Serum 25-Hydroxyvitamin D and Intact Parathyroid Hormone Influence Muscle Outcomes in Children and Adolescents.

Increases in 25-hydroxyvitamin D concentrations are shown to improve strength in adults; however, data in pediatric populations are scant and equivocal. In this ancillary study of a larger-scale, multi-sited, double-blind, randomized, placebo-controlled vitamin D intervention in US children and adolescents, we examined the associations between changes in vitamin D metabolites and changes in muscle mass, strength, and composition after 12 weeks of vitamin D3 supplementation. Healthy male and female, black and white children and adolescents between the ages of 9 and 13 years from two US states (Georgia 34°N and Indiana 40°N) were enrolled in the study and randomly assigned to receive an oral vitamin D3 dose of 0, 400, 1000, 2000, or 4000 IU/d for 12 weeks between the winter months of 2009 to 2011 (N = 324). Analyses of covariance, partial correlations, and regression analyses of baseline and 12-week changes (post-baseline) in vitamin D metabolites (serum 25(OH)D, 1,25(OH)2 D, intact parathyroid hormone [iPTH]), and outcomes of muscle mass, strength, and composition (total body fat-free soft tissue [FFST], handgrip strength, forearm and calf muscle cross-sectional area [MCSA], muscle density, and intermuscular adipose tissue [IMAT]) were assessed. Serum 25(OH)D and 1,25(OH)2 D, but not iPTH, increased over time, as did fat mass, FFST, forearm and calf MCSA, forearm IMAT, and handgrip strength (p < 0.05). Vitamin D metabolites were not associated with muscle strength at baseline nor after the 12-week intervention. Changes in serum 25(OH)D correlated with decreases in forearm IMAT, whereas changes in serum iPTH predicted increases in forearm and calf MCSA and IMAT (p < 0.05). Overall, increases in 25(OH)D did not influence muscle mass or strength in vitamin D-sufficient children and adolescents; however, the role of iPTH on muscle composition in this population is unknown and warrants further investigation. © 2018 American Society for Bone and Mineral Research.

Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism.

Combining anticatabolic agents with parathyroid hormone (PTH) to enhance bone mass has yielded mixed results in osteoporosis patients. Toward the goal of enhancing the efficacy of these regimens, we tested their utility in combination with loss of the transcription factor Nmp4 because disabling this gene amplifies PTH-induced increases in trabecular bone in mice by boosting osteoblast secretory activity. We addressed whether combining a sustained anabolic response with an anticatabolic results in superior bone acquisition compared with PTH monotherapy. Additionally, we inquired whether Nmp4 interferes with anticatabolic efficacy. Wild-type and Nmp4-/- mice were ovariectomized at 12 weeks of age, followed by therapy regimens, administered from 16 to 24 weeks, and included individually or combined PTH, alendronate (ALN), zoledronate (ZOL), and raloxifene (RAL). Anabolic therapeutic efficacy generally corresponded with PTH + RAL = PTH + ZOL > PTH + ALN = PTH > vehicle control. Loss of Nmp4 enhanced femoral trabecular bone increases under PTH + RAL and PTH + ZOL. RAL and ZOL promoted bone restoration, but unexpectedly, loss of Nmp4 boosted RAL-induced increases in femoral trabecular bone. The combination of PTH, RAL, and loss of Nmp4 significantly increased bone marrow osteoprogenitor number, but did not affect adipogenesis or osteoclastogenesis. RAL, but not ZOL, increased osteoprogenitors in both genotypes. Nmp4 status did not influence bone serum marker responses to treatments, but Nmp4-/- mice as a group showed elevated levels of the bone formation marker osteocalcin. We conclude that the heightened osteoanabolism of the Nmp4-/- skeleton enhances the effectiveness of diverse osteoporosis treatments, in part by increasing hyperanabolic osteoprogenitors. Nmp4 provides a promising target pathway for identifying barriers to pharmacologically induced bone formation.

Electroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells.

Electroacupuncture (EA) performed in rats and humans using limb acupuncture sites, LI-4 and LI-11, and GV-14 and GV-20 (humans) and Bai-hui (rats) increased functional connectivity between the anterior hypothalamus and the amygdala and mobilized mesenchymal stem cells (MSCs) into the systemic circulation. In human subjects, the source of the MSC was found to be primarily adipose tissue, whereas in rodents the tissue sources were considered more heterogeneous. Pharmacological disinhibition of rat hypothalamus enhanced sympathetic nervous system (SNS) activation and similarly resulted in a release of MSC into the circulation. EA-mediated SNS activation was further supported by browning of white adipose tissue in rats. EA treatment of rats undergoing partial rupture of the Achilles tendon resulted in reduced mechanical hyperalgesia, increased serum interleukin-10 levels and tendon remodeling, effects blocked in propranolol-treated rodents. To distinguish the afferent role of the peripheral nervous system, phosphoinositide-interacting regulator of transient receptor potential channels (Pirt)-GCaMP3 (genetically encoded calcium sensor) mice were treated with EA acupuncture points, ST-36 and LIV-3, and GV-14 and Bai-hui and resulted in a rapid activation of primary sensory neurons. EA activated sensory ganglia and SNS centers to mediate the release of MSC that can enhance tissue repair, increase anti-inflammatory cytokine production and provide pronounced analgesic relief. Stem Cells 2017;35:1303-1315.

