In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization.

UNLABELLED: In postmenopausal osteoporotic women and up to 3 years of treatment with strontium ranelate, strontium was present only in recently deposited bone tissue resulting from formation activity during the period of treatment. Strontium was shown to be dose-dependently deposited into this newly formed bone with preservation of the mineralization. INTRODUCTION: Interactions between strontium (Sr) and bone mineral and its effects on mineralization were investigated in women treated with strontium ranelate. METHODS: Bone biopsies from osteoporotic women were obtained over 5-year strontium ranelate treatment from phases II and III studies. Bone samples obtained over 3-year treatment were investigated by X-ray microanalysis for bone Sr uptake and focal distribution, and by quantitative microradiography for degree of mineralization. On some samples, Sr distribution (X-ray cartography) was analyzed on whole sample surfaces and the percentage of bone surface containing Sr was calculated. Bone Sr content was chemically measured on whole samples. RESULTS: In treated women, Sr was exclusively present in bone formed during treatment; Sr deposition depended on the dose with higher focal content in new bone structural units than in old ones constantly devoid of Sr, even after 3-year treatment. A plateau in global bone Sr content was reached after 3 years of treatment. Cartography illustrated the extent of surfaces containing Sr, and formation activity during strontium ranelate treatment was higher in cancellous than in cortical bone. Mineralization was maintained during treatment. CONCLUSION: The quality of bone mineral was preserved after treatment with strontium ranelate, supporting the safety of this agent at the bone tissue level.

The effects of long-term raloxifene and estradiol treatments on bone in a patient with congenital aromatase deficiency.

INTRODUCTION: In adult aromatase-deficient men, estrogen treatment has always resulted in a rapid skeletal maturation with epiphyseal closure and improved BMD. Raloxifene is a SERM with proven estrogen agonist action on bone that leads to an improvement in BMD and a reduction in bone turnover. The present study reports the effects of raloxifene and transdermal estradiol treatment, respectively, on epiphyseal closure and BMD in an aromatase-deficient man, over a 24-month follow-up, with the aim of obtaining further insight into the role of estrogens in the male skeletal homeostasis. MATERIALS AND METHODS: A 25-year-old Caucasian man with aromatase deficiency, a bone age of 15.3 years, unfused epiphyses and an impaired BMD was initially administered raloxifene (60 mg/day per os) for 12 months, while transdermal estradiol (25 microg twice weekly) was administered for the subsequent 12 months. During the follow-up, the effects of the two treatments on epiphyseal closure, BMD and bone turnover markers were investigated. An iliac crest bone biopsy was performed only before and after the raloxifene treatment, but it was not repeated after transdermal estradiol treatment. RESULTS: No changes in bone age were observed after raloxifene therapy, whereas a complete epiphyseal closure was achieved with transdermal estradiol treatment. Compared with baseline values, raloxifene treatment led to improved BMD both at the ultradistal forearm and 33% radius; the transdermal estradiol treatment resulted in a further slight increase in BMD at the 33% radius, but not at the ultradistal forearm. The baseline bone biopsy showed elevated bone remodelling in trabecular bone, while the second biopsy following raloxifene treatment revealed a decrease in remodelling. DISCUSSION: This study shows that the management of aromatase deficiency in the male cannot consider raloxifene as a first choice treatment, but should be still based on estrogen replacement treatment since in this patient the completion of bone maturation has only been obtained once estradiol substitution was performed. The present case also demonstrates that raloxifene is able to improve BMD in aromatase-deficient men.

Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis.

SUMMARY: Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis. INTRODUCTION: Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate. METHODS: A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated. RESULTS: Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction = 0.67, p < 0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p < 0.001). QoL, assessed by the QUALIOST(R), was significantly better (p = 0.025), and patients without back pain were greater (p = 0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups. CONCLUSION: In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.

The role of mineralization and organic matrix in the microhardness of bone tissue from controls and osteoporotic patients.

