In Vivo Assessment of Cortical Bone Fragility.

PURPOSE OF REVIEW: This review updates readers on recent developments in the assessment of cortical bone fragility in vivo. The review explains the clinical need that motivated the development of Cortical Bone Mechanics Technology™ (CBMT) as a scientific instrument, its unique capabilities, and its necessary further development as a medical device. RECENT FINDINGS: Clinical experience with dual-energy X-ray absorptiometry has led to calls for new clinical methods for assessing bone health. CBMT is a noninvasive, dynamic 3-point bending test that makes direct, functional measurements of the mechanical properties of cortical bone in ulnas of living people. Its technical validity in accurate measurements of ulna flexural rigidity and its clinical validity in accurate estimations of quasistatic ulna bending strength have been demonstrated. Because CBMT is a whole bone test, its measurements reflect the influences of bone quantity and bone quality at all hierarchical levels.

Response to "Clinical Evaluation of Bone Strength and Fracture Risk".

We read with great interest the recent review by de Bakker et al that summarized the state of several existing and emerging technologies for estimating bone strength and fracture risk in vivo. Much of their review focused on how well the measurements of selected technologies predicted experimental measurements of bone strength by ex vivo quasistatic mechanical testing (QMT) and on how well they tracked changes in mechanical properties of bone. The authors noted that the association of many common skeletal health measurements (e.g., DXA measures of trabecular bone score and areal and volumetric BMD) are only moderately associated with bone strength. The authors did not include mechanical response tissue analysis (MRTA) in their review. MRTA is a dynamic mechanical bending test that uses a vibration analysis technique to make immediate, direct, functional measurements of the mechanical properties (mass, stiffness, and damping) of long bones in humans in vivo. In this article we note our interest in the ability of MRTA to detect large changes in bone stiffness that go undetected by DXA. We also highlight results of our proprietary improvements to MRTA technology that have resulted in unmatched accuracy in QMT-validated measurements of the bending stiffness and estimates of the bending strength (both R2 = 0.99) of human ulna bones. To distinguish our improved technique from the legacy MRTA technology, we refer to it as Cortical Bone Mechanics Technology (CBMT). Further research will determine whether such CBMT measurements are clinically useful.

2014 female athlete triad coalition consensus statement on treatment and return to play of the female athlete triad.

The female athlete triad is a medical condition often observed in physically active girls and women and involves three components: (1) low energy availability with or without disordered eating, (2) menstrual dysfunction, and (3) low bone mineral density. Female athletes often present with one or more of the three triad components, and early intervention is essential to prevent its progression to serious end points that include clinical eating disorders, amenorrhea, and osteoporosis. This consensus statement presents a set of recommendations developed following the first (San Francisco, CA) and second (Indianapolis, IN) International Symposia on the Female Athlete Triad. This consensus statement was intended to provide clinical guidelines for physicians, athletic trainers, and other health care providers for the screening, diagnosis, and treatment of the female athlete triad and to provide clear recommendations for return to play. The expert panel has proposed a risk stratification point system that takes into account magnitude of risk to assist the physician in decision making regarding sport participation, clearance, and return to play. Guidelines are offered for clearance categories, management by a multidisciplinary team, and implementation of treatment contracts.

Energy availability in athletes.

This review updates and complements the review of energy balance and body composition in the Proceedings of the 2003 IOC Consensus Conference on Sports Nutrition. It argues that the concept of energy availability is more useful than the concept of energy balance for managing the diets of athletes. It then summarizes recent reports of the existence, aetiologies, and clinical consequences of low energy availability in athletes. This is followed by a review of recent research on the failure of appetite to increase ad libitum energy intake in compensation for exercise energy expenditure. The review closes by summarizing the implications of this research for managing the diets of athletes.

Improvements to mechanical response tissue analysis.

