Bone remodeling is regulated by the two branches of the autonomic nervous system: the adrenergic and the cholinergic branches. Adrenergic activity favors bone loss, whereas cholinergic activity has been recently shown to favor bone mass accrual. In vitro studies have reported that cholinergic activity induces proliferation and differentiation of bone cells. In vivo studies have shown that the inhibition of cholinergic activity favors bone loss, whereas its stimulation favors bone mass accrual. Clinical studies have shown that bone density is associated with the function of many cholinergic-regulated tissues such as the hypothalamus, salivary glands, lacrimal glands and langerhans cells, suggesting a common mechanism of control. Altogether, these observations and linked findings are of great significance since they improve our understanding of bone physiology. These discoveries have been successfully used recently to investigate new promising therapies for bone diseases based on cholinergic stimulation. Here, we review the current understanding of the cholinergic activity and its association with bone health.

It is well established that physical exercise modulates the function of many physiological systems, such as the musculoskeletal, the cardiovascular and the nervous system, by inducing various adaptations to the increased mechanical load and/or metabolic stress of exercise. Many of these changes occur through epigenetic alterations to DNA, such as histone modifications, DNA methylations, expression of microRNAs and changes of the chromatin structure. All these epigenetic alterations may have clinical relevance, thus playing an important role in the prevention and confrontation of neurophysiological disorders, metabolic syndrome, cardiovascular diseases and cancer. Herein we review the known epigenetic modifications induced by physical exercise in various physiological systems and pathologies, and discuss their potential clinical implications.

Objectives: A training intervention comparing resistance exercise with or without whole-body vibration (WBV) was conducted to compare acute and chronic effects on functional and molecular parameters. Methods: A six-week training intervention was performed including 26 healthy males (26 years, SD=4). Two groups were analyzed in a parallel design performing either resistive exercise (RE, n=13) or resistive vibration exercise (RVE, n=13) training with weekly increasing vibration frequencies (20–40Hz). Resting and exercising blood pressure and heart rate were measured before and after the 6-week intervention. Results: Both training interventions decreased resting systolic blood pressure (P=0.003). Resting diastolic blood pressure was significantly decreased only in the RVE group (P<0.01). Exercising diastolic blood pressure was significantly decreased during the final training session only in the RVE group (P<0.001) with no additional effect of superimposed vibrations. Resistance exercise with superimposed vibrations evoked back pain to a higher degree than resistance exercise alone when training at frequencies above 30Hz (P<0.01). Conclusions: These data suggest positive effects of resistance exercise upon cardiovascular health and vascular responsiveness and a further beneficial effect of superimposed vibrations in decreasing resting diastolic blood pressure. Finally, development of back pain may be fostered by superimposed vibrations to high training loads, particularly at higher frequencies.

Objectives: Preterm infants are born with low bone mineral. Neonatal stress further impedes bone mineralization. Clinical evidence suggests that tactile and kinesthetic stimulation (TKS) improves bone phenotype and decreases stress response. Clinical and translational studies indicate the IGF-1 axis, responsible for postnatal growth and bone mineralization, is a key player. We hypothesized that TKS would attenuate the negative impact of neonatal stress on bone phenotype and the IGF-1 axis in weanling rats. Methods: Neonatal stress (STRESS) or TKS (STRESS + 10min TKS) was administered from D6 to D10. Control animals received standard care. Tissue was harvested on D21. Dual energy x-ray absorptiometry (DXA) and bone morphometry were performed and serum osteocalcin, type I procollagen N-terminal propeptide (PINP), tartrate-resistant acid phosphatase (TRAP), and bone and liver mRNA levels of IGF-1, IGF-1 receptor (IGF-1R), and growth hormone receptor (GHR) were measured. Results: Neonatal stress increased bone mineral content (BMC), area (BA), growth plate width, liver IGF-1 mRNA, and serum IGF-1. TKS maintained areal bone mineral density (aBMD) and bone specific IGF-1 and IGF-1R mRNA while STRESS decreased compared to controls. Conclusions: Neonatal stress results in apparent accelerated growth response. TKS differed from STRESS with improved tibia aBMD and increased bone specific IGF-1 mRNA.

