Robyn K. Fuchs

Impact Exercise Increases BMC During Growth: An 8‐Year Longitudinal Study

Our aim was to assess BMC of the hip over 8 yr in prepubertal children who participated in a 7‐mo jumping intervention compared with controls who participated in a stretching program of equal duration. We hypothesized that jumpers would gain more BMC than control subjects. The data reported come from two cohorts of children who participated in separate, but identical, randomized, controlled, school‐based impact exercise interventions and reflect those subjects who agreed to long‐term follow‐up (N = 57; jumpers = 33, controls = 24; 47% of the original participants). BMC was assessed by DXA at baseline, 7 and 19 mo after intervention, and annually thereafter for 5 yr (eight visits over 8 yr). Multilevel random effects models were constructed and used to predict change in BMC from baseline at each measurement occasion. After 7 mo, those children that completed high‐impact jumping exercises had 3.6% more BMC at the hip than control subjects whom completed nonimpact stretching activities (p < 0.05) and 1.4% more BMC at the hip after nearly 8 yr (BMC adjusted for change in age, height, weight, and physical activity; p < 0.05). This provides the first evidence of a sustained effect on total hip BMC from short‐term high‐impact exercise undertaken in early childhood. If the benefits are sustained into young adulthood, effectively increasing peak bone mass, fracture risk in the later years could be reduced.

Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency

Objective:Selective serotonin reuptake inhibitors (SSRIs) treat depression by antagonizing the serotonin (5-hydroxytryptamine) transporter (5-HTT). These drugs may also have skeletal effects given the presence of functional serotonergic pathways in bone and evidence demonstrating detrimental effects of SSRIs on postmenopausal bone changes. This study aimed to explore the influence of an SSRI (fluoxetine hydrochloride) on the bone changes associated with estrogen deficiency in adult mice. Design:Adult, female, Swiss-Webster mice underwent ovariectomy (OVX) or sham OVX and were treated daily for 4 weeks with either fluoxetine hydrochloride (5 or 20 mg/kg) or a vehicle solution (control). In vivo assessments of hindlimb areal and tibial volumetric bone mineral density were performed at baseline and after 4 weeks of intervention. Femurs and lumbar vertebrae were subsequently removed and assessed ex vivo for bone mineral density and trabecular bone architecture and turnover. Results:In vivo and ex vivo skeletal measures found no interactions between OVX (estrogen deficiency) and 5-HTT inhibition, indicating that the skeletal effects of these interventions were independent. 5-HTT inhibition had detrimental skeletal effects, with the fluoxetine-treated groups having reduced bone mineral density and altered trabecular architecture. These changes resulted from both a decrease in bone formation and increase in bone resorption. Conclusions:These data indicate that a commonly prescribed SSRI has a negative influence on the adult skeleton, independent of estrogen deficiency. This finding supports clinical data demonstrating SSRI use to be associated with accelerated bone loss after menopause and highlights a need for further research into the skeletal effects of SSRIs.

Recovery of Trabecular and Cortical Bone Turnover After Discontinuation of Risedronate and Alendronate Therapy in Ovariectomized Rats

Alendronate (ALN) and risedronate (RIS) are bisphosphonates effective in reducing bone loss and fractures associated with postmenopausal osteoporosis. However, it is uncertain how long it takes bone turnover to be re‐established after treatment withdrawal, and whether this differs between the two drugs. The objective of this study was to determine the time required to re‐establish normal bone turnover after the discontinuation of ALN and RIS treatment in an animal model of estrogen‐deficiency osteoporosis. Two hundred ten, 6‐mo‐old female Sprague‐Dawley rats were ovariectomized and 6 wk later were randomized into baseline controls (n = 10) and four treatment groups (n = 50/group): vehicle‐treated controls (CON; 0.3 ml sterile water), ALN (2.4 μg/kg), low‐dose RIS (RIS low; 1.2 μg/kg), and high‐dose RIS (RIS high; 2.4 μg/kg). Treatments were administered 3 times/wk by subcutaneous injection. Baseline controls were killed at the initiation of treatment. Other groups were treated for 8 wk, and subgroups (n = 10/ treatment group) were killed 0, 4, 8, 12, and 16 wk after treatment was withdrawn. Static and dynamic histological analyses were performed for cortical (tibial diaphysis) and trabecular (proximal tibia and L4 vertebrae) bone. DXA and mechanical testing was performed on the L5 vertebra. After 8 wk of treatment, trabecular bone turnover rates were significantly suppressed in all drug‐treated animals. Trabecular bone formation rate (BFR/BS) remained significantly lower than vehicle in bisphosphonate‐treated animals through 12 wk. Sixteen weeks after treatment withdrawal, trabecular BFR/BS in the proximal tibia was re‐established in animals treated with RIS but not in animals treated with ALN compared with controls. BMD of the fifth lumbar vertebra remained significantly higher than controls 16 wk after treatment withdrawal in ALN‐treated animals but not in RIS‐treated animals. Despite reductions in BMD and increases in bone turnover, ultimate force of the fifth lumbar vertebra remained significantly higher in all drug‐treated animals through 16 wk after withdrawal.

