Osteoporosis: Lorenc R

Krieg MA, Barkmann R, Gonnelli S, Stewart A, Bauer DC, Del Rio Barquero L, Kaufman JJ, Lorenc R, Miller PD, Olszynski WP, Poiana C, Schott AM, Lewiecki EM, Hans D. · Lausanne University Hospital, Lausanne, Switzerland. <> · J Clin Densitom. · Pubmed #18442758 No free full text.

Abstract: Dual-energy X-ray absorptiometry (DXA) is commonly used in the care of patients for diagnostic classification of osteoporosis, low bone mass (osteopenia), or normal bone density; assessment of fracture risk; and monitoring changes in bone density over time. The development of other technologies for the evaluation of skeletal health has been associated with uncertainties regarding their applications in clinical practice. Quantitative ultrasound (QUS), a technology for measuring properties of bone at peripheral skeletal sites, is more portable and less expensive than DXA, without the use of ionizing radiation. The proliferation of QUS devices that are technologically diverse, measuring and reporting variable bone parameters in different ways, examining different skeletal sites, and having differing levels of validating data for association with DXA-measured bone density and fracture risk, has created many challenges in applying QUS for use in clinical practice. The International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference (PDC) addressed clinical applications of QUS for fracture risk assessment, diagnosis of osteoporosis, treatment initiation, monitoring of treatment, and quality assurance/quality control. The ISCD Official Positions on QUS resulting from this PDC, the rationale for their establishment, and recommendations for further study are presented here.

Delmas PD, Khaltaev N, Arriagada M, Brandi ML, Cannata J, Lau E, Lederman R, Lorenc R, Minne H, Morales-Torres J, Morii H, Sambrook P, Torralba T, Zanchetta J, Reginster JY. · No affiliation provided · J Musculoskelet Neuronal Interact. · Pubmed #15951625 links to  free full text

This publication has no abstract.

Meunier PJ, Slosman DO, Delmas PD, Sebert JL, Brandi ML, Albanese C, Lorenc R, Pors-Nielsen S, De Vernejoul MC, Roces A, Reginster JY. · Hôpital Edouard Herriot, 69437 Lyon, France. · J Clin Endocrinol Metab. · Pubmed #11994341 links to  free full text

Abstract: The aim of the strontium ranelate (SR) for treatment of osteoporosis (STRATOS) trial was to investigate the efficacy and safety of different doses of SR, a novel agent in the treatment of postmenopausal osteoporosis. A randomized, multicenter, double-blind, placebo-controlled trial was undertaken in 353 osteoporotic women with at least one previous vertebral fracture and a lumbar T-score <-2.4. Patients were randomized to receive placebo, 0.5 g, 1 g, or 2 g SR/d for 2 yr. The primary efficacy endpoint was lumbar bone mineral density (BMD), assessed by dual-energy x-ray absorptiometry. Secondary outcome measures included femoral BMD, incidence of new vertebral deformities, and biochemical markers of bone metabolism. Lumbar BMD, adjusted for bone strontium content, increased in a dose-dependent manner in the intention-to-treat population: mean annual slope increased from 1.4% with 0.5 g/d SR to 3.0% with 2 g/d SR, which was significantly higher than placebo (P < 0.01). There was a significant reduction in the number of patients experiencing new vertebral deformities in the second year of treatment with 2 g/d SR [relative risk 0.56; 95% confidence interval (0.35; 0.89)]. In the 2 g/d group, there was a significant increase in serum levels of bone alkaline phosphatase, whereas urinary excretion of cross-linked N-telopeptide, a marker of bone resorption, was lower with SR than with placebo. All tested doses were well tolerated; the 2 g/d dose was considered to offer the best combination of efficacy and safety. In conclusion, SR therapy increased vertebral BMD and reduced the incidence of vertebral fractures.

Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, Adami S, Weber K, Lorenc R, Pietschmann P, Vandormael K, Lombardi A. · Oregon Health Sciences University, Portland 97201, USA. · N Engl J Med. · Pubmed #10979796 links to  free full text

Abstract: BACKGROUND: Despite its association with disability, death, and increased medical costs, osteoporosis in men has been relatively neglected as a subject of study. There have been no large, controlled trials of treatment in men. METHODS: In a two-year double-blind trial, we studied the effect of 10 mg of alendronate or placebo, given daily, on bone mineral density in 241 men (age, 31 to 87 years; mean, 63) with osteoporosis. Approximately one third had low serum free testosterone concentrations at base line; the rest had normal concentrations. Men with other secondary causes of osteoporosis were excluded. All the men received calcium and vitamin D supplements. The main outcome measures were the percent changes in lumbar-spine, hip, and total-body bone mineral density. RESULTS: The men who received alendronate had a mean (+/-SE) increase in bone mineral density of 7.1+/-0.3 percent at the lumbar spine, 2.5+/-0.4 percent at the femoral neck, and 2.0+/-0.2 percent for the total body (P<0.001 for all comparisons with base line). In contrast, men who received placebo had an increase in lumbar-spine bone mineral density of 1.8+/-0.5 percent (P<0.001 for the comparison with base line) and no significant changes in femoral-neck or total-body bone mineral density. The increase in bone mineral density in the alendronate group was greater than that in the placebo group at all measurement sites (P<0.001). The incidence of vertebral fractures was lower in the alendronate group than in the placebo group (0.8 percent vs. 7.1 percent, P=0.02). Men in the placebo group had a 2.4-mm decrease in height, as compared with a decrease of 0.6 mm in the alendronate group (P=0.02). Alendronate was generally well tolerated. CONCLUSIONS: In men with osteoporosis, alendronate significantly increases spine, hip, and total-body bone mineral density and helps prevent vertebral fractures and decreases in height.