Human performance in microgravity is characterized by reversed skeletal muscle actions in terms of active vs. passive mode contractions of agonist/antagonist groups that may challenge principal biodynamics (biomechanical forces translated from muscle to bone) of the skeletal muscle-bone unit. We investigated active vs. passive muscle motions of the unloaded hindlimb skeletal muscle-bone unit in the 21 days tail-suspended (TS) rat using a newly designed stepper exercise device. The regimen included both active mode motions (TSA) and passive mode motions (TSP). A TS-only group and a normal cage group (CON) served as positive or negative controls. The muscle and bone decrements observed in TS-only group were not seen in the other groups except TSP. Active mode motions supported femur and tibia bone quality (5% BMD, 10% microtrabecular BV/TV, Tb.Th., Tb.N. parameters), whole soleus muscle/myofiber size per II distribution, 20% increased sarcolemma NOS1 immunosignals vs. CON, with 25% more hybrid fiber formation (remodeling sign) for all TS groups. We propose a new custom-made stepper device to be used in the TS rat model that allows for detailed insights of the unique biodynamic properties of the muscle-bone unit during resistive-load exercise countermeasure training in the ground or in microgravity.

Objectives: Treatment with Sclerostin antibody (Scl-Ab) has shown to enhance fracture healing in rodent and non-human primate models. The current study investigated the time-dependent changes during Scl-Ab treatment in a mouse osteotomy model. Methods: 1 day after osteotomy, C57BL mice received subcutaneous injection with vehicle or Scl-Ab at 25 mg/kg, twice/week for 2, 4, or 6 weeks. 20 mice from each group were necropsied at weeks 2, 4, and 6 for Micro-CT, histomorphometry and mechanical testing examinations. Results: The bone mineral apposition rate at fracture callus was significantly higher in the Scl-Ab treated groups at all the time points. Micro-CT analysis showed that the volumetric bone mineral density (vBMD) and bone volume over tissue volume (BV/TV) in the Scl-Ab treated groups at 4 and 6 weeks were significantly greater than that of vehicle control groups. Mechanical testing showed that the maximum load of failure at the fracture callus increased significantly by 68% at 6 weeks in the Scl-Ab treated groups. Conclusions: This study confirmed that mice treated with Scl-Ab increased bone formation from 2 weeks, bone density and bone volume at 4 weeks, followed by significant increase in bone strength at the fracture site at 6 weeks. These results suggest that applying sclerostin antibody at early stage fracture healing promotes fracture healing.

Some pharmacologic effects on bone modeling may not be evident in studies of remodeling skeletons. This study analyzes some effects of olpadronate on cortical bone modeling and post-yield properties in femurs diaphyses (virtually only-modeling bones) of young rats by mid-diaphyseal pQCT scans and bending tests. We studied 20/22 male/female animals treated orally with olpadronate (45-90 mg/kg/d, 3 months) and 8/9 untreated controls. Both OPD doses enhanced diaphyseal cross-sectional moments of inertia (CSMI) with no change in cortical vBMD and elastic modulus. Yield stiffness and strength were mildly increased. Post-yield strength, deflection and energy absorption were strikingly enhanced. Ultimate strength was enhanced mainly because of effects on bone mass/geometry and post-yield properties. The large improvement of post-yield properties could be explained by improvements in bone geometry. Improvements in bone mass/geometry over weight-bearing needs suggest an enhanced modeling-related response to mechanical stimuli. Effects on tissue microstructural factors (not measured) could not be excluded. Results reveal novel olpadronate effects on bone strength and toughness unrelated to tissue mineralization and stiffness, even at high doses. Further studies could establish whether this could also occur in modeling-remodeling skeletons. If so, they could counteract the negative impact of anti-remodeling effects of bisphosphonates on bone strength.

