bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Magnitude Mechanical Loading Is Osteogenic in Children With Disabling Conditions
Authors: Ward Kate , Alsop Chrissie , Caulton Janette , Rubin Clinton , Adams Judith , Mughal Zulf
Published: April 2006

The osteogenic potential of short durations of low-level mechanical stimuli was examined in children with disabling conditions. The mean change in tibia vTBMD was +6.3% in the intervention group compared with −11.9% in the control group. This pilot randomized controlled trial provides preliminary evidence that low-level mechanical stimuli represent a noninvasive, non-pharmacological treatment of low BMD in children with disabling conditions.

Introduction: Recent animal studies have demonstrated the anabolic potential of low-magnitude, high-frequency mechanical stimuli to the trabecular bone of weight-bearing regions of the skeleton. The main aim of this prospective, double-blind, randomized placebo-controlled pilot trial (RCT) was to examine whether these signals could effectively increase tibial and spinal volumetric trabecular BMD (vTBMD; mg/ml) in children with disabling conditions.

Materials and Methods: Twenty pre-or postpubertal disabled, ambulant, children (14 males, 6 females; mean age, 9.1 ± 4.3 years; range, 4–19 years) were randomized to standing on active (n = 10; 0.3g, 90 Hz) or placebo (n = 10) devices for 10 minutes/day, 5 days/week for 6 months. The primary outcomes of the trial were proximal tibial and spinal (L2) vTBMD (mg/ml), measured using 3-D QCT. Posthoc analyses were performed to determine whether the treatment had an effect on diaphyseal cortical bone and muscle parameters.

Results and Conclusions: Compliance was 44% (4.4 minutes per day), as determined by mean time on treatment (567.9 minutes) compared with expected time on treatment over the 6 months (1300 minutes). After 6 months, the mean change in proximal tibial vTBMD in children who stood on active devices was 6.27 mg/ml (+6.3%); in children who stood on placebo devices, vTBMD decreased by −9.45 mg/ml (−11.9%). Thus, the net benefit of treatment was +15.72 mg/ml (17.7%; p = 0.0033). In the spine, the net benefit of treatment, compared with placebo, was +6.72 mg/ml, (p = 0.14). Diaphyseal bone and muscle parameters did not show a response to treatment. The results of this pilot RCT have shown for the first time that low-magnitude, high-frequency mechanical stimuli are anabolic to trabecular bone in children, possibly by providing a surrogate for suppressed muscular activity in the disabled. Over the course of a longer treatment period, harnessing bone's sensitivity to these stimuli may provide a non-pharmacological treatment for bone fragility in children.
Assessing Bone Status Beyond BMD: Evaluation of Bone Geometry and Porosity by Quantitative Ultrasound of Human Finger Phalanges
Authors: Sakata Satoru , Barkmann Reinhard , Lochmüller Eva-Maria , Heller Martin , Glüer Claus-Christian
Published: April 2006

In an in vitro study, we found significant associations between QUS variables and properties and geometrical parameters of the compact bone of human finger phalanges. QUS variables were not only related to BMD but also to other skeletal properties, which explained 70% of the variability of speed of sound.

Introduction: Transverse transmission quantitative ultrasound (QUS) measurements at the finger phalanges are known to be correlated with BMD and to predict osteoporotic fractures. To determine which other skeletal properties are affected by ultrasound, we investigated the impact of density, geometry, and porosity on QUS variables in vitro.

Materials and Methods: Ultrasound variables were correlated with density, porosity, and geometrical characteristics of cortical bone. Additionally, we tested which combinations of geometry and bone properties best predicted the ultrasound results observed. Forty-four proximal phalanges from the middle finger were investigated at their distal metaphysis, similar to the typical clinical measurement procedure. Donor age ranged from 52 to 98 years (15 males and 29 females; mean age, 80.9 ± 9.4 years). QUS variables were measured on the metaphysis of the phalanges using the DBMSonic 1200. Quantitative CT was used for the measurement of BMD, and high-resolution MRI was used for the measurement of porosity and geometrical variables.

Results: Speed of sound (SOS) and the clinically used variable AD-SOS correlated significantly with area, relative area, density, and porosity of the compact bone (R2 = 0.28-0.58, p < 0.0001). Signal amplitude correlated significantly only with relative area of the compact bone and area of the medullary canal (R2 = 0.18-0.20, p < 0.01). The combination of cortical area, density, and porosity improved the determination of SOS to R2 = 0.70, with a residual unexplained variability of 54 m/s (3.2%).

Conclusions: These results clarify the impact of skeletal properties on QUS variables. SOS is affected by cortical area, cortical bone density, and cortical porosity, whereas attenuation only depends on geometry of the medulla. AD-SOS, the variable routinely measured in clinical practice, is primarily affected by cortical area. QUS of the finger phalanges is not only related to BMD but also to other skeletal properties.
Genetics of Bone Mineral Density: Evidence for a Major Pleiotropic Effect From an Intercontinental Study
Authors: Livshits Gregory , Deng Hong-Wen , Nguyen Tuan V , Yakovenko Konstantin , Recker Robert R , Eisman John A
Published: April 2006

BMD is a primary predictor of osteoporotic fracture, and its genetic determination is still unclear. This study showed that the correlation between BMD at different skeletal sites is caused by an underlying genetic structure of common genetic effects. In addition to possible shared (pleiotropic) genetic and environmental effects, each of the BMD variables may also be determined by site-specific genetic factors.

