Stuart J. Warden

The Wnt Co-receptor LRP5 Is Essential for Skeletal Mechanotransduction but Not for the Anabolic Bone Response to Parathyroid Hormone Treatment

The cell surface receptor, low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass. Loss-of-function mutations in LRP5 cause the human skeletal disease osteoporosis-pseudoglioma syndrome, an autosomal recessive disorder characterized by severely reduced bone mass and strength. We investigated the role of LRP5 on bone strength using mice engineered with a loss-of-function mutation in the gene. We then tested whether the osteogenic response to mechanical loading was affected by the loss of Lrp5 signaling. Lrp5-null (Lrp5-/-) mice exhibited significantly lower bone mineral density and decreased strength. The osteogenic response to mechanical loading of the ulna was reduced by 88 to 99% in Lrp5-/- mice, yet osteoblast recruitment and/or activation at mechanically strained surfaces was normal. Subsequent experiments demonstrated an inability of Lrp5-/- osteoblasts to synthesize the bone matrix protein osteopontin after a mechanical stimulus. We then tested whether Lrp5-/- mice increased bone formation in response to intermittent parathyroid hormone (PTH), a known anabolic treatment. A 4-week course of intermittent PTH (40 μg/kg/day; 5 days/week) enhanced skeletal mass equally in Lrp5-/- and Lrp5+/+ mice, suggesting that the anabolic effects of PTH do not require Lrp5 signaling. We conclude that Lrp5 is critical for mechanotransduction in osteoblasts. Lrp5 is a mediator of mature osteoblast function following loading. Our data suggest an important component of the skeletal fragility phenotype in individuals affected with osteoporosis-pseudoglioma is inadequate processing of signals derived from mechanical stimulation and that PTH might be an effective treatment for improving bone mass in these patients.

Bone Adaptation to a Mechanical Loading Program Significantly Increases Skeletal Fatigue Resistance

Using a mechanical loading program to induce bone adaptation, we found that small (<2‐fold) changes in the structural properties of the rat ulna increased its fatigue resistance >100‐fold. This indicates that a moderate exercise program may be an effective preventative strategy for stress fractures.

In-Home Virtual Reality Videogame Telerehabilitation in Adolescents With Hemiplegic Cerebral Palsy

UNLABELLED Golomb MR, McDonald BC, Warden SJ, Yonkman J, Saykin AJ, Shirley B, Huber M, Rabin B, AbdelBaky M, Nwosu ME, Barkat-Masih M, Burdea GC. In-home virtual reality videogame telerehabilitation in adolescents with hemiplegic cerebral palsy. OBJECTIVE To investigate whether in-home remotely monitored virtual reality videogame-based telerehabilitation in adolescents with hemiplegic cerebral palsy can improve hand function and forearm bone health, and demonstrate alterations in motor circuitry activation. DESIGN A 3-month proof-of-concept pilot study. SETTING Virtual reality videogame-based rehabilitation systems were installed in the homes of 3 participants and networked via secure Internet connections to the collaborating engineering school and childrens hospital. PARTICIPANTS Adolescents (N=3) with severe hemiplegic cerebral palsy. INTERVENTION Participants were asked to exercise the plegic hand 30 minutes a day, 5 days a week using a sensor glove fitted to the plegic hand and attached to a remotely monitored videogame console installed in their home. Games were custom developed, focused on finger movement, and included a screen avatar of the hand. MAIN OUTCOME MEASURES Standardized occupational therapy assessments, remote assessment of finger range of motion (ROM) based on sensor glove readings, assessment of plegic forearm bone health with dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), and functional magnetic resonance imaging (fMRI) of hand grip task. RESULTS All 3 adolescents showed improved function of the plegic hand on occupational therapy testing, including increased ability to lift objects, and improved finger ROM based on remote measurements. The 2 adolescents who were most compliant showed improvements in radial bone mineral content and area in the plegic arm. For all 3 adolescents, fMRI during grip task contrasting the plegic and nonplegic hand showed expanded spatial extent of activation at posttreatment relative to baseline in brain motor circuitry (eg, primary motor cortex and cerebellum). CONCLUSIONS Use of remotely monitored virtual reality videogame telerehabilitation appears to produce improved hand function and forearm bone health (as measured by DXA and pQCT) in adolescents with chronic disability who practice regularly. Improved hand function appears to be reflected in functional brain changes.