Cortical Bone Mechanics Technology™ (CBMT) comprises certain improvements over a previous method known as Mechanical Response Tissue Analysis (MRTA). Both methods are dynamic 3-point bending tests intended for measuring the mechanical properties of cortical bone in living people. MRTA presented a theoretical potential for direct measurement of skeletal fragility, but it had acquired a reputation for error and fallen into disuse. We found sources of error in both MRTA data collection and data analysis. We describe here the fundamentals of MRTA, the major sources of error we found in MRTA, and our innovations for avoiding them. •Data collection at many sites across the mid-shaft of the ulna bone in the forearm.•Parameter estimation by fitting analytical complex compliance and stiffness transfer functions to empirical complex compliance and stiffness frequency response functions.•Optimization by selecting results from frequency response functions with the smallest deviations between fits to compliance and stiffness frequency response functions.

A new noninvasive mechanical bending test accurately predicts ulna bending strength in cadaveric human arms.

BACKGROUND: High error rates in the prediction of fragility fractures by bone mineral density have motivated searches for better clinical indicators of bone strength, and the high incidence of non-hip, non-spine fractures has raised interest in cortical bone. The aim of this study was to assess the accuracy of Cortical Bone Mechanics Technology™. CBMT is a new non-invasive 3-point bending technique for measuring the mechanical properties of cortical bone in the ulnas of living humans. METHODS: 35 cadaveric human arms were obtained from small women and large men ranging widely in age (17 < Age < 99 years) and body size (14 < BMI < 40 kg/m2). Noninvasive CBMT measurements of the flexural rigidity of the ulna bones within these arms (EICBMT) were compared to measurements of EI by Quasistatic Mechanical Testing in the ulnas excised from those arms (EIQMT). Ulna bending strength was also measured by QMT as the peak moment before fracture (Mpeak). The open source BoneJ plugin to ImageJ image processing software was used to calculate cortical porosity (CP) in micro-computed tomography images of a 2 mm length of the mid-shaft of each fractured ulna, and the interosseous diameter (IOD) of each ulna was also measured in those images. RESULTS: EICBMT measurements (13 < EICBMT < 97 Nm2) explained 99% of the variance in QMT measurements of ulna bending strength (11 < Mpeak < 90 Nm), but EICBMT was biased high by 30% (p < 0.0001) relative to EIQMT (11 < EIQMT < 69 Nm2). After correcting this bias, EICBMT and EIQMT measurements lay along the identity line (y = 1.00x, R2 = 0.99, SEE = 3.1 Nm2). Predictions of Mpeak by EICBMT were less accurate than predictions by EIQMT (both R2 = 0.99; SEECBMT = 5.9 Nm vs SEEQMT = 4.5 Nm, F = 2.92, p = 0.001), but EICBMT predictions were substantially more accurate than those by IOD (R2 = 0.79; SEEIOD = 10.6 Nm, F = 3.30, p < 0.001) and CP (R2 = 0.35; SEECP = 18.9 Nm, F = 10.45, p < 10-9). Predictions by EICBMT were also more accurate than predictions by arm donor height (R2 = 0.63; SEE = 14.3 Nm, F = 5.87, p < 10-6), body weight (R2 = 0.77; SEE = 11.1 Nm, F = 3.54, p < 0.001) and BMI (R2 = 0.64; SEE = 14.1 Nm, F = 2.39, p < 0.01). In forward stepwise multiple regression beginning with EICBMT, only age explained any additional variance in ulna bending strength (ΔR2 = 0.3%, F = 8.03, p = 0.008). CONCLUSION: Noninvasive CBMT measurements of ulna EI explain 99% of individual differences in QMT measurements of ulna bending strength in cadaveric human arms.

Low energy availability in the marathon and other endurance sports.

Energy availability is the amount of dietary energy remaining after exercise training for all other metabolic processes. Excessively low energy availability impairs reproductive and skeletal health, although genetics and age may alter an individual's initial conditions and sensitivity when low energy availability is imposed. Many marathon runners and other endurance athletes reduce energy availability either (i) intentionally to modify body size and composition for improving performance; (ii) compulsively in a psychopathological pattern of disordered eating; or (iii) inadvertently because there is no strong biological drive to match energy intake to activity-induced energy expenditure. Inadvertent low energy availability is more extreme when consuming a low fat, high carbohydrate diet. Low energy availability, reproductive disorders, low bone mineral density and stress fractures are more common in female than male athletes. Functional menstrual disorders caused by low energy availability should be diagnosed by excluding diseases that also disrupt menstrual cycles. To determine energy availability (in units of kilocalories or kilojoules per kilogram of fat-free mass), athletes can record their diets and use diet analysis software to calculate energy intake, measure energy expenditure during exercise using a heart monitor and measure fat-free mass using a bioelectrical impedance body composition scale. All are commercially available at consumer prices.