Introduction: BMD is a primary predictor of osteoporotic fracture and a key phenotype for the genetic study of osteoporosis. The interindividual variation in BMD measured at a given skeletal site is largely regulated by genetic factors. A strong phenotypic covariation exists for BMD at different skeletal sites. This study tests the hypothesis that the covariation is in fact caused by an underlying genetic structure of common genetic effects and that, in addition to possible shared (pleiotropic) genetic effects, each of the BMD variables may also be determined by site-specific genetic factors

Materials and Methods: A bivariate complex segregation analysis as implemented in statistical package PAP was conducted to explore various models of pleiotropic genetic and environmental transmission in lumbar spine and femoral neck BMD, as well as in compact and spongious segments of hand phalanges. The BMD was obtained in three ethnically, culturally, and socially heterogeneous samples of white pedigrees, with 2549 individuals between 18 and 100 years of age, from Australia, Europe, and North America.

Results and Conclusions: The genetic correlation between BMD measures ranged between 0.50 ± 0.09 and 0.79 ± 0.04 in the three samples. In each sample, the model incorporated a major locus pleiotropic effect, and residual correlation was found to be the most parsimonious model. Estimated parameters from the model indicated a significant pleiotropic major gene effect on both lumbar spine and femoral neck BMD, with the existence of a significant residual correlation (0.51 ± 0.07 to 0.66 ± 0.04). These results suggest that the covariation in BMD at different skeletal sites, and between mostly compact versus mostly trabecular bone, was largely determined by common genetic factors that are pleiotropic or in close linkage and linkage disequilibirum, while at the same time, exhibiting considerable evidence of shared environmental effects. The results, for the first time, suggest that the possibility of pleiotropic genetic effect may be controlled by a major genetic locus. Identification of the major locus could open new opportunity to understanding the liability and pathogenic processes in which they are involved in the determination of fracture risk.
Female Premenopausal Fracture Risk Is Associated With Gc Phenotype
Authors: Lauridsen Anna Lis , Vestergaard Peter , Hermann Anne Pernille , Moller Holger Jon , Mosekilde Leif , Nexo Ebba
Published: April 2006

The phenotype of the vitamin D binding and macrophage activating protein, Gc, is a predictor of premenopausal bone fracture risk, possibly mediated through activation of osteoclasts. This was concluded from a study on 595 Danish perimenopausal women 45-58 years of age (30,040 person years).

Introduction: The multifunctional plasma protein Gc, also known as group-specific component, Gc globulin, or vitamin D binding protein (DBP), has two functions with relation to bone tissue: it is the major carrier protein of vitamin D in the circulation, and deglycosylation converts it into a very potent macrophage- and osteoclast-activating factor (Gc-MAF). There are several phenotypes of Gc, and in this study, we examined the relation between Gc phenotype and bone fragility.

Materials and Methods: By isoelectric focusing we identified the Gc phenotype of 595 white recent postmenopausal women enrolled into the Danish Osteoporosis Prevention Study (DOPS) and identified three groups: Gc1-1 (n = 323), Gc1-2 (n = 230), and Gc2-2 (n = 42). Differences between the three groups were examined with respect to number of fractures before enrollment, BMC and BMD, and various biochemical and clinical parameters, including the concentration of Gc measured by immunonephelometry and the concentration of the macrophage marker soluble CD163 measured by ELISA.

Results and Conclusions: The risk of having at least one premenopausal bone fracture (total number of women with fracture = 179) differed significantly (p = 0.017) in women with phenotype Gc1-1 (110/323 = 0.34), Gc1-2 (63/230 = 0.27), and Gc2-2 (6/42 = 0.14). The differences were even more striking (p = 0.005) for fractures caused by low-energy traumas. Using logistic regression, we found the relative risk of premenopausal fracture to be 0.32 (0.13-0.80) in Gc2-2 compared with Gc1-1. We propose that the Gc phenotypes cause differences in osteoclast activity, a theory supported by our finding of lower levels of Gc and of soluble CD163 in women with Gc2-2 compared with Gc1-1.
A Meta-Analysis of Prior Corticosteroid Use and Fracture Risk
Authors: Kanis John A , Johansson Helena , Oden Anders , Johnell Olof , de Laet Chris , Melton L Joseph , Tenenhouse Alan , Reeve Jonathan , Silman Alan J , Pols Huibert AP , Eisman John A , McCloskey Eugene V , Mellstrom Dan
Published: April 2006

The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of ∼42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD.

Introduction: The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk.

Materials and Methods: We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted β coefficients.

Results: Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63-1.71, and for hip fracture 4.42-2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD.