In a pQCT study of running-trained and untrained men and women we had shown that bone mass distribution along the tibia was adapted to the usage-derived stress pattern. To study the possible association between the efficiency of diaphyseal design and bone material stiffness, we extend the analysis of the same sample to correlate pQCT indicators of the distribution (CSMIs), mass (BMC), and density (vBMD) of cortical bone tissue as descriptors of “distribution/mass” (d/m) or “distribution/quality” (d/q) relationships. The d/m and d/c curves followed positive (exponential) and negative (hyperbolic-like) equations, respectively. Distribution curves of r coefficients throughout the bone were all bell-shaped, reaching a maximum towards the mid-diaphysis. The CSMIs and BMC were higher, and vBMD was lower in men than women and in runners than non-runners. The d/m relationships were described by unique curves for all groups while d/q relationships were better adjusted to separate curves for men and women. Results support that: 1. diaphyseal design reflects the relative influence of bending/torsion stress along the bones, tending to minimize bone mass; 2. there is a trade-off between cortical bone “quality” and distribution; 3. d/m and d/q relationships are related to bone mechanical environment, and 4. d/q relationships are affected by sex.

Objective: The aim of this study was to compare geometric indices of hip bone strength in female football players and controls. Methods: 18 adult female football players and 18 adult sedentary females participated in this study. The two groups were paired for age, weight and body mass index (BMI). Daily calcium intake (DCI) and daily protein intake (DPI) were evaluated by questionnaires. Total hip bone mineral density (BMD) and femoral neck BMD were measured by DXA. Cross-sectional area (CSA), an index of axial compression strength, section modulus (Z), an index of bending strength and cortical thickness (CT) were evaluated at the femoral neck (FN), the intertrochanteric (IT) and the femoral shaft (FS) regions by the hip structure analysis (HSA) program. Results: Age, weight, height, BMI, DCI and DPI were not different between the two groups. FN BMD, FN CSA, FN Z, FN CT, IT CSA, IT Z, IT CT, FS CSA and FS Z were significantly higher in football players compared to controls (crude percentage differences between the two groups varied between 8 and 19%; P<0.05). After adjusting for body weight using a one-way analysis of covariance (ANCOVA), TH BMD, FN BMD, FN CSA, FN Z, FN CT, IT CSA, IT Z, IT CT, FS CSA and FS Z remained significantly higher in football players compared to controls (adjusted percentage differences between the two groups varied between 7 and 17%; P<0.05). Conclusion: This study suggests that, in adult females, football practice is associated with greater geometric indices of hip bone strength.

Objective: We sought to procure age- and gender- related reference data and study the characteristics of body weight related peak force (pF_rel), body mass related peak power (pPrel) for counter movement jumps (single two-legged jumps, s2LJ) and chair rising tests (CRT) in children. Methods: We examined 868 healthy participants (436 female) aged 3 to 19 years. Weight-related results of the s2LJ and CRT Mechanography parameters were reported. Results: pPrel during s2LJ (pPrel_s2LJ) increased linearly with age for males age 5 to 19 and female age 5 to 11 at a rate of 4.6 W/kg per year. pPrel_s2LJ for females age 12 to 19 increased only by 2.5 W/kg. CRT time per repetition was 1.065 s, independent of age and gender. pPrel per body mass during the rise phase (pPrel_CRT) showed similar but smaller age and gender relations as peak power during s2LJ. pF_rel was 2.5 g (multiples of earth’s gravity) for s2LJ and 1.5 g for CRT. Conclusion: This data from normal children from a healthy Caucasian population provide reference values for tests that reflect everyday motor function.

Objective: We sought to study and procure reference values for weight-related maximum isometric grip force (MIGF), maximum voluntary force in relation to body weight (Fmvrel) and peak whole body stiffness (pKwb) in multiple one-legged hopping (m1LH) in childhood. Methods: We examined 868 children and adolescents (436 female) aged 3 to 19 yrs. Weight-related results are reported as multiples of earth’s gravity (g). Results: MIFG and Fmvrel_m1LH are highly linearly correlated with body weight. After adjustment for weight, mean Fmvrel_m1LH increases from the age of 3 to 6 yrs, then remains at 3.33 g (SD 0.31 g) between 6 and 19 yrs, independent of age and gender. The difference between legs decreases from 10% at 3 yrs to a constant 5.5% after the age of 7 yrs. Weight-adjusted MIGF also increases steeply from 3 to 6 yrs, then shows a further linear, less steep increase—in males through to age 19 yrs while females show a near-standstill after the age of 12 yrs. pKwb_m1LH increases from the age of 7 yrs. Conclusion: This data from normal children from a healthy Caucasian population provide a reference for tests of motor function.