Skowrońska-Jóźwiak E, Płudowski P, Karczmarewicz E, Lorenc R, Lewiński A, Anonymous00036. · Department of Endocrinology and Metabolic Diseases, Medical University, Łódź · Endokrynol Pol. · Pubmed #19396748 No free full text.

Abstract: INTRODUCTION: The aim of the study was the determination of the prevalence of asymptomatic vertebral deformities in healthy persons of the Polish population, based on morphometric X-ray absorptiometry (MXA), and comparison of the results with data from literature, obtained by other techniques. MATERIAL AND METHODS: The study involved 829 persons, including 520 women and 309 men, aged 18-79 years, untreated for osteoporosis before. The Th(4) to L(4) vertebrae were examined. Lateral scans of the thoracic-lumbar spine were made by an Expert-XL densitometer. Six point digitization was used to calculate the anterior (Ha), central (Hc), and posterior (Hp) height of the Th(4)-L(4) vertebral bodies. The vertebrae were defined as having prevalent deformities when at least one ratio value (Ha/Hp, Hc/Hp, Hp/Hp up, or Hp/Hp low) fell 3 SDs below or even more than the reference mean of that ratio at any vertebral level. RESULTS: The analysis was performed on 9629 vertebrae, of which 167 (1.75%), evaluated as deformed and considered as fractures, were observed in 113 patients (13.63 % of the examined patients). In 81 persons (74% of the patients with fractures; 9.7% of the studied population), single fractures were demonstrated, while in 28 persons, multiple deformities prevailed. Fractures occurred in 108 women (20.7% of the examined women) and 42 men (13.5% of the examined men). The highest incidence of deformities was observed in women over 55 years of age. First-degree deformities dominated. Deformities of the Th(8) and Th(6) vertebrae were most frequently observed. CONCLUSIONS: 1. Using MXA, it was found that in the Polish population deformities of vertebrae are common, as was demonstrated in X-ray morphometric studies in the European Vertebral Observation Study (EVOS). 2. Densitometric morphometry, as a non-invasive technique, may become a useful tool in the diagnostics of vertebral fractures.

Kaptoge S, da Silva JA, Brixen K, Reid DM, Kröger H, Nielsen TL, Andersen M, Hagen C, Lorenc R, Boonen S, de Vernejoul MC, Stepan JJ, Adams J, Kaufman JM, Reeve J. · Department of Medicine and Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK. · Bone. · Pubmed #18519175 No free full text.

Abstract: We collected population-based young normal hip and spine BMD data from 17 centres across Europe to assess between centre differences and to compare reference values with the US NHANES-III data. There was strong evidence of between country heterogeneity, but not between centres within countries. Hip BMD mean values were lower in European women, but SD's differed little from the NHANES-III USA results in both sexes. It may be necessary to adjust NHANES-III based T-scores by adding/subtracting a country-specific adjustment factor. INTRODUCTION: It remains unclear whether young normal BMD reference values specific to an American population can be validly used for T-score calculation in Europeans. METHODS: We collected population based BMD data from 1163 men and 329 women aged 19-29 years from 17 centres across Europe to compare mean and SD values with the NHANES-III study USA results. BMD(g/cm2) was measured at the hip and spine using DXA densitometers cross-calibrated with the European Spine Phantom (ESP). The only exclusions were for technically inadequate scans. A linear regression model was used to derive reference values. To allow for direct comparison with published NHANES III study data, the cross-calibrated BMD values were converted using the ESP equations to Hologic QDR 1000 units. RESULTS: In men, the overall mean(SD) BMD values expressed in Hologic-QDR1000 units of measurement, were: femoral neck 0.912(0.132); trochanter 0.793(0.124); and L2-L4 spine 1.027(0.123). The respective estimates in women were: 0.826(0.115); 0.670(0.093); and 0.983(0.107). However the I2 statistic for heterogeneity indicated moderate to strong evidence of between-centre heterogeneity. There was, however, no significant heterogeneity observed between centres within countries, suggesting that this variation arose from national differences. Compared to the NHANES III population-based US data, the mean values in women were significantly lower at both sites due to some lower national European means. However, at all sites and in both sexes the SD's were very similar between the US and Europe. There was some evidence that recruiting volunteers resulted in biased values in women. CONCLUSION: Our T-score normal values for the lumbar spine (L2-L4) should be more reliable for spine-specific risk assessment than some non-representative normal ranges, and should be evaluated for that purpose in Europe. If T-scores are to be used to compare individual data with ranges seen in normal young subjects of the same nationality, it may be necessary to adjust femoral NHANES III-based T-scores by adding (or subtracting) a country-specific adjustment factor. In risk assessment it is probably sufficient to use NHANES III-based hip T-scores, as supplied for the hip by densitometer manufacturers, interpreting them in light of recent international meta-analysis data on the relationship between BMD and fracture risk.

