Continuous treatment with odanacatib for up to 8 years in postmenopausal women with low bone mineral density: a phase 2 study.

UNLABELLED: The efficacy and safety of weekly oral odanacatib (ODN) 50 mg for up to 8 years were assessed in postmenopausal women with low bone mineral density (BMD). Treatment with ODN for up to 8 years resulted in continued or maintained increases in BMD at multiple sites and was well tolerated. INTRODUCTION: ODN is a selective inhibitor of cathepsin K. In a 2-year phase 2b study (3/10/25/50 mg ODN once weekly [QW] or placebo) and extensions (50 mg ODN QW or placebo), ODN treatment for 5 years progressively increased BMD and decreased bone resorption markers in postmenopausal women with low BMD ( ClinicalTrials.gov NCT00112437). METHODS: In this prespecified interim analysis at year 8 of an additional 5-year extension (years 6 to 10), patients (n = 117) received open-label ODN 50 mg QW plus weekly vitamin D3 (5600 IU) and calcium supplementation as needed. Primary end points were lumbar spine BMD and safety. Patients were grouped by ODN exposure duration. RESULTS: Mean (95 % confidence interval [CI]) lumbar spine BMD changes from baseline were 4.6 % (2.4, 6.7; 3-year continuous ODN exposure), 12.9 % (8.1, 17.7; 5 years), 12.8 % (10.0, 15.7; 6 years), and 14.8 % (11.0, 18.6; 8 years). Similar patterns of results were observed for BMD of trochanter, femoral neck, and total hip versus baseline. Geometric mean changes from baseline to year 8 for bone resorption markers were approximately -50 % (uNTx/Cr) and -45 % (sCTx), respectively (all groups); bone formation markers remained near baseline levels. No osteonecrosis of the jaw, delayed fracture union, or morphea-like skin reactions were reported. CONCLUSIONS: Treatment with ODN for up to 8 years resulted in gains in BMD at multiple sites. Bone resorption markers remained reduced, with no significant change observed in bone formation markers. Treatment with ODN for up to 8 years was well tolerated.

Study description and baseline characteristics of the population enrolled in a multinational observational study of extended teriparatide use (ExFOS).

OBJECTIVE: To better characterize patients who are currently being prescribed teriparatide in Europe, this article describes the study design and baseline characteristics of participants of the Extended Forsteo * Observational Study (ExFOS). RESEARCH DESIGN AND METHODS: ExFOS is a noninterventional, multicenter, prospective, observational study in men and women with osteoporosis treated with teriparatide during the course of normal clinical practice for up to 24 months and with a post-treatment follow-up of at least 18 months. MAIN OUTCOME MEASURES: Baseline characteristics, including history of fracture and back pain, and health-related quality of life (HRQoL, assessed using the EuroQol-5 Dimension [EQ-5D]). RESULTS: Of 1607 patients enrolled, 90.9% were women. At baseline, mean (standard deviation [SD]) age was 70.3 (9.8) years, and 85.8% of patients had a history of fracture (64.7% with ≥2 fragility fractures). Of those with historic fractures, 90.8% had vertebral fractures (67.8% had thoracic fractures). The mean (SD) of reported bone mineral density T-scores were -3.0 (1.2), -2.4 (1.0), and -2.5 (0.9) for lumbar spine, total hip (left), and femoral neck (left), respectively. Overall, 39.3% of patients had experienced ≥1 fall during the 12 months before enrollment. At baseline, 11.4% of patients were osteoporosis-treatment naïve and 15% were currently using glucocorticoids. The mean (SD) visual analog scale score for back pain during the last month was 50.7 (26.9), and 62.1% of patients experienced daily or almost daily back pain. The median EQ-5D health state value at baseline was 0.62 (first and third quartiles: 0.19, 0.74). CONCLUSIONS: Baseline characteristics of the ExFOS study cohort indicate that patients prescribed teriparatide in Europe have severe osteoporosis with highly prevalent vertebral fractures, frequent and disabling back pain, and a poor HRQoL, despite previous pharmacotherapy for osteoporosis. Limitations include non-randomization, lack of a comparator group, and patient self-report for data on prior medication and fracture history.

