Risk Factor For Osteoporotic Fractures Research Articles

Leitlinie Bewegungstherapie und Physiotherapie bei Osteoporose – Methoden und Ergebnisdarstellung

BACKGROUND: To achieve the best possible effect in preventing osteoporosis associated impairments and fractures, specially tailored exercise regimes need to be integrated. Evident programmes with the potential to preserve bone mass, reduce incidence of falls, and decrease fear of falling are therefore important. OBJECTIVE: This guideline aims to provide evidence-based recommendations on exercise regimes in primary, secondary and tertiary prevention of osteoporotic fractures. METHOD: A systematic literature search for randomised controlled trials was conducted using the databases Medline, Cinahl und Embase. Evidence-based recommendations were made in accordance with the PEDro scale quality assessment, clinical relevance evaluation and expert panel judgement. RESULTS: Evidence for the efficacy of exercise programmes for the prevention of osteoporotic fractures is insufficient. There is medium to high evidence that physical exercise regimes are effective in preventing loss of bone mass, reducing incidence of falling and minimizing fear of falling. CONCLUSION: The efficacy of exercise regime on major risk factors for osteoporotic fractures is proven. Following these principles, community-based exercise programmes should be implemented.

Leitlinie Physiotherapie und Bewegungstherapie bei Osteoporose

BACKGROUND: The potential of preventing osteoporotic fractures by tailored exercise regimes to preserve bone mass, reduce incidence of falls and decrease fear of falling is not widely used. OBJECTIVE: This guideline aims to provide evidence-based recommendations on exercise regimes in primary, secondary and tertiary prevention of osteoporotic fractures. METHOD: A systematic literature search for randomised controlled trials was conducted using the databases Medline, Cinahl und Embase. On the basis of quality assessment with the PEDro scale, clinical relevance evaluation and expert panel judgement evidence-based recommendations were posed. RESULTS: Evidence for the efficacy of exercises programmes for the prevention of osteoporotic fractures is insufficient. There is medium to high evidence that physical exercise regimes are effective in preventing loss of bone mass, reducing incidence of falling and minimizing fear of falling. CONCLUSION: The efficacy of exercise regime on major risk factors for osteoporotic fractures is proven. Following these principles, community-based exercise programmes should be implemented.

In Vitro and in Vivo Effects of Adiponectin on Bone

Fat mass impacts on both bone turnover and bone density and is a critical risk factor for osteoporotic fractures. Adipocyte-derived hormones may contribute to this relationship, and adiponectin is a principal circulating adipokine. However, its effects on bone remain unclear. We have, therefore, investigated the direct effects of adiponectin on primary cultures of osteoblastic and osteoclastic cells in vitro and determined its integrated effects in vivo by characterizing the bone phenotype of adiponectin-deficient mice. Adiponectin was dose-dependently mitogenic to primary rat and human osteoblasts ( approximately 50% increase at 10 microg/ml) and markedly inhibited osteoclastogenesis at concentrations of 1 microg/ml or greater. It had no effect on osteoclastogenesis in RAW-264.7 cells or on bone resorption in isolated mature osteoclasts. In adiponectin knockout (AdKO) male C57BL/6J mice, trabecular bone volume and trabecular number (assessed by microcomputed tomography) were increased at 14 wk of age by 30% (P = 0.02) and 38% (P = 0.0009), respectively. Similar, nonsignificant trends were observed at 8 and 22 wk of age. Biomechanical testing showed lower bone fragility and reduced cortical hardness at 14 wk. We conclude that adiponectin stimulates osteoblast growth but inhibits osteoclastogenesis, probably via an effect on stromal cells. However, the AdKO mouse has increased bone mass, suggesting that adiponectin also has indirect effects on bone, possibly through modulating growth factor action or insulin sensitivity. Because adiponectin does influence bone mass in vivo, it is likely to be a contributor to the fat-bone relationship.