van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellström D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG, Anonymous00179. · Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · JAMA. · Pubmed #18349089 links to  free full text

Abstract: CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

Langdahl BL, Uitterlinden AG, Ralston SH, Trikalinos TA, Balcells S, Brandi ML, Scollen S, Lips P, Lorenc R, Obermayer-Pietsch B, Reid DM, Armas JB, Arp PP, Bassiti A, Bustamante M, Husted LB, Carey AH, Pérez Cano R, Dobnig H, Dunning AM, Fahrleitner-Pammer A, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, Masi L, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, Mosekilde L, Nogués X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Ioannidis JP, Anonymous00126, Anonymous00127, Anonymous00128, Anonymous00129, Anonymous00130, Anonymous00131, Anonymous00132, Anonymous00133. · Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark. · Bone. · Pubmed #18284942 No free full text.

Abstract: INTRODUCTION: The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results. METHODS: We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G-1639-A (G-800-A, rs1800468), C-1348-T (C-509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures. RESULTS: There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (-12 mg/cm2) in men with the T-1348 allele (p<0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09-2.64), p<0.05. CONCLUSIONS: This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C-1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies.

Stakkestad JA, Lakatos P, Lorenc R, Sedarati F, Neate C, Reginster JY. · CECOR AS, Nygårdsvegen 6, P.O. Box 1364 Gard, 5507, Haugesund, Norway. · Clin Rheumatol. · Pubmed #18180976 No free full text.

Abstract: Oral ibandronate is the first bisphosphonate licensed for once-monthly treatment of postmenopausal osteoporosis. The 2-year Monthly Oral iBandronate In LadiEs (MOBILE) registration study assessed bone mineral density (BMD) and markers of bone turnover and showed that monthly oral ibandronate was at least as effective and well tolerated as a 2.5-mg daily oral regimen. In this study, we report the first year of a long-term extension study to MOBILE and a post hoc analysis of patients receiving 3 years of continuous treatment with monthly ibandronate. Patients who completed MOBILE were eligible for the partially randomized, double-blind extension study and received 100 mg (n = 359) or 150 mg (n = 360) monthly oral ibandronate. A post hoc analysis included patients who received either 100 mg (n = 173) or 150 mg (n = 169) monthly ibandronate continuously throughout the original 2-year MOBILE study and during the first year of the extension study. After one additional year of treatment (total of 3 years), mean lumbar spine BMD increased a further 1.5 and 1.1% in the 150 and 100 mg arms, respectively, compared with 2-year data (original MOBILE study). Total hip BMD changed by 0.3 and -0.08%, respectively. In the post hoc analysis, 3-year increases in lumbar spine BMD were significant in patients receiving ibandronate 150 mg monthly (7.6%; p < 0.0001 vs. baseline) and 100 mg monthly (6.4%; p < 0.0001 vs. baseline). Both groups achieved significant increases in total hip BMD after 3 years compared with baseline (3.4%, 100 mg; 4.1%, 150 mg; p < 0.0001). Serum C-telopeptide of the alpha chain of type I collagen decreased significantly over 3 years' treatment (p < 0.001; all comparisons vs. baseline), remaining within the premenopausal range. Once-monthly oral ibandronate was well tolerated with a low incidence of clinical osteoporotic fractures and upper gastrointestinal events. In conclusion, 150-mg monthly oral ibandronate is an effective and well-tolerated long-term treatment for postmenopausal osteoporosis, with consistent improvement in BMD and bone turnover during 3 years' continuous treatment.

Seeman E, Devogelaer JP, Lorenc R, Spector T, Brixen K, Balogh A, Stucki G, Reginster JY. · Austin Health, University of Melbourne, Melbourne, Australia. · J Bone Miner Res. · Pubmed #17997711 No free full text.