Vitamin D Supplementation Does Not Impact Insulin Resistance in Black and White Children.

CONTEXT: Vitamin D supplementation trials with diabetes-related outcomes have been conducted almost exclusively in adults and provide equivocal findings. OBJECTIVE: The objective of this study was to determine the dose-response of vitamin D supplementation on fasting glucose, insulin, and a surrogate measure of insulin resistance in white and black children aged 9­13 years, who participated in the Georgia, Purdue, and Indiana University (or GAPI) trial: a 12-week multisite, randomized, triple-masked, dose-response, placebo-controlled vitamin D trial. DESIGN: Black and white children in the early stages of puberty (N = 323, 50% male, 51% black) were equally randomized to receive vitamin D3 (0, 400, 1000, 2000, or 4000 IU/day) for 12 weeks. Fasting serum 25-hydroxyvitamin D (25(OH)D), glucose and insulin were assessed at baseline and weeks 6 and 12. Homeostasis model assessment of insulin resistance was used as a surrogate measure of insulin resistance. Statistical analyses were conducted as intent-to-treat using a mixed effects model. RESULTS: Baseline serum 25(OH)D was inversely associated with insulin (r = −0.140, P = 0.017) and homeostasis model assessment of insulin resistance (r = −0.146, P = 0.012) after adjusting for race, sex, age, pubertal maturation, fat mass, and body mass index. Glucose, insulin, and insulin resistance increased (F > 5.79, P < .003) over the 12 weeks, despite vitamin D dose-dependent increases in serum 25(OH)D. CONCLUSIONS: Despite significant baseline inverse relationships between serum 25(OH)D and measures of insulin resistance, vitamin D supplementation had no impact on fasting glucose, insulin, or a surrogate measure of insulin resistance over 12 weeks in apparently healthy children.

Effects of exercise and manual therapy on pain associated with hip osteoarthritis: a systematic review and meta-analysis.

AIM: To explore the effects of exercise (water-based or land-based) and/or manual therapies on pain in adults with clinically and/or radiographically diagnosed hip osteoarthritis (OA). METHODS: A systematic review and meta-analysis was performed, with patient reported pain assessed using a visual analogue scale (VAS) or the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. Data were grouped by follow-up time (0-3 months=short term; 4-12 months=medium term and; >12 months=long term), and standardised mean differences (SMD) with 95% CIs were used to establish intervention effect sizes. Study quality was assessed using modified PEDro scores. RESULTS: 19 trials were included. Four studies showed short-term benefits favouring water-based exercise over minimal control using the WOMAC pain subscale (SMD -0.53, 95% CI -0.96 to -0.10). Six studies supported a short-term benefit of land-based exercise compared to minimal control on VAS assessed pain (SMD -0.49, 95% CI -0.70 to -0.29). There were no medium (SMD -0.23, 95% CI -0.48 to 0.03) or long (SMD -0.22, 95% CI -0.51 to 0.06) term benefits of exercise therapy, or benefit of combining exercise therapy with manual therapy (SMD -0.38, 95% CI -0.88 to 0.13) when compared to minimal control. CONCLUSIONS: Best available evidence indicates that exercise therapy (whether land-based or water-based) is more effective than minimal control in managing pain associated with hip OA in the short term. Larger high-quality RCTs are needed to establish the effectiveness of exercise and manual therapies in the medium and long term.

Instrument-assisted cross fiber massage increases tissue perfusion and alters microvascular morphology in the vicinity of healing knee ligaments.

