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Biomedical subjects

P D Delmas

Publications and source records attributed to P D Delmas.

At least 19 recordsLinked to original sources
PubMed2006

Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease.

Minimal trauma fractures in bone diseases are the result of bone fragility. Rather than considering bone fragility as being the result of a reduced amount of bone, we recognize that bone fragility is the result of changes in the material and structural properties of bone. A better understanding of the contribution of each component of the material composition and structure and how these interact to maintain whole bone strength is obtained by the study of metabolic bone diseases. Disorders of collagen (osteogenesis imperfecta and Paget's disease of bone), mineral content, composition and distribution (fluorosis and osteomalacia); diseases of high remodeling (postmenopausal osteoporosis, hyperparathyroidism, and hyperthyroidism) and low remodeling (osteopetrosis, pycnodysostosis); and other diseases (idiopathic male osteoporosis, corticosteroid-induced osteoporosis) produce abnormalities in the material composition and structure that lead to bone fragility. Observations in patients and in animal models provide insights on the biomechanical consequences of these illnesses and the nature of the qualities of bone that determine its strength.

Animals↗
PubMed2006

Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases.

Numerous experimental and clinical observations suggest that overall changes in bone resorption during menopause or treatment with hormone replacement therapy (HRT) are combined effects of changes in osteoclast number and function. Moreover, due to a coupling between osteoclastic bone resorption and osteoblastic bone formation, pronounced alteration of osteoclast number will eventually lead to alteration of osteoblastic bone formation. Fragments of type I collagen, such as the C- and N-terminal telopeptides of collagen type I (CTX and NTX, respectively), are generated during bone resorption and hence can be used as surrogate markers of osteoclast function. Circulating levels of different enzymes in the serum, such as TRAP 5b and cathepsin K are proportional to the number of osteoclasts, and hence can be used as surrogate markers of osteoclast number. Since antiresorptive effects can be obtained in different ways, we felt it was timely to discuss the different scenarios, highlight differences specific to different pharmacological interventions with different mechanisms of action, and discuss how these bone markers can assist us in a deeper analysis of the pharmacodynamics and safety profile of existing and upcoming drug candidates.

Acid Phosphatase↗
PubMed2006

Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study.

INTRODUCTION: Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3) have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. METHODS: 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. RESULTS: 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r(2)=0.023, p<0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. CONCLUSIONS: In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health.

Absorptiometry, Photon↗
PubMed2006

Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study.

INTRODUCTION: Randomized clinical trials have shown that risedronate and alendronate reduce fractures among women with osteoporosis. The aim of this observational study was to observe, in clinical practice, the incidence of hip and nonvertebral fractures among women in the year following initiation of once-a-week dosing of either risedronate or alendronate. METHODS: Using records of health service utilization from July 2002 through September 2004, we created two cohorts: women (ages 65 and over) receiving risedronate (n = 12,215) or alendronate (n = 21,615). Cox proportional hazard modeling was used to compare the annual incidence of nonvertebral fractures and of hip fractures between cohorts, adjusting for potential differences in risk factors for fractures. RESULTS: There were 507 nonvertebral fractures and 109 hip fractures. Through one year of therapy, the incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2% - 32%) than in the alendronate cohort (2.3%). The incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13% - 63%) than in the alendronate cohort (0.6%). These results were consistent across a number of sensitivity analyses. CONCLUSION: Patients receiving risedronate have lower rates of hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate.

Aged↗
PubMed2006

Which screening strategy using BMD measurements would be most cost effective for hip fracture prevention in elderly women? A decision analysis based on a Markov model.