Abstract: Many fractures occur in women with moderate fracture risk caused by osteopenia. Strontium ranelate was studied in 1431 postmenopausal women with osteopenia. Vertebral fracture risk reduction of 41-59% was shown depending on the site and fracture status at baseline. This is the first report of antivertebral fracture efficacy in women with vertebral osteopenia. INTRODUCTION: Women with osteoporosis are at high risk for fracture. However, more than one half of all fractures in the community originate from the larger population at more moderate risk of fracture caused by osteopenia. Despite this, evidence for antifracture efficacy in these persons is limited. The aim of this study was to determine whether strontium ranelate, a new drug that reduces fracture risk in women with osteoporosis, is also effective in women with osteopenia. MATERIALS AND METHODS: Data from the Spinal Osteoporosis Therapeutic Intervention study (SOTI; n = 1649) and the TReatment Of Peripheral OSteoporosis (TROPOS; n = 5091) were pooled to evaluate the antivertebral fracture efficacy of strontium ranelate in women with lumbar spine (LS) osteopenia with any BMD value at the femoral neck (FN; N = 1166) and in 265 women with osteopenia at both sites (intention-to-treat analysis). The women were randomized to strontium ranelate 2 g/d orally or placebo for 3 yr. RESULTS: No group differences were present in baseline characteristics that may influence fracture outcome independent of therapy. In women with LS osteopenia, treatment reduced the risk of vertebral fracture by 41% (RR = 0.59; 95% CI, 0.43-0.82), by 59% (RR = 0.41; 95% CI, 0.17-0.99) in the 447 patients with no prevalent fractures, and by 38% (RR = 0.62; 95% CI, 0.44-0.88) in the 719 patients with prevalent fractures. In women with osteopenia at both sites, treatment reduced the risk of fracture by 52% (RR = 0.48; 95% CI, 0.24-0.96). CONCLUSIONS: Strontium ranelate safely reduces the risk of vertebral fractures in women with osteopenia with or without a prevalent fracture.

Napierała K, Miazgowski T, Hoszowski K, Bieńkowska R, Lorenc R, Czekalski S. · Oddział Nefrologii, Wojewódzki Szpital Zespolony, Szczecin. · Ortop Traumatol Rehabil. · Pubmed #17597688 No free full text.

Abstract: Background. The efficacy of bisphosphonates in treatment of established osteoporosis has been well-documented; less data have been published on their efficacy in the prophylaxis of postmenopausal bone loss in women with osteopenia. The aim of study was to evaluate the effect of clodronate on bone loss in early postmenopausal women with vertebral osteopenia. Materials and methods. Forty five women aged 52.3+/-3.8 yr with a lumbar spine (Spine) t-score between -1 and -2.5 SD received clodronate 400 mg/day or placebo for 12 months. Bone mineral density (BMD) was measured by DXA in Spine and femoral neck (Femur). Serum osteocalcin (OC) was assessed by RIA. BMD and OC were measured at the baseline, after 1 year of treatment and after further 1 and 2 years of follow-up. Results. BMD slightly decreased in clodronate group: Spine by 0.2% after 1 year (N.S.), 0.5% after 2 years (N.S.) and 0.9% after 3 years (P<0.05 vs. placebo group); Femur by 0.2%, 0.9% and 1.3% (N.S.). OC did not change in placebo group but significantly decreased in clodronate group (15.2%; P<0.05). Conclusions. Clodronate 400 mg daily given postmenopausal women with osteopenia is effective in decreasing OC but an effect on BMD is just detectable and its clinical significance is unclear.

Uitterlinden AG, Ralston SH, Brandi ML, Carey AH, Grinberg D, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Reeve J, Reid DM, Amedei A, Amidei A, Bassiti A, Bustamante M, Husted LB, Diez-Perez A, Dobnig H, Dunning AM, Enjuanes A, Fahrleitner-Pammer A, Fang Y, Karczmarewicz E, Kruk M, van Leeuwen JP, Mavilia C, van Meurs JB, Mangion J, McGuigan FE, Pols HA, Renner W, Rivadeneira F, van Schoor NM, Scollen S, Sherlock RE, Ioannidis JP, Anonymous00178, Anonymous00179, Anonymous00180, Anonymous00181, Anonymous00182, Anonymous00183, Anonymous00184. · Erasmus MC, Rotterdam, The Netherlands. · Ann Intern Med. · Pubmed #16908916 links to  free full text

Abstract: BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures. DESIGN: Prospective multicenter large-scale association study. SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. PARTICIPANTS: 26,242 participants (18,405 women). MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

Ralston SH, Uitterlinden AG, Brandi ML, Balcells S, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Scollen S, Bustamante M, Husted LB, Carey AH, Diez-Perez A, Dunning AM, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, del Monte F, Pols HA, Reeve J, Reid DM, Renner W, Rivadeneira F, van Schoor NM, Sherlock RE, Ioannidis JP, Anonymous00302. · Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital Edinburgh, Edinburgh, United Kingdom. · PLoS Med. · Pubmed #16475872 links to  free full text

Abstract: BACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. METHODS AND FINDINGS: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. CONCLUSIONS: Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

Kaptoge S, Benevolenskaya LI, Bhalla AK, Cannata JB, Boonen S, Falch JA, Felsenberg D, Finn JD, Nuti R, Hoszowski K, Lorenc R, Miazgowski T, Jajic I, Lyritis G, Masaryk P, Naves-Diaz M, Poor G, Reid DM, Scheidt-Nave C, Stepan JJ, Todd CJ, Weber K, Woolf AD, Roy DK, Lunt M, Pye SR, O'neill TW, Silman AJ, Reeve J. · Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK. · Bone. · Pubmed #15777673 No free full text.

