bluuebunny/crossref_metadata_2025 huggingface dataset:
Femoral Neck Bone Loss Predicts Fracture Risk Independent of Baseline BMD
Authors: Nguyen Tuan V , Center Jacqueline R , Eisman John A
Published: April 2006

Whereas low BMD is known to be a risk factor for fracture, it is not clear whether loss of BMD is also a risk factor. In elderly women, greater loss of BMD at the femoral neck was associated with increased risk of fracture, independent of baseline BMD and age.

Introduction: Baseline measurement of BMD predicts fracture risk. However, it is not clear whether short-term bone loss is an independent risk factor for fractures. This study was designed to investigate the relationship between changes in BMD and fracture risk in elderly women in the general population.

Materials and Methods: A total of 966 women ≥60 years of age (mean, 70 ± 6.7 [SD] years), who had been followed for an average of 10.7 years, were studied. Atraumatic fracture of the proximal femur (hip), symptomatic vertebral fracture, and other major fractures, excluding pathological fractures or those resulting from severe trauma, were recorded and confirmed by radiographs. Femoral neck and lumbar spine BMD was measured by DXA.

Results: During the follow-up period, 224 had sustained a fracture (including 43 hip, 71 symptomatic vertebrae, 37 proximal humerus, 46 forearm and wrist, and 27 rib and pelvis fractures). The annual rate of change in BMD in fracture women (−2.1 ± 4.2%) was significantly higher than that in nonfracture women (−0.8 ± 2.8%; p = 0.005). In the multivariable Cox's proportional hazards analysis, the following factors were significant predictors of fracture risk: femoral neck bone loss (relative hazard [RH], 1.4; 95% CI, 1.1-1.8 per 5% loss), baseline femoral neck BMD (RH, 2.0; 95% CI, 1.7-2.7 per SD), and advancing age (RH, 1.2; 95% CI, 1.1-1.4). The proportion of fractures attributable to the three factors was 45%. For hip fracture, the attributable risk fraction was ∼90%.

Conclusion: Bone loss at the femoral neck is a predictor of fracture risk in elderly women, independent of baseline BMD and age.
Angiogenesis Is Required for Successful Bone Induction During Distraction Osteogenesis
Authors: Fang Tony D , Salim Ali , Xia Wei , Nacamuli Randall P , Guccione Samira , Song HanJoon M , Carano Richard A , Filvaroff Ellen H , Bednarski Mark D , Giaccia Amato J , Longaker Michael T
Published: April 2006

The role of angiogenesis during mechanically induced bone formation is incompletely understood. The relationship between the mechanical environment, angiogenesis, and bone formation was determined in a rat distraction osteogenesis model. Disruption of either the mechanical environment or endothelial cell proliferation blocked angiogenesis and bone formation. This study further defines the role of the mechanical environment and angiogenesis during distraction osteogenesis.

Introduction: Whereas successful fracture repair requires a coordinated and complex transcriptional program that integrates mechanotransductive signaling, angiogenesis, and osteogenesis, the interdependence of these processes is not fully understood. In this study, we use a system of bony regeneration known as mandibular distraction osteogenesis (DO) in which a controlled mechanical stimulus promotes bone induction after an osteotomy and gradual separation of the osteotomy edges to examine the relationship between the mechanical environment, angiogenesis, and osteogenesis.

Materials and Methods: Adult Sprague-Dawley rats were treated with gradual distraction, gradual distraction plus the angiogenic inhibitor TNP-470, or acute distraction (a model of failed bony regeneration). Animals were killed at the end of distraction (day 13) or at the end of consolidation (day 41) and examined with μCT, histology, and immunohistochemistry for angiogenesis and bone formation (n = 4 per time-point per group). An additional group of animals (n = 6 per time-point per group) was processed for microarray analysis at days 5, 9, 13, 21, and 41.

Results and Conclusions: Either TNP-470 administration or disruption of the mechanical environment prevented normal osteogenesis and resulted in a fibrous nonunion. Subsequent analysis of the regenerate showed an absence of angiogenesis by gross histology and immunohistochemical localization of platelet endothelial cell adhesion molecule in the groups that failed to heal. Microarray analysis revealed distinct patterns of expression of genes associated with osteogenesis, angiogenesis, and hypoxia in each of the three groups. Our findings confirm the interdependence of the mechanical environment, angiogenesis, and osteogenesis during DO, and suggest that induction of proangiogenic genes and the proper mechanical environment are both necessary to support new vasculature for bone induction in DO.
Ovariectomy-Induced Bone Loss Varies Among Inbred Strains of Mice
Authors: Bouxsein Mary L , Myers Kelly S , Shultz Kathryn L , Donahue Leah R , Rosen Clifford J , Beamer Wesley G
Published: April 2006

There is a subset of women who experience particularly rapid bone loss during and after the menopause. However, the factors that lead to this enhanced bone loss remain obscure. We show that patterns of bone loss after ovariectomy vary among inbred strains of mice, providing evidence that there may be genetic regulation of bone loss induced by estrogen deficiency.