Davis and Cavanagh (1993) have proposed a solution to avoid the footstep targeting by using a large force plate but several points of Davis and Cavanagh’s method remain unclear and hardly computable. Objective: to develop a method that decomposes left and right GRF profiles from the GRF profile recorded on a single platform. This method aims to include a systematic detection of the single to double stand-phase-instants in order to lead to accurate measurement of the vertical GRF component in typically developing children. Methods: Six children were asked to walk without targeting their footsteps on a set-up composed of independent force platforms. The vertical GRF component, independently measured on the different platforms, was numerically summed to obtain the corresponding global vertical GRF, to which the decomposition method was applied. Then, the validation consisted in comparing the vertical GRF computed from this decomposition to the independently measured vertical GRF. Results: The mean relative error between the computed vertical GRF and the corresponding measured vertical GRF of 36 double stances (6 double stances × 6 children) is equal to 3.8±2.6 %. Conclusion: implemented a new method to assess with known accuracy the vertical GRF component under each foot using a unique large force platform.

Nowadays, bipedal walking is undergoing extensive study. Several methods can be used in physiotherapeutic research for identifying defects in bipedal walking as a result of pathology of the musculoskeletal or nervous system. Our work focuses on studying asymmetry of walking based on synchronized bilateral knee-knee cyclograms. Participants presenting with peroneal nerve palsy and foot drop were included in the study. The bilateral cyclograms, also called angle-angle diagrams, were created to quantify gait asymmetry before and immediately after application of a brace. In order to quantify the asymmetry of human walking, we have described and tested the application of the method based on the inclination angle of the synchronized bilateral cyclograms. The symmetry index (SI) was used as a comparative method to evaluate the symmetry of bipedal walking. The method based on the orientation of the cyclograms can be used as an additional method for determining the gait asymmetry. The new technique has never been applied before to study the gait asymmetry in patients with peroneal nerve palsy or patients with leg brace.

Long term bisphosphonate use has been associated with “atypical” subtrochanteric and diaphyseal fractures of the femoral shaft. We are reporting a case of pelvic fractures in addition to atypical long bone fractures, in a patient with osteopenia treated with bisphosphonate for 8 years, and teriparatide for 2 years. After 5 years of bisphosphonate therapy the patient suffered an atraumatic fracture of the femoral shaft. With an additional 3 years of bisphosphonate use she fractured both the upper and lower pubic rami on the left side. Bone histomorphometry performed on a biopsy of right iliac crest was negative for malignancy and calcification defects. It showed normal to low/normal bone turnover which correlated well with a low NTX level. Post-surgical X-rays revealed cortical thickening of the femur and beaking at the femoral shaft fracture, the classic findings associated with alendronate-related fractures. The pelvic fractures also reveal beaking at the fracture sites. Spontaneous fracture of the pelvis with unusual characteristics, in a patient with an atypical fracture of the femur suggests that the pelvic fracture may be related to long term bisphosphonate therapy.

In our article, “Pressure pain thresholds at the diabetic Charcot-foot: an exploratory study”, J Musculoskelet Neuronal Interact 2012;12(2):95-101. The foot-muscle studied was incorrectly termed musculus hallucis longus. The correct term is musculus abductor hallucis.

In our article, “Pressure pain perception at the injured foot: impact of diabetic neuropathy”, J Musculoskelet Neuronal Interact 2012;12(4):254-261. The foot-muscle studied was incorrectly termed musculus hallucis longus. The correct term is musculus abductor hallucis.