Abstract: We have previously shown that center- and sex-specific fall rates explained one-third of between-center variation in upper limb fractures across Europe. In this current analysis, our aim was to determine how much of the between-center variation in fractures could be attributed to repeated falling, bone mineral density (BMD), and other risk factors in individuals, and to compare the relative contributions of center-specific BMD vs. center-specific fall rates. A clinical history of fracture was assessed prospectively in 2451 men and 2919 women aged 50-80 from 20 centers participating in the European Prospective Osteoporosis Study (EPOS) using standardized questionnaires (mean follow-up = 3 years). Bone mineral density (BMD, femoral neck, trochanter, and/or spine) was measured in 2103 men and 2565 women at these centers. Cox regression was used to model the risk of incident fracture as a function of the person-specific covariates: age, BMD, personal fracture history (PFH), family hip fracture history (FAMHIP), time spent walking/cycling, number of 'all falls' and falls not causing fracture ('fracture-free') during follow-up, alcohol consumption, and body mass index. Center effects were modeled by inclusion of multiplicative gamma-distributed random effects, termed center-shared frailty (CSF), with mean 1 and finite variance theta (theta) acting on the hazard rate. The relative contributions of center-specific fall risk and center-specific BMD on the incidence of limb fractures were evaluated as components of CSF. In women, the risk of any incident nonspine fracture (n = 190) increased with age, PFH, FAMHIP, > or =1 h/day walking/cycling, and number of 'all falls' during follow-up (all P < 0.074). 'Fracture-free' falls (P = 0.726) and femoral neck BMD did not have a significant effect at the individual level, but there was a significant center-shared frailty effect (theta = 0.271, P = 0.001) that was reduced by 4% after adjusting for mean center BMD and reduced by 19% when adjusted for mean center fall rate. Femoral trochanter BMD was a significant determinant of lower limb fractures (n = 53, P = 0.014) and the center-shared frailty effect was significant for upper limb fractures (theta = 0.271, P = 0.011). This upper limb fracture center effect was unchanged after adjusting for mean center BMD but was reduced by 36% after adjusting for center mean fall rates. In men, risk of any nonspine fracture (n = 75) increased with PFH, fall during follow-up (P < 0.026), and with a decrease in trochanteric BMD [RR 1.38 (1.08, 1.79) per 1 SD decrease]. There was no center effect evident (theta = 0.081, P = 0.096). We conclude that BMD alone cannot be validly used to discriminate between the risk of upper limb fractures across populations without taking account of population-specific variations in fall risk and other factors. These variations might reflect shared environmental or possibly genetic factors that contribute quite substantially to the risk of upper limb fractures in women.

Reeve J, Lunt M, Felsenberg D, Silman AJ, Scheidt-Nave C, Poor G, Gennari C, Weber K, Lorenc R, Masaryk P, Cannata JB, Dequeker J, Reid DM, Pols HA, Benevolenskaya LI, Stepan JJ, Miazgowski T, Bhalla A, Bruges Armas J, Eastell R, Lopes-Vaz A, Lyritis G, Jajic I, Woolf AD, Banzer D, Reisinger W, Todd CJ, Felsch B, Havelka S, Hoszowski K, Janott J, Johnell O, Raspe HH, Yershova OB, Kanis JA, Armbrecht G, Finn JD, Gowin W, O'Neill TW, Anonymous00161. · Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom. · J Bone Miner Res. · Pubmed #12968676 No free full text.

Abstract: More severe vertebral fractures have more personal impact. In the European Prospective Osteoporosis Study, more severe vertebral collapse was predictable from prior fracture characteristics. Subjects with bi-concave or crush fractures at baseline had a 2-fold increase in incident fracture size and thus increased risk of a disabling future fracture. INTRODUCTION: According to Euler's buckling theory, loss of horizontal trabeculae in vertebrae increases the risk of fracture and suggests that the extent of vertebral collapse will be increased in proportion. We tested the hypothesis that the characteristics of a baseline deformity would influence the size of a subsequent deformity. METHODS: In 207 subjects participating in the European Prospective Osteoporosis Study who suffered an incident spine fracture in a previously normal vertebra, we estimated loss of volume (fracture size) from plane film images of all vertebral bodies that were classified as having a new fracture. The sum of the three vertebral heights (anterior, mid-body, and posterior) obtained at follow-up was subtracted from the sum of the same measures at baseline. Each of the summed height loss for vertebrae with a McCloskey-Kanis deformity on the second film was expressed as a percentage. RESULTS AND CONCLUSIONS: In univariate models, the numbers of baseline deformities and the clinical category of the most severe baseline deformity were each significantly associated with the size of the most severe incident fracture and with the cumulated sum of all vertebral height losses. In multivariate modeling, age and the clinical category of the baseline deformity (crush > bi-concave > uni-concave > wedge) were the strongest determinants of both more severe and cumulative height loss. Baseline biconcave and crush fractures were associated at follow-up with new fractures that were approximately twice as large as those seen with other types of deformity or who previously had undeformed spines. In conclusion, the characteristics of a baseline vertebral deformity determines statistically the magnitude of vertebral body volume lost when a subsequent fracture occurs. Because severity of fracture and number of fractures are determinants of impact, the results should improve prediction of the future personal impact of osteoporosis once a baseline prevalent deformity has been identified.