Introduction: Both low BMD and increased rate of bone loss are risk factors for fracture. Bone loss during and after the menopause is influenced by multiple hormonal factors. However, specific determinants of the rate of bone loss are poorly understood, although it has been suggested that genetic factors may play a role. We tested whether genetic factors may modulate bone loss subsequent to estrogen deficiency by comparing the skeletal response to ovariectomy in inbred strains of mice.

Materials and Methods: Four-month-old mice from five inbred mouse strains (C3H/HeJ, BALB/cByJ, CAST/EiJ, DBA2/J, and C57BL/6J) underwent ovariectomy (OVX) or sham-OVX surgery (n = 6-9/group). After 1 month, mice were killed, and μCT was used to compare cortical and trabecular bone response to OVX.

Results: The effect of OVX on trabecular bone varied with mouse strain and skeletal site. Vertebral trabecular bone volume (BV/TV) declined after OVX in all strains (−15 to −24%), except for C3H/HeJ. In contrast, at the proximal tibia, C3H/HeJ mice had a greater decline in trabecular BV/TV (−39%) than C57BL/6J (−18%), DBA2/J (−23%), and CAST/EiJ mice (−21%). OVX induced declines in cortical bone properties, but in contrast to trabecular bone, the effect of OVX did not vary by mouse strain. The extent of trabecular bone loss was greatest in those mice with highest trabecular BV/TV at baseline, whereas cortical bone loss was lowest among those with high cortical bone parameters at baseline.

Conclusions: We found that the skeletal response to OVX varies in a site- and compartment-specific fashion among inbred mouse strains, providing support for the hypothesis that bone loss during and after the menopause is partly genetically regulated.
Differential Effects of Teriparatide and Alendronate on Bone Remodeling in Postmenopausal Women Assessed by Histomorphometric Parameters
Authors: Arlot Monique , Meunier Pierre J , Boivin Georges , Haddock Lillian , Tamayo Juan , Correa-Rotter Ricardo , Jasqui Salomón , Donley David W , Dalsky Gail P , Martin Javier San , Eriksen Erik Fink
Published: April 2006

An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 μg with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment.

Introduction: Alendronate and teriparatide increased BMD, assessed by DXA, by different mechanisms of action, supported by changes in biochemical markers of bone turnover. The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment.

Materials and Methods: Patients were a cohort from a randomized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 μg and alendronate 10 mg in postmenopausal women with osteoporosis. Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months (n = 23) or 18 months (n = 14); 5 additional patients were biopsied from contralateral sides at 6 and 18 months. Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months (teriparatide, n = 8; alendronate, n = 9) and 15 patients at 18 months (teriparatide, n = 8; alendronate, n = 7). Data were analyzed by two-sample tests.

Results: Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months, whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months. Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group, returning to levels comparable with untreated postmenopausal women. In the teriparatide group, the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen, a biochemical marker of bone formation. The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups.

Conclusions: These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide.
Racial Differences in Rate of Decline in Bone Mass in Older Men: The Baltimore Men's Osteoporosis Study
Authors: Tracy J Kathleen , Meyer Walter A , Flores Raymond H , Wilson P David , Hochberg Marc C
Published: April 2006

Older black men have higher adjusted BMD than older white men. Using data from a longitudinal cohort study of older men followed for a mean of 18.8 ± 6.5 (SD) months, we found that older black men have a higher rate of decline in femoral neck and total hip BMD and femoral neck BMAD than older white men.

Introduction: Older black men have higher adjusted BMD compared with older white men. The difference in BMD may be caused by having attained higher peak bone mass as young adults and/or having a slower rate of decline in bone mass as adults. There are few published longitudinal data on change in bone mass in older white men and no published data for older black men.

Materials and Methods: Three hundred forty-nine white men and 119 black men ⩾65 of age (mean age, 75 ± 5.7 and 72 ± 5.6 years, respectively) who participated in the longitudinal component of the Baltimore Men's Osteoporosis Study returned for a second visit after a mean of 18.8 ± 6.5 (SD) months and were not taking medications used to treat low bone mass at either visit. BMD was measured at the femoral neck and total hip by Hologic-certified technicians using a QDR 2000 at the baseline visit (V1) and QDR 4500 at the first follow-up visit (V2). Participants also completed self-administered and interviewer-administered questionnaires and underwent standardized clinic examinations. Bone mineral apparent density (BMAD) at the femoral neck was calculated as an estimate of volumetric BMD. Annual crude and multiple variable adjusted percent changes in BMD and BMAD were calculated.