In vitro and in vivo effects of adiponectin on bone

Fat mass impacts on both bone turnover and bone density and is a critical risk factor for osteoporotic fractures. Adipocyte-derived hormones may contribute to this relationship, and adiponectin is a principal circulating adipokine. However, its effects on bone remain unclear. We have, therefore, investigated the direct effects of adiponectin on primary cultures of osteoblastic and osteoclastic cells in vitro and determined its integrated effects in vivo by characterizing the bone phenotype of adiponectin-deficient mice. Adiponectin was dose-dependently mitogenic to primary rat and human osteoblasts ( approximately 50% increase at 10 microg/ml) and markedly inhibited osteoclastogenesis at concentrations of 1 microg/ml or greater. It had no effect on osteoclastogenesis in RAW-264.7 cells or on bone resorption in isolated mature osteoclasts. In adiponectin knockout (AdKO) male C57BL/6J mice, trabecular bone volume and trabecular number (assessed by microcomputed tomography) were increased at 14 wk of age by 30% (P = 0.02) and 38% (P = 0.0009), respectively. Similar, nonsignificant trends were observed at 8 and 22 wk of age. Biomechanical testing showed lower bone fragility and reduced cortical hardness at 14 wk. We conclude that adiponectin stimulates osteoblast growth but inhibits osteoclastogenesis, probably via an effect on stromal cells. However, the AdKO mouse has increased bone mass, suggesting that adiponectin also has indirect effects on bone, possibly through modulating growth factor action or insulin sensitivity. Because adiponectin does influence bone mass in vivo, it is likely to be a contributor to the fat-bone relationship.

Epistasis between QTLs for bone density variation in Copenhagen x dark agouti F2 rats.

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation.

The association between socioeconomic status and osteoporotic fracture in population-based adults: a systematic review

Although socioeconomic status (SES) is inversely related to most diseases, this systematic review showed a paucity of good quality data examining influences of SES on osteoporotic fracture to confirm this relationship. Further research is required to elucidate the issue and any underlying mechanisms as a necessary precursor to considering intervention implications. The association between socioeconomic status (SES) and musculoskeletal disease is little understood, despite there being an inverse relationship between SES and most causes of morbidity. We evaluated evidence of SES as a risk factor for osteoporotic fracture in population-based adults. Computer-aided search of Medline, EMBASE, CINAHL, and PsychINFO from January 1966 until November 2007 was conducted. Identified studies investigated the relationship between SES parameters of income, education, occupation, type of residence and marital status, and occurrence of osteoporotic fracture. A best-evidence synthesis was used to summarize the results. Eleven studies were identified for inclusion, which suggested a lack of literature in the field. Best evidence analysis identified strong evidence for an association between being married/living with someone and reduced risk of osteoporotic fracture. Limited evidence exists of the relationship between occupation type or employment status and fracture, or for type of residence and fracture. Conflicting evidence exists for the relationship between osteoporotic fracture and level of income and education. Limited good quality evidence exists of the role SES might play in osteoporotic fracture. Further research is required to identify whether a relationship exists, and to elucidate underlying mechanisms, as a necessary precursor to considering intervention implications.

Simply Ask Them About Their Balance--Future Fracture Risk in a Nationwide Cohort Study of Twins

The principal causal components of an osteoporotic fracture are a fall and weakened bone strength. While bone quality measures have been frequently studied, the ability of simple measures of impaired balance to predict fracture risk has received less attention. Computer-assisted telephone interviews were conducted between 1998 and 2000 among 24,598 Swedish twins aged 55 years or older. Impaired balance at the time of interview was reported by 2,890 (12%) of the twins. Twin pairs who were discordant with regard to impaired balance were selected for analysis and followed for fractures through 2005. In a pairwise analysis, the odds ratio for hip fracture was 3.13 (95% confidence interval (CI): 1.62, 6.05) among twins with impaired balance as compared with their co-twins with normal balance. When previously recognized clinical risk factors for osteoporotic fracture were considered in the model, the odds ratio for hip fracture with impaired balance was 3.88 (95% CI: 1.40, 10.72). Approximately 40% of all hip fractures were attributable to impaired balance. The odds ratios for any fracture and any osteoporotic fracture for twins with impaired balance were 2.00 (95% CI: 1.29, 3.11) and 2.39 (95% CI: 1.49, 3.82), respectively. These results imply that self-reported impaired balance is a novel and readily assessed risk factor for future fractures in the elderly.

