Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis.

OBJECTIVE: Cartilage loss observed in osteoarthritis (OA) is prevented when osteoclasts in the subchondral bone are inhibited in mice. Here, we investigated the role of the osteoclast secretome and of the lipid mediator sphingosine 1-phosphate (S1P) in chondrocyte metabolism and OA. MATERIALS AND METHODS: We used SphK1LysMCre and wild type mice to assess the effect of murine osteoclast secretome in chondrocyte metabolism. Gene and protein expressions of matrix metalloproteinase (Mmp) were quantified in chondrocytes and explants by RT-qPCR and Western blots. SphK1LysMCre mice or wild type mice treated with S1P2 receptor inhibitor JTE013 or anti-S1P neutralizing antibody sphingomab are analyzed by OA score and immunohistochemistry. RESULTS: The osteoclast secretome increased the expression of Mmp3 and Mmp13 in murine chondrocytes and cartilage explants and activated the JNK signaling pathway, which led to matrix degradation. JTE013 reversed the osteoclast-mediated chondrocyte catabolism and protected mice against OA, suggesting that osteoclastic S1P contributes to cartilage damage in OA via S1P/S1P2 signaling. The activity of sphingosine kinase 1 (SphK1) increased with osteoclast differentiation, and its expression was enhanced in subchondral bone of mice with OA. The expression of Mmp3 and Mmp13 in chondrocytes was low upon stimulation with the secretome of Sphk1-lacking osteoclasts. Cartilage damage was significantly reduced in SphK1LysMCre mice, but not the synovial inflammation. Finally, intra-articular administration of sphingomab inhibited the cartilage damage and synovial inflammation. CONCLUSIONS: Lack of S1P in myeloid cells and local S1P neutralization alleviates from osteoarthritis in mice. These data identify S1P as a therapeutic target in OA.

Microcracks in subchondral bone plate is linked to less cartilage damage.

OBJECTIVES: Osteoarthritis (OA) is a disease of the whole joint characterized by cartilage loss and subchondral bone remodeling. The role of microcracks in cartilage integrity and subchondral bone homeostasis is not fully understood. The main goal of this work was to evaluate microcrack density in both calcified cartilage and subchondral bone plate in relation to cartilage damage in humans and to better define the association of microcracks and osteocyte density in subchondral bone. METHODS: We investigated 18 bone cores from cadaveric human knees that were stained with En-Bloc Basic Fuchsin. We quantified microcrack density, osteocyte density, cartilage surfaces and cartilage damage. The presence of microcracks was confirmed for each bone core by scanning electron microscopy. Finally, trabecular subchondral bone parameters were measured by micro-CT. RESULTS: Microcracks were detected in both calcified cartilage and subchondral bone plate. The density of microcracks in both calcified cartilage (CC) and subchondral bone plate (SBP) was negatively correlated with cartilage damage (r = -0.45, p < 0.05). The presence of microcracks in SBP was associated with a lower histological OA score. Osteocytes formed a dendrite network that abruptly stopped at the border of calcified cartilage. Osteocyte density in subchondral bone plate was increased in the presence of microcracks in calcified cartilage. CONCLUSIONS: Subchondral bone plate microcracks might be required for maintaining cartilage homeostasis. Microcracks in calcified cartilage may trigger osteocyte density in subchondral bone plate with subsequent regulation of subchondral bone remodeling to prevent cartilage damage.

Secular trends of hip fractures in France: impact of changing characteristics of the background population.

INTRODUCTION: Hip fractures are a societal burden because of their high morbidity and mortality and the cost they generate. With the aging of the population, worries grow about an increase of the incidence and incidence rate of hip fracture in the future. Controversial data have been provided in relation to the referencepopulation used. The aim of this study was to assess the impact of the choice of the reference population in the incidence rate of hip fracture. METHODS: Data were extracted from the French National Hospital Database related to the hospitalizations for hip fracture in France between 2002 and 2013 in patients over 59 years and were classified by gender and age (59-74, 75-84, over 84 years, over 59 years). The crude incidence rates of hip fracture were calculated by dividing the number of hospitalizations for hip fracture by the corresponding populations. To assess the impact of the choice of the reference population, we then calculated the adjusted incidence rates using direct standardization on age for the 2013 reference population. RESULTS: From 2002 to 2013, the incidence of hip fracture rose by 4.8% in women (from 49,287 to 51,661) and 21.8% in men (from 12,716 to 15,482) aged over 59 years. Meanwhile, French population over 59 years increased more with a rise of 21.3% in women and 28.7% in men, resulting in a decrease in the crude incidence rates of 13.6% in women and 5.4% in men. However, this decrease was larger after direct standardization on the 2013 population of reference as 25.6% in women and 19.2% in men as a result of a difference in age-structure of the population. CONCLUSIONS: The incidence of hip fractures continues to grow despite a reduced incidence rate throughout a 12-year-period.