Cortical and trabecular bone adaptation to incremental load magnitudes using the mouse tibial axial compression loading model

The mouse tibial axial compression loading model has recently been described to allow simultaneous exploration of cortical and trabecular bone adaptation within the same loaded element. However, the model frequently induces cortical woven bone formation and has produced inconsistent results with regards to trabecular bone adaptation. The aim of this study was to investigate bone adaptation to incremental load magnitudes using the mouse tibial axial compression loading model, with the ultimate goal of revealing a load that simultaneously induced lamellar cortical and trabecular bone adaptation. Adult (16 weeks old) female C57BL/6 mice were randomly divided into three load magnitude groups (5, 7 and 9N), and had their right tibia axially loaded using a continuous 2-Hz haversine waveform for 360 cycles/day, 3 days/week for 4 consecutive weeks. In vivo peripheral quantitative computed tomography was used to longitudinally assess midshaft tibia cortical bone adaptation, while ex vivo micro-computed tomography and histomorphometry were used to assess both midshaft tibia cortical and proximal tibia trabecular bone adaptation. A dose response to loading magnitude was observed within cortical bone, with increasing load magnitude inducing increasing levels of lamellar cortical bone adaptation within the upper two thirds of the tibial diaphysis. Greatest cortical bone adaptation was observed at the midshaft where there was a 42% increase in estimated mechanical properties (polar moment of inertia) in the highest (9N) load group. A dose response to load magnitude was not clearly evident within trabecular bone, with only the highest load (9N) being able to induce measureable adaptation (31% increase in trabecular bone volume fraction at the proximal tibia). The ultimate finding was that a load of 9N (engendering a tensile strain of 1833 με on medial surface of the midshaft tibia) was able to simultaneously induce measurable lamellar cortical and trabecular bone adaptation when using the mouse tibial axial compression loading model in 16 week old female C57BL/6 mice. This finding will help plan future studies aimed at exploring simultaneous lamellar cortical and trabecular bone adaptation within the same loaded element.

Psychotropic drugs have contrasting skeletal effects that are independent of their effects on physical activity levels.

Popular psychotropic drugs, like the antidepressant selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), and the mood stabilizer lithium, may have skeletal effects. In particular, preclinical observations suggest a direct negative effect of SSRIs on the skeleton. A potential caveat in studies of the skeletal effects of psychotropic drugs is the hypoactive (skeletal unloading) phenotype they induce. The aim of this study was to investigate the contribution of physical inactivity to the skeletal effects of psychotropic drugs by studying bone changes in cage control and tail suspended mice treated with either vehicle, SSRI, TCA or lithium. Tail suspension was used to control for drug differences on physical activity levels by normalizing skeletal loading between groups. The psychotropic drugs were found to have contrasting skeletal effects which were independent of drug effects on animal physical activity levels. The latter was evident by an absence of statistical interactions between the activity and drug groups. Pharmacological inhibition of the 5-hydroxytryptamine (5-HT) transporter (5-HTT) using a SSRI reduced in vivo gains in lower extremity BMD, and negatively altered ex vivo measures of femoral and spinal bone density, architecture and mechanical properties. These effects were mediated by a decrease in bone formation without a change in bone resorption suggesting that the SSRI had anti-anabolic skeletal effects. In contrast, glycogen synthase kinase-3[beta] (GSK-3[beta]) inhibition using lithium had anabolic effects improving in vivo gains in BMD via an increase in bone formation, while TCA-mediated inhibition of the norepinephrine transporter had minimal skeletal effect. The observed negative skeletal effect of 5-HTT inhibition, combined with recent findings of direct and indirect effects of 5-HT on bone formation, are of interest given the frequent prescription of SSRIs for the treatment of depression and other affective disorders. Likewise, the anabolic effect of GSK-3[beta] inhibition using lithium reconfirms the importance of Wnt/beta-catenin signaling in the skeleton and its targeting by recent drug discovery efforts. In conclusion, the current study demonstrates that different psychotropic drugs with differing underlying mechanisms of action have contrasting skeletal effects and that these effects do not result indirectly via the generation of animal physical inactivity.