INTRODUCTION: Hip fractures are responsible for excessive mortality, decreasing the 5-year survival rate by about 20%. From an economic perspective, they represent a major source of expense, with direct costs in hospitalization, rehabilitation, and institutionalization. The incidence rate sharply increases after the age of 70, but it can be reduced in women aged 70-80 years by therapeutic interventions. Recent analyses suggest that the most efficient strategy is to implement such interventions in women at the age of 70 years. As several guidelines recommend bone mineral density (BMD) screening of postmenopausal women with clinical risk factors, our objective was to assess the cost-effectiveness of two screening strategies applied to elderly women aged 70 years and older. METHODS: A cost-effectiveness analysis was performed using decision-tree analysis and a Markov model. Two alternative strategies, one measuring BMD of all women, and one measuring BMD only of those having at least one risk factor, were compared with the reference strategy "no screening". Cost-effectiveness ratios were measured as cost per year gained without hip fracture. Most probabilities were based on data observed in EPIDOS, SEMOF and OFELY cohorts. RESULTS: In this model, which is mostly based on observed data, the strategy "screen all" was more cost effective than "screen women at risk." For one woman screened at the age of 70 and followed for 10 years, the incremental (additional) cost-effectiveness ratio of these two strategies compared with the reference was 4,235 euros and 8,290 euros, respectively. CONCLUSION: The results of this model, under the assumptions described in the paper, suggest that in women aged 70-80 years, screening all women with dual-energy X-ray absorptiometry (DXA) would be more effective than no screening or screening only women with at least one risk factor. Cost-effectiveness studies based on decision-analysis trees maybe useful tools for helping decision makers, and further models based on different assumptions should be performed to improve the level of evidence on cost-effectiveness ratios of the usual screening strategies for osteoporosis.

Absorptiometry, Photon↗
PubMed2006

Severity of vertebral fracture reflects deterioration of bone microarchitecture.

INTRODUCTION: Bone microarchitecture, a component of bone strength, is generally measured on transiliac bone biopsy samples. The objective of this study was to determine whether assessment of four grades of vertebral fracture severity could serve as a noninvasive surrogate marker for trabecular bone volume and microarchitecture. METHODS: Baseline vertebral fracture severity was determined by semiquantitative assessment of spine radiographs from 190 postmenopausal women with osteoporosis. Bone-structure indices were obtained by 2D histomorphometry and 3D microcomputed tomography (CT) analyses. Significance of differences was determined after adjusting for age, height, and lumbar spine bone mineral density. RESULTS: There were significant (P < 0.05) trends in decreasing bone volume, trabecular number, and connectivity, and increasing trabecular separation with greater vertebral fracture severity. Histomorphometric bone volume was 25 and 36% lower (P < 0.05) in women with moderate and severe fractures than in women with no fractures, respectively. Compared with women without fractures, women with mild, moderate, and severe fractures had lower (P < 0.05) microCT bone volume (23, 30, and 51%, respectively). CONCLUSIONS: Microarchitectural deterioration was progressively worse in women with increasing severity of vertebral fractures. We conclude that assessment of vertebral fracture severity is an important clinical tool to evaluate the severity of postmenopausal osteoporosis.

Aged↗
PubMed2006

MMP and non-MMP-mediated release of aggrecan and its fragments from articular cartilage: a comparative study of three different aggrecan and glycosaminoglycan assays.

OBJECTIVE: Aggrecan is the major proteoglycan in articular cartilage and is known to be degraded by various proteases, including matrix metalloproteinases (MMPs). The present study was undertaken to develop immunoassays detecting aggrecan and its fragments generated by MMP and non-MMP-mediated proteolysis. METHODS: Two immunoassays were developed: (1) the G1/G2 sandwich assay employing a monoclonal antibody (F-78) both as a capturing and a detecting antibody, and (2) the 342-G2 sandwich assay substituting the capturing antibody in the G1/G2 test with a monoclonal antibody, AF-28 recognizing the 342FFGVG neo-epitope generated by MMP cleavage. These assays were compared to the commercially available glycosaminoglycan (GAG) assay. RESULTS: In supernatants of Oncostatin M and Tumor Necrosis Factor alpha (OSM/TNFalpha) stimulated explants, high levels of G1/G2 fragments and GAGs were released in the initial phase (days 2-5), followed by low levels in the intermediate (days 9-12) and late phase (days 12-21). MMP-generated fragments were detected in the late phase only. In the presence of the general MMP inhibitor GM6001, 342-G2 was not detected, whereas the G1/G2 profile remained virtually unchanged. In patients with rheumatoid arthritis (RA), the release of G1/G2 molecules was decreased (27.3%), and that of the 342-G2 fragments increased compared to healthy controls (33.3%). CONCLUSION: The stimulation of bovine articular cartilage explants with OSM/TNFalpha released aggrecan fragments both in an MMP and non-MMP-mediated route. These immunoassays carry a potential as diagnostic tools for the quantitative assessment of the cartilage turnover in RA patients in addition to their utility in ex vivo explant cultures.

