Association between hip muscle strength/function and hip cartilage defects in sub-elite football players with hip/groin pain.

OBJECTIVE: To explore associations between hip muscle strength and cartilage defects (presence and severity) on magnetic resonance imaging (MRI) in young adults with hip/groin pain participating in sub-elite football. DESIGN: Sub-elite football players with hip/groin pain (>6 months) completed assessments of isometric hip strength and functional task performance. Hip cartilage defects were assessed using the Scoring Hip Osteoarthritis with MRI tool. This exploratory, cross-sectional study used logistic and negative binomial models to assess the relationships between hip muscle strength or functional task performance and hip cartilage defects, controlling for body mass index, age, testing site and cam morphology, incorporating sex-specific interaction terms. RESULTS: One hundred and eighty-two (37 women) sub-elite (soccer or Australian football) players with hip/groin pain (age 26 ± 7 years) were included. Greater hip extension strength was associated with higher cartilage total score (adjusted incidence rate ratio [aIRR] 1.01, 95%CI: 1.0 to 1.02, p = 0.013) and superolateral cartilage score (adjusted odds ratio (aOR) 1.03, 95% confidence interval (CI): 1.01 to 1.06, p < 0.01). In female sub-elite football players, greater hip external rotation strength was associated with lateral cartilage defects (aOR 1.61, 95%CI: 1.05 to 2.48, p = 0.03) and higher cartilage total score (aIRR 1.25, 95%CI: 1.01 to 1.66, p = 0.042). A one-repetition increase in one-leg rise performance was related to lower odds of superomedial cartilage defects (aOR 0.96, 95%CI: 0.94 to 0.99, p < 0.01). CONCLUSIONS: Overall, there were few associations between peak isometric hip muscle strength and overall hip cartilage defects. It is possible that other factors may have relevance in sub-elite football players. Additional studies are needed to support or refute our findings that higher one leg rise performance was associated with reduced superomedial cartilage defect severity and greater hip extension strength was related to higher cartilage defect severity scores.

Is running good or bad for your knees? A systematic review and meta-analysis of cartilage morphology and composition changes in the tibiofemoral and patellofemoral joints.

BACKGROUND: The general health benefits of running are well-established, yet concern exists regarding the development and progression of osteoarthritis. AIM: To systematically review the immediate (within 20 min) and delayed (20 min-48 h) effect of running on hip and knee cartilage, as assessed using magnetic resonance imaging (MRI). METHOD: Studies using MRI to measure change in hip or knee cartilage within 48 h pre- and post-running were identified. Risk of bias was assessed using a modified Newcastle-Ottawa Scale. Percentage change in cartilage outcomes were estimated using random-effects meta-analysis. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation tool. RESULTS: Twenty-four studies were included, evaluating 446 knees only. One third of studies were low risk of bias. Knee cartilage thickness and volume decreased immediately after running, with declines ranging from 3.3% (95% confidence interval [CI]: 2.6%, 4.1%) for weight-bearing femoral cartilage volume to 4.9% (95% CI: 4.43.6%, 6.2%) for patellar cartilage volume. T1ρ and T2 relaxation times were also reduced immediately after running, with the largest decline being 13.1% (95% CI: -14.4%, -11.7%) in femoral trochlear cartilage. Tibiofemoral cartilage T2 relaxation times recovered to baseline levels within 91 min. Existing cartilage defects were unchanged within 48 h post-run. CONCLUSIONS: There is very low certainty evidence that running immediately decreases the thickness, volume, and relaxation times of patellofemoral and tibiofemoral cartilage. Hip cartilage changes are unknown, but knee changes are small and appear transient suggesting that a single bout of running is not detrimental to knee cartilage.

