Return to sport following low-risk and high-risk bone stress injuries: a systematic review and meta-analysis.

OBJECTIVE: Bone stress injuries (BSIs) are classified in clinical practice as being at low- or high-risk for complication based on the injury location. However, this dichotomous approach has not been sufficiently validated. The purpose of this systematic review was to examine the prognostic role of injury location on return-to-sport (RTS) and treatment complications after BSI of the lower extremity and pelvis. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane CENTRAL and Google Scholar databases were searched from database inception to December 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Peer-reviewed studies that reported site-specific RTS of BSIs in athletes. RESULTS: Seventy-six studies reporting on 2974 BSIs were included. Sixteen studies compared multiple injury sites, and most of these studies (n=11) described the anatomical site of injury as being prognostic for RTS or the rate of treatment complication. Pooled data revealed the longest time to RTS for BSIs of the tarsal navicular (127 days; 95% CI 102 to 151 days) and femoral neck (107 days; 95% CI 79 to 135 days) and shortest duration of time for BSIs of the posteromedial tibial shaft (44 days, 95% CI 27 to 61 days) and fibula (56 days; 95% CI 13 to 100 days). Overall, more than 90% of athletes successfully returned to sport. Treatment complication rate was highest in BSIs of the femoral neck, tarsal navicular, anterior tibial shaft and fifth metatarsal; and lowest in the fibula, pubic bone and posteromedial tibial shaft. CONCLUSION: This systematic review supports that the anatomical site of BSIs influences RTS timelines and the risk of complication. BSIs of the femoral neck, anterior tibial shaft and tarsal navicular are associated with increased rates of complications and more challenging RTS. PROSPERO REGISTRATION NUMBER: CRD42021232351.

Effects of Gabapentin and Pregabalin on Calcium Homeostasis: Implications for Physical Rehabilitation of Musculoskeletal Tissues.

PURPOSE OF REVIEW: In this review, we discuss the mechanism of action of gabapentinoids and the potential consequences of long-term treatment with these drugs on the musculoskeletal system. RECENT FINDINGS: Gabapentinoids, such as gabapentin (GBP) and pregabalin (PGB) were designed as antiepileptic reagents and are now commonly used as first-line treatment for neuropathic pain and increasingly prescribed off-label for other pain disorders such as migraines and back pain. GBP and PGB exert their analgesic actions by selectively binding the α2δ1 auxiliary subunit of voltage-sensitive calcium channels, thereby inhibiting channel function. Numerous tissues express the α2δ1 subunit where GBP and PGB can alter calcium-mediated signaling events. In tissues such as bone, muscle, and cartilage, α2δ1 has important roles in skeletal formation, mechanosensation, and normal tissue function/repair that may be affected by chronic use of gabapentinoids. Long-term use of gabapentinoids is associated with detrimental musculoskeletal outcomes, including increased fracture risk. Therefore, understanding potential complications is essential for clinicians to guide appropriate treatments.

Preventing Bone Stress Injuries in Runners with Optimal Workload.

Bone stress injuries (BSIs) occur at inopportune times to invariably interrupt training. All BSIs in runners occur due to an "error" in workload wherein the interaction between the number and magnitude of bone tissue loading cycles exceeds the ability of the tissue to resist the repetitive loads. There is not a single optimal bone workload, rather a range which is influenced by the prevailing scenario. In prepubertal athletes, optimal bone workload consists of low-repetitions of fast, high-magnitude, multidirectional loads introduced a few times per day to induce bone adaptation. Premature sports specialization should be avoided so as to develop a robust skeleton that is structurally optimized to withstand multidirectional loading. In the mature skeleton, optimal workload enables gains in running performance but minimizes bone damage accumulation by sensibly progressing training, particularly training intensity. When indicated (e.g., following repeated BSIs), attempts to reduce bone loading magnitude should be considered, such as increasing running cadence. Determining the optimal bone workload for an individual athlete to prevent and manage BSIs requires consistent monitoring. In the future, it may be possible to clinically determine bone loads at the tissue level to facilitate workload progressions and prescriptions.

Radiographic imaging, densitometry and disease severity in Autosomal dominant osteopetrosis type 2.