Degree of mineralization of bone (DMB) is a major intrinsic determinant of bone strength at the tissue level but its contribution to the microhardness (Vickers indentation) at the intermediary level of organization of bone tissue, i.e., Bone Structural Units (BSUs), has never been assessed. The purpose of this study was to analyze the relationship between the microhardness, the DMB and the organic matrix, measured in BSUs from human iliac bone biopsies. Iliac bone samples from controls and osteoporotic patients (men and women), embedded in methyl methacrylate, were used. Using a Vickers indenter, microhardness (kg/mm2) was measured, either globally on surfaced blocks or focally on 100 microm-thick sections from bone samples (load of 25 g applied during 10 sec; CV=5%). The Vickers indenter was more suited than the Knoop indenter for a tissue like bone in which components are diversely oriented. Quantitative microradiography performed on 100 microm-thick sections, allowed measurement of parameters reflecting the DMB (g/cm3). Assessed on the whole bone sample, both microhardness and DMB were significantly lower (-10% and -7%, respectively) in osteoporotic patients versus controls (p<0.001). When measured separately at the BSU level, there were significant positive correlations between microhardness and DMB in controls (r2=0.36, p<0.0001) and osteoporotic patients (r2=0.43, p<0.0001). Mineralization is an important determinant of the microhardness, but did not explain all of its variance. To highlight the role of the organic matrix in bone quality, microhardness of both osteoid and adjacent calcified matrix were measured in iliac samples from subjects with osteomalacia. Microhardness of organic matrix is 3-fold lower than the microhardness of calcified tissue. In human calcanei, microhardness was significantly correlated with DMB (r2=0.33, p=0.02) and apparent Young's modulus (r2=0.26, p=0.03). In conclusion, bone microhardness measured by Vickers indentation is an interesting methodology for the evaluation of bone strength and its determinants at the BSU level. Bone microhardness is linked to Young's modulus of bone and is strongly correlated to mineralization, but the organic matrix accounts for about one third of its variance.

Strontium ranelate prevents quality of life impairment in post-menopausal women with established vertebral osteoporosis.

UNLABELLED: Strontium ranelate reduces the risk of fracture in post-menopausal osteoporotic women with prevalent fractures for whom quality of life is severely impaired. The SOTI study, which used the SF-36 questionnaire and disease-specific QUALIOST module, demonstrated that treatment with strontium ranelate improved osteoporotic women's quality of life compared with placebo. INTRODUCTION: The Spinal Osteoporosis Therapeutic Intervention (SOTI) study demonstrated the effect of orally administered strontium ranelate versus placebo on the incidence of new vertebral fractures and compared impact on quality of life (QoL). METHODS: QoL was assessed 6 monthly over 3 years using the QUALIOST and SF-36 questionnaires in post-menopausal osteoporotic women with prevalent fracture taking strontium ranelate or placebo 2 g/day. A total of 1,240 women were included (strontium ranelate: n=618 and placebo: n=622). RESULTS: The QUALIOST total score decreased in the strontium ranelate group, indicating preserved QoL compared with a deterioration in the placebo group (P=0.016). Strontium ranelate patients had reduced QUALIOST emotional and physical dimension scores (P=0.019 and 0.032, respectively, versus placebo), indicating beneficial effects on emotional and physical functioning. There was a trend towards better SF-36 scores in the strontium ranelate group, although there were no significant between-group differences. More strontium ranelate patients (+31%) were free from back pain over 3 years versus placebo (P=0.005), with a significant effect from the first year of treatment (P=0.023). CONCLUSION: Strontium ranelate has beneficial effects on QoL in women with post-menopausal osteoporosis compared with placebo.

Combining clinical factors and quantitative ultrasound improves the detection of women both at low and high risk for hip fracture.