Aggrecans↗
PubMed2006

Bone width is correlated positively with the upper to the lower segment ratio in elderly men--the MINOS study.

Before puberty, limbs grow more rapidly than the spine. During puberty, lengthening of the spine and increase in bone width accelerate. Correlation of parameters with lengths of the upper and lower segments and with the upper/lower segment ratio may indicate the period of growth critical for their determination. We assessed the association of bone mineral and width with the upper/lower segment ratio in 542 elderly men from the MINOS cohort. Areal bone mineral density (aBMD) was measured at the lumbar spine and right hip using pencil-beam dual-energy X-ray absorptiometry and at the distal forearm using single energy X-ray absorptiometry. Upper/lower segment ratio correlated positively with bone mineral content (BMC), aBMD and width of third lumbar vertebra (L3), femoral neck and distal radius. Men in the highest quartile of the upper/lower segment ratio had larger bones by 2.5 to 5.0% (0.3-0.4 SD, p<0.02-0.002) compared with the lowest quartile. Bone width correlated more strongly with the upper segment length than with that of the lower one. Volumetric BMD (vBMD) did not correlate with the upper/lower segment ratio nor with the lengths of the body segments. At the femoral neck and distal radius, men in the highest quartile of the upper/lower segment ratio had higher estimated cortical thickness (5.3%, 0.41 SD, p<0.01 and 4.0%, 0.31 SD, p<0.03), bigger cortical area (8.0%, 0.54 SD and 6.8%, 0.52 SD, p<0.0001) and higher estimated bending strength (9.3 to 13.3%, 0.46 to 0.54 SD, p<0.0001). Elderly men with the higher upper/lower segment ratio had higher BMC and bending strength because they had wider bones, not higher vBMD. The bone size correlated positively with the length of the upper segment, not negatively with that of the lower segment. Our data may suggest an important role of pubertal growth for both bone width and strength in men but do not establish the determinants of this association. Given methodological limitations, these results need to be confirmed in a younger and more representative group of men.

Absorptiometry, Photon↗
PubMed2006

Contribution of the advanced glycation end product pentosidine and of maturation of type I collagen to compressive biomechanical properties of human lumbar vertebrae.

Collagen characteristics contribute to bone biomechanical properties. Yet, few studies have analyzed the independent contributions of bone mineral density (BMD) and post-translational modifications of type I collagen to whole bone strength. Thus, the aim of this study was to determine the relative contributions of BMD and both enzymatic and non-enzymatic collagen crosslink concentration to the biomechanical properties of human vertebrae. Nineteen L3 vertebrae were collected after necropsy (age 26-93; 10 males, 9 females). BMD of the vertebral body was measured by DXA, and the vertebrae were compressed to failure to assess the stiffness, failure load and work to fracture. After mechanical testing, the concentration of both enzymatic crosslinks pyridinoline (PYD), and deoxypyridinoline (DPD) as well as, and the non-enzymatic crosslinks pentosidine (PEN) were analyzed in trabecular and cortical bone by reversed-phase HPLC. The extent of aspartic acid isomerization of type I collagen C telopeptide (CTX) was evaluated by ELISA of native (alpha CTX) and isomerized (beta CTX) forms. BMD was significantly positively related with stiffness (R(2) = 0.74; P < 0.0001), failure load (R(2) = 0.69; P < 0.0001) and work to fracture (R(2) = 0.44; P = 0.002). Bivariate regression analysis showed no association between collagen traits and biomechanical properties. However, in a multiple regression model, BMD and trabecular PEN were both significantly associated with failure load and work to fracture (multiple R(2) = 0.83, P = 0.001 and R(2) = 0.67, P = 0.001, respectively). Similarly, BMD and trabecular alpha/beta CTX ratio were both associated with stiffness (multiple R(2) = 0.83, P = 0.015). These findings indicate that post-translational modifications of type I collagen have an impact on skeletal fragility.