OBJECTIVE: To characterize relationships between quantitative computed tomography bone mineral density measurements and other qualitative and quantitative imaging measures, as well as clinical metrics, in patients with autosomal dominant osteopetrosis type 2 (ADO2). MATERIALS AND METHODS: Clinical and radiologic parameters of 9 adults and 3 children with autosomal dominant osteopetrosis type 2 were assessed including lumbar spine quantitative computed tomography (QCT), radiographic skeletal survey (skull base thickening; Erlenmeyer flask deformity; endobone pattern; and spine density pattern (endplate sclerosis, "anvil" appearance, or diffuse sclerosis)), dual-energy x-ray absorptiometry (DXA), tibial peripheral quantitative computed tomography (pQCT) volumetric bone mineral density (vBMD), bone turnover markers, and bone marrow failure or visual impairment. RESULTS: The skeletal parameter most divergent from normal was lumbar spine QCT Z-score (+ 3.6 to + 38.7). Lumbar QCT Z-score correlated positively with pQCT tibial diaphysis vBMD (Pearson correlation r = 0.73, p = 0.02) and pQCT tibial metaphysis vBMD (r = 0.87, p < 0.01). A trend towards positive lumbar QCT Z-score correlation with serum P1NP/CTX ratio (r = 0.54, p = 0.10) and lumbar DXA Z-score (r = 0.55, p = 0.10) were observed. Bone marrow failure and vision impairment occurred in those with most severe quantitative and qualitative measures, while those with less severe radiographic features had the lowest QCT Z-scores. CONCLUSION: Lumbar spine QCT provided the most extreme skeletal assessment in ADO2, which correlated positively with other radiologic and clinical markers of disease severity. Given the quantification of trabecular bone and greater variation from normal with wider range of values, lumbar QCT Z-scores may be useful to determine or detect impact of future treatments.

Taking the Next Steps in Regenerative Rehabilitation: Establishment of a New Interdisciplinary Field.

The growing field of regenerative rehabilitation has great potential to improve clinical outcomes for individuals with disabilities. However, the science to elucidate the specific biological underpinnings of regenerative rehabilitation-based approaches is still in its infancy and critical questions regarding clinical translation and implementation still exist. In a recent roundtable discussion from International Consortium for Regenerative Rehabilitation stakeholders, key challenges to progress in the field were identified. The goal of this article is to summarize those discussions and to initiate a broader discussion among clinicians and scientists across the fields of regenerative medicine and rehabilitation science to ultimately progress regenerative rehabilitation from an emerging field to an established interdisciplinary one. Strategies and case studies from consortium institutions-including interdisciplinary research centers, formalized courses, degree programs, international symposia, and collaborative grants-are presented. We propose that these strategic directions have the potential to engage and train clinical practitioners and basic scientists, transform clinical practice, and, ultimately, optimize patient outcomes.

Voluntary Wheel Running Has Beneficial Effects in a Rat Model of CKD-Mineral Bone Disorder (CKD-MBD).

BACKGROUND: Reduced bone and muscle health in individuals with CKD contributes to their higher rates of morbidity and mortality. METHODS: We tested the hypothesis that voluntary wheel running would improve musculoskeletal health in a CKD rat model. Rats with spontaneous progressive cystic kidney disease (Cy/+ IU) and normal littermates (NL) were given access to a voluntary running wheel or standard cage conditions for 10 weeks starting at 25 weeks of age when the rats with kidney disease had reached stage 2-3 of CKD. We then measured the effects of wheel running on serum biochemistry, tissue weight, voluntary grip strength, maximal aerobic capacity (VO2max), body composition and bone micro-CT and mechanics. RESULTS: Wheel running improved serum biochemistry with decreased creatinine, phosphorous, and parathyroid hormone in the rats with CKD. It improved muscle strength, increased time-to-fatigue (for VO2max), reduced cortical porosity and improved bone microarchitecture. The CKD rats with voluntary wheel access also had reduced kidney cystic weight and reduced left ventricular mass index. CONCLUSIONS: Voluntary wheel running resulted in multiple beneficial systemic effects in rats with CKD and improved their physical function. Studies examining exercise interventions in patients with CKD are warranted.

Baseball and Softball Pitchers are Distinct Within-Subject Controlled Models for Exploring Proximal Femur Adaptation to Physical Activity.