American College of Sports Medicine position stand. The female athlete triad.

The female athlete triad (Triad) refers to the interrelationships among energy availability, menstrual function, and bone mineral density, which may have clinical manifestations including eating disorders, functional hypothalamic amenorrhea, and osteoporosis. With proper nutrition, these same relationships promote robust health. Athletes are distributed along a spectrum between health and disease, and those at the pathological end may not exhibit all these clinical conditions simultaneously. Energy availability is defined as dietary energy intake minus exercise energy expenditure. Low energy availability appears to be the factor that impairs reproductive and skeletal health in the Triad, and it may be inadvertent, intentional, or psychopathological. Most effects appear to occur below an energy availability of 30 kcal.kg(-1) of fat-free mass per day. Restrictive eating behaviors practiced by girls and women in sports or physical activities that emphasize leanness are of special concern. For prevention and early intervention, education of athletes, parents, coaches, trainers, judges, and administrators is a priority. Athletes should be assessed for the Triad at the preparticipation physical and/or annual health screening exam, and whenever an athlete presents with any of the Triad's clinical conditions. Sport administrators should also consider rule changes to discourage unhealthy weight loss practices. A multidisciplinary treatment team should include a physician or other health-care professional, a registered dietitian, and, for athletes with eating disorders, a mental health practitioner. Additional valuable team members may include a certified athletic trainer, an exercise physiologist, and the athlete's coach, parents and other family members. The first aim of treatment for any Triad component is to increase energy availability by increasing energy intake and/or reducing exercise energy expenditure. Nutrition counseling and monitoring are sufficient interventions for many athletes, but eating disorders warrant psychotherapy. Athletes with eating disorders should be required to meet established criteria to continue exercising, and their training and competition may need to be modified. No pharmacological agent adequately restores bone loss or corrects metabolic abnormalities that impair health and performance in athletes with functional hypothalamic amenorrhea.

The response of luteinizing hormone pulsatility to 5 days of low energy availability disappears by 14 years of gynecological age.

CONTEXT: The incidence of menstrual disorders declines during adolescence. The mechanism responsible is unknown. OBJECTIVE: The objective of the study was to test the hypothesis, formulated a priori, that the dependence of LH pulsatility and ovarian function on energy availability declines with gynecological age (years since menarche). DESIGN: The study was a controlled experiment repeated in two menstrual cycles, performed 2001-2004. SETTING: The study was conducted at a university laboratory and general clinical research center. PARTICIPANTS: The study population consisted of healthy, habitually sedentary, young women of normal body composition with 5-8 yr (adolescents, n = 9) and 14-18 yr (adults, n = 10) of gynecological age recruited by advertisement from approximately 9000 women aged 18-34 yr in a college community. Samples were similar in age of menarche, length of menstrual cycle and luteal phase, body size and composition, aerobic capacity, and dietary intake. None were withdrawn due to adverse effects. INTERVENTIONS: Interventions included energy availabilities of 45 and 10 kcal/kg of fat-free mass per day for 5 d in the early follicular phases of separate menstrual cycles in random order. MAIN OUTCOME MEASURES: LH pulsatility, estradiol, and luteal phase length were measured. RESULTS: Low energy availability reduced LH pulse frequency in adolescents (P < 0.01) but not adults (P = 0.39), did not increase LH pulse amplitude in either group (both P = 0.13), and suppressed 24-h mean LH in adolescents (P = 0.01) but not adults (P = 0.72). Estradiol was unaffected (both P = 0.48), but the subsequent luteal phase was shorter in adolescents (P < 0.01). CONCLUSIONS: In women of normal body composition, the response of LH pulsatility and ovarian function to 5 d of low energy availability disappears by 14 yr of gynecological age.

Menstrual disorders in athletes.