UNLABELLED: We hypothesized that combining clinical risk factors (CRF) with the heel stiffness index (SI) measured via quantitative ultrasound (QUS) would improve the detection of women both at low and high risk for hip fracture. Categorizing women by risk score improved the specificity of detection to 42.4%, versus 33.8% using CRF alone and 38.4% using the SI alone. This combined CRF-SI score could be used wherever and whenever DXA is not readily accessible. INTRODUCTION AND HYPOTHESIS: Several strategies have been proposed to identify women at high risk for osteoporosis-related fractures; we wanted to investigate whether combining clinical risk factors (CRF) and heel QUS parameters could provide a more accurate tool to identify women at both low and high risk for hip fracture than either CRF or QUS alone. METHODS: We pooled two Caucasian cohorts, EPIDOS and SEMOF, into a large database named "EPISEM", in which 12,064 women, 70 to 100 years old, were analyzed. Amongst all the CRF available in EPISEM, we used only the ones which were statistically significant in a Cox multivariate model. Then, we constructed a risk score, by combining the QUS-derived heel stiffness index (SI) and the following seven CRF: patient age, body mass index (BMI), fracture history, fall history, diabetes history, chair-test results, and past estrogen treatment. RESULTS: Using the composite SI-CRF score, 42% of the women who did not report a hip fracture were found to be at low risk at baseline, and 57% of those who subsequently sustained a fracture were at high risk. Using the SI alone, corresponding percentages were 38% and 52%; using CRF alone, 34% and 53%. The number of subjects in the intermediate group was reduced from 5,400 (including 112 hip fractures) and 5,032 (including 111 hip fractures) to 4,549 (including 100 including fractures) for the CRF and QUS alone versus the combination score. CONCLUSIONS: Combining clinical risk factors to heel bone ultrasound appears to correctly identify more women at low risk for hip fracture than either the stiffness index or the CRF alone; it improves the detection of women both at low and high risk.

Zoledronic acid efficacy and safety over five years in postmenopausal osteoporosis.

UNLABELLED: In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges. INTRODUCTION: After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis. METHODS: In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed. RESULTS: All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity. CONCLUSIONS: This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients.

Intrinsic mechanical properties of trabecular calcaneus determined by finite-element models using 3D synchrotron microtomography.

To determine intrinsic mechanical properties (elastic and failure) of trabecular calcaneus bone, chosen as a good predictor of hip fracture, we looked for the influence of image's size on a numerical simulation. One cubic sample of cancellous bone (9 x 9 x 9 mm(3)) was removed from the body of the calcaneus (6 females, 6 males, 79+/-9 yr). These samples were tested under compressive loading. Before compressive testing, these samples were imaged at 10.13 microm resolution using a 3D microcomputed tomography (muCT) (ESRF, France). The muCT images were converted to finite-element models. Depending on the bone density values (BV/TV), we compared two different finite element models: a linear hexahedral and a linear beam finite element models. Apparent experimental Young's modulus (E(app)(exp)) and maximum apparent experimental compressive stress (sigma(max)(exp)) were significantly correlated with bone density obtained by Archimedes's test (E(app)(exp)=236+/-231 MPa [19-742 MPa], sigma(max)(exp)=2.61+/-1.97 MPa [0.28-5.81 MPa], r>0.80, p<0.001). Under threshold at 40 microm, the size of the numerical samples (5.18(3) and 6.68(3)mm(3)) seems to be an important parameter on the accuracy of the results. The numerical trabecular Young's modulus was widely higher (E(trabecular)(num)=34,182+/-22,830 MPa [9700-87,211 MPa]) for the larger numerical samples and high BV/TV than those found classically by other techniques (4700-15,000 MPa). For rod-like bone samples (BV/TV<12%, n=7), Young's modulus, using linear beam element (E(trabecular)(num-skeleton): 10,305+/-5500 MPa), were closer to the Young's modulus found by other techniques. Those results show the limitation of hexahedral finite elements at 40 microm, mostly used, for thin trabecular structures.

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.

Estimation of direct unit costs associated with non-vertebral osteoporotic fractures in five European countries.