Results: In univariate analyses, black men had lower percent decline in femoral neck and total hip BMD and femoral neck BMAD than white men. In addition, older age at baseline, lower baseline weight, current smoking, and lower baseline BMD were associated with greater percent decline per year in femoral neck BMD; older age at baseline, current smoking, and lower baseline BMD were associated with greater percent decline per year in total hip BMD; and older age at baseline and lower baseline femoral neck BMAD were associated with greater percent decline per year in femoral neck BMAD. Racial differences in bone loss persisted in multiple variable models that controlled for other factors associated with change in BMD and BMAD.

Conclusions: Older black men seem to lose bone mass at a slower rate than older white men. These differences in the rate of bone loss may account, in part, for the racial disparities in BMD and BMAD and risk of osteoporotic fractures among older men.
Monthly Oral Ibandronate Therapy in Postmenopausal Osteoporosis: 1-Year Results From the MOBILE Study
Authors: Miller Paul D , Mcclung Michael R , Macovei Liviu , Stakkestad Jacob A , Luckey Marjorie , Bonvoisin Bernard , Reginster Jean-Yves , Recker Robert R , Hughes Claire , Lewiecki E Michael , Felsenberg Dieter , Delmas Pierre D , Kendler David L , Bolognese Michael A , Mairon Nicole , Cooper Cyrus
Published: April 2006

Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year.

Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens.

Materials and Methods: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly.

Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated.

Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.
Asymptomatic Vertebral Deformity as a Major Risk Factor for Subsequent Fractures and Mortality: A Long‐Term Prospective Study
Authors: Pongchaiyakul Chatlert , Nguyen Nguyen D , Jones Graeme , Center Jacqueline R , Eisman John A , Nguyen Tuan V
Published: April 2006

In elderly men and women, asymptomatic vertebral deformity was found to be associated with subsequent risk of symptomatic fractures, particularly vertebral fracture, and increased risk of mortality after a fracture.

Introduction: Vertebral deformity is associated with an increased risk of fracture and mortality. However, it is unclear whether the three events of vertebral deformity, fracture, and mortality are linked with each other and what role BMD plays in these linkages.

Materials and Methods: Vertebral deformity was determined from quantitative analysis of thoracolumbar spine X‐rays in 300 randomly individuals (114 men and 186 women) ⩾60 years of age (as of mid‐1989), who were randomly selected from the prospective Dubbo Osteoporosis Epidemiology Study. Incidence of atraumatic fractures and subsequent mortality were ascertained from 1989 to 2003. Cox's proportional hazards model was used to determine the association between asymptomatic vertebral deformities, osteoporotic fractures, and risk of mortality.

Results: The prevalence of asymptomatic vertebral deformity was 31% in men and 17% in women. During the follow‐up period, subjects with vertebral deformity had a significantly higher risk of any fracture than those without vertebral deformity (44% versus 29%; hazards ratio [HR], 2.2; 95% CI, 1.4‐3.7), particularly symptomatic vertebral fracture (relative risk [RR], 7.4; 95% CI, 3.2‐17.0). Mortality rate was highest after a symptomatic fracture among those with vertebral deformity (HR, 9.0; 95% CI, 3.1‐26.0). These associations were independent of age, sex, and BMD.

Conclusion: Vertebral deformity was a strong predictor of subsequent risk of fractures, particularly symptomatic vertebral fracture, and may modify fracture‐associated mortality in both elderly men and women.
Type XIII Collagen Strongly Affects Bone Formation in Transgenic Mice
Authors: Ylönen Riikka , Kyrönlahti Tuomo , Sund Malin , Ilves Mika , Lehenkari Petri , Tuukkanen Juha , Pihlajaniemi Taina
Published: April 2006

To characterize the function of type XIII collagen, a transmembrane protein occurring at cell adhesion sites, we generated transgenic mice overexpressing it. High transgene expression was detected in cartilage and bone. The overexpression mice developed an unexpected skeletal phenotype marked by a massive increase in bone mass caused by increased bone formation rather than impaired resorption.

Introduction: Type XIII collagen is a type II transmembrane protein that is expressed in many tissues throughout development and adult life. It is located in focal adhesions of cultured fibroblasts and other cells and in the adhesive structures of tissues. To further characterize the function of this protein, we generated transgenic mice overexpressing it. High transgene expression was detected in cartilage and bone in locations also containing the endogenous protein.

Materials and Methods: Col13a1 5′-flanking sequences were tested for their efficiencies to drive gene expression. Skeletal tissues of transgenic mice and wildtype littermates were compared using histological, immunohistochemical, and bone histomorphometrical analyses. Bone formation rate was measured by tetracycline double-labeling. Osteoclast number and resorption activity were determined using standard methods. RNA samples from transgenic and wildtype femurs were analyzed by Northern blotting and quantitative RT-PCR.