Within-subject controlled models in individuals who preferentially load one side of the body enable efficient exploration of the skeletal benefits of physical activity. There is no established model of physical activity-induced side-to-side differences (i.e., asymmetry) at the proximal femur. Proximal femur asymmetry was assessed via dual-energy X-ray absorptiometry in male jumping athletes (JMP, n = 16), male baseball pitchers (BB, n = 21), female fast-pitch softball pitchers (SB, n = 22), and controls (CON, n = 42). The jumping leg was the dominant leg in JMP, whereas in BB, SB and CON the dominant leg was contralateral to the dominant/throwing arm. BB and SB had 5.5% (95% CI 3.9-7.0%) and 6.5% (95% CI 4.8-8.2%) dominant-to-nondominant leg differences for total hip areal bone mineral density (aBMD), with the asymmetry being greater than both CON and JMP (p < 0.05). BB and SB also possessed dominant-to-nondominant leg differences in femoral neck and trochanteric aBMD (p < 0.001). SB had 9.7% (95% CI 6.4-13.0%) dominant-to-nondominant leg differences in femoral neck bone mineral content, which was larger than any other group (p ≤ 0.006). At the narrow neck, SB had large (> 8%) dominant-to-nondominant leg differences in cross-sectional area, cross-sectional moment of inertia and section modulus, which were larger than any other group (p ≤ 0.02). Male baseball and female softball pitchers are distinct within-subject controlled models for exploring adaptation of the proximal femur to physical activity. They exhibit adaptation in their dominant/landing leg (i.e., leg contralateral to the throwing arm), but the pattern differs with softball pitchers exhibiting greater femoral neck adaptation.

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.

Throwing enhances humeral shaft cortical bone properties in pre-pubertal baseball players: a 12-month longitudinal pilot study.

OBJECTIVES: To explore throwing athletes as a prospective, within-subject controlled model for studying the response of the skeleton to exercise. METHODS: Male pre-pubertal throwing athletes (n=12; age=10.3±0.6 yrs) had distal humerus cortical volumetric bone mineral density (Ct.vBMD), cortical bone mineral content (Ct.BMC), total area (Tt.Ar), cortical area (Ct.Ar), medullary area (Me.Ar), cortical thickness (Ct.Th) and polar moment of inertia (IP) assessed within their throwing (exercised) and nonthrowing (control) arms by peripheral quantitative computed tomography at baseline and 12 months. Throwing-to-nonthrowing arm percent differences (i.e. bilateral asymmetry) were compared over time. RESULTS: Over 12 months, the throwing arm gained 4.3% (95% Cl=1.1% to 7.5%), 2.9% (95% Cl=0.3% to 5.4%), 3.9% (95% Cl=0.7% to 7.0%), and 8.2% (95% Cl=2.0% to 6.8%) more Ct.BMC, Ct.Ar, Tt.Ar, and IP than the nonthrowing arm, respectively (all p<0.05). There was no significant effect of throwing on Ct.vBMD, Ct.Th and Me.Ar (all p=0.18-0.82). CONCLUSION: Throwing induced surface-specific cortical bone adaptation at the distal humeral diaphysis that contributed to a gain in estimated strength. These longitudinal pilot data support the utility of throwing athletes as a within-subject controlled model to explore factors influencing exercise-induced bone adaptation during the critical growing years.

Physical Activity for Strengthening Fracture Prone Regions of the Proximal Femur.

PURPOSE OF REVIEW: Physical activity improves proximal femoral bone health; however, it remains unclear whether changes translate into a reduction in fracture risk. To enhance any fracture-protective effects of physical activity, fracture prone regions within the proximal femur need to be targeted. RECENT FINDINGS: The proximal femur is designed to withstand forces in the weight-bearing direction, but less so forces associated with falls in a sideways direction. Sideways falls heighten femoral neck fracture risk by loading the relatively weak superolateral region of femoral neck. Recent studies exploring regional adaptation of the femoral neck to physical activity have identified heterogeneous adaptation, with adaptation principally occurring within inferomedial weight-bearing regions and little to no adaptation occurring in the superolateral femoral neck. There is a need to develop novel physical activities that better target and strengthen the superolateral femoral neck within the proximal femur. Design of these activities may be guided by subject-specific musculoskeletal modeling and finite-element modeling approaches.

Physical activity when young provides lifelong benefits to cortical bone size and strength in men.