Multiscale and multimodality computed tomography for cortical bone analysis.

In clinical studies, high resolution peripheral quantitative computed tomography (HR-pQCT) is used to separately evaluate cortical bone and trabecular bone with an isotropic voxel of 82 µm3, and typical cortical parameters are cortical density (D.comp), thickness (Ct.Th), and porosity (Ct.Po). In vitro, micro-computed tomography (micro-CT) is used to explore the internal cortical bone micro-structure with isotropic voxels and high resolution synchrotron radiation (SR); micro-CT is considered the 'gold standard'. In 16 tibias and 8 femurs, HR-pQCT measurements were compared to conventional micro-CT measurements. To test modality effects, conventional micro-CT measurements were compared to SR micro-CT measurements at 7.5 µm3; SR micro-CT measurements were also tested at different voxel sizes for the femurs, specifically, 7.5 µm3 versus 2.8 µm3. D.comp (r = -0.88, p < 10-3) was the parameter best correlated with porosity (Po.V/TV). The correlation was not affected by the removal of pores under 130 µm. Ct.Th was also significantly highly correlated (r = -0.89 p < 10-3), while Ct.Po was correlated with its counterpart Po.V/TV (r = 0.74, p < 10-3). From SR micro-CT and conventional micro-CT at 7.5 µm3 in matching areas, Po.V/TV and pore diameter were underestimated in conventional micro-CT with mean ± standard deviation (SD) biases of -2.5 ± 1.9% and -0.08 ± 0.08 mm, respectively. In contrast, pore number (Po.N) and pore separation (Po.Sp) were overestimated with mean ± SD biases of +0.03 ± 0.04 mm-1 and +0.02 ± 0.04 mm, respectively. The results from the tibia and femur were similar when the results of SR micro-CT at 7.5 µm3 and 2.8 µm3 were compared. Po.V/TV, specific surface of pores (Po.S/Po.V), and Po.N were underestimated with mean biases of -1.7 ± 0.9%, -4.6 ± 4.4 mm-1, and -0.26 ± 0.15 mm-1, respectively. In contrast, pore spacing was overestimated at 7.5 µm3 compared to 2.8 µm3 with mean biases of 0.05 ± 0.03 mm. Cortical bone measurements from HR-pQCT images provided consistent results compared to those obtained using conventional micro-CT at the distal tibia. D.comp was highly correlated to Po.V/TV because it considers both the micro-porosity (Haversian systems) and macro-porosity (resorption lacunae) of cortical bone. The complexity of canal organization, (including shape, connectivity, and surface) are not fully considered in conventional micro-CT in relation to beam hardening and cone beam reconstruction artifacts. With the exception of Po.V/TV measurements, morphological and topological measurements depend on the characteristics of the x-ray beam, and to a lesser extent, on image resolution.

Prognostic factors of gingival-alveolar squamous cell carcinoma of the maxilla.