Heritability of impaired balance: a nationwide cohort study in twins

In this large population-based twin study, a self-estimated impaired balance, an important risk factor for osteoporotic fractures, had a modest heritability of 0.27. Individual-specific environmental influences seem to be the dominating cause for impaired balance. The principal causal components of an osteoporotic fracture are falls and weakened bone strength. While bone strength has a strong genetic origin, the heritable influences on impaired balance that contribute to the risk of injurious falls at older age are uncertain. To evaluate the heritability and environmental influence on self-reported impaired balance in older men and women, we used data from a sample of 22,998 Swedish twins, 55 to 99 years of age. An impaired balance was reported by 2,890 (12.3%) of the twins. The tetrachoric correlation for impaired balance was only slightly lower for like-sex dizygotic twins (0.31) compared to monozygotic twins (0.36). These correlations indicate a modest familial (genetic and shared environmental) influence. Model fitting results indicate that the age- and sex-adjusted heritability for impaired balance was 0.27 (95%CI = 0.01-0.45). Individual-specific environmental influences differed only slightly by sex and age. These results imply that a self-reported impaired balance, an independent risk factor for osteoporotic fractures, has a modestly heritable etiology in older subjects. Our observation can partly explain the previously observed modest heritability for osteoporotic fractures even though there is a high heritability for bone mineral density.

Poverty is a risk factor for osteoporotic fractures

This study assesses the possible association between poverty and osteoporosis and/or fragility fractures in a population of postmenopausal women. We found that postmenopausal women with low socioeconomic status had lower values of BMD at the lumbar spine, a higher prevalence of densitometric osteoporosis, and a higher prevalence of total and vertebral fractures. Some lifestyles are related to the presence of osteoporosis and/or fragility fractures, whereas poverty is related to some lifestyles. Because of this, we studied the possible association of poverty with osteoporosis and fractures. This was an observational, cross-sectional study performed in the Canary Islands, Spain. Participants consisted of a total of 1,139 ambulatory postmenopausal women aged 50 years or older with no previous osteoporosis diagnosis and who were enrolled in some epidemiological studies. The prevalence of fractures (vertebral and non-vertebral) and the prevalence of osteoporosis (T-score <-2.5 either at the lumbar spine or the femoral neck). A previously validated questionnaire elicited the most important risk factors for osteoporosis: socioeconomic status, defined by the annual income was also assessed by a personal interview. A dorso-lateral X-ray of the spine was performed, and bone mineral density (BMD) was measured by DXA in the lumbar spine (L2-L4) and proximal femur. Compared to women with a medium and high socioeconomic status (n = 665), those who were classified into poverty (annual family income lower than 6,346.80 Euros, in a one-member family, n = 474), were older and heavier and had lower height, lower prevalence of tobacco and alcohol consumption, lower use of HRT and higher use of thiazides. After correcting for age and body mass index (BMI), women in poverty had lower spine BMD values than women with a medium and high socioeconomic status (0.840 g/cm(2) vs. 0.867 g/cm(2), p = 0.005), but there were no statistical differences in femoral neck BMD between groups. The prevalence of osteoporosis was also higher in women in poverty [40.6% vs. 35.6%, (OR 1.35, CI 95%: 1.03; 1.76)] after adjusting by age and BMI. Moreover, 37.8% of women in poverty had a history of at least one fragility fracture compared to 27.7% of women not in poverty (OR: 1.45, CI 95%: 1.11; 1.90). The prevalence of vertebral fractures was also higher in women in poverty 24.7% vs. 13.4%, (OR 2.01, CI 95%: 1.44; 2.81). Postmenopausal women with low socioeconomic status had lower values of BMD at the lumbar spine, and a higher prevalence of densitometric osteoporosis, and a higher prevalence of total and vertebral fractures. Because of this, apart from the well known risk factors for osteoporosis, poverty should be taken into account as a possible risk factor for both osteoporosis and fragility fractures, in order to establish sanitary strategies to protect unfavoured postmenopausal women.