Reference data and calculators for second-generation HR-pQCT measures of the radius and tibia at anatomically standardized regions in White adults.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a powerful tool to assess bone health. To determine how an individual's or population of interest's HR-pQCT outcomes compare to expected, reference data are required. This study provides reference data for HR-pQCT measures acquired in a population of White adults. PURPOSE: To provide age- and sex-specific reference data for high-resolution peripheral quantitative computed tomography (HR-pQCT) measures of the distal and diaphyseal radius and tibia acquired using a second-generation scanner and percent-of-length offsets proximal from the end of the bone. METHODS: Data were acquired in White adults (aged 18-80 years) living in the Midwest region of the USA. HR-pQCT scans were performed at the 4% distal radius, 30% diaphyseal radius, 7.3% distal tibia, and 30% diaphyseal tibia. Centile curves were fit to the data using the LMS approach. RESULTS: Scans of 867 females and 317 males were included. The fitted centile curves reveal HR-pQCT differences between ages, sexes, and sites. They also indicate differences when compared to data obtained by others using fixed length offsets. Excel-based calculators based on the current data were developed and are provided to enable computation of subject-specific percentiles, z-scores, and t-scores and to plot an individual's outcomes on the fitted curves. In addition, regression equations are provided to convert estimated failure load acquired with the conventional criteria utilized with first-generation scanners and those specifically developed for second-generation scanners. CONCLUSION: The current study provides unique data and resources. The combination of the reference data and calculators provide clinicians and investigators an ability to assess HR-pQCT outcomes in an individual or population of interest, when using the described scanning and analysis procedure. Ultimately, the expectation is these data will be expanded over time so the wealth of information HR-pQCT provides becomes increasingly interpretable and utilized.

Whole egg consumption and cortical bone in healthy children.

Eggs contain bioactive compounds thought to benefit pediatric bone. This cross-sectional study shows a positive link between childhood egg intake and radius cortical bone. If randomized trials confirm our findings, incorporating eggs into children's diets could have a significant impact in preventing childhood fractures and reducing the risk of osteoporosis. INTRODUCTION: This study examined the relationships between egg consumption and cortical bone in children. METHODS: The cross-sectional study design included 294 9-13-year-old black and white males and females. Three-day diet records determined daily egg consumption. Peripheral quantitative computed tomography measured radius and tibia cortical bone. Body composition and biomarkers of bone turnover were assessed using dual-energy X-ray absorptiometry and ELISA, respectively. RESULTS: Egg intake was positively correlated with radius and tibia cortical bone mineral content (Ct.BMC), total bone area, cortical area, cortical thickness, periosteal circumference, and polar strength strain index in unadjusted models (r = 0.144-0.224, all P < 0.050). After adjusting for differences in race, sex, maturation, fat-free soft tissue mass (FFST), and protein intakes, tibia relationships were nullified; however, egg intake remained positively correlated with radius Ct.BMC (r = 0.138, P = 0.031). Egg intake positively correlated with total body bone mineral density, BMC, and bone area in the unadjusted models only (r = 0.119-0.224; all P < 0.050). After adjusting for covariates, egg intake was a positive predictor of radius FFST (ß = 0.113, P < 0.050) and FFST was a positive predictor of Ct.BMC (ß = 0.556, P < 0.050) in path analyses. There was a direct influence of egg on radius Ct.BMC (ß = 0.099, P = 0.035), even after adjusting for the mediator, FFST (ß = 0.137, P = 0.020). Egg intake was positively correlated with osteocalcin in both the unadjusted (P = 0.005) and adjusted (P = 0.049) models. CONCLUSION: If the positive influence of eggs on Ct.BMC observed in this study is confirmed through future randomized controlled trials, whole eggs may represent a viable strategy to promote pediatric bone development and prevent fractures.

Progressive skeletal benefits of physical activity when young as assessed at the midshaft humerus in male baseball players.