Conclusion: We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case-finding strategies.
Arthritis Induces Lymphocytic Bone Marrow Inflammation and Endosteal Bone Formation
Authors: Görtz Birgit , Hayer Silvia , Redlich Kurt , Zwerina Jochen , Tohidast-Akrad Makyieh , Tuerk Birgit , Hartmann Christine , Kollias George , Steiner Günter , Smolen Josef S , Schett Georg
Published: April 2006

Arthritis can destroy the cortical bone barrier and expose bone marrow to synovial tissue. This study examines bone marrow changes in arthritis and its effects on cortical bone remodeling. Bone marrow next to arthritic lesions exhibits B-lymphocyte-rich infiltrates, which express BMPs and stimulate endosteal bone formation. Thus, bone marrow actively participates in the arthritic process.

Introduction: Imaging studies have shown that bone marrow changes occur in patients with rheumatoid arthritis (RA). To examine whether bone marrow is affected during arthritis, human TNF transgenic (hTNFtg) mice, which constitute an established animal model of human RA, were examined for bone marrow changes.

Materials and Methods: The hind paws (tarsal area) of 22 untreated hTNFtg mice, 5 hTNFtg mice treated with anti-TNF (infliximab), and 5 wildtype (WT) mice were examined histologically, immunohistochemically, and by means of mRNA in situ hybridization.

Results and Conclusions: All untreated hTNFtg mice with moderate (n = 10) and severe (n = 7) disease developed inflammatory bone marrow lesions during the course of disease, whereas no such lesions appeared in hTNFtg mice with mild disease (n = 5) and WT mice. Bone marrow infiltrates were almost exclusively composed of lymphocytes, and the overwhelming proportion (>80%) was B-cells. Presence and extent of bone marrow infiltrates were closely linked to severity of arthritis. In addition, blockade of TNF effectively reduced bone marrow inflammation. Interestingly, osteoblast numbers were increased at the endosteal surface in the vicinity of these lesions. Moreover, osteoid deposition; expression of bone matrix proteins, such as osteocalcin and osteopontin; and mineralization were enhanced, suggesting that inflammatory bone marrow infiltrates induce bone formation. Indeed, B-lymphocytes of these lesions expressed bone morphogenetic protein (BMP)-6 and −7, which are important stimulators of new bone formation. Thus, we conclude that bone marrow actively participates in destructive arthritis by generating B-lymphocyte-rich bone marrow lesions and inducing endosteal bone formation.
Dietary Protein Intake and Risk of Osteoporotic Hip Fracture in Elderly Residents of Utah
Authors: Wengreen Heidi J , Munger Ronald G , West Nancy A , Cutler D Richard , Corcoran Christopher D , Zhang Jianjun , Sassano Nancy E
Published: April 2006

The role of protein intake in osteoporosis is unclear. In a case-control study in Utah (n = 2501), increasing level of protein intake was associated with a decreased risk of hip fracture in men and women 50–69 years of age but not in those 70–89 years of age. Protein intake may be important for optimal bone health.

Introduction: Protein is an important component of bone, but the role of dietary protein intake in osteoporosis and fracture risk remains controversial.

Material and Methods: The role of dietary protein intake in osteoporotic hip fracture was evaluated in a statewide case-control study in Utah. Patients, 50–89 years of age, with hip fracture (cases) were ascertained through surveillance of 18 Utah hospitals during 1997–2001. Age- and gender-matched controls were randomly selected. Participants were interviewed in their place of residence, and diet was assessed using a picture-sort food frequency questionnaire previously reported to give a useful measure of usual dietary intake in the elderly Utah population. The association between protein intake and risk of hip fracture was examined across quartiles of protein intake and stratified by age group for 1167 cases (831 women, 336 men) and 1334 controls (885 women, 449 men).

Results: In logistic regression analyses that controlled for gender, body mass index, smoking status, alcohol use, calcium, vitamin D, potassium, physical activity, and estrogen use in women, the odds ratios (OR) of hip fracture decreased across increasing quartiles of total protein intake for participants 50–69 years of age (OR: 1.0 [reference]; 0.51 [95% CI: 0.30–0.87]; 0.53 [0.31–0.89]; 0.35 [0.21–0.59]; p < 0.001). No similar associations were observed among participants 70–89 years of age. Results from analyses stratified by low and high calcium and potassium intake did not differ appreciably from the results presented above.

Conclusion: Higher total protein intake was associated with a reduced risk of hip fracture in men and women 50–69 years of age but not in men and women 70–89 years of age. The association between dietary protein intake and risk of hip fracture may be modified by age. Our study supports the hypothesis that adequate dietary protein is important for optimal bone health in the elderly 50–69 years of age.
Loss of Chaotic Trabecular Structure in OPG-Deficient Juvenile Paget's Disease Patients Indicates a Chaogenic Role for OPG in Nonlinear Pattern Formation of Trabecular Bone
Authors: Salmon Phil
Published: April 2006

The RANK-RANKL-OPG system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear “chaogenic” parameters, such as friction, forcing frequency, feedback, and boundary forcing.