Cost-effectiveness analysis of hip fracture prevention with vitamin D supplementation: a Markov micro-simulation model applied to the French population over 65 years old without previous hip fracture.

UNLABELLED: We performed a cost-effectiveness analysis of four vitamin D supplementation strategies for primary prevention of hip fracture among the elderly population and found that the most cost-effective strategy was screening for vitamin D insufficiency followed by adequate treatment to attain a minimum 25(OH) serum level. INTRODUCTION: Vitamin D supplementation has a demonstrated ability to reduce the incidence of hip fractures. The efficiency of lifetime supplementation has not yet been assessed in the population over 65 years without previous hip fracture. The objective was to analyze the efficiency of various vitamin D supplementation strategies for that population. METHODS: A Markov micro-simulation model was built with data extracted from published studies and from the French reimbursement schedule. Four vitamin D supplementation strategies were evaluated on our study population: (1) no treatment, (2) supplementation without any serum level check; (3) supplementation with a serum level check 3 months after initiation and subsequent treatment adaptation; (4) population screening for vitamin D insufficiency followed by treatment based on the vitamin D serum level. RESULTS: "Treat, then check" and "screen and treat" were two cost-effective strategies and dominated "treat without check" with incremental cost-effectiveness ratios of €5,219/quality-adjusted life-years (QALY) and €9,104/QALY, respectively. The acceptability curves showed that over €6,000/QALY, the "screen and treat" strategy had the greatest probability of being cost-effective, and the "no treatment" strategy would never be cost-effective if society were willing to spend over €8,000/QALY. The sensitivity analysis showed that among all parameters varying within realistic ranges, the cost of vitamin D treatment had the greatest effect and yet remained below the WHO cost-effectiveness thresholds. CONCLUSIONS: Population screening for vitamin D insufficiency followed by treatment based on the vitamin D serum level is the most cost-effective strategy for preventing hip fracture occurrence in the population over 65 years old.

Cephalometric assessment of craniofacial dysmorphologies in relation with Msx2 mutations in mouse.

OBJECTIVES: To determine the role of Msx2 in craniofacial morphology and growth, we used a mouse model and performed a quantitative morphological characterization of the Msx2 (-/-) and the Msx2 (+/-) phenotype using a 2D cephalometric analysis applied on micrographs. MATERIALS AND METHODS: Forty-four three-and-a-half-month-old female CD1 mice were divided into the following three groups: Msx2 (+/+) (n = 16), Msx2 (+/-) (n = 16), and Msx2 (-/-) (n = 12). Profile radiographs were scanned. Modified cephalometric analysis was performed to compare the three groups. RESULTS: Compared with the wild-type mice, the Msx2 (-/-) mutant mice presented an overall craniofacial size decrease and modifications of the shape of the different parts of the craniofacial skeleton, namely the neurocranium, the viscerocranium, the mandible, and the teeth. In particular, dysmorphologies were seen in the cochlear apparatus and the teeth (taurodontism, reduced incisor curvature). Finally contrary to previous published results, we were able to record a specific phenotype of the Msx2 (+/-) mice with this methodology. This Msx2 (+/-) mouse phenotype was not intermediate between the Msx2 (-/-) and the wild-type animals. CONCLUSION: Msx2 plays an important role in craniofacial morphogenesis and growth because almost all craniofacial structures were affected in the Msx2(-/-) mice including both intramembranous and endochondral bones, the cochlear apparatus, and the teeth. In addition, Msx2 haploinsufficiency involves a specific phenotype with subtle craniofacial structures modifications compared with human mutations.

The role of muscle strength & activation patterns in patellofemoral pain.