Physical activity benefits the skeleton, but there is contrasting evidence regarding whether benefits differ at different stages of growth. The current study demonstrates that physical activity should be encouraged at the earliest age possible and be continued into early adulthood to gain most skeletal benefits. INTRODUCTION: The current study explored physical activity-induced bone adaptation at different stages of somatic maturity by comparing side-to-side differences in midshaft humerus properties between male throwing athletes and controls. Throwers present an internally controlled model, while inclusion of control subjects removes normal arm dominance influences. METHODS: Throwing athletes (n = 90) and controls (n = 51) were categorized into maturity groups (pre, peri, post-early, post-mid, and post-late) based on estimated years from peak height velocity (<-2, -2 to 2, 2 to 4, 4 to 10, and >10 years). Side-to-side percent differences in midshaft humerus cortical volumetric bone mineral density (Ct.vBMD) and bone mineral content (Ct.BMC); total (Tt.Ar), medullary (Me.Ar), and cortical (Ct.Ar) areas; average cortical thickness (Ct.Th); and polar Strength Strain Index (SSIP) were assessed. RESULTS: Significant interactions between physical activity and maturity on side-to-side differences in Ct.BMC, Tt.Ar, Ct.Ar, Me.Ar, Ct.Th, and SSIP resulted from the following: (1) greater throwing-to-nonthrowing arm differences than dominant-to-nondominant arm differences in controls (all p < 0.05) and (2) throwing-to-nonthrowing arm differences in throwers being progressively greater across maturity groups (all p < 0.05). Regional analyses revealed greatest adaptation in medial and lateral sectors, particularly in the three post-maturity groups. Years throwing predicted 59% of the variance of the variance in throwing-to-nonthrowing arm difference in SSIP (p < 0.001). CONCLUSION: These data suggest that physical activity has skeletal benefits beginning prior to and continuing beyond somatic maturation and that a longer duration of exposure to physical activity has cumulative skeletal benefits. Thus, physical activity should be encouraged at the earliest age possible and be continued into early adulthood to optimize skeletal benefits.

Achilles tendon material properties are greater in the jump leg of jumping athletes.

PURPOSE: The Achilles tendon (AT) must adapt to meet changes in demands. This study explored AT adaptation by comparing properties within the jump and non-jump legs of jumping athletes. Non-jumping control athletes were included to control limb dominance effects. METHODS: AT properties were assessed in the preferred (jump) and non-preferred (lead) jumping legs of male collegiate-level long and/or high jump (jumpers; n=10) and cross-country (controls; n=10) athletes. Cross-sectional area (CSA), elongation, and force during isometric contractions were used to estimate the morphological, mechanical and material properties of the ATs bilaterally. RESULTS: Jumpers exposed their ATs to more force and stress than controls (all p≤0.03). AT force and stress were also greater in the jump leg of both jumpers and controls than in the lead leg (all p<0.05). Jumpers had 17.8% greater AT stiffness and 24.4% greater Young's modulus in their jump leg compared to lead leg (all p<0.05). There were no jump versus lead leg differences in AT stiffness or Young's modulus within controls (all p>0.05). CONCLUSION: ATs chronically exposed to elevated mechanical loading were found to exhibit greater mechanical (stiffness) and material (Young's modulus) properties.

A Phase 2 Randomized Study Investigating the Efficacy and Safety of Myostatin Antibody LY2495655 versus Placebo in Patients Undergoing Elective Total Hip Arthroplasty.

BACKGROUND: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty. OBJECTIVES: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty. DESIGN: Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period. SETTING: Forty-two sites in 11 countries. PARTICIPANTS: Individuals (N=400) aged ≥50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 ± 6 days after randomization. INTERVENTION: Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24. MEASUREMENTS: Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time. RESULTS: Participants: 59% women, aged 69 ± 8 years, BMI 29 ± 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected. CONCLUSION: Dose-dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective.

Association of adenovirus 36 infection with adiposity and inflammatory-related markers in children.