Results: There was no defect in early skeletal development, but the high bone mass phenotype became apparent in heterozygous mice at the age of 3-4 weeks. The changes were most noticeable in proximal long bones but were also detectable in calvarial bones. The cortical bone cross-sectional area and the volumetric BMD were highly increased, but the bone marrow was well formed. Histological and histomorphometric analysis showed that trabecular bone volume was not significantly altered. Because of the normal epiphyseal growth plates, the longitudinal growth was not affected. Bone formation rate was several times higher in the overexpression mice than in their normal littermates, whereas the osteoclast number and resorption activity were normal. RNA analysis revealed increased expression in the transcription factor Runx2 and IGF-II, both known to be involved in bone biology.

Conclusion: Overexpression of type XIII collagen in skeletal tissues leads postnatally to an abnormally high bone mass caused by increased bone formation rather than impaired resorption. The findings suggest that type XIII collagen has an important role in bone modeling, and in particular, it may have a function in coupling the regulation of bone mass to mechanical use.
Thapsigargin Modulates Osteoclastogenesis Through the Regulation of RANKL-Induced Signaling Pathways and Reactive Oxygen Species Production
Authors: Yip Kirk Hm , Zheng Ming H , Steer James H , Giardina Tindaro M , Han Renzhi , Lo Susan Z , Bakker Anthony J , Cassady A Ian , Joyce David A , Xu Jiake
Published: April 2006

The mechanism by which TG modulates osteoclast formation and apoptosis is not clear. In this study, we showed a biphasic effect of TG on osteoclast formation and apoptosis through the regulation of ROS production, caspase-3 activity, cytosolic Ca2+, and RANKL-induced activation of NF-κB and AP-1 activities.

Introduction: Apoptosis and differentiation are among the consequences of changes in intracellular Ca2+ levels. In this study, we investigated the effects of the endoplasmic reticular Ca2+-ATPase inhibitor, thapsigargin (TG), on osteoclast apoptosis and differentiation.

Materials and Methods: Both RAW264.7 cells and primary spleen cells were used to examine the effect of TG on RANKL-induced osteoclastogenesis. To determine the action of TG on signaling pathways, we used reporter gene assays for NF-κB and activator protein-1 (AP-1) activity, Western blotting for phospho-extracellular signal-related kinase (ERK), and fluorescent probes to measure changes in levels of intracellular calcium and reactive oxygen species (ROS). To assess rates of apoptosis, we measured changes in annexin staining, caspase-3 activity, and chromatin and F-actin microfilament structure.

Results: At concentrations that caused a rapid rise in intracellular Ca2+, TG increased caspase-3 activity and promoted apoptosis in osteoclast-like cells (OLCs). Low concentrations of TG, which were insufficient to measurably alter intracellular Ca2+, unexpectedly suppressed caspase-3 activity and enhanced RANKL-induced osteoclastogenesis. At these lower concentrations, TG potentiated ROS production and RANKL-induced NF-κB activity, but suppressed RANKL-induced AP-1 activity and had little effect on ERK phosphorylation.

Conclusion: Our novel findings of a biphasic effect of TG are incompletely explained by our current understanding of TG action, but raise the possibility that low intensity or local changes in subcellular Ca2+ levels may regulate intracellular differentiation signaling. The extent of cross-talk between Ca2+ and RANKL-mediated intracellular signaling pathways might be important in determining whether cells undergo apoptosis or differentiate into OLCs.
A New Population of Human Adult Dental Pulp Stem Cells: A Useful Source of Living Autologous Fibrous Bone Tissue (LAB)
Authors: Laino Gregorio , D'Aquino Riccardo , Graziano Antonio , Lanza Vladimiro , Carinci Francesco , Naro Fabio , Pirozzi Giuseppe , Papaccio Gianpaolo
Published: April 2006

Stem cells, derived from human adult dental pulp of healthy subjects 30-45 years of age, were cultured, and cells were selected using a FACSorter. A new c-kit+/CD34+/CD45− cell population of stromal bone producing cells (SBP/DPSCs) was selected, expanded, and cultured. These SBP/DPSCs are highly clonogenic and, in culture, differentiate into osteoblast precursors (CD44+/RUNX-2+), still capable of self-renewing, and then in osteoblasts, producing, in vitro, a living autologous fibrous bone (LAB) tissue, which is markedly positive for several bone antibodies. This tissue constitute an ideal source of osteoblasts and mineralized tissue for bone regeneration. In fact, after in vivo transplantation into immunocompromised rats, LAB formed lamellar bone-containing osteocytes.