Patellar taping and bracing for the treatment of chronic knee pain: A systematic review and meta‐analysis

OBJECTIVE To evaluate the evidence for patellar taping and bracing in the management of chronic knee pain. METHODS Randomized or quasi-randomized studies assessing patellar taping or bracing effects on chronic knee pain were sourced from 7 electronic databases (to November 2006), and assessed using the Physiotherapy Evidence Database scale. Weighted mean differences were determined, and pooled estimates of taping and bracing effects were obtained using random-effects models. RESULTS Of 16 eligible trials, 13 investigated patellar taping or bracing effects in individuals with anterior knee pain, and 3 investigated taping effects in individuals with knee osteoarthritis (OA). The methodologic quality of the taping studies was significantly higher than the bracing studies (mean+/-SD 4.8+/-2.1 versus 2.8+/-0.8; P<0.05). On a 100-mm scale, tape applied to exert a medially-directed force on the patella decreased chronic knee pain compared with no tape by 16.1 mm (95% confidence interval [95% CI] -22.2, -10.0; P<0.001) and sham tape by 10.9 mm (95% CI -18.4, -3.4; P<0.001). For anterior knee pain and OA, medially-directed tape decreased pain compared with no tape by 14.7 mm (95% CI -22.8, -6.9; P<0.001) and 20.1 mm (95% CI -26.0, -14.3; P<0.001), respectively. There was disputable evidence from low-quality studies for patellar bracing benefits. CONCLUSION There was evidence that tape applied to exert a medially-directed force on the patella produces a clinically meaningful change in chronic knee pain. There was limited evidence to demonstrate the efficacy of patellar bracing. These outcomes were limited by the presence of high heterogeneity between study outcomes and significant publication bias.

Ground reaction forces and bone parameters in females with tibial stress fracture.

PURPOSE Tibial stress fracture is a common overuse running injury that results from the interplay of repetitive mechanical loading and bone strength. This research project aimed to determine whether female runners with a history of tibial stress fracture (TSF) differ in ground reaction force (GRF) parameters during running, regional bone density, and tibial bone geometry from those who have never sustained a stress fracture (NSF). METHODS Thirty-six female running athletes (13 TSF; 23 NSF) ranging in age from 18 to 44 yr were recruited for this cross-sectional study. The groups were well matched for demographic, training, and menstrual parameters. A force platform measured selected GRF parameters (peak and time to peak for vertical impact and active forces, and horizontal braking and propulsive forces) during overground running at 4.0 m.s.(-1). Lumbar spine, proximal femur, and distal tibial bone mineral density were assessed by dual energy x-ray absorptiometry. Tibial bone geometry (cross-sectional dimensions and areas, and second moments of area) was calculated from a computerized tomography scan at the junction of the middle and distal thirds. RESULTS There were no significant differences between the groups for any of the GRF, bone density, or tibial bone geometric parameters (P > 0.05). Both TSF and NSF subjects had bone density levels that were average or above average compared with a young adult reference range. Factor analysis followed by discriminant function analysis did not find any combinations of variables that differentiated between TSF and NSF groups. CONCLUSION These findings do not support a role for GRF, bone density, or tibial bone geometry in the development of tibial stress fractures, suggesting that other risk factors were more important in this cohort of female runners.