CONTEXT: Although animal studies suggest that adenovirus 36 (Ad36) infection is linked to obesity and systemic inflammation, human data are scant and equivocal. OBJECTIVE: Associations of Ad36 infection with total body adiposity and inflammatory-related markers were determined in 291 children aged 9-13 years (50% female, 49% black). DESIGN: Fasting blood samples were measured for presence of Ad36-specific antibodies and TNF-α, IL-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1). Fat mass and fat-free soft tissue mass were measured by dual-energy X-ray absorptiometry. RESULTS: The overall prevalence of Ad36 seropositivity [Ad36(+)] was 42%. There was a higher percentage of Ad36(+) children in the highest tertiles of TNF-α and IL-6 compared with their respective middle and lowest tertiles (both P < .03). There was also a trend toward a higher prevalence of Ad36(+) children in the highest tertile of VEGF compared with tertiles 1 and 2 (P = .05). Multinomial logistic regression, adjusting for age, race, sex, and fat-free soft tissue mass, revealed that compared with children with the lowest TNF-α, IL-6, and VEGF levels (tertile 1), the adjusted odds ratios for Ad36(+) were 2.2 [95% confidence interval (CI) 1.2-4.0], 2.4 (95% CI 1.4-4.0), and 1.8 (95% CI 1.0-3.3), respectively, for those in the highest TNF-α, IL-6, and VEGF levels (tertile 3). No association was observed between Ad36(+) and greater levels of fat mass or MCP-1 (all P > .05). CONCLUSIONS: In children, our data suggest that Ad36(+) may be associated with biomarkers implicated in inflammation but not with greater levels of fat mass.

Physical activity completed when young has residual bone benefits at 94 years of age: a within-subject controlled case study.

Physical activity is recommended for skeletal health because bones adapt to mechanical loading. The young skeleton shows greatest plasticity to physical activity-related mechanical loads, but bones are most at risk of failure later in life. The discrepancy raises the question of whether the skeletal benefits of physical activity completed when young persist with aging. Here we present a unique case wherein the cortical bone benefit of physical activity completed over five decades earlier could be established within an individual aged in their tenth decade of life. Specifically, we compared bone properties at the midshaft humerus between the throwing and nonthrowing arms of a 94-year-old former Major League Baseball player who ceased throwing 55 years earlier. By performing analyses within-subject, the long-term skeletal benefit of physical activity completed when young could be assessed independent of inherited and systemic traits. Also, as the subject threw left-handed during his throwing career, but was right-hand dominant in all other activities throughout life, any lasting skeletal benefits in favor of the throwing arm could not be attributable to simple arm dominance. Analyses indicated that any cortical bone mass, area and thickness benefits of throwing-related physical activity completed when young were lost with aging, possibly due to accelerated intracortical remodeling. In contrast, the subject's throwing (nondominant) arm had greater total cross-sectional area and estimated strength (polar moment of inertia) than in his dominant arm, despite muscle indices favoring the latter. These data indicate that physical activity completed when young can have lasting benefits on bone size and strength, independent of the maintenance of bone mass benefits.

A randomized trial of vitamin D3 supplementation in children: dose-response effects on vitamin D metabolites and calcium absorption.

CONTEXT: Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D3 in healthy children are unknown. OBJECTIVE: Our objective was to examine the dose-response effects of supplemental vitamin D3 on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes. DESIGN: Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D3 (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope 44Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption. RESULTS: The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from -10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)2D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D. CONCLUSION: Large increases in serum 25(OH)D with vitamin D3 supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children.

Racial differences in cortical bone and their relationship to biochemical variables in Black and White children in the early stages of puberty.