Roy DK, O'Neill TW, Finn JD, Lunt M, Silman AJ, Felsenberg D, Armbrecht G, Banzer D, Benevolenskaya LI, Bhalla A, Bruges Armas J, Cannata JB, Cooper C, Dequeker J, Diaz MN, Eastell R, Yershova OB, Felsch B, Gowin W, Havelka S, Hoszowski K, Ismail AA, Jajic I, Janott I, Johnell O, Kanis JA, Kragl G, Lopez Vaz A, Lorenc R, Lyritis G, Masaryk P, Matthis C, Miazgowski T, Gennari C, Pols HA, Poor G, Raspe HH, Reid DM, Reisinger W, Scheidt-Nave C, Stepan JJ, Todd CJ, Weber K, Woolf AD, Reeve J, Anonymous00444. · ARC Epidemiology Unit, University of Manchester, Manchester, UK. · Osteoporos Int. · Pubmed #12577181 No free full text.

Abstract: The aim of this analysis was to determine the influence of lifestyle, anthropometric and reproductive factors on the subsequent risk of incident vertebral fracture in men and women aged 50-79 years. Subjects were recruited from population registers from 28 centers across Europe. At baseline, they completed an interviewer-administered questionnaire and had lateral thoraco-lumbar spine radiographs performed. Repeat spinal radiographs were performed a mean of 3.8 years later. Incident vertebral fractures were defined morphometrically and also qualitatively by an experienced radiologist. Poisson regression was used to determine the influence of the baseline risk factor variables on the occurrence of incident vertebral fracture. A total of 3173 men (mean age 63.1 years) and 3402 women (mean age 62.2 years) contributed data to the analysis. In total there were 193 incident morphometric and 224 qualitative fractures. In women, an age at menarche 16 years or older was associated with an increased risk of vertebral fracture (RR = 1.80; 95%CI 1.24, 2.63), whilst use of hormonal replacement was protective (RR = 0.58; 95%CI 0.34, 0.99). None of the lifestyle factors studied including smoking, alcohol intake, physical activity or milk consumption showed any consistent associations with incident vertebral fracture. In men and women, increasing body weight and body mass index were associated with a reduced risk of vertebral fracture though, apart from body mass index in men, the confidence intervals embraced unity. For most variables the strengths of the associations observed were similar using the qualitative and morphometric approaches to fracture definition. In conclusion our data suggest that modification of other lifestyle risk factors is unlikely to have a major impact on the population occurrence of vertebral fractures. The important biological mechanisms underlying vertebral fracture risk need to be explored using new investigational strategies.

Roy DK, Pye SR, Lunt M, O'Neill TW, Todd C, Raspe H, Reeve J, Silman AJ, Weber K, Dequeker J, Jajic I, Stepan J, Delmas PD, Marchand F, Reisinger W, Banzer D, Felsenberg D, Janott J, Kragl G, Schiedt-Nave C, Felsch B, Raspe H, Matthis C, Lyritis G, Poor G, Gennari C, Pols HA, Falch JA, Miazgowski T, Hoszowski K, Lorenc R, Bruges Armas J, Lopes Vaz A, Benevolenskaya LI, Masaryk P, Rapado A, Cannata JB, Naves-Diaz M, Johnell O, Dilsen G, Reid DM, Bhalla AK, Todd C, Reeve J, Finn JD, Ismail A, Lunt M, O'Neill TW, Pye SR, Roy DK, Kanis JA, Cooper C, Woolf AD, Anonymous00260. · ARC Epidemiology Unit, University of Manchester, UK. · Bone. · Pubmed #12531567 No free full text.