Introduction: Recently it has been reported that human dental pulp stem cells (DPSCs) are detectable, in humans, only up to the age of 30 years and that they are able to produce in vitro only sporadic calcified nodules and to form, after transplantation in vivo, a mineralized tissue.

Materials and Methods: Stem cells, derived from human adult dental pulp of healthy subjects 30-45 years of age, were cultured, and cells were selected using a FACSorter. Light microscope, histochemistry, immunofluorescence, and RT-PCR analyses were performed to study both stem and differentiating cells.

Results and Conclusions: A new c-kit+/CD34+/CD45− cell population of stromal bone producing cells (SBP/DPSCs) has been selected by FACSorting, expanded, and cultured. These SBP/DPSCs are highly clonogenic and, in culture, differentiate into osteoblast precursors (CD44+/RUNX-2+), still capable of self-renewing, and in osteoblasts, producing, in vitro, a living autologous fibrous bone (LAB) tissue. This new-formed tissue is markedly positive for several antibodies for bone, including osteonectin, bone sialoprotein, osteocalcin, fibronectin, collagen III, and bone alkaline phosphatase (BALP). Cells producing LAB can be stored at −80°C for a long period of time and are an extraordinary source of osteoblasts and mineralized fibrous bone tissue. In this study, we also showed that, in aged humans, stem cells can be detected from their pulps. The produced LAB is a fibrous bone tissue resembling the human bone during mineralization, with an external layer formed by osteoblasts markedly positive for osteocalcin. This newly formed tissue constitute an ideal source of osteoblasts and mineralized tissue for bone regeneration. In fact, after in vivo transplantation into immunocompromised rats, LAB formed lamellar bone containing osteocytes.
Relationship Between Bone Morphology and Bone Quality in Male Tibias: Implications for Stress Fracture Risk
Authors: Tommasini Steven M , Nasser Philip , Schaffler Mitchell B , Jepsen Karl J
Published: April 2006

Biomechanical properties were assessed from the tibias of 17 adult males 17-46 years of age. Tissue-level mechanical properties varied with bone size. Narrower tibias were comprised of tissue that was more brittle and more prone to accumulating damage compared with tissue from wider tibias.

Introduction: A better understanding of the factors contributing to stress fractures is needed to identify new prevention strategies that will reduce fracture incidence. Having a narrow (i.e., more slender) tibia relative to body mass has been shown to be a major predictor of stress fracture risk and fragility in male military recruits and male athletes. The intriguing possibility that slender bones, like those shown in animal models, may be composed of more damageable material has not been considered in the human skeleton.

Materials and Methods: Polar moment of inertia, section modulus, and antero-posterior (AP) and medial-lateral (ML) widths were determined for tibial diaphyses from 17 male donors 17-46 years of age. A slenderness index was defined as the inverse ratio of the section modulus to tibia length and body weight. Eight prismatic cortical bone samples were generated from each tibia, and tissue-level mechanical properties including modulus, strength, total energy, postyield strain, and tissue damageability were measured by four-point bending from monotonic (n = 4/tibia) and damage accumulation (n = 4/tibia) test methods. Partial correlation coefficients were determined between each geometrical parameter and each tissue-level mechanical property while taking age into consideration.

Results: Significant correlations were observed between tibial morphology and the mechanical properties that characterized tissue brittleness and damageability. Positive correlations were observed between measures of bone size (AP width) and measures of tissue ductility (postyield strain, total energy), and negative correlations were observed between bone size (moment of inertia, section modulus) and tissue modulus.

Conclusions: The correlation analysis suggested that bone morphology could be used as a predictor of tissue fragility and stress fracture risk. The average mechanical properties of cortical tissue varied as a function of the overall size of the bone. Therefore, under extreme loading conditions (e.g., military training), variation in bone quality parameters related to damageability may be a contributing factor to the increased risk of stress fracture for individuals with more slender bones.
Effect of Hormone Replacement, Alendronate, or Combination Therapy on Hip Structural Geometry: A 3-Year, Double-Blind, Placebo-Controlled Clinical Trial
Authors: Greenspan Susan L , Beck Thomas J , Resnick Neil M , Bhattacharya Rajib , Parker Robert A
Published: April 2006

This study examined the effect of hormone replacement, alendronate, or combination therapy on hip structural geometry in 373 postmenopausal women over 3 years. We found that antiresorptive agents alone or in combination result in improvement in parameters of hip structural geometry and BMD. These data provide additional information regarding potential mechanisms for fracture reduction with antiresorptive therapy.

Introduction: Fracture reduction is only partially explained by increased BMD. The aim of this study was to examine changes in structural geometry of the hip, derived from DXA in postmenopausal women after treatment with antiresorptive agents.