The RANK-RANKL-osteoprotegerin (OPG) system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease (JPD) patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear “chaogenic” parameters, such as friction, forcing frequency, feedback, and boundary forcing. The Belousov-Zhabotinsky reaction-diffusion system, the catalytic oxidation of CO on platinum surfaces, and thermal diffusion in liquid helium allow visualization of nonlinear emergent patterns such as labyrinthine structures, turbulence, and cellular structures, all of which bear some resemblance to trabecular bone. In JPD, the gene for OPG (TNFRSF11B) is subject to an inactivating mutation, leading to increased resorption and accelerated remodeling. Histomorphometric images of iliac crest trabecular bone from teenagers suffering from JPD show a highly unusual array of parallel, regular trabecular plates, instead of the typical chaotic, fractal patterns of normal trabecular bone. Loss of OPG function is associated with a change from chaotic to regular structure, suggesting that the RANK-RANKL-OPG system is controlling key nonlinear “chaogenic” parameters. Looking at trabecular bone from the perspective of nonlinear pattern formation may help understand other phenomena, such as the marked dependence of trabecular bone's architectural and mechanical quality on remodeling rate independent of the trabecular bone mass.
The Chloride Channel Inhibitor NS3736 Prevents Bone Resorption in Ovariectomized Rats Without Changing Bone Formation
Authors: Schaller Sophie , Henriksen Kim , Sveigaard Christina , Heegaard Anne-Marie , Hélix Nathalie , Stahlhut Martin , Ovejero Maria C , Johansen Jens V , Solberg Helene , Andersen Thomas L , Hougaard Dorit , Berryman Mark , Shiødt Christine B , Sørensen Bjørn H , Lichtenberg Jens , Christophersen Palle , Foged Niels T , Delaissé Jean-Marie , Engsig Michael T , Karsdal Morten A
Published: April 2006

Chloride channel activity is essential for osteoclast function. Consequently, inhibition of the osteoclastic chloride channel should prevent bone resorption. Accordingly, we tested a chloride channel inhibitor on bone turnover and found that it inhibits bone resorption without affecting bone formation. This study indicates that chloride channel inhibitors are highly promising for treatment of osteoporosis.

Introduction: The chloride channel inhibitor, NS3736, blocked osteoclastic acidification and resorption in vitro with an IC50 value of 30 μM. When tested in the rat ovariectomy model for osteoporosis, daily treatment with 30 mg/kg orally protected bone strength and BMD by ∼50% 6 weeks after surgery. Most interestingly, bone formation assessed by osteocalcin, mineral apposition rate, and mineralized surface index was not inhibited.

Materials and Methods: Analysis of chloride channels in human osteoclasts revealed that ClC-7 and CLIC1 were highly expressed. Furthermore, by electrophysiology, we detected a volume-activated anion channel on human osteoclasts. Screening 50 different human tissues showed a broad expression for CLIC1 and a restricted immunoreactivity for ClC-7, appearing mainly in osteoclasts, ovaries, appendix, and Purkinje cells. This highly selective distribution predicts that inhibition of ClC-7 should specifically target osteoclasts in vivo. We suggest that NS3736 is inhibiting ClC-7, leading to a bone-specific effect in vivo.

Results and Conclusion: In conclusion, we show for the first time that chloride channel inhibitors can be used for prevention of ovariectomy-induced bone loss without impeding bone formation. We speculate that the coupling of bone resorption to bone formation is linked to the acidification of the resorption lacunae, thereby enabling compounds that directly interfere with this process to be able to positive uncouple this process resulting in a net bone gain.
Nongenomic Androgen Activation of Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in MC3T3-E1 Osteoblasts
Authors: Kang Hong-Yo , Cho Chung-Lung , Huang Kai-Lieh , Wang Jyh-Chwan , Hu Yueh-Chiang , Lin Hui-Kuan , Chang Chawnshang , Huang Ko-En
Published: April 2006

Androgens have important effects on the bone metabolism. However, the effect and mechanism of androgen action on the osteoblasts remains unknown. Here we showed that androgens increase phosphorylation and nuclear translocation of Akt. siRNA-AR prevented androgen-induced Akt activation in MC3T3-E1 cells. This suggests that nongenomic androgen activation of Akt is mediated by androgen receptor in osteoblasts.

Introduction: Androgens have important effects on the human skeleton in both males and females. However, the mechanism of androgen action on bone metabolism remains unknown. The aims of this study were to determine the effect and mechanism of androgen action on the osteoblast cells.

Materials and Methods: Here we showed that 5α-dihydrotestosterone (DHT) accelerates cell growth of the MC3T3-E1 cell line in a time- and dose-dependent manner. The specific phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002 and kinase-deficient Akt mutant can repress the androgen effect on MC3T3-E1 cells. Western blot analysis showed that DHT, 17β-estradiol, and testosterone (T) induce a rapid and transient phosphorylation of Akt in MC3T3-E1 cells. This activation reached to a plateau after 15 minutes and gradually diminished after 60 minutes of DHT treatment.

Results: Fluorescence microscopy showed a distinct increase in immunostaining intensity in the nuclear interior after androgen treatment but no change in the subcellular distribution of Akt when the cells were pretreated with hydroxyflutamide (HF) or LY294002. In addition, small interfering RNA against androgen receptor (siRNA-AR) prevented DHT-induced Akt phosphorylation and cell growth.