Absorptiometry, Photon↗
PubMed2006

Effectiveness of instant vertebral assessment to detect prevalent vertebral fracture.

INTRODUCTION: Vertebral fracture is currently underdiagnosed, despite its common severity and its value to predict further osteoporotic fracture. Morphometry using dual X-ray absorptiometry (DXA) [vertebral fracture assessment (VFA)] is a new technique that may facilitate detection of many vertebral fractures, as images are obtained at the same time as bone mineral density (BMD) measurement, and would also allow avoiding spine radiographs. METHODS: We conducted a cross-sectional study to assess the diagnostic value of Instant Vertebral Assessment (IVA), which is a morphometry scan using the Hologic Delphi densitometer, to detect prevalent vertebral fracture in postmenopausal women. Interobserver precision was assessed, then IVA scans were compared with lateral spine radiographs, considered the gold standard, to test diagnostic agreement between the two techniques. Sensitivity, specificity and predictive values were calculated, as well as the likelihood ratio of the positive test, using sensitivity and specificity at each vertebral level. RESULTS: Among 85 patients of whom 50% had at least one vertebral fracture identified with radiographs, we found that interobserver precision was moderate, with frequent difficulties in discerning upper thoracic vertebrae. On a per-vertebra basis, sensitivity was around 70% from L4 to T11 and lower above T11 whereas specificity was above 90% for all vertebrae, and the negative predictive value remained above 80% from L4 to T7 and decreased above T7. On a per-patient basis, sensitivity was 0.69, specificity 0.74, positive predictive value equalled 0.72 and negative predictive value 0.71. When only grades 2 and 3 fractures were considered, results were comparable, with slightly improved specificity. Then, with the likelihood ratios calculated in our sample, we obtained posttest probabilities using the prevalence of vertebral fracture at lumbar and thoracic levels in a large sample of postmenopausal women with osteopenia and osteoporosis with and without vertebral fracture [baseline data in women of the Multiple Outcomes on Raloxifene Evaluation (MORE) trial]. At levels where fractures were most common, likelihood ratios of the positive test were good or excellent, associated with sizeable posttest probabilities. CONCLUSION: IVA allowed diagnosis of vertebral fracture at levels where vertebral fracture were most common, i.e., the lumbar and mid and lower thoracic levels, but its value was weaker at the upper thoracic levels.

Absorptiometry, Photon↗
PubMed2006

Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover.

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.

Adult↗
PubMed2005

The role of collagen in bone strength.

Bone is a complex tissue of which the principal function is to resist mechanical forces and fractures. Bone strength depends not only on the quantity of bone tissue but also on the quality, which is characterized by the geometry and the shape of bones, the microarchitecture of the trabecular bones, the turnover, the mineral, and the collagen. Different determinants of bone quality are interrelated, especially the mineral and collagen, and analysis of their specific roles in bone strength is difficult. This review describes the interactions of type I collagen with the mineral and the contribution of the orientations of the collagen fibers when the bone is submitted to mechanical forces. Different processes of maturation of collagen occur in bone, which can result either from enzymatic or nonenzymatic processes. The enzymatic process involves activation of lysyl oxidase, which leads to the formation of immature and mature crosslinks that stabilize the collagen fibrils. Two type of nonenzymatic process are described in type I collagen: the formation of advanced glycation end products due to the accumulation of reducible sugars in bone tissue, and the process of racemization and isomerization in the telopeptide of the collagen. These modifications of collagen are age-related and may impair the mechanical properties of bone. To illustrate the role of the crosslinking process of collagen in bone strength, clinical disorders associated with bone collagen abnormalities and bone fragility, such as osteogenesis imperfecta and osteoporosis, are described.

Animals↗
PubMed2005

Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study.