Materials and Methods: This was a double-blind, placebo-controlled, randomized clinical trial of 373 women over the age of 65 years, who were randomized to hormone replacement therapy, alendronate, combination therapy, or placebo for 3 years. The outcomes included the DXA-derived hip structure analysis program by Beck, which is an engineering interpretation of the DXA data. The indices included cross-sectional area, section modulus (a measure of bending strength), outer diameter, cortical thickness, and buckling ratio (an index of cortical bone stability). Properties were measured in cross-sectional regions traversing the femur at the narrowest point on the femoral neck, the intertrochanteric region, and the proximal shaft.

Results: In the femoral neck, improvement in the hip structure analysis indices were generally significantly greater with combination therapy than either monotherapy; increases were also greater at the intertrochanter compared with hormone replacement therapy. For example, the section modulus at the intertrochanter and narrow neck increased 10.6% and 10.3%, respectively, with combination therapy, 9.1% and 7.3% with alendronate, 5.8% and 6.9% with hormone replacement therapy, and 3.4% and 3.2% with placebo (p < 0.01 across the four groups). Buckling ratio increased, suggesting decreased stability in the placebo group, whereas there was either no change or significant improvements (p < 0.05) in each active treatment group.

Conclusions: We conclude that changes in the distribution of bone mass underlying the improvements in density with antiresorptive agents in combination or alone have positive effects on structural strength and stability at the proximal femur. This study provides additional information on the potential mechanisms for fracture reduction with antiresorptive agents.
Skeletal Effects of Raloxifene After 8 Years: Results from the Continuing Outcomes Relevant to Evista (CORE) Study
Authors: Siris Ethel S , Harris Steven T , Eastell Richard , Zanchetta Jose R , Goemaere Stefan , Diez-Perez Adolfo , Stock John L , Song Jingli , Qu Yongming , Kulkarni Pandurang M , Siddhanti Suresh R , Wong Mayme , Cummings Steven R
Published: April 2006

In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE.

Introduction: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial.

Materials and Methods: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were ≥80% compliant with study medication in CORE.

Results: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio {HR}, 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene.

Conclusion: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.
New QCT Analysis Approach Shows the Importance of Fall Orientation on Femoral Neck Strength
Authors: Carpenter R Dana , Beaupré Gary S , Lang Thomas F , Orwoll Eric S , Carter Dennis R
Published: April 2006

The influence of fall orientation on femur strength has important implications for understanding hip fracture risk. A new image analysis technique showed that the strength of the femoral neck in 37 males varied significantly along the neck axis and that bending strength varied by a factor of up to 2.8 for different loading directions.

Introduction: Osteoporosis is associated with decreased BMD and increased hip fracture risk, but it is unclear whether specific osteoporotic changes in the proximal femur lead to a more vulnerable overall structure. Nonhomogeneous beam theory, which is used to determine the mechanical response of composite structures to applied loads, can be used along with QCT to estimate the resistance of the femoral neck to axial forces and bending moments.

Materials and Methods: The bending moment {My(θ)} sufficient to induce yielding within femoral neck sections was estimated for a range of bending orientations (θ) using in vivo QCT images of 37 male (mean age, 73 years; range, 65–87 years) femora. Volumetric BMD, axial stiffness, average moment at yield (My,avg), maximum and minimum moment at yield (My,max and My,min), bone strength index (BSI), stress-strain index (SSI), and density-weighted moments of resistance (Rx and Ry) were also computed. Differences among the proximal, mid-, and distal neck regions were detected using ANOVA.

Results: My(θ) was found to vary by as much as a factor of 2.8 for different bending directions. Axial stiffness, My,avg, My,max, My,min, BSI, and Rx differed significantly between all femoral neck regions, with an overall trend of increasing axial stiffness and bending strength when moving from the proximal neck to the distal neck. Mean axial stiffness increased 62% between the proximal and distal neck, and mean My,avg increased 53% between the proximal and distal neck.

Conclusions: The results of this study show that femoral neck strength strongly depends on both fall orientation and location along the neck axis. Compressive yielding in the superior portion of the femoral neck is expected to initiate fracture in a fall to the side.
Runx1/AML1/Cbfa2 Mediates Onset of Mesenchymal Cell Differentiation Toward Chondrogenesis
Authors: Wang YongJun , Belflower Ruth M , Dong Yu-Feng , Schwarz Edward M , O'Keefe Regis J , Drissi Hicham
Published: April 2006

Runx proteins mediate skeletal development. We studied the regulation of Runx1 during chondrocyte differentiation by real-time RT-PCR and its function during chondrogenesis using overexpression and RNA interference. Runx1 induces mesenchymal stem cell commitment to the early stages of chondrogenesis.

Introduction: Runx1 and Runx2 are co-expressed in limb bud cell condensations that undergo both cartilage and bone differentiation during murine development. However, the cooperative and/or compensatory effects these factors exert on skeletal formation have yet to be elucidated.