The objective of this study was to estimate the unit costs of non-vertebral osteoporotic fractures in five European countries based on the results of the SOTI and TROPOS clinical trials in postmenopausal osteoporotic women. The information recorded in the Case Report Forms was used. The perspective of third party payers was adopted. Hip fracture unit cost was the highest. The ranges of costs among countries was narrow for hip from 8,346 euros (Italy) to 9,907euros (France), but wider for other fractures: 890 euros (Spain) to 2,022 euros (Italy) for wrist, 1,167euros (Spain) to 3,268 euros (Italy) for pelvis, 837euros (Spain) to 2,116 euros (Italy) for sternum/clavicle, 565 euros (Spain) to 908 euros (France) for rib, 1,518 euros (Spain) to 3,651 euros (Belgium) for humerus, 1,805 euros (Spain) to 3,521 euros (Italy) for leg. The costs of those fractures should be considered when estimating the cost of osteoporosis.

Fluorotoxic metabolic bone disease: an osteo-renal syndrome caused by excess fluoride ingestion in the tropics.

BACKGROUND: There is scant data available on the pathogenetic mechanisms of varied clinical presentation of bone disease in patients with excess fluoride ingestion in the Indian subcontinent. The present study is comprehensive and state of the art, incorporating all essential elements of bone mineral metabolism in patients with excess fluoride ingestion. METHODS: We studied 24 patients (age 31 +/- 16 years) with fluorotoxic metabolic bone disease (FMBD) for their clinical, radiological and biochemical parameters like serum calcium, phosphorous, alkaline phosphatase (SAP), 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, and parathyroid hormone levels, nephrologic parameters that assess renal handling of calcium and phosphorous and skeletal dynamics as revealed by bone histomorphometry. FINDINGS: Major clinical manifestations were bone pain (79%), Tetany (12.5%) and dental mottling (38%). Radiological findings included osteosclerosis (96%), pseudofracture and ligamentous calcification (50%). These patients manifested hypocalcemia and raised SAP with normal serum phosphorus. There was a positive correlation between serum creatinine and phosphorous excretion index (PEI) and a negative correlation between declining endogenous creatinine clearance (Cr.Cl) and increasing renal loss of calcium and phosphorus as indicated by increased calcium to creatinine ratio and PEI. Bone histomorphometry revealed impairment of primary mineralization with hypomineralized lacunae, interstitial mineralization defects and very thick and extended osteoid seams. Autopsy findings in a patient who died of azotemia showed tubular atrophy with secondary glomerular changes. INTERPRETATION: Fluoride intoxication plays an important role in the pathogenesis of the unique osteo-renal syndrome.

Addressing the musculoskeletal components of fracture risk with calcium and vitamin D: a review of the evidence.

Osteoporotic fractures are an extremely common and serious health problem in the elderly. This article presents the rationale for calcium and vitamin D supplementation in the prevention and treatment of osteoporotic fractures and reviews the literature evidence on the efficacy of this strategy. Two musculoskeletal risk factors are implicated in osteoporotic fractures in the elderly: the loss of bone mass due to secondary hyperparathyroidism and the increased propensity to falls. Calcium and vitamin D reverse secondary hyperparathyroidism with resultant beneficial effects on bone mineral density (BMD). Additionally, calcium and vitamin D supplementation significantly improves body sway and lower extremity strength, reducing the risk of falls. The effects of combined calcium and vitamin D on parathyroid function and BMD provide a strong rationale for the use of this therapy in the prevention and treatment of osteoporosis and osteoporotic fractures. There is general agreement that, in patients with documented osteoporosis, calcium and vitamin D supplementation should be an integral component of the management strategy, along with antiresorptive or anabolic treatment. Frail elderly individuals constitute another major target population for calcium and vitamin D because evidence from randomized studies in institutionalized elderly subjects demonstrates that these supplements reduce osteoporotic fracture risk, particularly in the presence of dietary deficiencies. However, the results of trials in community-dwelling subjects have been equivocal. Within the primary-care setting, further research is required to establish appropriate target subgroups for calcium and vitamin D supplementation; overall, the data are consistent with a benefit individuals with insufficient calcium and/or vitamin D, although patients with documented osteoporosis will derive further benefit in terms of fracture prevention from the addition of an antiresorptive agent.

