for age, function, and symptom severity (Victorian Institute of Sports Assessment–Achilles [VISA-A]). Outcomes included function and symptoms (VISA-A), self-reported tendon pain during activity (visual analog pain scale [VAS]), tendon thickness and intratendinous vascularity (ultrasonographic imaging and Doppler signal), and muscle function (heel-rise test). Outcomes were assessed at baseline and at 6, 12, and 24 weeks of follow-up. Results: VISA-A scores improved in all groups at all time points (P < .05), with greater improvement in the HVI group (mean ± SEM, 6 weeks = 27 ± 3 points; 12 weeks = 29 ± 4 points) versus PRP (6 weeks = 14 ± 4; 12 weeks = 15 ± 3) and placebo (6 weeks = 10 ± 3; 12 weeks = 11 ± 3) at 6 and 12 weeks (P < .01) and in the HVI (22 ± 5) and PRP (20 ± 5) groups versus placebo (9 ± 3) at 24 weeks (P < .01). VAS scores improved in all groups at all time points (P < .05), with greater decrease in HVI (6 weeks = 49 ± 4 mm; 12 weeks = 45 ± 6 mm; 24 weeks = 34 ± 6 mm) and PRP (6 weeks = 37 ± 7 mm; 12 weeks = 41 ± 7 mm; 24 weeks = 37 ± 6 mm) versus placebo (6 weeks = 23 ± 6 mm; 12 weeks = 30 ± 5 mm; 24 weeks = 18 ± 6 mm) at all time points (P < .05) and in HVI versus PRP at 6 weeks (P < .05). Tendon thickness showed a significant decrease only in HVI and PRP groups during the intervention, and this was greater in the HVI versus PRP and placebo groups at 6 and 12 weeks (P < .05) and in the HVI and PRP groups versus the placebo group at 24 weeks (P < .05). Muscle function improved in the entire cohort with no difference between the groups. Conclusion: Treatment with HVI or PRP in combination with eccentric training in chronic AT seems more effective in reducing pain, improving activity level, and reducing tendon thickness and intratendinous vascularity than eccentric training alone. HVI may be more effective in improving outcomes of chronic AT than PRP in the short term. Registration: NCT02417987 (ClinicalTrials.gov identifier).

Skeletal muscle adaptation to immobilization and subsequent retraining in elderly men: No effect of anti-inflammatory medication

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) may enhance resistance training induced gain in skeletal muscle mass and strength, but it is unknown if NSAIDs affects muscle loss during periods of inactivity in elderly individuals. Thus, we studied the influence of NSAID treatment on human skeletal muscle during immobilization and rehabilitation resistance training (retraining). METHODS 19 men (60-80yrs, range) were randomly assigned to ibuprofen (1200mg/d, Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2weeks and retrained for 6weeks. Moreover, whey protein isolate was ingested (2×20g/d) throughout the whole study period. Plasma inflammatory markers, quadriceps muscle mass and strength, and muscle gene expression were investigated. RESULTS Muscle mass and strength decreased after 2weeks of immobilization (P<0.001), but returned to baseline levels after 2weeks of retraining combined with whey protein supplementation (P<0.001). Furthermore, muscle mass and strength reached beyond baseline levels after 6weeks of retraining (p<0.05), and NSAID did not significantly affect this (p>0.05). No group-differences, but differences over time, were observed for muscle gene expression of proteolytic and anabolic factors. Plasma inflammatory markers were unaffected by the study intervention and NSAID treatment. CONCLUSION Two weeks of lower limb immobilization lead to a reduction in muscle mass and strength, but these parameters were restored already after2 weeks of retraining and whey protein supplementation. After 6weeks of retraining and whey protein supplementation, muscle mass and strength increased beyond baseline levels, and NSAID treatment did not significantly influence this in elderly.

Tendon collagen synthesis declines with immobilization in elderly humans: no effect of anti-inflammatory medication