BACKGROUND: To investigate the extent to which quadriceps muscle activation and strength are responsible for patellofemoral pain. METHODS: A pain on-off switch system synchronized with a force transducer and surface electromyography was utilized on 32 volunteer patellofemoral pain patients during maximal isometric and squat exercises. FINDINGS: There were 26 patients out of the 32 tested who complained of pain during the squat or isometric test, of these 20 subjects presented a significant advantage for the vastus lateralis compared to the vastus medialis obliquis activation and 12 patients had decreased quadriceps strength of the symptomatic compared to the non symptomatic leg. All patients who demonstrated weak vastus medialis obliquis activation during the isometric exercise possessed the same symptoms during the squat. On the other hand, 9 patients who showed diminished vastus medialis obliquis activation during the squat displayed equal activation between the vastus medialis obliquis and the vastus lateralis during the isometric task. With regard to the timing for the onset of muscle activation, there were only 4 patients who had a difference (P=0.03) between the symptomatic (0.042 s) and non-symptomatic legs (0.011 s). INTERPRETATION: Causes for patellofemoral pain vary and are not necessarily a result of quadriceps strength deficit or vastus medialis obliquis activation weakness. Patellofemoral pain patients who possess lower vastus medialis obliquis activation compared to the vastus lateralis do not necessarily have quadriceps weakness while patients presenting with quadriceps strength deficits do not always have an imbalance between vastus medialis obliquis and vastus lateralis activation.

Efficacy and safety of risedronate 150-mg once a month in the treatment of postmenopausal osteoporosis: 2-year data.

UNLABELLED: This study showed that risedronate 150-mg once a month provides similar efficacy and safety at 2 years compared with risedronate 5-mg daily for the treatment of postmenopausal osteoporosis. This adds to the range of risedronate dosing options and provides an alternative for patients who prefer once-a-month dosing. INTRODUCTION: Risedronate is effective in the treatment of postmenopausal osteoporosis in oral daily, weekly, or on two consecutive days per month doses. This 2-year randomized, double-blind, multicenter study assesses the efficacy and safety of a single risedronate 150-mg once-a-month oral dose compared with the 5-mg daily regimen. METHODS: Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5-mg daily (n = 642) or 150-mg once a month (n = 650) for 2 years. Bone mineral density (BMD), bone turnover markers, new vertebral fractures, and adverse events were evaluated. The primary efficacy endpoint was the mean percent change from baseline in lumbar spine BMD after 1 year. RESULTS: Four hundred ninety-eight subjects in the daily group (77.6 %) and 513 subjects in the once-a-month group (78.9 %) completed the study. After 24 months, the mean percent change in lumbar spine BMD was 3.9 % (95 % confidence interval [CI], 3.43 to 4.42 %) and 4.2 % (95 % CI, 3.68 to 4.65 %) in the daily and once-a-month groups, respectively. The once-a-month regimen was determined to be non-inferior to the daily regimen. The mean percent changes in BMD at the hip were similar in both dose groups, as were changes in biochemical markers of bone turnover. The incidence of adverse events, adverse events leading to withdrawal, and upper gastrointestinal tract adverse events were similar in the two treatment groups. CONCLUSIONS: After 2 years, treatment with risedronate 150-mg once a month provided similar efficacy and tolerability to daily dosing and provides an alternative for patients who prefer once-a-month oral dosing.

Centrosome fine ultrastructure of the osteocyte mechanosensitive primary cilium.

The centrosome is the principal microtubule organization center in cells, giving rise to microtubule-based organelles (e.g., cilia, flagella). The aim was to study the osteocyte centrosome morphology at an ultrastructural level in relation to its mechanosensitive function. Osteocyte centrosomes and cilia in tibial cortical bone were explored by acetylated alpha-tubulin (AαTub) immunostaining under confocal microscopy. For the first time, fine ultrastructure and spatial orientation of the osteocyte centrosome were explored by transmission electron microscopy on serial ultrathin sections. AαTub-positive staining was observed in 94% of the osteocytes examined (222/236). The mother centriole formed a short primary cilium and was longer than the daughter centriole due to an intermediate zone between centriole and cilium. The proximal end of the mother centriole was connected with the surface of daughter centriole by striated rootlets. The mother centriole exhibited distal appendages that interacted with the cell membrane and formed a particular structure called "cilium membrane prolongation." The primary cilium was mainly oriented perpendicular to the long axis of bone. Mother and daughter centrioles change their original mutual orientation during the osteocyte differentiation process. The short primary cilium is hypothesized as a novel type of fluid-sensing organelle in osteocytes.

Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis.

UNLABELLED: In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (P < 0.01). Vertebral and nonvertebral fracture incidence was lower between 5 and 10 years than in a matched placebo group over 5 years (P < 0.05). Strontium ranelate's antifracture efficacy appears to be maintained long term. INTRODUCTION: Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years. METHODS: Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (n = 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm. RESULTS: The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years. CONCLUSIONS: Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.

Efficacy and safety of a novel delayed-release risedronate 35 mg once-a-week tablet.

UNLABELLED: Dosing regimens of oral bisphosphonates are inconvenient and contribute to poor compliance. The bone mineral density response to a once weekly delayed-release formulation of risedronate given before or following breakfast was non-inferior to traditional immediate-release risedronate given daily before breakfast. Delayed-release risedronate is a convenient regimen for oral bisphosphonate therapy. INTRODUCTION: We report the results of a randomized, controlled, clinical study assessing the efficacy and safety of a delayed-release (DR) 35 mg weekly oral formulation of risedronate that allows patients to take their weekly risedronate dose before or immediately after breakfast. METHODS: Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5 mg immediate-release (IR) daily (n = 307) at least 30 min before breakfast, or risedronate 35 mg DR weekly, either at least 30 min before breakfast (BB, n = 308) or immediately following breakfast (FB, n = 307). Bone mineral density (BMD), bone turnover markers (BTMs), fractures, and adverse events were evaluated. The primary efficacy variable was percent change from baseline in lumbar spine BMD at Endpoint. RESULTS: Two hundred fifty-seven subjects (83.7%) in the IR daily group, 252 subjects (82.1%) in the DR FB weekly group, and 258 subjects (83.8%) in the DR BB weekly group completed 1 year. Both DR weekly groups were determined to be non-inferior to the IR daily regimen. Mean percent changes in hip BMD were similar across groups. The magnitude of BTM response was similar across groups; some statistical differences were seen that were small and deemed by investigators to have no major clinical importance. The incidence of adverse events leading to withdrawal and serious adverse events were similar across treatment groups. All three regimens were well tolerated. CONCLUSIONS: Risedronate 35 mg DR weekly is similar in efficacy and safety to risedronate 5 mg IR daily, and will allow patients to take their weekly risedronate dose immediately after breakfast.

Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice.

SUMMARY: This study evaluates the effect of hydrolyzed collagen (HC) on bone health of ovariectomized mice (OVX) at different ages. Twenty-six weeks after the OVX procedure, HC ingestion was still able to improve significantly bone mineral density (BMD) and some femur biomechanical parameters. Moreover, HC ingestion for 1 month before surgery prevented BMD decrease. INTRODUCTION: HC can play an important role in preserving BMD before osteoporosis appears. The aim of this study was to evaluate the effect of HC on bone health of ovariectomized mice at different ages. METHODS: Female C3H mice were either OVX at 3 or 6 months and fed for 6 months (first experiment) or 3 months (second experiment) with diet including 0, 10, or 25 g/kg of HC. In the second experiment, one group received HC 1 month before surgery, and two groups received the supplementation immediately after surgery, one fed ad libitum and the other by gavage. Mice treated with raloxifene were used as a positive control. BMD, femur intrinsic and extrinsic biomechanical properties, and type I collagen C-terminal telopeptide were measured after 12 and 26 weeks. Food intake and spontaneous physical activity were also recorded. RESULTS: The OVX procedure increased body weight, while food intake decreased, thus suggesting that resting metabolism was decreased. Ingestion of 25 g/kg of HC for 3 or 6 months reduced bone loss significantly in, respectively, 3- and 6-month-old OVX mice. The lowest HC concentration was less efficient. HC ingestion for 3 months is as efficient as raloxifene to protect 3-month-old OVX mice from bone loss. Our results also demonstrated that HC ingestion before surgery prevented the BMD decreases. CONCLUSION: This study confirms that dietary collagen reduces bone loss in OVX mice by increasing the diameter of the cortical areas of femurs and can have a preventive effect.