[Phototype, vitamin D status and bone mineral density among women at risk of osteoporosis]. / Phototype, statut en vitamine D et densité minérale osseuse chez des femmes à risque d'ostéoporose.

PURPOSE: The aim of this study was to test the influence of phototype and vitamin D status feature on the bone mineral density (BMD) of the femoral neck in a group of middle-aged women considered at risk of osteoporosis (low levels of vitamin D [25(OH)D3<78 nmol/L] and hyperparathyroidism [parathormone level>36 pg/mL]). METHODS: This two-step study was conducted on 122 French women enrolled in the SUVIMAX (supplémentation en vitamines et minéraux antioxydants: antioxidant vitamin and mineral supplementation) cohort. The impact of various variables on BMD, including age, body mass index (BMI), vitamin D status, alcohol intake, sun exposure intensity and phototype was investigated using regression models. RESULTS: No statistical link was found between BMD and the variables documenting vitamin D status and parathormone levels, nor phototype. Nevertheless, fair phototypes tended to be associated with lower BMD values. However, BMD decreased with age and increased with BMI and physical activity level. CONCLUSIONS: Whatever their phototype, adult women concerned about precarious vitamin D status should undergo a vitamin D supplementation in combination with an adequate calcium intake all year long and a proper sun protection. Moreover, a physical activity maintenance should provide an additional benefit for prevention of osteoporosis.

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.

Quantitative ultrasound parameters as well as bone mineral density are better predictors of trochanteric than cervical hip fractures in elderly women. Results from the EPIDOS study.

RATIONALE: Hip fractures can be separated into cervical and trochanteric fractures. Trochanteric fractures have been associated with up to twice the short-term mortality of cervical fractures in the elderly. There is also evidence suggesting that the mechanisms are different. Evidence from the literature remains limited on the predictive power of bone mineral density (BMD) and quantitative ultrasounds (QUS) for both types of hip fractures. METHODS: 5703 elderly women aged 75 years or more, who were recruited from the voting lists in the EPIDOS study, and had baseline calcaneal ultrasounds (QUS) and DXA measurements at the hip and the whole body, were analyzed in this paper. Among those, 192 hip fractures occurred during an average follow-up of 4 years, 108 cervical and 84 trochanteric fractures. RESULTS: Femoral neck, trochanteric and whole body BMD were able to predict trochanteric hip fracture (RR's and 95% CI were, respectively, 3.2 (2.4-4.2); 4.8 (3.5-6.6); and 2.8 (2.2-3.6)) more accurately than cervical fractures (respectively, 2.1 (1.7-2.7); 2.3 (1.8-3.0); 1.2 (1.0-1.6)). All ultrasound parameters, SOS, BUA, and stiffness index (SI) were significant predictors of trochanteric (RR's respectively 3.0 (2.2-4.1), 2.5(2.0-3.1), and 3.5(2.6-4.7)) but not cervical fractures. After adjustment for femoral neck or trochanteric BMD ultrasound parameters were still significant predictors of trochanteric fracture, and stiffness tended to be a better predictor of trochanteric fractures than either BUA or SOS with a relative risk of 2.25 (1.6-3.1). CONCLUSIONS: A significant decrease of all bone measurements, BMD and QUS, was highly predictive of trochanteric fractures, whereas a decrease of femoral neck and trochanteric BMD were only associated with a slight increase in cervical fracture risk and a low total body BMD or QUS parameters were not significant predictors of cervical fractures. In women who sustained a hip fracture, the decrease of BMD and QUS values increases the risk of trochanteric fracture as compared to cervical fracture. Trochanteric fractures were mostly a consequence of a generalized low BMD and QUS, whereas other parameters might be involved in cervical fractures.