BACKGROUND: Reducing bisphosphonate dosing frequency may improve suboptimal adherence to treatment and therefore therapeutic outcomes in postmenopausal osteoporosis. Once-monthly oral ibandronate has been developed to overcome this problem. OBJECTIVE: To confirm the 1 year results and provide more extensive safety and tolerability information for once-monthly dosing by a 2 year analysis. METHODS: MOBILE, a randomised, phase III, non-inferiority study, compared the efficacy and safety of once-monthly ibandronate with daily ibandronate, which has previously been shown to reduce vertebral fracture risk in comparison with placebo. RESULTS: 1609 postmenopausal women were randomised. Substantial increases in lumbar spine bone mineral density (BMD) were seen in all treatment arms: 5.0%, 5.3%, 5.6%, and 6.6% in the daily and once-monthly groups (50 + 50 mg, 100 mg, and 150 mg), respectively. It was confirmed that all once-monthly regimens were at least as effective as daily treatment, and in addition, 150 mg was found to be better (p<0.001). Substantial increases in proximal femur (total hip, femoral neck, trochanter) BMD were seen; 150 mg produced the most pronounced effect (p<0.05 versus daily treatment). Independent of the regimen, most participants (70.5-93.5%) achieved increases above baseline in lumbar spine or total hip BMD, or both. Pronounced decreases in the biochemical marker of bone resorption, sCTX, observed in all arms after 3 months, were maintained throughout. The 150 mg regimen consistently produced greater increases in BMD and sCTX suppression than the 100 mg and daily regimens. Ibandronate was well tolerated, with a similar incidence of adverse events across groups. CONCLUSIONS: Once-monthly oral ibandronate is at least as effective and well tolerated as daily treatment. Once-monthly administration may be more convenient for patients and improve therapeutic adherence, thereby optimising outcomes.

Administration, Oral↗
PubMed2005

Urinary CTX-II and glucosyl-galactosyl-pyridinoline are associated with the presence and severity of radiographic knee osteoarthritis in men.

OBJECTIVE: To investigate the association between biochemical markers of bone, cartilage, and synovial turnover with the presence and severity of knee osteoarthritis (OA) in men. METHODS: 176 men aged 59-70 years from the MRC Hertfordshire Cohort were studied. Weightbearing anteroposterior and lateral semiflexed radiographs were taken of both knees. A lifestyle questionnaire including basic demographic details and a questionnaire detailing knee pain was completed. This random sample was stratified based on the Kellgren and Lawrence (K&L) score, and the following biochemical markers were analysed: serum osteocalcin, serum C-terminal crosslinked telopeptide of type I collagen (CTX-I), urinary C-terminal crosslinked telopeptide of type II collagen (CTX-II), and urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-Pyd). RESULTS: Age, body mass index (BMI), social class, smoking, and alcohol consumption were similar across K&L grades. Only one subject had a grade 4 K&L score, and was amalgamated with grade 3 subjects. A strong significant association was found between the presence of knee OA and urinary CTX-II and urinary Glc-Gal-Pyd (p=0.0001 and p=0.009), which persisted after adjustment for age and BMI. A significant positive association was also found between urinary CTX-II and urinary Glc-Gal-Pyd and the severity of K&L grade, joint space narrowing, and osteophytes scores, which persisted after adjustment for age and BMI. No associations between the presence and severity of knee OA were found for serum CTX-I or serum osteocalcin. CONCLUSIONS: Urinary CTX-II and Glc-Gal-Pyd, but not systemic markers of bone turnover, are strongly associated with disease severity and the presence of OA at the tibiofemoral and patellofemoral joints in men.

Aged↗
PubMed2005

Structural determinants of hip fracture in elderly women: re-analysis of the data from the EPIDOS study.