Materials and Methods: Runx1/Cbfa2 and Runx2/Cbfa1 were examined at different stages of embryonic development by immunohistochemistry. In vitro studies used mouse embryonic limb bud cells and assessed Runx expressions by immunohistochemistry and real-time RT-PCR in the presence and absence of TGFβ and BMP2. Runx1 was overexpressed in mesenchymal cell progenitors using retroviral infection.

Results: Immunohistochemistry showed that Runx1 and Runx2 are co-expressed in undifferentiated mesenchyme, had similar levels in chondrocytes undergoing transition from proliferation to hypertrophy, and that there was primarily Runx2 expression in hypertrophic chondrocytes. Overall, the expression of Runx1 remained significantly higher than Runx2 mRNA levels during early limb bud cell maturation. Treatment of limb bud micromass cultures with BMP2 resulted in early induction of both Runx1 and Runx2. However, upregulation of Runx2 by BMP2 was sustained, whereas Runx1 decreased in later time-points when type X collagen was induced. Although TGFβ potently inhibits Runx2 and type X collagen, it induces type II collagen mRNA and mildly but significantly inhibits Runx1 isoforms in the early stages of chondrogenesis. Virus-mediated overexpression of Runx1 in mouse embryonic mesenchymal cells resulted in a potent induction of the early chondrocyte differentiation markers but not the hypertrophy marker, type X collagen. Knockdown or Runx1 potently inhibits type II collagen, alkaline phosphatase, and Runx2 and has a late inhibitory effect on type X collagen.

Conclusion: These findings show a distinct and sustained role for Runx proteins in chondrogenesis and subsequent chondrocyte maturation. Runx1 is highly expressed during chondrogenesis in comparison with Runx2, and Runx1 gain of functions stimulated this process. Thus, the Runx genes are uniquely expressed and have distinct roles during skeletal development.
Contribution of Hip Strength Indices to Hip Fracture Risk in Elderly Men and Women
Authors: Ahlborg Henrik G , Nguyen Nguyen D , Nguyen Tuan V , Center Jacqueline R , Eisman John A
Published: April 2006

In this prospective, case-control study, femoral neck diameter, cross-sectional moment of inertia, or section modulus was an independent predictor of hip fracture risk after adjustment for BMD. However, the contribution of each of these indices to hip fracture prediction was modest in the presence of BMD.

Introduction: The relative contribution of measures of hip strength to hip fracture prediction is unclear. This study was designed to characterize the association between hip strength indices and hip fracture risk in relation to BMD in elderly men and women.

Materials and Methods: Seventy-one women and 25 men ≥60 years of age, who sustained a hip fracture during the study period of 1989–2003, were selected from the prospective, population-based Dubbo Osteoporosis Epidemiology Study. These fracture cases were randomly matched for age and sex in a 1:2 ratio with nonfracture individuals. BMD at the femoral neck was measured before the fracture event by DXA (Lunar DPX-L). Hip strength indices, including femoral neck diameter (FND), cross-sectional moment of inertia (CSMI), and section modulus (Z), were estimated by reanalysis of the image files using hip strength analysis software.

Results: In women, after adjustment for BMD, increased risk of hip fracture was associated with smaller FND (OR, 1.6; 95% CI, 1.0, 2.7), lower CSMI (OR, 1.8; 95% CI, 1.0, 3.2), or Z (OR, 1.6; 95% CI, 1.1, 5.1). In men, none of these hip strength indices were significant predictors of fracture risk. However, using the results in women as a prior distribution, it was estimated that the BMD-adjusted OR for FND (OR, 1.5; 95% CI, 1.0, 2.3), CSMI (OR, 1.6; 95% CI, 1.0, 2.5), or Z (OR, 2.3; 95% CI, 1.4, 3.9) was each significantly associated with hip fracture risk in men. In the logistic regression model, BMD alone accounted for 32% and 16% of the variance of fracture liability in women and men, respectively. The addition of FND, CSMI, or Z to the model increased the respective variance proportion to 34% and 19%.

Conclusions: These data suggest that smaller FND and lower CSMI or Z is an independent risk factor for hip fracture in both women and men. However, the contribution of these measures to hip fracture prediction over and above BMD is likely modest.
Identification of High‐Risk Individuals for Hip Fracture: A 14‐Year Prospective Study
Authors: Nguyen Nguyen D , Pongchaiyakul Chatlert , Center Jacqueline R , Eisman John A , Nguyen Tuan V
Published: April 2006

In this 14‐year prospective study, men and women were found to share a common set of risk factors for hip fracture: low BMD, postural instability and/or quadriceps weakness, a history of falls, and prior fracture. The combination of these risk factors accounted for 57% and 37% of hip fractures in women and men, respectively.