Conclusion: These findings represents the first physiological finding to indicate how steroid hormones such as androgens can mediate the nuclear localization of Akt/PKB in osteoblasts that has previously mainly been linked to growth factor-induced events occurring at the plasma membrane level.
Prevention of Bone Loss in Paraplegics Over 2 Years With Alendronate
Authors: Zehnder Yvonne , Risi Simone , Michel Dieter , Knecht Hans , Perrelet Romain , Kraenzlin Marius , Zäch Guido A , Lippuner Kurt
Published: April 2006

To assess the effects of long-term treatment of bone loss with alendronate in a group of paraplegic men, 55 patients were evaluated in a prospective randomized controlled open label study that was 2 years in duration comparing alendronate and calcium with calcium alone. Bone loss was stopped at all cortical and trabecular infralesional sites (distal tibial epiphysis, tibial diaphysis, total hip) with alendronate 10 mg daily.

Introduction: Bone loss after spinal cord injury (SCI) leads to increased fracture risk in the lower limbs of paraplegics. The aim of this study was to document long-term treatment of bone loss with alendronate in a group of paraplegic men with complete motor lesion after SCI.

Materials and Methods: Sixty-five men with complete motor post-traumatic medullary lesion between T1 and L3 with total motor and sensory loss (Frankel classification, stage A) or with total motor and partial sensory loss (Frankel classification, stage B) after SCI were included in this prospective randomized controlled open label study that was 2 years in duration. The patients were randomized to either the treatment group with alendronate 10 mg daily and elemental calcium 500 mg daily or to the control group with elemental calcium 500 mg daily alone. The primary endpoint was defined as the effect over 24 months of alendronate and calcium compared with calcium alone on the BMD values at the distal tibial epiphysis (as a surrogate for trabecular bone in the paralyzed zone). The secondary endpoints were changes in BMD at supra- and infralesional sites of measurement. Biochemical markers of bone turnover were assessed.

Results: Fifty-five subjects, 0.1-29.5 years post-SCI, completed the study over 24 months. BMD at the distal tibial epiphysis significantly decreased from baseline in the calcium group (−10.8 ± 2.7% at 24 months, p < 0.001), whereas it remained stable in the alendronate plus calcium group (−2.0 ± 2.9% at 24 months, p = not significant versus baseline), leading to a significant intergroup difference over time (p = 0.017). At the tibial diaphysis, similar significant results were observed. At the ultradistal radius and the radial shaft, BMD did not change significantly from baseline in either treatment group. At the total hip, BMD decreased significantly in the calcium group (−4.1 ± 1.6%, p = 0.038) but remained stable in the alendronate plus calcium group (+0.43 ± 1.2%), with a significant intergroup difference (p = 0.037). At the lumbar spine, BMD increased significantly (p < 0.0001) from baseline in both groups. Biochemical markers of bone resorption were significantly decreased with alendronate versus baseline and control. Alendronate and calcium were generally safe and well tolerated.

Conclusions: In paraplegic men, SCI bone loss was stopped at all measured cortical and trabecular infralesional sites over 24 months with alendronate 10 mg daily.
Loss of Regularity in the Curvature of the Thoracolumbar Spine: A Measure of Structural Failure
Authors: Zebaze Roger MD , Maalouf Ghassan , Maalouf Naim , Seeman Ego
Published: April 2006

Departure from regularity (smoothness) in the curvature of the spine was quantified and correlated with the number of fractures, deficits in height, BMD, and identified women with vertebral fractures.

Introduction: Differences in anterior and posterior vertebral heights (VHs) form the thoracolumbar curvature needed for stability in bipedal gait. Modest differences in VHs within and between adjacent vertebrae allow the spine curve to change its trajectory gently. Large differences in VHs, as occur following a fracture, produce abrupt changes in the direction of the curve, producing a departure from regularity (i.e., irregularity or loss of smoothness).

Materials and Methods: VHs and BMD were measured using DXA in 697 Lebanese women 20-87 years of age. Regularity of the spinal curvature was measured by comparing the ratio of the anterior to the posterior VHs of one vertebra to this ratio of adjacent vertebrae. If these ratios are similar, there is a smooth transition in the trajectory of the spinal curve. Departure from this regularity (smoothness) was measured at each pair of adjacent vertebrae in each individual and expressed as the spinal curvature irregularity index (SCII) for the entire thoracolumbar spine.

Results and Conclusions: In premenopausal women, the mean SCII was 8.5% (range, 4-15%); that is, regularity was 91.5%. Only 0.8% of women had a SCII >17%. In postmenopausal women, the mean SCII was 10% (range, 4-36%) and was correlated with age (r = 0.25), height (r = −0.21), BMD (r = −0.13), and the number of deformities assessed by quantitative vertebral morphometry (QVM; r = 0.31-0.60; all p < 0.001). About 5% of women had an SCII >17%, and this group had 3- to 9-fold more deformities (as defined by QVM) than women with SCII <17%, reduced lumbar spine BMD (−1.01 SD), and 2- to 4-fold greater height deficits (−0.5 SD) than women with deformities (by QVM). The SCII is a robust method of identifying structural failure that is easy to compute and does not require controls.
Risk-Benefit Profile for Raloxifene: 4-Year Data From the Multiple Outcomes of Raloxifene Evaluation (MORE) Randomized Trial
Authors: Barrett-Connor Elizabeth , Cauley Jane A , Kulkarni Pandurang M , Sashegyi Andreas , Cox David A , Geiger Mary Jane
Published: April 2006

Posthoc analysis of the MORE osteoporosis treatment trial assessed risk-benefit profile of raloxifene in 7705 postmenopausal women. A major disease outcomes global index resulted in annual rates of 1.39% and 1.83% in the raloxifene and placebo groups, respectively (HR, 0.75; 95% CI, 0.62-0.92), compatible with a favorable risk-benefit profile for raloxifene for treating postmenopausal osteoporosis.