Comparative Accuracy of Magnetic Resonance Imaging and Ultrasonography in Confirming Clinically Diagnosed Patellar Tendinopathy

Background Diagnosis of patellar tendinopathy is based primarily on clinical examination; however, it is commonplace to image the patellar tendon for diagnosis confirmation, with the imaging modalities of choice being magnetic resonance imaging (MRI) and ultrasonography (US). The comparative accuracy of these modalities has not been established. Hypothesis Magnetic resonance imaging and US have good (>80%) accuracy and show substantial agreement in confirming clinically diagnosed patellar tendinopathy. Study Design Cohort study (diagnosis); Level of evidence, 2. Methods Magnetic resonance imaging and US (gray scale [GS-US] and color Doppler [CD-US]) features of 30 participants with clinically diagnosed patellar tendinopathy and 33 activity-matched, asymptomatic participants were prospectively compared. Accuracy, sensitivity, specificity, positive and negative predictive values, and the likelihood of positive and negative test results were determined for each technique. Results The accuracy of MRI, GS-US, and CD-US was 70%, 83%, and 83%, respectively (P = .04; MRI vs GS-US). The likelihood of positive MRI, GS-US, and CD-US was 3.1, 4.8, and 11.6, respectively. The MRI and GS-US had equivalent specificity (82% vs 82%; P = 1.00); however, the sensitivity of GS-US was greater than MRI (87% vs 57%; P = .01). Sensitivity (70% vs 87%; P = .06) and specificity (94% vs 82%; P = .10) did not differ between CD-US and GS-US. Conclusions Ultrasonography was more accurate than MRI in confirming clinically diagnosed patellar tendinopathy. GS-US and CD-US may represent the best combination for confirming clinically diagnosed patellar tendinopathy because GS-US had the greatest sensitivity, while a positive CD-US test result indicated a strong likelihood an individual was symptomatic.

Modulation of Wnt Signaling Influences Fracture Repair

While the importance of Wnt signaling in skeletal development and homeostasis is well documented, little is known regarding its function in fracture repair. We hypothesized that activation and inactivation of Wnt signaling would enhance and impair fracture repair, respectively. Femoral fractures were generated in Lrp5 knockout mice (Lrp5−/−) and wild‐type littermates (Lrp5+/+), as well as C57BL/6 mice. Lrp5−/− and Lrp5+/+ mice were untreated, while C57BL/6 mice were treated 2×/week with vehicle or anti‐Dkk1 antibodies (Dkk1 Ab) initiated immediately postoperatively (Day 0) or 4 days postoperatively (Day 4). Fractures were radiographed weekly until sacrifice at day 28, followed by DXA, pQCT, and biomechanical analyses. Lrp5−/− mice showed impaired repair compared to Lrp5+/+ mice, as evidenced by reduced callus area, BMC, BMD, and biomechanical properties. The effects of Dkk1 Ab treatment depended on the timing of initiation. Day 0 initiation enhanced repair, with significant gains seen for callus area, BMC, BMD, and biomechanical properties, whereas Day 4 initiation had no effect. These results validated our hypothesis that Wnt signaling influences fracture repair, with prompt activation enhancing repair and inactivation impairing it. Furthermore, these data suggest that activation of Wnt signaling during fracture repair may have clinical utility in facilitating fracture repair.

Mechanobiology of the Skeleton

Mechanical force induces osteogenesis by repressing the production of sclerostin, an inhibitor of Wnt signaling. Mechanical loading of the skeleton is essential for the development, growth, and maintenance of strong, weight-bearing bones. Bone strength is plastic and can be modulated in adults, as illustrated by the increased bone mass in the playing arms of athletes as compared with their nonplaying arms. Our studies have shown that mechanical loading improves bone strength by inducing bone formation in regions of high strain energy. Therefore, bone tissue has a mechanosensing apparatus that directs osteogenesis to where it is most needed to increase bone strength. The most likely sensors of mechanical loading are the osteocytes, which are visco-elastically coupled to the bone matrix so that their biological response increases with loading rate; thus, increasing loading frequency improves the responsiveness of bone to loading. The osteocyte-specific protein sclerostin, an inhibitor of the Wnt signaling pathway, appears to be one of the mediators of the mechanical loading response. Mechanical loading suppresses osteocyte sclerostin secretion, which allows Wnt signaling–dependent bone formation to occur. Intracellular calcium signaling, adenosine triphosphate signaling, and signaling through second messengers, such as prostaglandins and nitric oxide, precede sclerostin secretion. Stretch-activated ion channels and focal adhesion proteins may play a role in triggering these pathways upstream of sclerostin. In particular, focal adhesion kinase and proline-rich tyrosine kinase 2 appear to be sensors of mechanical loads in bone cells.