Alcohol and bone: review of dose effects and mechanisms.

Alcohol is widely consumed across the world. It is consumed in both social and cultural settings. Until recently, two types of alcohol consumption were recognized: heavy chronic alcohol consumption or light consumption. Today, there is a new pattern of consumption among teenagers and young adults namely: binge drinking. Heavy alcohol consumption is detrimental to many organs and tissues, including bones, and is known to induce secondary osteoporosis. Some studies, however, have reported benefits from light alcohol consumption on bone parameters. To date, little is known regarding the effects of binge drinking on bone health. Here, we review the effects of three different means of alcohol consumption: light, heavy, and binge drinking. We also review the detailed literature on the different mechanisms by which alcohol intake may decrease bone mass and strength. The effects of alcohol on bone are thought to be both direct and indirect. The decrease in bone mass and strength following alcohol consumption is mainly due to a bone remodeling imbalance, with a predominant decrease in bone formation. Recent studies, however, have reported new mechanisms by which alcohol may act on bone remodeling, including osteocyte apoptosis, oxidative stress, and Wnt signalling pathway modulation. The roles of reduced total fat mass, increased lipid content in bone marrow, and a hypoleptinemia are also discussed.

Low bone accrual is associated with osteocyte apoptosis in alcohol-induced osteopenia.

INTRODUCTION: Alcohol is known to decrease bone mineral density (BMD) and to induce trabecular microarchitecture deterioration. However, little is known about the effects of chronic alcohol consumption on osteocytes in situ. The aim of this study was to assess the effects of a high alcohol dose on osteocytes in an alcohol-induced osteopenia model. MATERIALS AND METHODS: 24 male Wistar rats, 2-months old were separated in 2 groups: Control (C) or Alcohol (A35). The rats in the A35 group drank a beverage composed of 35% ethanol v/v mixed to water for 17 weeks. BMD was assessed by DXA, while the microarchitecture was analyzed using µCT. Bone remodeling was studied measuring serum concentration of osteocalcin, NTx and TRAP. Bone marrow adiposity, osteoblastic lineage differentiation, osteocyte morphology and apoptosis were assessed using bright field, epifluorescence, transmission electron and confocal microscopy. RESULTS: BMD, trabecular thickness, TRAP and NTx concentration were significantly decreased in A35, while cortical thickness was thinner. There were 10 fold more cells stained with cleaved caspase-3, and 35% more empty lacunae in A35, these data indicating a large increase in osteocyte apoptosis in the A35 group. The number of lipid droplets in the marrow was increased in A35 (7 fold). Both the osteocyte apoptosis and the fat bone marrow content strongly correlated with femur BMD (p=0.0017, r = -0.72 and p=0.002, r = -0.70) and whole body BMD. CONCLUSION: These data suggest that low BMD is associated with osteocyte apoptosis and bone marrow fat content in alcohol-induced osteopenia.

Genetic algorithm and image processing for osteoporosis diagnosis.

Osteoporosis is considered as a major public health threat. It is characterized by a decrease in the density of bone, decreasing its strength and leading to an increased risk of fracture. In this work, the morphological, topological and mechanical characteristics of 2 populations of arthritic and osteoporotic trabecular bone samples are evaluated using artificial intelligence and recently developed skeletonization algorithms. Results show that genetic algorithms associated with image processing tools can precisely separate the 2 populations.

Increase in vertebral body size in postmenopausal women with osteoporosis.