Introduction: The Women's Health Initiative (WHI) trial reported overall risks that exceeded benefits from use of estrogen-progestin in healthy postmenopausal women. The objective of this posthoc analysis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial was to assess the safety profile of raloxifene, a selective estrogen receptor modulator indicated for the prevention and treatment of osteoporosis, using the global index method from the WHI trial.

Materials and Methods: A total of 7705 postmenopausal women (mean age, 67 years) were enrolled in the MORE osteoporosis treatment trial and randomly assigned to receive placebo or one of two doses of raloxifene (60 or 120 mg/day) for 4 years. A global index of clinical outcomes, defined as described for the WHI trial (the earliest occurrence of coronary heart disease, stroke, pulmonary embolism, invasive breast cancer, endometrial cancer, colorectal cancer, hip fracture, or death because of other causes) was applied to the MORE trial data. Physicians blinded to treatment assignment adjudicated events. Intention-to-treat survival analysis of time-to-first-event was performed using a proportional hazards model.

Results and Conclusions: The annualized rate of global index events was 1.83% in the placebo group and 1.39% in the combined raloxifene dose groups (hazard ratio [HR], 0.75; 95% CI, 0.62-0.92). Analyzing individual dose groups separately yielded the same results (HR for 60 mg/day, 0.75; 95% CI, 0.60-0.96: HR for 120 mg/day, 0.75; 95% CI, 0.59-0.95). Subgroup analyses showed no significant interactions between age or hysterectomy status and the effect of raloxifene on the global index (interaction p > 0.1), whereas the global index risk reduction seemed to be greater in obese women compared with nonobese women (interaction p = 0.03). The significant 25% reduction in global index is compatible with a favorable risk-benefit safety profile when raloxifene is used for osteoporosis treatment in postmenopausal women. These results require confirmation in ongoing clinical trials.
Effects of Secreted Frizzled-Related Protein 3 on Osteoblasts In Vitro
Authors: Chung Yoon-Sok , Baylink David J , Srivastava Apurva K , Amaar Yousef , Tapia Blanca , Kasukawa Yuji , Mohan Subburaman
Published: April 2006

To examine if sFRP3s act as decoy receptors for Wnt, we examined the effects of recombinant sFRP3 on mouse osteoblast proliferation and differentiation. We found that sFRP3 unexpectedly increased osteoblast differentiation, suggesting it may act through other mechanisms besides acting as a decoy receptor for Wnt's.

Introduction: Secreted frizzled-related proteins (sFRPs) are a truncated form of frizzled receptor, missing both the transmembrane and cytosolic domains. Because previous studies have shown that sFRPs bind and act as decoy receptors for Wnt proteins that promote osteoblast differentiation, we postulated that sFRP3 acts as an inhibitor of osteoblast differentiation.

Materials and Methods: We examined the effects of mouse recombinant sFRP3 and/or Wnt-3A on cell proliferation and differentiation using MC3T3-E1 mouse osteoblasts and primary cultures of mouse bone marrow stromal cells. We evaluated the effects of sFRP3 on β-catenin levels using Western immunoblot analyses.

Results: We found that sFRP3 suppressed osteoblast cell number in a dose-dependent manner that was the result of a decrease in proliferation and not because of an increase in apoptosis. Surprisingly, sFRP3 increased osteoblast differentiation, which could not be explained based on sFRP3 acting as a decoy receptor for stimulatory Wnt's. Furthermore, sFRP3 did not inhibit Wnt3A-induced increase in alkaline phosphatase (ALP) activity. Wnt3A, but not sFRP3 treatment, increased cellular β-catenin levels, and sFRP3 failed to block Wnt3A-induced increase in cellular β-catenin levels. Treatment with endostatin, an agent known to degrade β-catenin, did not inhibit sFRP3-induced increase in ALP activity. sFRP1, like sFRP3, inhibited proliferation and stimulated ALP activity in MC3T3-E1 mouse osteoblasts.

Conclusions: Based on our findings, we conclude that sFRP3 decreased osteoblast proliferation and unexpectedly increased parameters of osteoblast differentiation. Based on our findings, we propose that sFRP3 may stimulate differentiation through a β-catenin-independent pathway in addition to its previously known function as a decoy receptor for Wnt's.
Different Aspects of Visual Impairment as Risk Factors for Falls and Fractures in Older Men and Women
Authors: de Boer Michiel R , Pluijm Saskia MF , Lips Paul , Moll Annette C , Völker-Dieben Hennie J , Deeg Dorly JH , van Rens Ger HMB
Published: April 2006

Visual impairment has been implicated as a risk factor for falling and fractures, but results of previous studies have been inconsistent. The relationship between several aspects of vision and falling/fractures were examined in a prospective cohort study in 1509 older men and women. The analyses showed that impaired vision is an independent risk factor for both recurrent falling and fractures.