Bisphosphonates do not alter the rate of secondary mineralization.

Bisphosphonates function to reduce bone turnover, which consequently increases the mean degree of tissue mineralization at an organ level. However, it is not clear if bisphosphonates alter the length of time required for an individual bone-modeling unit (BMU) to fully mineralize. We have recently demonstrated that it takes ~350 days (d) for normal, untreated cortical bone to fully mineralize. The aim of this study was to determine the rate at which newly formed trabecular BMUs become fully mineralized in rabbits treated for up to 414 d with clinical doses of either risedronate (RIS) or alendronate (ALN). Thirty-six, 4-month old virgin female New Zealand white rabbits were allocated to RIS (n=12; 2.4 μg/kg body weight), ALN (n=12; 2.4 μg/kg body weight), or volume-matched saline controls (CON; n=12). Fluorochrome labels were administered at specific time intervals to quantify the rate and level of mineralization of trabecular bone from the femoral neck (FN) by Fourier transform infrared microspectroscopy (FTIRM). The organic (collagen) and inorganic (phosphate and carbonate) IR spectral characteristics of trabecular bone from undecalcified 4 micron thick tissue sections were quantified from fluorescently labels regions that had mineralized for 1, 8, 18, 35, 70, 105, 140, 210, 280, and 385 d (4 rabbits per time point and treatment group). All groups exhibited a rapid increase in mineralization over the first 18 days, the period of primary mineralization, with no significant differences between treatments. Mineralization continued to increase, at a slower rate up, to 385 days (secondary mineralization), and was not different among treatments. There were no significant differences between treatments for the rate of mineralization within an individual BMU; however, ALN and RIS both increased global tissue mineralization as demonstrated by areal bone mineral density from DXA. We conclude that increases in tissue mineralization that occur following a period of bisphosphonate treatment is a function of the suppressed rate of remodeling that allows for a greater number of BMUs to obtain a greater degree of mineralization.

Research Summit III Proceedings on Dosing in Children With an Injured Brain or Cerebral Palsy: Executive Summary

Children with brain injuries or cerebral palsy (CP) comprise a large percentage of pediatric clients served by physical therapists. There is no consensus on what the basic parameters should be for different treatment protocols. A very important parameter of intervention that is pivotal for treatment efficacy is dosing. Dosing decisions are complex. To date, the minimum doses for changing structure and function, activity, and participation in children with various disabilities are unknown. This article describes the process and outcomes of a research summit with the goals of: (1) fostering a critical debate that would result in recommendations for the development of large-scale, second-generation research proposals to address thresholds for effective dosing of interventions for children with brain injuries or CP and (2) enhancing the research capacity of pediatric physical therapists through collaborative research networks. The summit brought together an interdisciplinary cadre of researchers (physical therapists, basic and clinical scientists), representatives from funding agencies, and consumers to an intensive 2.5-day think tank. The summit targeted questions of treatment dosage related to 3 areas: practice and neuroplasticity, structure-behavior connections, and clinical trial design. The consensus was that the intervention must demonstrate some evidence of effectiveness before optimal dosing can be investigated. Constraint-induced movement therapy (CIMT) is used as an example of an intervention that has demonstrated effectiveness and that requires dosing-related research. Summit results, including factors that merit special consideration and recommendations for future dose-related studies, are highlighted. Physical therapy is an important service for children with physical disabilities, particularly those with an injured brain resulting in neuromotor impairments and functional limitations.1 These children typically have multiple health complications that often result in complex functional limitations and require extensive health care, education, and vocational training. The costs of interventions result in substantial financial and social challenges for families and society.2 …

