Paul Lips

Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis

CONTEXTnMutations 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.nnnOBJECTIVEnTo 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.nnnDESIGN AND SETTINGnProspective, 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.nnnMAIN OUTCOME MEASURESnBone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.nnnRESULTSnThe 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.nnnCONCLUSIONSnCommon 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.

Osteocyte density changes in aging and osteoporosis

Recently, it was suggested that osteocytes are involved in the regulation of bone remodeling. We have examined human trabecular bone of the iliac crest of fracture patients and control subjects to determine if osteoporosis is associated with changes in osteocyte density or osteocyte death. The relationships of these parameters with age was also investigated. It was found that osteocyte death was not related to age, nor was it increased in osteoporosis compared with the controls. In healthy adults ranging from 30 to 91 years, lacunar number per bone area decreases with advancing age, from about 210/mm(2) to 150/mm(2). Significantly higher lacunar and osteocyte numbers per bone tissue volume were found in osteoporotics than in controls (17,100 lacunae/mm(3) and 13,300 osteocytes/mm(3) vs. 12,900 lacunae/mm(3) and 10,500 osteocytes/mm(3), respectively), whereas lacunar area was significantly reduced in osteoporotics (from 44.1 mu m(3) to 39.1 mu m(2)). These findings are compatible with the hypothesis that, in osteoporosis, osteoblasts produce less bone per cell. This can in turn explain the reduced wall thickness, which has previously been described as characteristic for osteoporosis.

Bone density reduction in various measurement sites in men and women with osteoporotic fractures of spine and hip: the European quantitation of osteoporosis study.

Abstract. We have measured bone mineral density (BMD) using dual X-ray absorptiometry (DXA) of the spine and hip, spinal quantitative computed tomography (QCTspi), and peripheral radial quantitative computed tomography (pQCTrad) in 334 spine and 51 hip fracture patients. The standardized hip and spine BMD for each patient was calculated and compared with the combined reference ranges published previously, each densitometer having been cross-calibrated with the prototype European Spine Phantom (ESPp) or the European Forearm Phantom (EFP).Male and female fracture cases had similar BMD values after adjusting for body size, where appropriate. This suggests that the relationship between bone density (mass per unit volume) and fracture risk is similar between men and women. However, compared with age-matched controls, mean decreases in BMD ranged from 0.78 SD units (women with hip fracture, DXAspi) to 2.57 SD units (men with spine fractures, QCTspi).The proportion of spine and hip fracture patients falling below the cutoff for osteoporosis (T-score <−2.5 SD) proposed by the World Health Organization (WHO) study group varied according to different BMD measurement procedures (range 18–94%). This finding suggests that the WHO definition requires different thresholds when used with non-DXA BMD measurement techniques.Receiver operator characteristic (ROC) analysis was used to compare measurement techniques for their ability to discriminate between cases and controls. Among DXA sites, the proximal femur was preferred when evaluating generalized bone loss, particularly in elderly people. An additional spinal BMD measurement may add clinical value if spine fracture risk assessment has a high priority. Both axial and peripheral QCT techniques performed comparably to DXA in spinal osteoporosis, so investigators and clinicians may use any of the three technologies with similar degrees of confidence for the diagnosis of generalized or site-specific bone loss providing straightforward clinical guidelines are followed.

Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis : The GENOMOS study

INTRODUCTIONnThe 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.nnnMETHODSnWe 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.nnnRESULTSnThere 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.nnnCONCLUSIONSnThis 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.

Dual X-ray absorptiometry—cross-calibration and normative reference ranges for the spine: Results of a European Community Concerted Action

Bone density measurements by dual X-ray absorptiometry (DXA) of the spine can now be made precisely, but there is no uniformity in reporting results and in presenting reference data. A European Union Concerted Action therefore devised a uniform procedure for cross-calibrating and standardizing instruments, using the European spine phantom (ESP) prototype. This phantom differs in a number of respects from the final version of the ESP. Eighteen centers in nine countries obtained 1619 records (1035 women) from Caucasian subjects, aged 20-80 years, drawn from normal populations. The DXA machines used were made by the Hologic, Lunar, and Norland companies. Highly statistically significant differences were evident between populations, both in apparent rates of bone loss with age and in the spread of values about the age-adjusted means. There were small residual differences in the results obtained with the three machine brands which could have been due to the relatively large between-center population differences we observed. The alternative or additional explanation that they were attributable, in part, to the design differences between the ESP prototype and the definitive ESP, which became available after this study was completed, was shown to be a valid possibility. Results from postmenopausal women reported in relation to the years that have elapsed since menopause showed reduced population variance when compared with conventional reporting in relation to age. After cross-calibration, the center with the highest age-adjusted normal density value averaged 23% more than the center with the lowest. It is therefore crucially important to select appropriate reference data in clinical and epidemiological studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of 2-year vitamin B treatment on cognitive performance; Secondary data from an RCT

Objective: We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels. Methods: This multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 µg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721). Results: Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval −5.3 to −4.7) µmol/L in the B-vitamin group and 1.3 (−1.6 to −0.9) µmol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (−0.2 to 0.0) in the B-vitamin group and 0.3 (−0.4 to −0.2) in the placebo group (p = 0.05), as determined by an independent t test. Conclusions: Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance. Classification of evidence: This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.