Introduction: Falls and fractures are a major health problem among the elderly. Visual impairment has been implicated as a risk factor for both falls and fractures. However, results from studies are inconsistent. The inconsistency between findings can primarily be attributed to differences in the designs of these studies. Most studies have been cross-sectional or case-control studies, and many have not correctly adjusted for potential confounders. Furthermore, until now, the potential mediating effects of functional limitation, physical performance, and physical activity have not been examined.

Materials and Methods: A total of 1509 people was examined in 1995-1996. Contrast sensitivity was assessed with the VCTS_6000-1 chart for near vision. In addition, self-reported visual impairment was assessed by questions on recognizing faces from a distance of 4 m, reading the small print in the newspaper, and problems with glare. Furthermore, many potential confounders and mediators were assessed. Falls and fractures were assessed prospectively during a 3-year follow-up period. The associations between the vision variables and falls and fractures were examined using Cox proportional hazards analyses.

Results: After adjustment for potential confounders, contrast sensitivity was shown to be associated with recurrent falling (hazard ratio [HR] = 1.5), and the question on recognizing faces was shown to be associated with fractures (HR = 3.1). Furthermore, functional limitations and physical performance were shown to be mediators in the relationship between vision variables and recurrent falling/fractures.

Conclusions: The results indicate that impaired vision is an independent risk factor for falling and fractures, but different aspects of visual functioning may have different relationships to falling and fractures.
Role of the Androgen Receptor in Skeletal Homeostasis: The Androgen-Resistant Testicular Feminized Male Mouse Model
Authors: Vandenput Liesbeth , Swinnen Johannes V , Boonen Steven , Van Herck Erik , Erben Reinhold G , Bouillon Roger , Vanderschueren Dirk
Published: April 2006

The role of androgen receptor-mediated androgen action on bone was investigated in testicular feminized male (Tfm) mice. Cortical bone was found to be unresponsive to testosterone (T) in orchidectomized Tfm mice, whereas cortical thickness as well as trabecular BMD and structure were fully maintained by T in the corresponding Tabby control mice. These data show an essential role for androgen receptor-mediated androgen action in periosteal bone formation.

Introduction: Androgens can affect the male skeleton both directly—through activation of the androgen receptor (AR)—and indirectly—through stimulation of estrogen receptors after aromatization. We assessed the importance of AR-mediated androgen action on bone in a mouse model of androgen resistance.

Materials and Methods: Eight-week-old androgen-resistant testicular feminized male (Tfm) and Tabby control mice were orchidectomized (ORX) and treated for 4 weeks with a slow-release testosterone (T) pellet (delivering 167 μg/day) or a placebo pellet. A comprehensive analysis of the skeletal effects of androgen deficiency and replacement was performed using histomorphometry, QCT, and biochemical assessment of bone turnover.

Results: As expected, T increased trabecular BMD, volume, number, and width in ORX Tabby mice. In ORX Tfm mice, however, T had less effect on trabecular BMD and no effect on trabecular bone structure. T action on trabecular bone was associated with opposite changes in bone turnover: trabecular and endocortical bone turnover and serum levels of osteocalcin were all reduced by T in ORX Tabby mice, but not in ORX Tfm mice. T also increased cortical thickness (+16%), area, and density in ORX Tabby mice, but not in Tfm mice, resulting in greater bone strength in the Tabby control strain. The positive effects of T on cortical bone reflected a stimulatory effect on periosteal bone formation (+137%), which was again absent in Tfm mice.

Conclusions: These data show that, in male mice, AR-mediated T action is essential for periosteal bone formation and contributes to trabecular bone maintenance.
Quantitative Trait Loci That Modulate Femoral Mechanical Properties in a Genetically Heterogeneous Mouse Population
Authors: Volkman Suzanne K , Galecki Andrzej T , Burke David T , Miller Richard A , Goldstein Steven A
Published: April 2006

The goal of this study was to investigate genetic effects on mechanical properties of the mouse femur. We found evidence for QTL on eight chromosomes that affect mechanical traits. Some of these QTL may have primary effects on body weight or femoral geometry, and others seem to affect bone quality directly.

Introduction: Previous studies have shown a dependence of fragility-related fracture risk on genetic background. Although many of these studies investigated the effect of genetics on BMD, basic measures of bone geometry and mechanical integrity may provide a more comprehensive characterization of the genetic effects on bone fragility. The purpose of this study was to identify quantitative trait loci (QTL) that affect mechanical and material properties of cortical bone in a genetically heterogeneous mouse population.

Materials and Methods: A total of 486 female UM-HET3 mice was used for this study. UM-HET3 mice are produced as the offspring of (BALB/cJ × C57BL/6J) F1 females and (C3H/HeJ × DBA/2J) F1 males. Femurs from 18-month-old mice were tested to failure in four-point bending to assess mechanical properties of cortical bone; these properties were compared with genotype data from 185 biallelic loci. A permutation-based test was used to detect significant associations between genetic markers and mechanical traits. This test generates p values that account for the effect of testing multiple hypotheses. Throughout the experiment, p ≤ 0.05 was considered statistically significant. Analysis of covariance was used to examine possible effects of body weight and femoral geometry.