OBJECTIVES: To determine prognostic factors in gingivo-alveolar squamous cell carcinoma of the maxilla (GA-SCC-M), and particularly the prognostic value of both vertical and antero-posterior tumor spread. MATERIAL AND METHODS: Our retrospective study included all naïve-treatment patients treated in our center between 2006 and 2013 for GA-SCC-M. Posterior involvement was considered when the tumor extended behind the mesial side of the first maxillary molar. Spread posterior to the maxillary tuberosity was defined by the spread to at least one of the following structures: pterygomaxillary fissure, pterygoid muscles, and processes. Involvement of the maxillary sinus floor, nasal fossa, and orbital floor was assessed, concerning the vertical spread. RESULTS: A radiological tumor spread to the nasal fossa, maxillary sinus floor, and orbital floor were prognostic factors independently of age, cervical lymph node metastasis and positive margins in multivariate analysis (p < 0.05). Radiological suggested spread tended to be noticeably more predictive of a poor prognosis than histological proven tumoral spread. The prognosis was not significantly different between clinical tumoral spread anteriorly or posteriorly to the first molar (p = 0.46). The prognosis was not worsened, even in case of radiological suggested spread posterior to the maxillary tuberosity (p = 0.09). CONCLUSION: A vertical radiological spread of GA-SCC-M was a prognostic factor but not the extension posteriorly to the maxillary tuberosity. T4b tumors were mostly resectable, proving that a T4b stage was not predictive of unresectability in GA-SCC-M of the maxilla.

Disrupted trabecular bone micro-architecture in middle-aged male HIV-infected treated patients.

OBJECTIVES: HIV-infected individuals are at increased risk of incident fractures. Evaluation of trabecular bone micro-architecture is an important tool to assess bone strength, but its use has not yet been reported in middle-aged HIV-infected male individuals. The aim of the study was to compare bone micro-architecture between HIV-infected and HIV-uninfected men. METHODS: In this cross-sectional study, 53 HIV-infected male individuals with a mean (± standard deviation) age of 49 ± 9 years who had been receiving antiretroviral therapy including tenofovir disoproxil fumarate (DF) for at least 60 months were compared with 50 HIV-uninfected male controls, matched for age and ethnic origin. We studied the volumetric bone density and micro-architecture of the radius and tibia using high-resolution peripheral quantitative computed tomography (HR-p QCT). RESULTS: Volumetric trabecular bone density was 17% lower in the tibia (P < 10(-4) ) and 16% lower in the radius (P < 10(-3) ) in HIV-infected patients compared with controls. By contrast, the cortical bone density was normal at both sites. The tibial trabecular micro-architecture differed markedly between patients and controls: bone volume/total volume (BV/TV) and trabecular number were each 13% lower (P < 10(-4) for both). Trabecular separation and inhomogeneity of the network were 18% and 24% higher in HIV-infected patients than in controls, respectively. The radial BV/TV and trabecular thickness were each 13% lower (P < 10(-3) and 10(-2) , respectively). Cortical thickness was not different between the two groups. CONCLUSIONS: The findings of lower volumetric trabecular bone density and disrupted trabecular micro-architectural parameters in middle-aged male HIV-infected treated patients help to explain bone frailty in these patients.

Dementia is a major risk factor for hip fractures in patients with chronic kidney disease.

UNLABELLED: Chronic kidney disease increases the risk of hip fractures which can be promoted by dementia. We here showed that dementia increased the risk of hip fractures in dialysis patients, but in a similar manner than without dialysis. Attention should be paid to dementia to prevent hip fractures. INTRODUCTION: Hip fractures (HF) are associated with significant morbidity and is further increased in patients with chronic kidney disease (CKD). Dementia, frequent in CKD, might be a risk factor for HF. We here aimed to assess if dementia increased the risk of hip fracture in CKD. METHODS: The study was derived from the French National Database of Hospitalization. Data were obtained over the period 2011-2013. Three populations of subjects >60 years were extracted. Hip fractures, dialysis, and dementia were the main studied factors. The three populations were crossed to estimate the fracture risk based on dementia or dialysis, adjusted for age and gender. The fracture risk was calculated using a multiple logistic regression model. RESULTS: Over this period, 213,180 patients experienced a HF, 660,434 patients were diagnosed for dementia, and 47,430 patients were on dialysis. There was an effect of age and gender on the incidence of HF and dementia. In CKD patients, the risk of HF was significantly higher in demented patients compared to those without dementia: OR 2.0 [95 % CI 1.7-2.4], this being the same for men (OR 2.4 [1.8-3.1]) and women (OR 2.6 [2.0-3.3]) and at any age. However, the adjusted risk for HF in demented patients on dialysis therapy is not different than in demented patients without CKD (OR 1.3 [1.0-1.6]). CONCLUSIONS: Dementia significantly increases the risk of HF in patients on dialysis, but this risk in demented patients is equally high whether receiving dialysis therapy or not. These results highlight dementia as a major risk factor for HF in dialysis and indicate that reduction of fracture risk should include dementia as a risk factor.