The skeleton shows greatest plasticity to physical activity-related mechanical loads during youth but is more at risk for failure during aging. Do the skeletal benefits of physical activity during youth persist with aging? To address this question, we used a uniquely controlled cross-sectional study design in which we compared the throwing-to-nonthrowing arm differences in humeral diaphysis bone properties in professional baseball players at different stages of their careers (n = 103) with dominant-to-nondominant arm differences in controls (n = 94). Throwing-related physical activity introduced extreme loading to the humeral diaphysis and nearly doubled its strength. Once throwing activities ceased, the cortical bone mass, area, and thickness benefits of physical activity during youth were gradually lost because of greater medullary expansion and cortical trabecularization. However, half of the bone size (total cross-sectional area) and one-third of the bone strength (polar moment of inertia) benefits of throwing-related physical activity during youth were maintained lifelong. In players who continued throwing during aging, some cortical bone mass and more strength benefits of the physical activity during youth were maintained as a result of less medullary expansion and cortical trabecularization. These data indicate that the old adage of "use it or lose it" is not entirely applicable to the skeleton and that physical activity during youth should be encouraged for lifelong bone health, with the focus being optimization of bone size and strength rather than the current paradigm of increasing mass. The data also indicate that physical activity should be encouraged during aging to reduce skeletal structural decay.

Tibial Bone Strength is Enhanced in the Jump Leg of Collegiate-Level Jumping Athletes: A Within-Subject Controlled Cross-Sectional Study.

An efficient method of studying skeletal adaptation to mechanical loading is to assess side-to-side differences (i.e., asymmetry) within individuals who unilaterally exercise one side of the body. Within-subject controlled study designs have been used to explore skeletal mechanoadaptation at upper extremity sites; however, there is no established model in the lower extremities. The current study assessed tibial diaphysis and distal tibia asymmetry in collegiate-level jumping athletes (N = 12). To account for normal crossed asymmetry, data in jumping athletes were compared to asymmetry in a cohort of athletic controls not routinely exposed to elevated unilateral lower extremity loading (N = 11). Jumpers exhibited side-to-side differences between their jump and lead legs at both the tibial diaphysis and distal tibia, with differences at the former site persisting following comparison to dominant-to-nondominant leg differences in controls. In particular, jump-to-lead leg differences for cortical area and thickness at the tibial diaphysis in jumpers were 3.6% (95% CI 0.5-6.8%) and 3.5% (95% CI 0.4-6.6%) greater than dominant-to-nondominant differences in controls, respectively (all p < 0.05). Similarly, jump-to-lead leg differences in jumpers for tibial diaphysis maximum second moment of area and polar moment of inertia were 7.2% (95% CI 1.2-13.2%) and 5.7% (95% CI 1.7-9.8%) greater than dominant-to-nondominant differences in controls, respectively (all p < 0.05). Assessment of region-specific differences of the tibial diaphysis in jumpers indicated that the jump leg had greater pericortical radii on the medial and posterior sides and greater radial cortical thickness posteromedially when compared to the lead leg. These data suggest that athletes who perform repetitive and forceful unilateral jumping may be a useful and efficient within-subject controlled model for studying lower extremity skeletal mechanoadaptation.

Do Selective Serotonin Reuptake Inhibitors (SSRIs) Cause Fractures?

Recent meta-analyses report a 70 % increase in fracture risk in selective serotonin reuptake inhibitor (SSRI) users compared to non-users; however, included studies were observational and limited in their ability to establish causality. Here, we use the Bradford Hill criteria to explore causality between SSRIs and fractures. We found a strong, consistent, and temporal relationship between SSRIs and fractures, which appears to follow a biological gradient. However, specificity and biological plausibility remain concerns. In terms of specificity, the majority of available data have limitations due to either confounding by indication or channeling bias. Self-controlled case series address some of these limitations and provide relatively strong observational evidence for a causal relationship between SSRIs and fracture. In doing so, they suggest that falls contribute to fractures in SSRI users. Whether there are also underlying changes in skeletal properties remains unresolved. Initial studies provide some evidence for skeletal effects of SSRIs; however, the pathways involved need to be established before biological plausibility can be accepted. As the link between SSRIs and fractures is based on observational data and not evidence from prospective trials, there is insufficient evidence to definitively determine a causal relationship and it appears premature to label SSRIs as a secondary cause of osteoporosis. SSRIs appear to contribute to fracture-inducing falls, and addressing any fall risk associated with SSRIs may be an efficient approach to reducing SSRI-related fractures. As fractures stemming from SSRI-induced falls are more likely in individuals with compromised bone health, it is worth considering bone density testing and intervention for those presenting with risk factors for osteoporosis.