The various menstrual disorders in athletes may reflect different degrees of exposure to a disrupting factor or differences in the susceptibility of various women to disruption. The incidences of these disorders are not well documented, but they appear to be highest in aesthetic, endurance and weight-class sports, and at younger ages, higher training volumes and lower bodyweights. The morbid effects of these disorders include infertility, low bone mass, impaired endothelium-dependent vasodilation, and impaired skeletal muscle oxidative metabolism. The high incidences of menstrual disorders in athletes may derive in part from the self-selection of extraneously affected women into athletics, but many women acquire their menstrual disorders in athletics by failing to adequately increase dietary energy intake in compensation for exercise energy expenditure. Applied research is needed to develop effective dietary interventions that are acceptable to athletes.

The effect of stress on menstrual function.

Historically difficult to define, stress is, in one sense, the factor that stressors have in common in their impact on the body. Menstrual function is disrupted by stressors that activate the hypothalamic-pituitary-adrenal (HPA) axis; this activation is part of a catabolic response of the whole body that mobilizes metabolic fuels to meet energy demand. Functional menstrual disorders are associated with an increase in cortisol and with a broad spectrum of other symptoms of energy deficiency. Recent experiments suggest that exercise and other stressors have no disruptive effect on reproductive function beyond the impact of their energy cost on energy availability. These studies suggest that treatments for functional menstrual disorders should aim at dietary reform and that stress is simply low energy availability. Future experiments should carefully test this hypothesis.

The effects of testosterone and insulin-like growth factor 1 on motor system form and function.

In this perspective article, we review the effects of selected anabolic hormones on the motoric system and speculate on the role these hormones may have on influencing muscle and physical function via their impact on the nervous system. Both muscle strength and anabolic hormone levels decline around middle age into old age over a similar time period, and several animal and human studies indicate that exogenously increasing anabolic hormones (e.g., testosterone and insulin-like growth factor-1 (IGF-1)) in aged subjects is positively associated with improved muscle strength. While most studies in humans have focused on the effects of anabolic hormones on muscle growth, few have considered the impact these hormones have on the motoric system. However, data from animals demonstrate that administering either testosterone or IGF-1 to cells of the central and peripheral motor system can increase cell excitability, attenuate atrophic changes, and improve regenerative capacity of motor neurons. While these studies do not directly indicate that changes in anabolic hormones contribute to reduced human performance in the elderly (e.g., muscle weakness and physical limitations), they do suggest that additional research is warranted along these lines.

Dose-response relationships between energy availability and bone turnover in young exercising women.

UNLABELLED: To help refine nutritional guidelines for military servicewomen, we assessed bone turnover after manipulating the energy availability of 29 young women. Bone formation was impaired by less severe restrictions than that which increased bone resorption. Military servicewomen and others may need to improve their nutrition to avoid these effects. INTRODUCTION: We determined the dose-response relationship between energy availability (defined as dietary energy intake minus exercise energy expenditure) and selected markers of bone turnover in 29 regularly menstruating, habitually sedentary, young women of normal body composition. MATERIALS AND METHODS: For 5 days in the early follicular phase of two menstrual cycles separated by at least 2 months, subjects expended 15 kcal/kgLBM/day in supervised exercise at 70% of aerobic capacity and consumed controlled amounts of a clinical dietary product in balanced (45 kcal/kgLBM/day) and one of three restricted (either 10, 20, or 30 kcal/kgLBM/day) energy availability treatments in random order. Blood was sampled at 10-minute intervals, and urine was collected for 24 h. Samples were assayed for plasma osteocalcin (OC), serum type I procollagen carboxy-terminal propeptide (PICP), and urinary N-telopeptide (NTX). RESULTS: NTX concentrations (p < 0.01) and indices of bone resorption/formation uncoupling (Z(NTX-OC) and Z(NTX-PICP); both p < 10(-4)) were increased by the 10 kcal/kgLBM/day treatment. OC and PICP concentrations were suppressed by all restricted energy availability treatments (all p < 0.05). PICP declined linearly (p < 10(-6)) with energy availability, whereas most of the suppression of OC occurred abruptly between 20 and 30 kcal/kgLBM/day (p < 0.05). CONCLUSIONS: These dose-response relationships closely resembled those of particular reproductive and metabolic hormones found in the same experiment and reported previously: similar relationships were observed for NTX and estradiol; for PICP and insulin; and for OC, triiodothyronine (T3), and insulin-like growth factor (IGF)-I. The uncoupling of bone resorption and formation by severely restricted energy availability, if left to continue, may lead to irreversible reductions in BMD, and the suppression of bone formation by less severe restrictions may prevent young women from achieving their genetic potential for peak bone mass. More prolonged experiments are needed to determine the dose-response relationships between chronic restrictions of energy availability and bone turnover.

Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women.

To investigate the dependence of LH pulsatility on energy availability (dietary energy intake minus exercise energy expenditure), we measured LH pulsatility after manipulating the energy availability of 29 regularly menstruating, habitually sedentary, young women of normal body composition for 5 d in the early follicular phase. Subjects expended 15 kcal/kg of lean body mass (LBM) per day in supervised exercise at 70% of aerobic capacity while consuming a clinical dietary product to set energy availability at 45 and either 10, 20, or 30 kcal/kg LBM.d in two randomized trials separated by at least 2 months. Blood was sampled daily during treatments and at 10-min intervals for the next 24 h. Samples were assayed for LH, FSH, estradiol (E2), glucose, beta-hydroxybutyrate, insulin, cortisol, GH, IGF-I, IGF-I binding protein (IGFBP)-1, IGFBP-3, leptin, and T3. LH pulsatility was unaffected by an energy availability of 30 kcal/kg LBM.d (P > 0.3), but below this threshold LH pulse frequency decreased, whereas LH pulse amplitude increased (all P < 0.04). This disruption was more extreme in women with short luteal phases (P < 0.01). These incremental effects most closely resembled the effects of energy availability on plasma glucose, beta-hydroxybutyrate, GH, and cortisol and contrasted with the dependencies displayed by the other metabolic hormones (simultaneously P < 0.05). These results demonstrate that LH pulsatility is disrupted only below a threshold of energy availability deep into negative energy balance and suggest priorities for future investigations into the mechanism that mediates the nonlinear dependence of LH pulsatility on energy availability.

Introduction to menstrual disturbances in athletes.

The first symposium on this topic at an annual meeting of ACSM was presented 22 yr ago when the high prevalence of menstrual disorders in athletes was becoming increasingly apparent. The clinical consequences and need for treatment for menstrual disturbances in athletes have been recognized by ACSM through the publication of its 1997 Position Stand on the Female Athlete Triad. This mini-symposium presents an update on recent scientific advances on this topic. The first review in this symposium concentrates on a menstrual disturbance in which the length of the luteal phase is abbreviated and luteal function is suppressed. Such luteal suppression occurs in a large proportion of even the most regularly menstruating athletes. The next two papers summarize what has been learned about the mechanism of these disturbances from prospective experiments that have employed diet, exercise, cold exposure, and pharmacological blockers of metabolic pathways to disrupt menstrual cycles in monkeys and humans as well as estrous cycles and reproductive behavior in hamsters.

Accuracy and reproducibility of bending stiffness measurements by mechanical response tissue analysis in artificial human ulnas.

Osteoporosis is characterized by reduced bone strength, but no FDA-approved medical device measures bone strength. Bone strength is strongly associated with bone stiffness, but no FDA-approved medical device measures bone stiffness either. Mechanical Response Tissue Analysis (MRTA) is a non-significant risk, non-invasive, radiation-free, vibration analysis technique for making immediate, direct functional measurements of the bending stiffness of long bones in humans in vivo. MRTA has been used for research purposes for more than 20 years, but little has been published about its accuracy. To begin to investigate its accuracy, we compared MRTA measurements of bending stiffness in 39 artificial human ulna bones to measurements made by Quasistatic Mechanical Testing (QMT). In the process, we also quantified the reproducibility (i.e., precision and repeatability) of both methods. MRTA precision (1.0±1.0%) and repeatability (3.1 ± 3.1%) were not as high as those of QMT (0.2 ± 0.2% and 1.3+1.7%, respectively; both p<10(-4)). The relationship between MRTA and QMT measurements of ulna bending stiffness was indistinguishable from the identity line (p=0.44) and paired measurements by the two methods agreed within a 95% confidence interval of ± 5%. If such accuracy can be achieved on real human ulnas in situ, and if the ulna is representative of the appendicular skeleton, MRTA may prove clinically useful.