Bone status and fractures in 85 adults with Wilson's disease.

UNLABELLED: Wilson's disease is characterized by copper deposition, especially in the liver and central nervous system. We assessed the prevalent fractures and bone mineral density (BMD) and related risk factors in 85 patients. BMD was normal, but patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk for fractures. INTRODUCTION: Wilson's disease (WD) is characterized by copper deposition, especially in the liver and central nervous system. Two studies showed a high prevalence of osteoporosis in WD patients. We wanted to assess the prevalent fractures and bone mineral density (BMD) and to identify risk factors for bone loss and fractures in a large group of WD patients. METHODS: In this prospective cross-sectional survey at National center of reference for WD, we included 85 patients, 47 women, and 38 men, with a mean age of 35 ± 10 years, and mean time from diagnosis to study of 21 ± 9 years; 57 (67%) patients had neurological signs. Peripheral fractures, prevalent radiological vertebral fractures (VFx), and dual-energy X-ray absorptiometry BMD measurements at the femoral neck (FN) and lumbar spine (LS) were studied. RESULTS: Mean LS and FN Z-score was normal (-0.37 ± 1.20 at LS and -0.06 ± 1.20 at FN). BMI <19 kg/m(2) and amenorrhea were associated with low BMD. Prevalent peripheral fractures were noted in 43 (51%) and VF in 7 (8%) patients. Severity of neurological involvement and male sex was associated with peripheral fractures, whereas older age, severe neurological involvement, and low BMD and Z-score values were associated with VF. CONCLUSION: Our data showing normal BMD overall do not support routine bone status evaluation in adults with WD. However, patients with severe neurological involvement, low BMI, and/or amenorrhea are at risk factors for fractures and may require specific monitoring.

Incidence and risk factors for hip fractures in dialysis patients.

UNLABELLED: This study described the incidence of hip fractures, associated diseases, and related costs generated in dialysis versus non-dialysis patients. INTRODUCTION: Skeletal fractures are a great concern in chronic kidney disease patients and, in particular, hip fractures that enhance the mortality. We aimed to accurately determine the incidence of hip fractures and associated diseases and to calculate the costs generated in dialysis patients. METHODS: We obtained data from the 2010 French National Hospital Database. We first extracted the hospital stays related to hip fractures as a primary diagnosis according to the ICD-10 codes and then the hospitalizations for dialysis. We compared the frequency of comorbidities in both populations. RESULTS: Among the 88,962 patients who suffered from hip fractures, 362 were on dialysis. The incidence was significantly higher in dialysis patients (x4) compared to non-dialysis patients. Women on dialysis experienced hip fractures at an earlier age than non-dialysis women. Dementia was identified as a major risk factor in the dialysis patients (72 vs. 26%, p < 0.0001). Moreover, diabetes and cardiovascular diseases were comorbidities strongly associated with hip fractures in both gender, but hypertension and malnutrition were observed exclusively in men on dialysis. Mortality rate and length of hospital stay were increased (5 days) in both genders. CONCLUSION: The incidence of hip fractures is increased in dialysis patients, affecting a larger percentage of men and women on dialysis than in the non-dialysis population and enhancing the financial burden and mortality. Dementia is a major risk factor for hip fractures in dialysis patients in addition to diabetes and cardiovascular diseases.

Strontium ranelate decreases the incidence of new caudal vertebral fractures in a growing mouse model with spontaneous fractures by improving bone microarchitecture.