Bone geometry plays a prominent role in bone strength. Cross-sectional studies have shown that advancing age is associated with increasing diameter of long bones, related to both periostal apposition and endosteal resorption. However, there are few data provided by prospective studies, especially concerning the changes in vertebral body dimensions. The objective of this prospective study was to measure the changes occurring in the vertebral body size of women with postmenopausal osteoporosis. Three-year data from placebo groups of the SOTI and TROPOS trials, performed in women with postmenopausal osteoporosis, were used for this study. In these trials, patients underwent lateral radiographs of the thoracic and lumbar spine at baseline and annually over 3 years, according to standardized procedures. Six-point digitization method was used: the four corner points of the vertebral body from T4 to L4 are marked, as well as an additional point in the middle of the upper and lower endplates. From these 6 points, the vertebral body perimeter, area and depth were measured at baseline and at 3 years. The analysis excluded all vertebrae with prevalent or incident fracture. A total of 2017 postmenopausal women (mean age 73.4+/-6.1 years) with a mean lumbar spine T score of -3.1+/-1.5, and a mean femoral neck T score of -3.0+/-0.7 are included in the analysis. Vertebral body dimensions increased over 3 years, by 2.1+/-5.5% (mean depth+/-SD), by 1.7+/-8.3% (mean area+/-SD) and by 1.5+/-4.9% (mean perimeter+/-SD) at the thoracic level (T4 to T12). At the lumbar level (L1 to L4), these dimensions increased as well: 1.4+/-3.6% (mean depth+/-SD), 1.4+/-5.7% (mean area+/-SD), 0.7+/-2.9% (mean perimeter+/-SD). A significant increase in vertebral body size was observed for each vertebral level from T5 to L4 for each of these parameters (p<0.01). These prospective results demonstrate that vertebral body dimensions increase over 3 years in women with postmenopausal osteoporosis.

Exercise and zoledronic acid on lipid profile and bone remodeling in ovariectomized rats: a paradoxical negative association?

Exercise (EXE) and amino-bisphosphonates (BP) are both considered as useful strategies in the prevention of post-menopausal bone loss. Exercise reduces lipid levels, and BP may induce increase in high-density lipoprotein cholesterol (HDL-C). We hypothesized that combined effects of BP and exercise would produce a better improvement of lipid profile. We studied the specific and combined effects of zoledronic acid (Z) and EXE on lipid profile and bone remodeling in mature ovariectomized (OVX) rats. Six-month old female rats were randomly assigned to either a sham-ovx group (n = 12) or one of four OVX groups (n = 12): vehicle-treated sedentary (OVX); OVX + EXE (OVX-E, running on a treadmill for 12 weeks); OVX + Z (20 microg/kg, i.v.), (OVX-Z); OVX + Z+EXE (OVX-ZE). Total cholesterol (TC), HDL-C and bone remodeling markers were measured at baseline and at the end of the study. We demonstrated that both Z and EXE prevented the increase in bone resorption resulting from OVX, and individually improved the atherosclerotic risk index. Therapy with Z resulted in significant increase (39.00 +/- 0.03 vs. 53.6 +/- 0.01 mg/dl; +37.4%, P < 0.05) in serum concentration of HDL-C and a non significant decrease in TC (135.30 +/- 0.03 vs. 144.80 +/- 0.05 mg/dl; -5.8%) in the OVX-Z group compared to the OVX group. Post-menopausal women have elevated risk of CVD and bone resorption, hence, these data ultimately demonstrate (except for the elevated ratio in the combined group) that exercise and zoledronic acid are useful in minimizing the impact of these two processes in women and the combination of the two may be clinically relevant.

Trabecular and cortical bone separately assessed at radius with a new ultrasound device, in a young adult population with various physical activities.