Introduction: Risk factors for hip fracture, including low BMD, identified in women, have not been shown to be useful in men. It is also not known whether fall‐related factors (muscle strength and postural instability) predict hip fracture. This study examined the association between falls‐related factors and hip fractures in elderly men and women.

Materials and Methods: This is an epidemiologic, community‐based prospective study, which included 960 women and 689 men ≥60 years of age who have been followed for a median of 12 years (interquartile range, 6–13). The number of person‐years was 9961 for women and 4463 for men. The outcome measure was incidence of hip fracture. Risk factors were femoral neck BMD (FNBMD), postural sway, quadriceps strength, prior fracture, and fall.

Results: Between 1989 and 2003, 115 (86 women) sustained a hip fracture. The risk of hip fracture (as measured by hazards ratio [HR]) was increased by 3.6‐fold (95% CI: 2.6–4.5) in women and 3.4‐fold (95% CI: 2.5–4.6) in men for each SD (0.12 g/cm2) reduction in FNBMD. After adjusting for BMD, the risk of hip fracture was also increased in individuals with the highest tertile of postural sway (HR: 2.7; 95% CI: 1.6–4.5) and low tertiles of quadriceps strength (HR: 3.0; 95% CI: 1.3–6.8). Furthermore, a history of fall during the preceding 12 months and a history of fracture were independent predictors of hip fracture. For each level of BMD, the risk of hip fracture increased linearly with the number of non‐BMD risk factors. Approximately 57% and 37% of hip fracture cases in women and men, respectively, were attributable to the presence of risk factors, osteoporosis (BMD T score ≤ −2.5), and advancing age.

Conclusions: Men and women had a common set of risk factors for hip fracture: low BMD, postural instability and/or quadriceps weakness, a history of falls, and prior fracture. Preventive strategies should simultaneously target reducing falls and improvement of bone strength in both men and women.
Increased Prevalence of Radiological Spinal Deformities in Active Acromegaly: A Cross-Sectional Study in Postmenopausal Women
Authors: Bonadonna Stefania , Mazziotti Gherardo , Nuzzo Monica , Bianchi Antonio , Fusco Alessandra , De Marinis Laura , Giustina Andrea
Published: April 2006

This cross-sectional study shows that high numbers of postmenopausal women with acromegaly develop vertebral fractures in relation to the activity of disease. In patients with active acromegaly, vertebral fractures occur even in presence of normal BMD, whereas in patients with controlled acromegaly, vertebral fractures are always accompanied by a pathological BMD.

Introduction: We studied the frequency of radiological vertebral fractures in a cohort of postmenopausal women with active or controlled acromegaly.

Materials and Methods: Thirty-six postmenopausal acromegalic patients (15 with active and 21 with controlled disease) were evaluated for BMD, bone metabolism (serum 25-hydroxyvitamin D, PTH, bone-specific alkaline phosphatase {BSALP}, and urinary deoxypyridinoline {Dpd}), and vertebral quantitative morphometry. Thirty-six nonacromegalic postmenopausal women, matched for age, were selected among the patients consulting the Bone Center as a control group for BMD evaluation and vertebral quantitative morphometry.

Results: Vertebral fractures were shown in 19 patients (52.8%) and 11 controls (30.6%; χ2: 3.7; p = 0.06). Fractured acromegalic women were older and had higher serum IGF-1, Dpd, and BSALP and lower T score and serum vitamin D values compared with nonfractured patients. Moreover, the fractured women had a longer diagnosis and were in the postmenopausal period for a longer period than the nonfractured women. The fracture rate was significantly higher in active than in controlled acromegaly (80% versus 33.3%; χ2: 7.6; p = 0.008). The patients with active acromegaly who fractured (12 cases) had significantly higher serum IGF-1 values (356 ng/ml; range: 212–950 versus 120 ng/ml; range: 84–217; p < 0.001) and T scores (−1.3 SD, range: −2.9 to +1.3 versus −2.7 SD, range: −3.4 to −1.5, p = 0.04) compared with the fractured women whose disease was controlled (7 cases). All fractured women with controlled acromegaly had T scores <−1.0 SD (57.1% of them had osteoporosis, and 42.9% were osteopenic). In contrast, 41.7% of women whose fractures were associated with active disease had a normal T score (>−1.0 SD), whereas osteopenia and osteoporosis were found only in 33.3% and 25.0% of them, respectively.

Conclusions: This cross-sectional study shows that high numbers of postmenopausal women with acromegaly develop vertebral fractures in relation to the activity of disease. Furthermore, our study shows that, in patients with active acromegaly, vertebral fractures occur even in the presence of normal BMD, whereas in patients with controlled acromegaly, vertebral fractures are always accompanied by a pathological BMD.