UNLABELLED: Young mice over-expressing Runx2 fail to gain bone relative to wild type mice with growth and present spontaneous fractures. It allows, for the first time in rodents, direct assessment of anti-fracture efficacy of strontium ranelate which was able to decrease caudal vertebrae fracture incidence through an improvement of trabecular and cortical architecture. INTRODUCTION: The aim was to investigate whether strontium ranelate was able to decrease fracture incidence in mice over-expressing Runx2, model of severe developmental osteopenia associated with spontaneous vertebral fractures. METHODS: Transgenic mice and their wild type littermates were treated by oral route with strontium ranelate or vehicle for 9 weeks. Caudal fracture incidence was assessed by repeated X-rays, resistance to compressive loading by biochemical tests, and bone microarchitecture by histomorphometry. RESULTS: Transgenic mice receiving strontium ranelate had significantly fewer new fractures occurring during the 9 weeks of the study (-60%, p < 0.05). In lumbar vertebrae, strontium ranelate improves resistance to compressive loading (higher ultimate force to failure, +120%, p < 0.05) and trabecular microarchitecture (higher bone volume and trabecular number, lower trabecular separation, +60%, +50%, -39%, p < 0.05) as well as cortical thickness (+17%, p < 0.05). In tibiae, marrow cavity cross-section area and equivalent diameter were lower (-39%, -21%, p < 0.05). The strontium level in plasma and bone was in the same range as the values measured in treated postmenopausal women. CONCLUSIONS: This model allows, for the first time, direct assessment of anti-fracture efficacy of strontium ranelate treatment in rodents. In these transgenic mice, strontium ranelate was able to decrease caudal vertebral fracture incidence through an improvement of trabecular and cortical architecture.

Complex segregation analysis accounting for GxE of bone mineral density in European pedigrees selected through a male proband with low BMD.

Osteoporosis is a common multifactorial disorder characterized by low bone mass (BMD) and high susceptibility to low-trauma fractures. Family and twin studies have found a strong genetic component in the determination of BMD, but the mode of inheritance of this trait is not yet fully understood. BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. Detection of potential gene-environment interactions is of great interest in the determination of bone health status. Here we have conducted segregation analyses, using the regressive class D models, in a sample of 100 European pedigrees (NEMO) with 713 subjects (524 measured for phenotypes) identified via a male with low BMD values at either the Lumbar Spine or the Femoral Neck. Segregation analyses were conducted on the residuals of LS-BMD and FN-BMD adjusted for gender, age and BMI. We tested for gene-covariate (GxE) interactions, and investigated the impact of significant GxE interactions on segregation results. Without GxE a major effect was found to be marginally significant in LS-BMD and highly significant in FN-BMD. For both traits the Mendelian hypothesis was rejected. Significant Age x gene and BMI x gene interactions were revealed. Accounting for GxE increased statistical evidence for a major factor in LS-BMD, and improved the fit of the data to the Mendelian transmission model for both traits. The best fitting models suggested a codominant major gene accounting for 45% (LS-BMD) and 44% (FN-BMD) of the adjusted BMDs. However, substantial residual correlations were also found, and these remained highly significant after accounting for the major gene.

Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II.

CONTEXT: Genetic factors are important determinants of bone mineral density (BMD). The fact that mutations in the ClC-7 chloride channel cause autosomal dominant osteopetrosis (ADOII) make the CLCN7 gene an attractive candidate for the regulation of bone density. OBJECTIVE: The objective of the study was to investigate the association between polymorphisms in the CLCN7 gene and BMD in postmenopausal women and with clinical variability in ADOII. DESIGN: This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene. PARTICIPANTS: A total of 425 postmenopausal women aged 64 +/- 7 yr participated in the study. We also investigated an ADOII family with low penetrance comprising 18 mutation carriers. MAIN OUTCOME MEASURE(S): In our postmenopausal cohort, individual single-nucleotide polymorphism genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and the femoral neck and with the bone resorption marker deoxypyridinoline (D-Pyr/Crea). The same polymorphisms on the nonmutated CLCN7 allele were investigated for association with the variability of the ADOII phenotype. RESULTS: Analysis by multiple linear regression revealed a significant association between the ss genotype of the VNTR and higher Z-score values (P = 0.029). The haplotype 4, which comprises the long allele of the VNTR, was found to be significantly associated with lower femoral neck Z-score values (P = 0.011). Furthermore, we found an association of the ss genotype of the VNTR with lower levels of the bone resorption marker D-Pyr/Crea (P = 0.015), whereas haplotype 4 was associated with higher D-Pyr/Crea levels (P = 0.039). In the ADOII family, we could demonstrate that haplotype 3, which contains the s-allele of the VNTR, is associated with a slightly higher probability that mutation carriers develop osteopetrosis (P = 0.029). In both cases the association seems largely to be driven by the VNTR genotype but is further strengthened if surrounding polymorphisms are added to the analysis. CONCLUSION: We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype.