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.

Biomechanical aspects of the muscle-bone interaction.

There is growing interest in the interaction between skeletal muscle and bone, particularly at the genetic and molecular levels. However, the genetic and molecular linkages between muscle and bone are achieved only within the context of the essential mechanical coupling of the tissues. This biomechanical and physiological linkage is readily evident as muscles attach to bone and induce exposure to varied mechanical stimuli via functional activity. The responsiveness of bone cells to mechanical stimuli, or their absence, is well established. However, questions remain regarding how muscle forces applied to bone serve to modulate bone homeostasis and adaptation. Similarly, the contributions of varied, but unique, stimuli generated by muscle to bone (such as low-magnitude, high-frequency stimuli) remains to be established. The current article focuses upon the mechanical relationship between muscle and bone. In doing so, we explore the stimuli that muscle imparts upon bone, models that enable investigation of this relationship, and recent data generated by these models.

Peripheral Quantitative Computed Tomography Predicts Humeral Diaphysis Torsional Mechanical Properties With Good Short-Term Precision.

Peripheral quantitative computed tomography (pQCT) is a popular tool for noninvasively estimating bone mechanical properties. Previous studies have demonstrated that pQCT provides precise estimates that are good predictors of actual bone mechanical properties at popular distal imaging sites (tibia and radius). The predictive ability and precision of pQCT at more proximal sites remain unknown. The aim of the present study was to explore the predictive ability and short-term precision of pQCT estimates of mechanical properties of the midshaft humerus, a site gaining popularity for exploring the skeletal benefits of exercise. Predictive ability was determined ex vivo by assessing the ability of pQCT-derived estimates of torsional mechanical properties in cadaver humeri (density-weighted polar moment of inertia [I(P)] and polar strength-strain index [SSI(P)]) to predict actual torsional properties. Short-term precision was assessed in vivo by performing 6 repeat pQCT scans at the level of the midshaft humerus in 30 young, healthy individuals (degrees of freedom = 150), with repeat scans performed by the same and different testers and on the same and different days to explore the influences of different testers and time between repeat scans on precision errors. IP and SSI(P) both independently predicted at least 90% of the variance in ex vivo midshaft humerus mechanical properties in cadaveric bones. Overall values for relative precision error (root mean squared coefficients of variation) for in vivo measures of IP and SSI(P) at the midshaft humerus were <1.5% and were not influenced by pQCT assessments being performed by different testers or on different days. These data indicate that pQCT provides very good prediction of midshaft humerus mechanical properties with good short-term precision, with measures being robust against the influences of different testers and time between repeat scans.

Infrapatellar fat pad volume is greater in individuals with patellofemoral joint osteoarthritis and associated with pain.

There is relatively little research specifically investigating patellofemoral joint osteoarthritis (PFJ OA). In particular, the source of pain in PFJ OA has not been established. One structure that may be an important contributor is the infrapatellar fat pad (IPFP). This cross-sectional study aimed to: (1) compare IPFP volume in individuals with and without PFJ OA and (2) assess the relationship between IPFP volume and pain in individuals with PFJ OA. Thirty-five participants with symptomatic and radiographic PFJ OA and 11 asymptomatic controls with no radiographic signs of OA were recruited. IPFP volume was measured in both groups from magnetic resonance images, and pain in the PFJ OA group was determined using the pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS-pain). The PFJ OA group had 23.6 % greater IPFP volume than the control group (p = 0.04). After the inclusion of covariates, IPFP volume remained 19.6 % greater in the PFJ OA group (p = 0.03). IPFP volume explained 20.1 % of the variance in KOOS-pain in the PFJ OA group, with a larger IPFP being associated with worse pain (p < 0.01). Individuals with PFJ OA had a larger IPFP than controls, and IPFP volume was directly related to PFJ OA pain. These data suggest a role for the IPFP in PFJ OA and highlight a need for further investigation into the casual relationship between IPFP and PFJ changes.