UNLABELLED: Osteoporotic fracture rates differ according to race with Blacks having up to half the rate of Whites. The current study demonstrates that racial divergence in cortical bone properties develops in early childhood despite lower serum 25-hydroxyvitamin D in Blacks. INTRODUCTION: Racial differences in bone structure likely have roots in childhood as bone size develops predominantly during growth. This study aimed to compare cortical bone health within the tibial diaphysis of Black and White children in the early stages of puberty and explore the contributions of biochemical variables in explaining racial variation in cortical bone properties. METHODS: A cross-sectional study was performed comparing peripheral quantitative computed tomography-derived cortical bone measures of the tibial diaphysis and biochemical variables in 314 participants (n = 155 males; n = 164 Blacks) in the early stages of puberty. RESULTS: Blacks had greater cortical volumetric bone mineral density, mass, and size compared to Whites (all p < 0.01), contributing to Blacks having 17.0 % greater tibial strength (polar strength-strain index (SSIP)) (p < 0.001). Turnover markers indicated that Blacks had higher bone formation (osteocalcin (OC) and bone-specific alkaline phosphatase) and lower bone resorption (N-terminal telopeptide) than Whites (all p < 0.01). Blacks also had lower 25-hydroxyvitamin D (25(OH)D) and higher 1,25-dihydroxyvitamin D (1,25(OH)2D) and parathyroid hormone (PTH) (all p < 0.05). There were no correlations between tibial bone properties and 25(OH)D and PTH in Whites (all p ≥ 0.10); however, SSIP was negatively and positively correlated with 25(OH)D and PTH in Blacks, respectively (all p ≤ 0.02). Variation in bone cross-sectional area and SSIP attributable to race was partially explained by tibial length, 25(OH)D/PTH, and OC. CONCLUSIONS: Divergence in tibial cortical bone properties between Blacks and Whites is established by the early stages of puberty with the enhanced cortical bone properties in Black children possibly being explained by higher PTH and OC.

Age-related changes in proximal humerus bone health in healthy, white males.

UNLABELLED: The proximal humerus is a common site for osteoporotic fracture. The current study demonstrates the rate of age-related decline in proximal humerus bone health. The data suggest aging is associated with considerable loss of bone mass, structural deterioration and reduced bone strength at the proximal humerus. INTRODUCTION: The proximal humerus is relatively under investigated despite being the fourth most common site for osteoporotic fracture. METHODS: A cross-sectional study was performed to assess age-related changes in dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) properties of the proximal humerus in a cohort of 170 healthy, white males. RESULTS: Regression models estimated considerable age-related loss of DXA measured bone quantity at the proximal humerus, with areal bone mineral density modeled to decline by 29% (95% confidence interval [CI], 17.5-35.0%) in the 50 years between ages 30 and 80 years (p < 0.001). pQCT measures indicated aging was associated with progressive periosteal and endosteal expansion, with the later occurring more rapidly as indicated by age-related declines in cortical bone mass, area and thickness (all p < 0.01). The net result of the density, mass and structural changes was a 26% (95% CI, 13.5-38.0%) decline in pQCT estimated proximal humerus bone strength in the 50 years between ages 30 and 80 years (p < 0.001). CONCLUSION: Aging is associated with considerable declines in proximal humeral bone health which, when coupled with a traumatic event such as a fall, may contribute to osteoporotic fracture at this site.

Models for the study of tendinopathy.

Tendinopathy refers to the clinical presentation of activity-related pain, focal tendon tenderness, and intratendinous imaging changes. The underlying pathology was once thought to be due to inflammation ('tendinitis'), but is now considered to predominantly result from degeneration ('tendinosis'). While some progress has been made in understanding tendinosis, the condition remains poorly understood and a need exists for suitable exploratory preclinical models. It is unlikely that one suitable model exists because of the complexity of the underlying pathology and myriad of possible causes. This paper provides an overview of current models utilized in tendinopathy research. It progresses hierarchically from in vitro and ex vivo models to in vivo models. For each model, rationale for use, pertinent findings, and advantages and disadvantages are discussed. By improving on these models, new methods for the prevention and treatment of tendinopathy may be explored with the ultimate outcome being a reduction in the occurrence and effects of the condition in humans.

Infrapatellar fat pad size, but not patellar alignment, is associated with patellar tendinopathy.