Abstract: There is important geographic variation in the occurrence of the major osteoporotic fractures across Europe. The aim of this study was to determine whether between-center variation in limb fracture rates across Europe could be explained by variation in the incidence of falls. Men and women, aged 50-79 years, were recruited from population-based registers in 30 European centers. Subjects were followed by postal questionnaire to ascertain the occurrence of incident fractures, and were also asked about the occurrence and number of recent falls. Self-reported fractures were confirmed, where possible, by review of the radiographs, medical record, or subject interview. The age- and gender-adjusted incidence of falls was calculated by center using Poisson regression. Poisson regression was also used to assess the extent to which between-center differences in the incidence of limb fractures could be explained by differences in the age- and gender-adjusted incidence of falls at those centers. In all, 6302 men (mean age 63.9 years) and 6761 women (mean age 63.1 years) completed at least one questionnaire concerning fractures and falls. During a median follow-up time of 3 years, 3647 falls were reported by men and 4783 by women. After adjusting for age and gender, there was evidence of significant between-center differences in the occurrence of falls. There was also between-center variation in the occurrence of upper limb, lower limb, and distal forearm fractures. Variation in the age- and gender-adjusted center-specific fall rates explained 24%, 14%, and 6% of the between-center variation in incidence of distal forearm and upper and lower limb fractures, respectively. Given the constraints inherent in such an analysis, in men and women aged 50-79 years, variation in fall rates could explain a significant proportion of the between-center variation in the incidence of limb fracture across Europe.

Ismail AA, Pye SR, Cockerill WC, Lunt M, Silman AJ, Reeve J, Banzer D, Benevolenskaya LI, Bhalla A, Bruges Armas J, Cannata JB, Cooper C, Delmas PD, Dequeker J, Dilsen G, Falch JA, Felsch B, Felsenberg D, Finn JD, Gennari C, Hoszowski K, Jajic I, Janott J, Johnell O, Kanis JA, Kragl G, Lopez Vaz A, Lorenc R, Lyritis G, Marchand F, Masaryk P, Matthis C, Miazgowski T, Naves-Diaz M, Pols HA, Poor G, Rapado A, Raspe HH, Reid DM, Reisinger W, Scheidt-Nave C, Stepan J, Todd C, Weber K, Woolf AD, O'Neill TW. · ARC Epidemiology Unit, University of Manchester, Manchester, UK. · Osteoporos Int. · Pubmed #12111017 No free full text.

Abstract: The aim of this population-based prospective study was to determine the incidence of limb fracture by site and gender in different regions of Europe. Men and women aged 50-79 years were recruited from population registers in 31 European centers. Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. Subjects were subsequently followed up using an annual postal questionnaire which included questions concerning the occurrence of new fractures. Self-reported fractures were confirmed where possible by radiograph, attending physician or subject interview. There were 6451 men and 6936 women followed for a median of 3.0 years. During this time there were 140 incident limb fractures in men and 391 in women. The age-adjusted incidence of any limb fracture was 7.3/1000 person-years [pyrs] in men and 19 per 1000 pyrs in women, equivalent to a 2.5 times excess in women. Among women, the incidence of hip, humerus and distal forearm fracture, though not 'other' limb fracture, increased with age, while in men only the incidence of hip and humerus fracture increased with age. Among women, there was evidence of significant variation in the occurrence of hip, distal forearm and humerus fractures across Europe, with incidence rates higher in Scandinavia than in other European regions, though for distal forearm fracture the incidence in east Europe was similar to that observed in Scandinavia. Among men, there was no evidence of significant geographic variation in the occurrence of these fractures. This is the first large population-based study to characterize the incidence of limb fracture in men and women over 50 years of age across Europe. There are substantial differences in the descriptive epidemiology of limb fracture by region and gender.

Vergnaud P, Lunt M, Scheidt-Nave C, Poor G, Gennari C, Hoszowski K, Vaz AL, Reid DM, Benevolenskaya L, Grazio S, Weber K, Miazgowski T, Stepan JJ, Masaryk P, Galan F, Armas JB, Lorenc R, Havelka S, Perez Cano R, Seibel M, Armbrecht G, Kaptoge S, O'Neill TW, Silman AJ, Felsenberg D, Reeve J, Delmas PD. · U. INSERM 403, Lyon, France. · Clin Chim Acta. · Pubmed #12104091 No free full text.

Abstract: BACKGROUND: In the European Prospective Osteoporosis Study (EPOS), a past spine fracture increased risk of an incident fracture 3.6 - 12-fold even after adjusting for BMD. We examined the possibility that biochemical marker levels were associated with this unexplained BMD-independent element of fracture risk. METHODS: Each of 182 cases in EPOS of spine or non-spine fracture that occurred in 3.8 years of follow-up was matched by age, sex and study centre with two randomly assigned never-fractured controls and one case of past fracture. Analytes measured blind were: osteocalcin, bone-specific alkaline phosphatase, total alkaline phosphatase, serum creatinine, calcium, phosphate and albumin, together with the collagen cross-links degradation products serum CTS and urine CTX. Most subjects also had bone density measured by DXA. RESULTS: Cases who had recent fractures did not differ in marker levels from cases who had their last fracture more than 3 years previously. No statistically significant effect of recent fracture was found for any marker except osteocalcin, which was 17.6% lower in recent peripheral cases compared to unfractured controls (p<0.05) and this was independent of BMD. CONCLUSION: Past fracture as a risk indicator for future fracture is not strongly mediated through increased bone turnover.