Physical therapies for Achilles tendinopathy: systematic review and meta-analysis

BackgroundAchilles tendinopathy (AT) is a common condition, causing considerable morbidity in athletes and non-athletes alike. Conservative or physical therapies are accepted as first-line management of AT; however, despite a growing volume of research, there remains a lack of high quality studies evaluating their efficacy. Previous systematic reviews provide preliminary evidence for non-surgical interventions for AT, but lack key quality components as outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement. The aim of this study was to conduct a systematic review and meta-analysis (where possible) of the evidence for physical therapies for AT management.MethodsA comprehensive strategy was used to search 11 electronic databases from inception to September 2011. Search terms included Achilles, tendinopathy, pain, physical therapies, electrotherapy and exercise (English language full-text publications, human studies). Reference lists of eligible papers were hand-searched. Randomised controlled trials (RCTs) were included if they evaluated at least one non-pharmacological, non-surgical intervention for AT using at least one outcome of pain and/or function. Two independent reviewers screened 2852 search results, identifying 23 suitable studies, and assessed methodological quality and risk of bias using a modified PEDro scale. Effect size calculation and meta-analyses were based on fixed and random effects models respectively.ResultsMethodological quality ranged from 2 to 12 (/14). Four studies were excluded due to high risk of bias, leaving 19 studies, the majority of which evaluated midportion AT. Effect sizes from individual RCTs support the use of eccentric exercise. Meta-analyses identified significant effects favouring the addition of laser therapy to eccentric exercise at 12 weeks (pain VAS: standardised mean difference −0.59, 95% confidence interval −1.11 to −0.07), as well as no differences in effect between eccentric exercise and shock wave therapy at 16 weeks (VISA-A:–0.55,–2.21 to 1.11). Pooled data did not support the addition of night splints to eccentric exercise at 12 weeks (VISA-A:–0.35,–1.44 to 0.74). Limited evidence from an individual RCT suggests microcurrent therapy to be an effective intervention.ConclusionsPractitioners can consider eccentric exercise as an initial intervention for AT, with the addition of laser therapy as appropriate. Shock wave therapy may represent an effective alternative. High-quality RCTs following CONSORT guidelines are required to further evaluate the efficacy of physical therapies and determine optimal clinical pathways for AT.

A New Direction for Ultrasound Therapy in Sports Medicine

AbstractUltrasound therapy is a widely available and frequently used electrophysical agent in sports medicine. However, systematic reviews and meta-analyses have repeatedly concluded that there is insufficient evidence to support a beneficial effect of ultrasound at dosages currently being introduced clinically. Consequently, the role of ultrasound in sports medicine is in question. This does not mean that ultrasound should be discarded as a therapeutic modality. However, it does mean that we may need to look in a new direction to explore potential benefits. A new direction for ultrasound therapy has been revealed by recent research demonstrating a beneficial effect of ultrasound on injured bone. During fresh fracture repair, ultrasound reduced healing times by between 30 and 38%. When applied to non-united fractures, it stimulated union in 86% of cases. These benefits were generated using low-intensity (>0.1 W/cm2) pulsed ultrasound (LIPUS), a dose alternative to that traditionally used in sports medicine. Although currently developed for the intervention of bone injuries, LIPUS has the potential to be used on tissues and conditions more commonly encountered in sports medicine. These include injuries to ligament, tendon, muscle and cartilage. This review discusses the effect of LIPUS on bone fractures, the dosages introduced and the postulated mechanisms of action. It concludes by discussing the relevance of these latest findings to sports medicine and how this evidence of a beneficial clinical effect may be implemented to intervene in sporting injuries to bone and other tissues. The aim of the paper is to highlight this latest direction in ultrasound therapy and stimulate new lines of research into the efficacy of ultrasound in sports medicine. In time this may lead to accelerated recovery from injury and subsequent earlier return to activity.