LRP5 gene polymorphisms and idiopathic osteoporosis in men.

Mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have demonstrated the role of LRP5 in bone mass acquisition. LRP5 variants were recently reported to contribute to the population-based variance in vertebral bone mass and size in males. To investigate whether LRP5 variants are implicated in idiopathic male osteoporosis, we studied 78 men with low BMD (<2.5 T score or < -2 Z score) aged less than 70 years (mean +/- SD: 50 +/- 16 years) in whom secondary causes of osteoporosis had been excluded and 86 controls (51 +/- 10 years). Genotypes and haplotypes were based on LRP5 missense substitutions in exons 9 (c.2047G > A, p.V667M) and 18 (c.4037C > T, p.A1330V), and their association with osteoporosis evaluated after adjustment for multiple clinical and environmental variables using logistic regression. The presence of osteoporosis was significantly associated with LRP5 haplotypes (P = 0.0036) independent of age (P = 0.006), weight (P = 0.004), calcium intake (P = 0.002), alcohol (P = 0.005) and tobacco (P = 0.004) consumption. Accordingly, the odds ratio for osteoporosis was 3.78 (95% CI 1.27-11.26, P < 0.001) in male carriers of haplotype 3 (c.2047A-4037T, n = 20 cases and 12 controls) versus homozygous carriers of haplotype 1 (c.2047G-4037C, n = 42 cases and 61 controls). In conclusion, these data indicate beyond a significant role for environmental factors, an association between LRP5 variants and idiopathic osteoporosis in males, pointing to a role of LRP5 in this disease.

BMD is reduced in HIV-infected men irrespective of treatment.

UNLABELLED: Osteoporosis has be reported to be a complication of active antiretroviral therapy of HIV infection. We studied 148 HIV-infected men stratified according to their treatment. Our data show that these patients have an average 9% decreased BMD, irrespective of their treatment. Low body mass index and high resorption markers were associated with low bone density. INTRODUCTION: Osteoporosis has been reported in HIV-infected (HIV+) patients, and it has been suggested that it may be linked to protease-inhibitor treatments (PI). MATERIALS AND METHODS: To assess this risk and to investigate its putative link with treatments, we compared the bone density of HIV+ men, who were either receiving treatment (including PI [PI+], n = 49; without PI [PI-], n = 51) or untreated (UT, n = 48). We included 81 age-matched control HIV-negative (HIV-) males (age, 40 +/- 8 years). RESULTS: BMD adjusted for age (Z-score) was lower in the HIV+ patients at the lumbar spine (HIV+: -1.08 +/- 1.21, HIV-: -0.06 +/- 1.26, p < 0.001) and the femoral neck (HIV+: -0.39 +/- 1.05, HIV-: 0.25 +/- 0.87, p < 0.001). The prevalence of osteoporosis was 16% in HIV+ and 4% in HIV- subjects (p < 0.01). In the HIV+ subjects, the Z-score was correlated only to body mass index (r = 0.27 at lumbar spine and 0.35 at femoral neck). Untreated HIV+ patients had a negative Z-score (-0.82 +/- 1.15 for the lumbar spine), which was not different from the one of treated HIV+ patients. In the PI+ and PI- groups, the Z-score did not depend on the presence of lipodystrophy or the proportion of fat in the abdomen and legs measured by DXA. Markers of bone remodeling were measured in the 132 HIV+ and 35 HIV- subjects. Compared with controls, HIV+ patients had lower bone alkaline phosphatase and higher urinary cross-laps/Cr, which was negatively correlated with the Z-score at both the femoral neck (r = -0.22) and lumbar spine (r = -0.21). TNFalpha was increased in untreated compared with treated HIV+ subjects and was not correlated to the Z-score. CONCLUSION: Our cross-sectional study does not show any deleterious effect of the treatment but does indicate a decrease in bone density in HIV+ patients irrespective of the treatment. This low bone density is in part related to the low body weight and is associated with increased bone resorption.