BACKGROUND: Ligament injuries are common clinical problems for which there are few established interventions. Instrument-assisted cross fiber massage (IACFM) was recently shown to accelerate the restoration of biomechanical properties in injured rodent knee medial collateral ligaments (MCL). The current study aimed to investigate the influence of IACFM on regional perfusion and vascularity in the vicinity of healing rodent knee MCL injuries. METHODS: Bilateral knee MCL injuries were induced in female Sprague-Dawley rats. Commencing 1 week post-injury, 1 minute of IACFM was introduced unilaterally 3 times/week for 3 weeks. The contralateral injured MCL served as an internal control. Regional tissue perfusion was assessed in vivo throughout healing using laser Doppler imaging, whereas regional microvascular morphology was assessed ex vivo via micro-computed tomography of vessels filled with contrast. RESULTS: IACFM had no effect on tissue perfusion when assessed immediately, or at 5, 10, 15 or 20 min following intervention (all p > 0.05). However, IACFM-treated hindlimbs had enhanced tissue perfusion when assessed 1 day following the 4th and 9th (last) treatment sessions (all p < 0.05). IACFM-treated hindlimbs also had greater perfusion when assessed 1 wk following the final treatment session (32 days post-injury) (p < 0.05). Subsequent investigation of microvascular morphology found IACFM to increase the proportion of arteriole-sized blood vessels (5.9 to <41.2 µm) in the tibial third of the ligament (p < 0.05). CONCLUSIONS: These findings suggest IACFM alters regional perfusion and vascularity in the vicinity of healing rodent knee MCL injuries. This effect may contribute to the beneficial effect of IACFM observed on the recovery of knee ligament biomechanical properties following injury.

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

BACKGROUND: Achilles 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. METHODS: A 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. RESULTS: Methodological 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. CONCLUSIONS: Practitioners 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.

Instrument-assisted cross-fiber massage accelerates knee ligament healing.

STUDY DESIGN: Controlled laboratory study. OBJECTIVES: To investigate the effects of instrument-assisted cross-fiber massage (IACFM) on tissue-level healing of knee medial collateral ligament (MCL) injuries. BACKGROUND: Ligament injuries are common and significant clinical problems for which there are few established interventions. IACFM represents an intervention that may mediate tissue-level healing following ligament injury. METHODS: Bilateral knee MCL injuries were created in 51 rodents, while 7 rodents were maintained as ligament-intact, control animals. IACFM was commenced 1 week following injury and introduced 3 sessions per week for 1 minute per session. IACFM was introduced unilaterally (IACFM-treated), with the contralateral, injured MCL serving as an internal control (nontreated). Thirty-one injured animals received 9 ACFM treatments, while the remaining 20 injured animals received 30 treatments. Ligament biomechanical properties and morphology were assessed at either 4 or 12 weeks postinjury. RESULTS: IACFM-treated ligaments were 43.1% stronger (P<.05), 39.7% stiffer (P<.01), and could absorb 57.1% more energy before failure (P<.05) than contralateral, injured, nontreated ligaments at 4 weeks postinjury. On histological and scanning electron microscopy assessment, IACFM-treated ligaments appeared to have improved collagen fiber bundle formation and orientation within the scar region than nontreated ligaments. There were minimal differences between IACFM-treated and contralateral, nontreated ligaments at 12 weeks postinjury, although IACFM-treated ligaments were 15.4% stiffer (P<.05). CONCLUSION: IACFM-accelerated ligament healing, possibly via favorable effects on collagen formation and organization, but had minimal effect on the final outcome of healing. These findings are clinically interesting, as there are few established interventions for ligament injuries, and IACFM is a simple and practical therapy technique. J Orthop Sports Phys Ther 2009;39(7):506-514, Epub 24 February 2009. doi:10.2519/jospt.2009.2997.

Preliminary evaluation of a load-bearing BMP-2 carrier for segmental defect regeneration.

Large segmental defects in bones can result from tumor removal, massive trauma, congenital malformation, or non-union fractures. Such defects often are difficult to manage and require multiple-phase surgery to achieve adequate union and function. In this study, we propose a novel design of bone morphogenetic protein 2 (BMP-2) carrier for tissue engineering of segmental defect regeneration. The tube-shaped BMP-2 carrier was fabrication from a poly(propylene fumarate)/tricalcium phosphate (PPF/TCP) composite via casting technique developed in our laboratory. An in vitro evaluation showed that the compressive strength of the carrier decreased about 48% in 12 weeks while maintained a pH in the 6.8-7.4 range. In vivo study was conducted by implanting carriers loaded with 10 microg of BMP-2 in 5 mm rat femur gap model for 15 weeks. X-ray evidence of bridging was first found in the BMP group at 3 weeks. Bridging in all animals (N = 4) in the BMP group was found at 9 weeks. No x-ray evidence of bridging was found in the No BMP group (N = 3). pQCT analysis indicated that the bone mineral density of the callus in the BMP group has reached the level of native femur at 15 weeks after implantation, while the callus in the No BMP group has a bone mineral density at a lower level of 84% to the native femur. Histology analysis shows that a normal fatty bone marrow was restored and mineralized callus formed and bridged the segmental defect.

Patellar tendinopathy.

Patellar tendinopathy is a common and serious condition in athletes. Although there have been many advances in the understanding of the histopathology, imaging, and surgical outcomes in this condition in the past decade, successful management of athletes with patellar tendinopathy remains a major challenge for both the practitioner and patient. There is a definite need for further prospective studies into etiological factors and randomized controlled trials into treatment choices.