The aim was to evaluate a new ultrasound device in a young adult population and to assess its reproducibility via comparison to DXA measurements and geometrical measurements from high-resolution radiographs. Ninety-three subjects aged between 20 and 51 years were recruited and divided into four groups according to their gender and physical activity status: 22 male athletes, 19 male controls, 21 female athletes, and 31 female controls. Ultrasonic measurements were assessed by the prototype LD-100 (Oyo Electric Co., Kyoto, Japan) on the dominant distal radius. Attenuation in the radius (dB), cortical bone thickness (mm), radius thickness (mm), mass density of cancellous bone (mg/cm(3)), and elasticity (GPa) of cancellous bone were obtained. BMD was measured by DXA at the dominant distal radius. Radius images were obtained with a direct high-resolution digital X-ray device (BMA, D(3)A Medical Systems), and radius and cortical thicknesses were estimated using a specific software (ImageJ, Bethesda, USA), in an area site-matched with LD-100. There was a significant positive correlation between site-matched BMD measurement and LD-100 parameters (p<0.004), X-ray radius thickness, and LD-100 parameters except elasticity (p<0.05, r>0.32), X-ray cortical thickness and LD-100 attenuation and cortical thickness (p<0.01). A significantly higher attenuation, cortical and radius thicknesses were found in athletes compared to controls (p<0.05). The radius thickness measured on radiographs was significantly higher in athletes versus controls in both sexes, and cortical thickness was significantly higher in male athletes versus controls. These data suggest a positive influence of physical activity on bone cortical measurements. This study also confirmed the particular interest of bone assessment by ultrasound.

Osteocyte: the unrecognized side of bone tissue.

INTRODUCTION: Osteocytes represent 95% of all bone cells. These cells are old osteoblasts that occupy the lacunar space and are surrounded by the bone matrix. They possess cytoplasmic dendrites that form a canalicular network for communication between osteocytes and the bone surface. They express some biomarkers (osteopontin, beta3 integrin, CD44, dentin matrix protein 1, sclerostin, phosphate-regulating gene with homologies to endopeptidases on the X chromosome, matrix extracellular phosphoglycoprotein, or E11/gp38) and have a mechano-sensing role that is dependent upon the frequency, intensity, and duration of strain. DISCUSSION: The mechanical information transmitted into the cytoplasm also triggers a biological cascade, starting with NO and PGE(2) and followed by Wnt/beta catenin signaling. This information is transmitted to the bone surface through the canalicular network, particularly to the lining cells, and is able to trigger bone remodeling by directing the osteoblast activity and the osteoclastic resorption. Furthermore, the osteocyte death seems to play also an important role. The outcome of micro-cracks in the vicinity of osteocytes may interrupt the canalicular network and trigger cell apoptosis in the immediate surrounding environment. This apoptosis appears to transmit a message to the bone surface and activate remodeling. The osteocyte network also plays a recognized endocrine role, particularly concerning phosphate regulation and vitamin D metabolism. Both the suppression of estrogen following menopause and chronic use of systemic glucocorticoids induce osteocyte apoptosis. On the other hand, physical activity has a positive impact in the reduction of apoptosis. In addition, some osteocyte molecular elements like sclerostin, connexin 43, E11/gp38, and DKK1 are emerging as promising targets for the treatment of various osteo-articular pathologies.

Hypoleptinaemia in extreme body mass models: the case of international rugby players.

Leptinaemia has been poorly studied in athlete populations with the consequences of athletic hypoleptinaemia yet to be examined. Our aim was to determine if systemic leptinaemia is influenced in high body mass athletes. We recruited 24 rugby players (21.5+/-4.7 years; 11.8+/-2.9h/week) and 26 controls (22.3+/-3.1 years; 1.9+/-1.4h/week). BMD (whole body (WB), limbs, lumbar spine and non-dominant femur) and body composition (WB Lean Mass (LM) and FM) were measured by Dual X-ray Absorptiometry. Circulating levels of serum leptin (ng/ml), adiponectin (microg/ml), insulin (ng/ml), osteocalcin (ng/ml) and CTx (ng/ml) were assessed by ELISA assays. BMD were significantly higher in rugby players vs controls, at all bone sites, yet after adjustments for body mass index. They had significantly higher LM and FM but no differences in %FM. They had significantly higher osteocalcin but lower CTx, insulin and leptin concentrations. Leptin levels were strongly correlated to %FM (r=0.85, p<0.0001), as well as to absolute FM (r=0.77, p=0.0002), in the rugbymen group. Rugby practice was associated to a bone remodelling process in favour of bone formation. There was a significant hypoleptinaemia in our rugby players, while their percent FM was equivalent and absolute FM significantly higher than the control levels. These data suggest that leptin is under control of physical activity and not just fat mass.