Exercise and bone health: optimising bone structure during growth is key, but all is not in vain during ageing

The reduction in bone strength and resultant increase in low-trauma fractures associated with ageing represents a prominent and growing societal problem. Although numerous pharmacological agents have been developed to prevent and treat reductions in bone strength as a means to reduce fractures, a commonly advocated intervention is the prescription of load-bearing exercise.1 The skeleton is mechanosensitive across the lifespan and responds and adapts to its prevailing mechanical environment. This concept is supported by two independent, yet related, articles in this issue of the BJSM .2 3 These papers highlight the potential role of exercise on bone health at two differing stages of the lifespan. Kato et al 2 performed a cross-sectional study to show that exercise when young may have lasting effects on bone health during ageing, whereas Martyn-St James and Carroll3 performed a systematic review and meta-analysis to demonstrate that exercise can have beneficial effects on the postmenopausal skeleton. A dichotomy exists between when the skeleton is most responsive to exercise and when it is prone to osteoporotic fracture. Reduced bone strength is predominantly an age-related phenomenon,4 whereas the ability of the skeleton to respond to mechanical loading is greatest during childhood and decreases with age.5 In fact, the skeletal benefit of a lifetime of exercise seems to occur mainly during the years of skeletal development.6 7 This disparate response of the skeleton to mechanical loading with ageing and the reduction in bone strength with age has raised the question of whether exercise-induced bone changes during growth persist into adulthood where they would be most advantageous in reducing fracture risk. Kato et al 2 address this issue in their study of postmenopausal bone health in former adolescent athletes and controls. Weight-bearing exercise when young was found to have persistent effects on bone mass …

Reduced gravitational loading does not account for the skeletal effect of botulinum toxin-induced muscle inhibition suggesting a direct effect of muscle on bone

Intramuscular injection of botulinum toxin (botox) into rodent hindlimbs has developed as a useful model for exploring muscle-bone interactions. Botox-induced muscle inhibition rapidly induces muscle atrophy and subsequent bone loss, with the latter hypothesized to result from reduced muscular loading of the skeleton. However, botox-induced muscle inhibition also reduces gravitational loading (as evident by reduced ground reaction forces during gait) which may account for its negative skeletal effects. The aim of this study was to investigate the skeletal effect of botox-induced muscle inhibition in cage control and tail suspended mice, with tail suspension being used to control for the reduced gravitational loading associated with botox. Female C57BL/6J mice were injected unilaterally with botox and contralaterally with vehicle, and subsequently exposed to tail suspension or normal cage activities for 6 weeks. Botox-induced muscle inhibition combined with tail suspension had the largest detrimental effect on the skeleton, causing the least gains in midshaft tibial bone mass, cortical area and cortical thickness, greatest gains in midshaft tibial medullary area, and lowest proximal tibial trabecular bone volume fraction. These data indicate botox-induced muscle inhibition has skeletal effects over and above any effect it has in altering gravitational loading, suggesting that muscle has a direct effect on bone. This effect may be relevant in the development of strategies targeting musculoskeletal health.

Specialized Connective Tissue: Bone, the Structural Framework of the Upper Extremity

Bone is a connective tissue containing cells, fibers, and ground substance. There are many functions in the body in which the bone participates, such as storing minerals, providing internal support, protecting vital organs, enabling movement, and providing attachment sites for muscles and tendons. Bone is unique because its collagen framework absorbs energy, whereas the mineral encased within the matrix allows bone to resist deformation. This article provides an overview of the structure and function of bone tissue from a macroscopic to microscopic level and discusses the physiological processes contributing to upper extremity bone health. It concludes by discussing common conditions influencing upper extremity bone health.