Hip fracture is the most disastrous osteoporotic fracture, characterized by high mortality, morbidity and institutionalization for the patient and by high economic costs for the health care system. The morphology of the upper part of the femur can influence the risk of hip fracture, e.g., a longer femoral neck is associated with a higher risk of cervical fractures, but not trochanteric ones. In this study, we evaluated the prediction of hip fracture risk by morphological parameters estimated from DXA measurements, and we compared their predictive value for cervical and trochanteric fractures in elderly women by reanalyzing previously published data (Duboeuf et al. J Bone Miner Res 1997 12 1895). This nested case-control study was performed in 232 elderly community-dwelling women from the EPIDOS cohort, including 65 women who sustained a hip fracture. After adjustment for confounding variables, women who sustained a cervical fracture had lower areal bone mineral density (aBMD), lower cortical thickness and a higher average buckling ratio (P<0.005 for all) as well as longer femoral neck (P<0.01) than controls. Women who sustained a trochanteric fracture had lower aBMD, lower cortical thickness and higher buckling ratio than controls (P<0.0001) and than women who sustained a cervical fracture (P<0.05). Their bending resistance (cross-sectional moment of inertia-CSMI, section modulus) was significantly lower in comparison with controls (P<0.05-0.001). A decrease in aBMD, cortical thickness, CSMI and section modulus as well as an increase in buckling ratio were predictive of all hip fractures (OR -1.42-2.46 per 1 SD, P<0.05-0.0001), but the ORs for all structural parameters were markedly higher for trochanteric than for cervical fractures. CSMI and section modulus were predictive of trochanteric, but not cervical fractures. However, aBMD was strongly correlated with the CSA, cortical thickness and buckling ratio (r2>0.74), which suggests that they convey the same information. CSMI and section modulus correlated with aBMD more weakly, but their OR lost statistical significance after adjustment for aBMD. In conclusion, low femoral neck aBMD, CSA and cortical thickness as well as a high buckling ratio are associated with the higher risk of hip fracture, especially trochanteric ones. These indices are highly correlated with aBMD and convey the same message. The calculated CSMI and section modulus predict trochanteric fractures, but not cervical fractures, and their statistical significance is lost after adjustment for aBMD, indicating that they reflect mainly aBMD, not mechanical properties. Thus, the independent contribution of the external diameter of the femoral neck to the risk of hip fracture cannot be reliably estimated by this technique.

Absorptiometry, Photon↗
PubMed2005

Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density.

CONTEXT: Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain. OBJECTIVE: The objective of this study was to investigate the relationships between VDR genotypes and fracture risk. DESIGN: A prospective population-based cohort was studied. SUBJECTS: A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr. MAIN OUTCOME MEASURE: The study measured incidents of vertebral and nonvertebral fractures. RESULTS: VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D. CONCLUSION: VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.

Adult↗
PubMed2005

Expression of Semaphorin-3A and its receptors in endochondral ossification: potential role in skeletal development and innervation.

Bone tissue is densely innervated, and there is increasing evidence for a neural control of bone metabolism. Semaphorin-3A is a very important regulator of neuronal targeting in the peripheral nervous system as well as in angiogenesis, and knockout of the Semaphorin-3A gene induces abnormal bone and cartilage development. We analyzed the spatial and temporal expression patterns of Semaphorin-3A signaling molecules during endochondral ossification, in parallel with the establishment of innervation. We show that osteoblasts and chondrocytes differentiated in vitro express most members of the Semaphorin-3A signaling system (Semaphorin-3A, Neuropilin-1, and Plexins-A1 and -A2). In vitro, osteoclasts express most receptor chains but not the ligand. In situ, these molecules are all expressed in the periosteum and by resting, prehypertrophic and hypertrophic chondrocytes in ossification centers before the onset of neurovascular invasion. They are detected later in osteoblasts and also osteoclasts, with differences in intensity and regional distribution. Semaphorin-3A and Neuropilin-1 are also expressed in the bone marrow. Plexin-A3 is not expressed by bone cell lineages in vitro. It is detected early in the periosteum and hypertrophic chondrocytes. After the onset of ossification, this chain is restricted to a network of cell processes in close vicinity to the cells lining the trabeculae, similar to the pattern observed for neural markers at the same stages. After birth, while the density of innervation decreases, Plexin-A3 is strongly expressed by blood vessels on the ossification front. In conclusion, Semaphorin-3A signaling is present in bone and seems to precede or coincide at the temporal but also spatial level with the invasion of bone by blood vessels and nerve fibers. Expression patterns suggest Plexin-A3/Neuropilin-1 as a candidate receptor in target cells for the regulation of bone innervation by Semaphorin-3A.

Animals↗