Does exercise modify the effects of zoledronic acid on bone mass, microarchitecture, biomechanics, and turnover in ovariectomized rats?

Regular activity has effects on bone size, shape, and density, resulting in an increase in mechanical strength. The mechanism of action that underlies this improvement in bone strength is mainly linked to an increase in bone formation. Zoledronic acid (Z), in contrast, may prevent bone strength changes in ovariectomized (OVX) rodents by its potent antiresorptive effects. Based on these assumptions we hypothesized that combined effects of exercise (E) and Z may produce higher benefits on bone changes resulting from estrogen deficiency than either intervention alone. At 6 months of age, 60 female Wistar rats were OVX or sham operated (SH) and divided into five groups: SH, OVX, OVX-E, OVX-Z, and OVX-ZE. OVX rats were treated with a single IV injection of Z (20 microg/kg) or vehicle and submitted or not to treadmill exercise (15 m/min, 60 min/day, 5 days/week) for 12 weeks. Whole-body BMD and bone turnover markers were analyzed longitudinally. At sacrifice, femurs were removed. BMD by DXA, three-point bending test, and microCT were performed to study biomechanical and trabecular structure parameters, respectively. After 12 weeks, bone volume fraction decreased in OVX rats, whereas bone turnover rate, trabecular spacing, and structure model index increased compared with those in the SH group (P < 0.05). Zoledronic acid prevented the ovariectomy-induced trabecular bone loss and its subsequent trabecular microarchitectural deterioration. Treadmill exercise running was shown to preserve the bone strength and to induce bone turnover changes in favor of bone formation. However, the combined effects of zoledronic acid and running exercise applied simultaneously did not produce any synergetic or additive effects.

Assessment of trabecular bone microarchitecture by two different x-ray microcomputed tomographs: a comparative study of the rat distal tibia using Skyscan and Scanco devices.

Important aspects of modern skeletal research depend on the phenotypical characterization of trabecular bone microarchitecture as assessed by microcomputed tomography (micro-CT). Until now, however, there have been no studies which compare the two most commonly utilized micro-CT devices, namely, Skyscan and Scanco. The purpose of the current study was to examine the reproducibility and accuracy of these two micro-CT devices in comparison to traditional histomorphometry in ovariectomized rats treated with either propranolol, salbutamol, or vehicle. 6 month old female Wistar rats were ovariectomized (n = 48) or sham operated (n = 12). OVX rats were divided into four groups and then subcutaneously injected with propranolol 0.1 mg/kg/day, propranolol 20 mg/kg/day, salbutamol 3 mg/kg/day, or vehicle for 10 weeks. At sacrifice, the left tibial trabecular bone microarchitecture was analyzed using both the micro-CT Skyscan 1072 (ex vivo) and Scanco vivaCT40 (in vivo). Histomorphometric analysis was performed on the right proximal tibia. Comparisons between the different methods were performed using regression analysis, Bland-Altman, Passing-Bablock, and Mountain plots. Correlations were highly significant for all parameters measured between the two micro-CT instruments and were less significant between histomorphometry and micro-CT measurements taken from either the Skyscan or Scanco apparatus. Micro-CT overestimated bone volume compared to histomorphometry. In the ovariectomized rat model, the two micro-CT instruments revealed the same difference between groups whereas histomorphometry revealed only the difference which displayed the largest disparity between groups. In regards to the comparison between the two micro-CT devices, Mountain plot methods indicated that BV/TV, BS/BV, and TbSp were equivalent, whereas a systematic bias was observed for TbN and TbTh. The authors were also able to describe the routine method used to determine the threshold between the two micro-CT devices, which may help explain these differences. While some minor differences in the absolute values of the morphometry parameters exist between the micro-CT measurements from the Skyscan and Scanco instruments, both of these devices display a high degree of accuracy and reproducibility.