Results: We found evidence for genes on maternal chromosomes 11 and 13 and paternal chromosomes 2, 4, 7, 10, 11, and 17 that affect mechanical and material properties of femoral bone. The total variance explained by genetic effects on each mechanical trait ranges from 2.9% to 15.4%. Most of the identified polymorphisms influence mechanical traits even after adjustment for body weight. Adjustment for femoral geometry reduces the effects of some of the QTL, but those on chromosomes 2 and 10 do not seem to be influenced by femoral geometry.

Conclusions:Many genes and chromosomes are involved in the genetic control over mechanical integrity of cortical bone. QTL on paternal chromosomes 4 and 11 may mediate mechanical properties, at least in part, by modulation of femoral geometry. Other QTL identified here may directly affect bone tissue quality.
Predictive Value of Low BMD for 1-Year Fracture Outcomes Is Similar for Postmenopausal Women Ages 50-64 and 65 and Older: Results From the National Osteoporosis Risk Assessment (NORA)
Authors: Siris Ethel S , Brenneman Susan K , Miller Paul D , Barrett-Connor Elizabeth , Chen Ya-Ting , Sherwood Louis M , Abbott Thomas A
Published: April 2006

The relationship of low bone mass and fracture in younger postmenopausal women has not been extensively studied. In a large cohort of postmenopausal women ≥50 years of age, we found the relationship of BMD measured at peripheral sites and subsequent 1-year fracture risk to be similar between women <65 and those ≥65 years of age.

Introduction: Low bone mass and fractures are prevalent in older postmenopausal women. However, the frequency of low bone mass and fracture in younger postmenopausal women has not been studied extensively. There are very limited data regarding the association between BMD measurements and fractures in postmenopausal women who are between the ages of 50 and 64.

Materials and Methods: In the National Osteoporosis Risk Assessment (NORA) we studied the frequency of low bone mass and its association with fracture in women 50-64 years of age in comparison with women ≥65 of age. NORA enrolled 200,160 postmenopausal women ≥50 years of age who had no prior diagnosis of osteoporosis. Baseline BMD was measured at the heel, forearm, or finger. A 1-year follow-up survey requesting incident fractures since baseline was completed by 163,935 women, 87,594 (53%) of whom were 50-64 years of age. The association between BMD and fracture was assessed using logistic regression, adjusted for important covariates.

Results: Thirty-one percent of women 50-64 years of age had low bone mass (T scores ≤ −1.0) compared to 62% of women ≥65 years of age. During the first year of follow-up, 2440 women reported fractures of wrist/forearm, rib, spine, or hip, including 440 hip fractures. Nine hundred four women 50-64 years of age reported fractures, including 86 hip fractures, accounting for 37% of fractures and 20% of hip fractures reported in the entire NORA cohort. Relative risk for osteoporotic fracture was 1.5 for each SD decrease in BMD for both the younger and older groups of women.

Conclusion: Low BMD in younger postmenopausal women 50-64 years of age showed a 1-year relative risk of fracture similar to that found in women ≥65 years of age.
Skeletal Changes in Transgenic Male Mice Expressing Human Cytochrome P450 Aromatase
Authors: Peng ZhiQi , Li XiangDong , Mäkelä Sari , Väänänen H Kalervo , Poutanen Matti
Published: April 2006

In this study, we showed that overexpressing P450 aromatase in male mice can increase bone mass and strengthen the tibia. Probably as a result of the action of products of local estrogen biosynthesis at different stages of life, the increased bone mass in young mice was induced by decreased bone turnover, but in aged animals, it was induced by increased bone formation.

Introduction: To understand the skeletal responses to the testosterone/estrogen balance, especially to excess estrogen produced by extragonadal biosynthesis, we investigated the bone changes in transgenic mice overexpressing human aromatase.

Materials and Methods: Sixty-one young (40 days) and 25 aged (9 months) transgenic and wildtype (WT) mice were used. Bone samples were analyzed using pQCT, histomorphometry, and mechanical testing. Concentrations of testosterone (T) and estradiol (E2) were measured in serum and testicular interstitial fluid.

Results and Conclusions: Young P450 aromatase-positive (AROM+) mice had much higher trabecular BMD in the proximal tibia than WT mice, and the tissue area was significantly smaller in the former. Histomorphometric data further showed that the longitudinal growth rate of the tibia was decreased in AROM+ mice, and the bone formation rate (BFR) was decreased in trabecular bone and periosteum. All the changes were more striking in males than in females. Aged male AROM+ mice showed similar changes in trabecular bone as young animals, but their BFR was obviously increased. Another dramatic change was in the tibias of aged AROM+ mice: length was shorter (−23.2%), whereas ash weight was much heavier (+24.0%), and bending strength was markedly higher (+21.2%) compared with WT mice. The concentration of T was decreased in both serum and testicular interstitial fluid in young AROM+ mice versus WT animals; E2 levels were increased only in the testes of young AROM+ mice. However, in aged AROM+ mice, the levels of T and E2 were highly increased in both serum and testis versus WT animals. These results are in agreement with the suggestion that enhanced production of estrogen from testosterone in the peripheral tissues as a result of aromatase action can affect skeletal growth and strengthen bone in males. The results also suggest a marked difference in response between femur and tibia.