Body mass index as a predictor of fracture risk: a meta-analysis.

Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.

Expression of PPARgamma and beta/delta in human primary osteoblastic cells: influence of polyunsaturated fatty acids.

As previously reported, the age-related association between bone loss and increased marrow adipose volume may involve inhibitory effects of polyunsaturated fatty acids (PUFAs) potentially released by medullary adipocytes on osteoblastic proliferation and cell cycle progression. Because PUFAs have been reported to activate peroxisome proliferator-activated receptors (PPARs), we investigated the expression of these nuclear receptors in human primary osteoblastic (hOB) cells and examined the effects of natural PPAR ligands on hOB cell proliferation. We demonstrated basic expressions of PPARgamma and PPARbeta/delta in hOB cells at the protein level. As already shown for PUFAs, a short-term treatment with 15deoxy-Delta(12,14) -prostaglandin J2 (15dPGJ2) or prostacyclin (PGI2), which are specific ligands for PPARgamma and PPARbeta/delta, respectively, also significantly inhibited hOB cell proliferation. Given that the cell cycle withdrawal resulting from PPARgamma activation was often associated with the induction of cell differentiation, long-term effects of PUFAs and 15dPGJ2 were also assessed on the expression levels of transcription factors. PUFAs and 15dPGJ2 enhanced the expression of PPARgamma in hOB cells. It is of interest to note that PPARgamma protein level was dose-dependently increased, whereas that of Cbfal was decreased by a fatty acid-rich serum. In conclusion, this study shows that PPARgamma and beta/delta are expressed by hOB cells. The results further suggest that the short-term antiproliferative effect of PUFAs may involve PPAR activation in hOB cells, resulting in a cell cycle withdrawal favorable for the long-term differentiating effects of fatty acids. Further studies are now required to confirm the functional role of PPARs in the antiproliferative effects of PUFAs in hOB cells.

Relationship between compressive properties of human os calcis cancellous bone and microarchitecture assessed from 2D and 3D synchrotron microtomography.

The aim of this study was to determine the contribution of 2D and 3D microarchitectural characteristics in the assessment of the mechanical strength of os calcis cancellous bone. A sample of cancellous bone was removed in a medio-lateral direction from the posterior body of calcaneus, taken at autopsy in 17 subjects aged 61-91 years. The sample was first used for the assessment of morphological parameters from 2D morphometry and 3D synchrotron microtomography (microCT) (spatial resolution=10 microm). The 2D morphometry was obtained from three slices extracted from the 3D microCT images. Very good concordance was shown between 3D microCT slices and the corresponding physical histologic slices. In 2D, the standard histomorphometric parameters, fractal dimension, mean intercept length, and connectivity were computed. In 3D, histomorphometric parameters were computed using both the 3D mean intercept length method and model-independent techniques. The 3D fractal dimension and the 3D connectivity, assessed by Euler density, were also evaluated. The cubic samples were subjected to elastic compressive tests in three orthogonal directions (X, Y, Z) close to the main natural trabecular network directions. A test was performed until collapse of trabecular network in the main direction (Z). The mechanical properties were significantly correlated to most morphological parameters resulting from 2D and 3D analysis. In 2D, the correlation between the mechanical strength and bone volume/tissue volume was not significantly improved by adding structural parameters or connectivity parameter (nodes number/tissue volume). In 3D, one architectural parameter (the trabecular thickness, Tb.Th) permitted to improve the estimation of the compressive strength from the bone volume/tissue volume alone. However, this improvement was minor since the correlation with the BV/TV alone was high (r=0.96). In conclusion, which is in agreement with the statistic's rules, we found, in this study, that the determination of the os calcis bone compressive strength using the 3D bone volume fraction cannot be improved by adding 3D architectural parameters.