Crabtree NJ, Kroger H, Martin A, Pols HA, Lorenc R, Nijs J, Stepan JJ, Falch JA, Miazgowski T, Grazio S, Raptou P, Adams J, Collings A, Khaw KT, Rushton N, Lunt M, Dixon AK, Reeve J. · University Department of Medicine, University of Cambridge, UK. · Osteoporos Int. · Pubmed #11883408 No free full text.

Abstract: Hip geometry and bone mineral density (BMD) have previously been shown to relate independently to hip fracture risk. Our objective was to determine by how much hip geometric data improved the identification of hip fracture. Lunar pencil beam scans of the proximal femur were obtained. Geometric and densitometric values from 800 female controls aged 60 years or more (from population samples which were participants in the European Prospective Osteoporosis Study, EPOS) were compared with data from 68 female hip fracture patients aged over 60 years who were scanned within 4 weeks of a contralateral hip fracture. We used Lunar DPX 'beta' versions of hip strength analysis (HSA) and hip axis length (HAL) applied to DPX(L) data. Compressive stress (Cstress), calculated by the HSA software to occur as a result of a typical fall on the greater trochanter, HAL, body mass index (BMI: weight/(height)2) and age were considered alongside femoral neck BMD (FN-BMD, g/cm2) as potential predictors of fracture. Logistic regression was used to generate predictors of fracture initially from FN-BMD. Next age, Cstress (as the most discriminating HSA-derived parameter), HAL and BMI were added to the model as potentially independent predictors. It was not necessary to include both HAL and Cstress in the logistic models, so the entire data set was examined without excluding the subjects missing HAL measurements. Cstress combined with age and BMI provided significantly better prediction of fracture than FN-BMD used alone as is current practice, judged by comparing areas under receiver operating characteristic (ROC) curves (p<0.001, deLong's test). At a specificity of 80%, sensitivity in identification was improved from 66% to 81%. Identifying women at high risk of hip fracture is thus likely to be substantially enhanced by combining bone density with age, simple anthropometry and data on the structural geometry of the hip. HSA might prove to be a valuable enhancement of DXA densitometry in clinical practice and its use could justify a more proactive approach to identifying women at high risk of hip fracture in the community.

Ismail AA, Cockerill W, Cooper C, Finn JD, Abendroth K, Parisi G, Banzer D, Benevolenskaya LI, Bhalla AK, Armas JB, Cannata JB, Delmas PD, Dequeker J, Dilsen G, Eastell R, Ershova O, Falch JA, Felsch B, Havelka S, Hoszowski K, Jajic I, Kragl U, Johnell O, Lopez Vaz A, Lorenc R, Lyritis G, Marchand F, Masaryk P, Matthis C, Miazgowski T, Pols HA, Poor G, Rapado A, Raspe HH, Reid DM, Reisinger W, Janott J, Scheidt-Nave C, Stepan J, Todd C, Weber K, Woolf AD, Ambrecht G, Gowin W, Felsenberg D, Lunt M, Kanis JA, Reeve J, Silman AJ, O'Neill TW. · ARC Epidemiology Unit, University of Manchester, UK. · Osteoporos Int. · Pubmed #11303719 No free full text.

Abstract: The presence of a vertebral deformity increases the risk of subsequent spinal deformities. The aim of this analysis was to determine whether the presence of vertebral deformity predicts incident hip and other limb fractures. Six thousand three hundred and forty-four men and 6788 women aged 50 years and over were recruited from population registers in 31 European centers and followed prospectively for a median of 3 years. All subjects had radiographs performed at baseline and the presence of vertebral deformity was assessed using established morphometric methods. Incident limb fractures which occurred during the follow- up period were ascertained by annual postal questionnaire and confirmed by radiographs, review of medical records and personal interview. During a total of 40348 person-years of follow-up, 138 men and 391 women sustained a limb fracture. Amongst the women, after adjustment for age, prevalent vertebral deformity was a strong predictor of incident hip fracture, (rate ratio (RR) = 4.5; 95% CI 2.1-9.4) and a weak predictor of 'other' limb fractures (RR = 1.6; 95% CI 1.1-2.4), though not distal forearm fracture (RR = 1.0; 95% CI 0.6-1.6). The predictive risk increased with increasing number of prevalent deformities, particularly for subsequent hip fracture: for two or more deformities, RR = 7.2 (95% CI 3.0-17.3). Amongst men, vertebral deformity was not associated with an increased risk of incident limb fracture though there was a nonsignificant trend toward an increased risk of hip fracture with increasing number of deformities. In summary, prevalent radiographic vertebral deformities in women are a strong predictor of hip fracture, and to a lesser extent humerus and 'other' limb fractures; however, they do not predict distal forearm fractures.