Patellar tendinopathy (PT) is one of the most common overuse injuries of the knee. Recent reports indicate that increased body mass is frequently associated with tendinopathy, not only biomechanically but biochemically. Abnormalities of other structures within the knee extensor mechanism [patellofemoral joint (PFJ) alignment and patellar tendon length] that can directly influence the strain distribution of the patellar tendon are inconsistently implicated in PT. The aim of this study was to compare the infrapatellar fat pad volume, patellar tendon length and PFJ alignment in people with chronic PT and a group of age-, gender-, height-, and activity-matched controls with normal tendons. Axial magnetic resonance (MR) images, from 26 participants with PT and 28 control participants were obtained. Fat pad size, patellar tendon length and PFJ alignment were measured digitally from the MR images, using measurement software, and the results compared between the PT group and control group. People with PT had a significantly larger fat pad than healthy controls when controlled for height (P=0.04). Patellar tendon length was not significantly different between groups (P=0.16), nor were there between-group differences for the measures of PFJ alignment (P=0.07-0.76). Thus, the infrapatellar fat pad may play an important role in PT.

Factors affecting short-term precision of musculoskeletal measures using peripheral quantitative computed tomography (pQCT).

UNLABELLED: Few studies have investigated factors influencing the precision of peripheral quantitative computed tomography (pQCT) measures. This study found time between repeat scans and subject anthropometric characteristics to influence short-term precision of pQCT-derived measures in the lower leg. These findings have implications for both investigators and clinicians utilizing pQCT outcomes. INTRODUCTION: Peripheral quantitative computed tomography (pQCT) is increasingly being used to investigate musculoskeletal changes associated with age, disease and/or intervention. Precision of pQCT measures is of paramount importance in this endeavor. This study aimed to establish the short-term precision of pQCT-derived musculoskeletal measures of the lower leg and investigate factors influencing this precision. METHODS: Thirty healthy subjects had a series of six pQCT scans of the lower leg (66% of tibial length proximal from its distal end) performed on two separate days by two different testers. The influences of different testers, time between repeat scans, and subject anthropometric characteristics on precision were explored. RESULTS: Overall precision error (root mean square) increased from bone (<1%) to muscle (<1.5%) to fat (3%). The two testers were equally precise in performing pQCT measures; however, precision error increased when repeat scans were repeated 1 week apart as opposed to on the same day. Subject anthropometric characteristics influenced precision errors with the general finding being that an increase in subject size was associated with less precise pQCT measures. CONCLUSIONS: pQCT is a relatively precise technique for the assessment of bone and muscle, but precision is influenced by time between repeat scans and subject anthropometric characteristics. Investigators and clinicians need to be aware of these factors influencing pQCT outcomes as they may influence statistical power in clinical studies and the characterization of change in individual patients.

Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from in vitro and animal-based studies.

The regulation of bone metabolism continues to be an area of intense investigation, with recent evidence indicating a potential contribution from the neural system. In particular, the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has been hypothesized to play a role in skeletal metabolism via its transporter (5-HTT). The 5-HTT is a plasma membrane transporter that is highly specific for the uptake of extracellular 5-HT, thereby facilitating the intracellular storage and/or degradation of 5-HT. The 5-HTT is clinically important as it is the key target of pharmaceutical agents aimed at treating affective disorders, such as major depressive disorder. By antagonizing the 5-HTT, selective serotonin reuptake inhibitors (SSRIs) potentiate 5-HT activity and effectively relieve the symptoms of depression. However, questions have been raised regarding the potential skeletal effects of SSRIs given the recent identification of a functional 5-HTT and functional 5-HT receptors in bone cells. This paper discusses the preclinical evidence for the skeletal effects of 5-HT and the inhibition of the 5-HTT. In particular, it discusses the: (1) role of 5-HT and the function of the 5-HTT; (2) presence of functional 5-HTTs in bone; (3) potential sources and response mechanisms for 5-HT in bone, and; (4) in vitro and in vivo skeletal effects of 5-HT and 5-HTT inhibition.

Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies.

The discovery of a functional serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) in bone has given rise to questions about the physiologic role of 5-HT in bone, and the possible clinical implications for humans. 5-HT is known to play a role in the pathophysiology of depression, and many antidepressant medications function by inhibiting the 5-HTT. Among the antidepressants, those that selectively block the 5-HTT (namely, selective serotonin reuptake inhibitors; SSRIs) appear to have skeletal effects. Several studies have demonstrated lower bone density, increased rates of bone loss at the hip, and increased rates of fracture among older individuals taking SSRIs. However, there remains uncertainty about whether it is the antidepressant medications themselves or the reason for their use (depression) that is responsible for these observed bone changes. This paper reviews the epidemiologic literature that explores the role of the 5-HTT in bone health, by looking at questions about how depression, antidepressant therapy and SSRIs impact bone health in humans. Further research will be important to better understand how these factors interact to influence skeletal status, and to characterize the biochemical mechanism through which 5-HT may mediate bone turnover and metabolism.

Low-intensity pulsed ultrasound for chronic patellar tendinopathy: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Patellar tendinopathy (PT) is a common and significant clinical condition for which there are few established interventions. One intervention that is currently being used clinically to manage PT symptoms is the introduction of low-intensity pulsed ultrasound (LIPUS). The aim of this study was to investigate the clinical efficacy of LIPUS in the management of PT symptoms. METHODS: A randomized, double-blind, placebo-controlled study was conducted. Volunteers with clinically and radiologically confirmed PT were randomly allocated to either an active-LIPUS (treatment) or inactive-LIPUS (placebo) group. LIPUS was self-administered by participants for 20 min/day, 7 days/week for 12 weeks. All participants also completed a daily, standardized eccentric exercise programme based on best practice. Primary outcomes were change in pain during the participant's most aggravating activity in the preceding week, measured on 10 cm visual analogue scales for both usual (VAS-U) and worst (VAS-W) tendon pain. RESULTS: Out of 156 individuals who volunteered, 37 met the eligibility criteria and were randomized to either active-LIPUS (n = 17) or inactive-LIPUS (n = 20). Using an intention-to-treat analysis, VAS-U and VAS-W for the entire cohort decreased by 1.6 +/- 1.9 cm (P < 0.01) and 2.5 +/- 2.4 cm (P < 0.01), respectively. There were no differences between the active- and inactive-LIPUS groups for change in VAS-U (-0.2 cm; 95% CI, -1.5, 1.1 cm) (P = 0.74) or VAS-W (-0.5 cm; 95% CI, -2.1, 1.1 cm) (P = 0.57). A per-protocol analysis provided similar results. CONCLUSIONS: These findings suggest that LIPUS does not provide any additional benefit over and above placebo in the management of symptoms associated with PT.

Animal models for the study of tendinopathy.

Tendinopathy is a common and significant clinical problem characterised by activity-related pain, focal tendon tenderness and intratendinous imaging changes. Recent histopathological studies have indicated the underlying pathology to be one of tendinosis (degeneration) as opposed to tendinitis (inflammation). Relatively little is known about tendinosis and its pathogenesis. Contributing to this is an absence of validated animal models of the pathology. Animal models of tendinosis represent potential efficient and effective means of furthering our understanding of human tendinopathy and its underlying pathology. By selecting an appropriate species and introducing known risk factors for tendinopathy in humans, it is possible to develop tendon changes in animal models that are consistent with the human condition. This paper overviews the role of animal models in tendinopathy research by discussing the benefits and development of animal models of tendinosis, highlighting potential outcome measures that may be used in animal tendon research, and reviewing current animal models of tendinosis. It is hoped that with further development of animal models of tendinosis, new strategies for the prevention and treatment of tendinopathy in humans will be generated.