Reduced bone mineral density in postmenopausal women self-reporting premenopausal wrist fractures.

Postmenopausal fractures are associated with low bone mass; however, the role of low peak bone mass in young adults in determining subsequent osteoporosis suggests that premenopausal fractures may also be relevant. We therefore sought to determine whether a self-reported previous history of premenopausal wrist and nonwrist fractures could also be associated with bone density and therefore be used to predict osteoporosis. We recruited 453 volunteer women with a median age of 64 years (range 50-83 years), with no metabolic bone disease, previous femoral neck fracture, or prevalent vertebral fracture. Bone density at the femoral neck (FN) and lumbar spine (LS) was measured using a Lunar DPX-L. As expected, the 319 women who did not report any fracture had a higher T score at LS (-0.93 +/- 1.44) than the 134 women who reported a previous fracture at any site and at any age (T score -1.60 +/- 1.21, p < 0.001). The findings for the FN were similar. Compared with fracture-free women, the women who reported a first wrist fracture before menopause now had a lower LS T score (-1.77 +/- 1.20, n = 15, p < 0.05), whereas those who reported a nonwrist fracture showed no significant decrease in their LS T score (-1.26 +/- 1.00, n = 36). When both wrist and nonwrist fractures had occurred after menopause, the T score was significantly lower. Twenty percent of the fracture-free women were osteoporosis patients. After adjusting for body weight, age, hormonal replacement therapy (HRT), and hip fracture in the family, the relative risk (RR) of osteoporosis for premenopausal wrist fractures was 2.7 (95% confidence interval 1.4-4.3) vs. 1.2 (0.7-2.4) for women with premenopausal nonwrist fractures. We conclude that self-reported premenopausal wrist fractures, but no other fractures occurring before menopause, are likely to be associated with osteoporosis at 65 years of age, and therefore constitute strong grounds for screening.

Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy.

BACKGROUND: The insulin-like growth factor (IGF) system plays a key role in regulation of bone formation. In patients with renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in different forms of renal osteodystrophy and hyperparathyroidism. METHODS: In a cross-sectional study, we investigated 319 patients with mild (N = 29), moderate (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N = 27), or renal transplantation (RTX; N = 30). As controls without renal failure, we recruited age-matched healthy subjects (N = 87) and patients with primary hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by specific immunometric assays. IGF system components and bone markers were correlated with clinical and bone histologic findings. Mean values +/- SEM are given. RESULTS: With declining renal function a significant increase was measured for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3-fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3- to 1. 6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold), and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free and total IGF-I levels showed significant negative correlations with IGFBP-1, IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF patients with mixed uremic bone disease and histologic evidence for osteopenia revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters of bone formation showed significant positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss. Moreover, dialysis patients with low bone turnover (N = 24) showed significantly (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high bone turnover. CONCLUSION: Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.

Shear, torsional, and tensile bond strengths of ceramic brackets using three adhesive filler concentrations.

The effect of changes in adhesive filler concentration on the shear, torsional, and tensile bond strength of a chemical, a mechanical, and a chemical/mechanical retained ceramic bracket was evaluated. Two hundred ten bovine teeth were bonded with one of three ceramic brackets using a 30%, 55%, or 80% filled adhesive. The brackets were debonded with a shear, torsional, or tensile force to test the bond strength and the site of bond failure. No significant difference was found in the shear, torsional, or tensile bond strength of each ceramic bracket type in relation to changes in the adhesive filler concentration. However, there was a trend toward increased bond strength with increasing filler concentration. Combining the data according to adhesive type revealed that the 80% filled adhesive displayed a significantly greater shear bond strength than the 30% or 55% filled adhesive and a greater torsional bond strength than the 30% filled adhesive. This supports the hypothesis of increased bond strength with increased adhesive filler concentration. The mechanically retained ceramic bracket showed greater shear bond strength and maximum shear bond strength in torsion than the chemical or chemical/mechanical retained ceramic bracket. The tensile bond strength of the mechanically retained ceramic bracket was similar to that of metal brackets reported in other studies, and the failure site was at the bracket-adhesive interface.