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used as pain killers during periods of unloading caused by traumatic occurrences or diseases. However, it is unknown how tendon protein turnover and mechanical properties respond to unloading and subsequent reloading in elderly humans, and whether NSAID treatment would affect the tendon adaptations during such periods. Thus we studied human patellar tendon protein synthesis and mechanical properties during immobilization and subsequent rehabilitating resistance training and the influence of NSAIDs upon these parameters. Nineteen men (range 60-80 yr) were randomly assigned to NSAIDs (ibuprofen 1,200 mg/day; Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2 wk and retrained for 6 wk. Tendon collagen protein synthesis, mechanical properties, size, expression of genes related to collagen turnover and remodeling, and signal intensity (from magnetic resonance imaging) were investigated. Tendon collagen synthesis decreased (P < 0.001), whereas tendon mechanical properties and size were generally unchanged with immobilization, and NSAIDs did not influence this. Matrix metalloproteinase-2 mRNA tended to increase (P < 0.1) after immobilization in both groups, whereas scleraxis mRNA decreased with inactivity in the Plc group only (P < 0.05). In elderly human tendons, collagen protein synthesis decreased after 2 wk of immobilization, whereas tendon stiffness and modulus were only marginally reduced, and NSAIDs had no influence upon this. This indicates an importance of mechanical loading for maintenance of tendon collagen turnover. However, reduced collagen production induced by short-term unloading may only marginally affect tendon mechanical properties in elderly individuals. NEW & NOTEWORTHY In elderly humans, 2 wk of inactivity reduces tendon collagen protein synthesis, while tendon stiffness and modulus are only marginally reduced, and NSAID treatment does not affect this. This indicates that mechanical loading is important for maintenance of tendon collagen turnover and that changes in collagen turnover induced by short-term immobilization may only have minor impact on the internal structures that are essential for mechanical properties in elderly tendons.

61 High Volume Injection, Platelet Rich Plasma And Placebo In Chronic Achilles Tendinopathy – A Double Blind Prospective Study

Introduction Chronic Achilles tendinopathy (AT) is a common and disabling injury. Injection therapy is often offered if conservative treatment fails, but only sparse scientific evidence exists for injection treatments. High volume injections have shown efficacy in case series [e.g. Chan, 2008]. Evidence for blood product injections is conflicting but they are commonly used in clinical practice [de Vos, 2010]. The aim of the study was to compare the effect of high volume injection (HVI) or platelet rich plasma (PRP) in combination with eccentric training to placebo treatment (sham injections and eccentric training). Methods Healthy males (21–59 years; n = 55) with AT were randomly assigned to either 1) HVI (50 mls;10 mls 0.5% bupivacaine hydrochloride and 20 mg of Depomedrol followed by 40 mls saline), 2) PRP (~ 4 mls) or 3) placebo treatment. Participants were treated on 4 successive occasions with 2 weeks interval (HVI was only performed once at baseline, the 3 following injections were placebo). The injections were done under ultrasound guidance. All subjects underwent a 12-week eccentric training program. Clinical effects were assessed as changes in symptoms and pain (VISA-A and VAS score), tendon ultrasound thickness and muscle function (one-legged heel-rise test). All outcome measures were recorded at baseline and again at 6, 12 and 24-weeks follow-up. Results VISA-A scores improved in all groups at each outcome time (p < 0.05). Improvement in VISA-A was significantly greater (p < 0.01) in the HVI (29 ± 4 points) versus PRP (15 ± 3) and placebo (11 ± 3) groups at 12-weeks follow-up. At 24-weeks VISA-A improved was significantly greater in both the HVI (22 ± 5) and PRP (20 ± 5) compared with placebo group (9 ± 3). VAS scores improved in all groups at each outcome time (p < 0.05). Decrease in VAS was significantly greater in the HVI (12 weeks = 45 ± 6 mm; 24 weeks=34 ± 6 mm) and PRP (12 weeks=41 ± 7 mm; 24 weeks = 37 ± 6 mm) compared with placebo group (12 weeks=30 ± 5 mm; 24 weeks=18 ± 6 mm) at 12-weeks and 24-weeks. Tendon thickness only showed a significant decrease (p < 0.05) in HVI and PRP. At 12-weeks the decrease in thickness was larger in HVI (2 ± 0.3 mm) vs PRP (0.8 ± 0.2 mm) and placebo (0.4 ± 0.2) (p < 0.01). At 24-weeks a larger decrease was found (p < 0.05) in HVI (1 ± 0.3 mm) and PRP (1 ± 0.1 mm) vs placebo (0.4 ± 0.2 mm). Muscle function improved in the entire cohort (p < 0.001) with no group interaction observed. Discussion Treatment with HVI or PRP in combination with a 12-week eccentric training regime in Achilles tendinopathy seems more effective in reducing pain symptoms, improving activity level and reducing tendon thickness than eccentric training alone. HVI was found to be more effective than PRP in the short-term (12 weeks). References Chan, O, et al . Disabil Rehabil. 2008;30:1697–1708. de Vos, RJ, et al . JAMA. 2010;303:144–49