Whole Bone Geometry and Bone Quality in Distal Forearm Fracture

Fracture of the distal radius is a sentinel for future increased risk of other "osteoporotic" fractures, in which the peak age for incidence of distal radius fracture is 5 to 10 years before that for spine and hip fractures. Mean bone mineral density (BMD) of the distal radius was lower in patients with osteoporosis compared with age- and sex-matched normal subjects. However, it has been shown that to predict the strength of the distal radius at the site where fractures occur requires more than measurement of bone mineral content (BMC) or BMD. Only moderate correlations have been found between forearm sites, which may be a result of differences in bone composition between sites. Different forearm sites may be used interchangeably for diagnostic purposes, but the prognostic value is not known. Using the distal radius as a screening tool for identifying individuals at risk of "osteoporotic" fracture shows that forearm site selection and accuracy of measurement can be important confounders in group studies.Improving resolution of computed tomography (CT) scanners has enabled quantitation of cortical bone density and cortical thickness. These measurements have enabled the mechanism of bone loss in the distal radius to be elucidated and show that, after menopause, bone loss is primarily through thinning of the cortex. CT imaging allows the precise localization of bone changes in individuals and should be of value in the assessment of the severity of osteoporosis. It also shows that this technology has the potential to determine the efficacy of therapeutic interventions. A concerted effort has been made to elucidate the interrelationships between the amount of bone and the geometry and that clinical imaging of BMC and/or cross-sectional area in the radius would provide improved prediction of an individual's risk of fracture.The technological tools are available, in the clinic, to accurately measure the 3-dimensional (3D) geometry of the distal radius and the amount of bone. In addition, the cortical and cancellous bone compartments can be analyzed separately. This capability, along with the easy accessibility of the distal radius to clinical imaging modalities, provides an excellent framework for longitudinal prospective studies to determine morphologic risk factors for osteoporotic fractures of the distal radius.

Identification ofLTBP2on Chromosome 14q as a Novel Candidate Gene for Bone Mineral Density Variation and Fracture Risk Association

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Chromosome 14q has previously been linked to BMD variation in several genome-wide linkage scans in Caucasian populations. Our objective was to replicate and identify the novel candidate genes in the quantitative trait loci (QTL) at chromosome 14q QTL. Eighteen microsatellite markers were genotyped for a 117-cM interval in 306 Southern Chinese pedigrees with 1459 subjects. Successful replication of the QTL was confirmed within this region for trochanter and total hip BMD. Using a gene prioritization approach as implemented in the Endeavour program, we genotyped 65 single-nucleotide polymorphisms in the top five ranking candidate genes within the linkage peak in 706 and 760 case-control subject pairs with extremely high and low trochanter and total hip BMD, respectively. Single-marker and haplotype analyses revealed that ESR2 and latent TGF-beta binding protein 2 (LTBP2) had significant associations with trochanter and total hip BMD. Multiple logistic regression revealed a strong genetic association between LTBP2 gene locus and total hip BMD variation (P=0.0004) and prevalent fracture (P=0.01). Preliminary in vitro study showed differential expression of LTBP2 gene in MC3T3-E1 mouse preosteoblastic cells in culture. Apart from ESR2, LTBP2 is a novel positional candidate gene in chromosome 14q QTL for BMD variation and fracture.

Daily practice using the guidelines for prevention and treatment of osteoporosis. Use of clinical risk factors for osteoporotic fractures in the evaluation of risk of future fracture

A number of clinical risk factors that provide information on fracture risk over and above that given by BMD have been defined. WHO proposed FRAX (fracture risk assessment tool) in which the fracture probability could be calculated by the use of risk factors with or without BMD. The proposed independent risk factors are age, a prior fragility fracture, a parental history of hip fracture, smoking, use of systemic corticosteroids, excess alcohol intake, secondary osteoporosis, and rheumatoid arthritis. Management algorithms in postmenopausal women based on an health analysis have been proposed in several countries including UK, Sweden, Germany, USA and Canada.

Clinical risk factors for osteoporotic fractures in Brazilian women and men: the Brazilian Osteoporosis Study (BRAZOS)

The Brazilian Osteoporosis Study (BRAZOS) is the first epidemiological study carried out in a representative sample of Brazilian men and women aged 40 years or older. The prevalence of fragility fractures is about 15.1% in the women and 12.8% in the men. Moreover, advanced age, sedentarism, family history of hip fracture, current smoking, recurrent falls, diabetes mellitus and poor quality of life are the main clinical risk factors associated with fragility fractures. The Brazilian Osteoporosis Study (BRAZOS) is the first epidemiological study carried out in a representative sample of Brazilian men and women aged 40 years or older with the purpose of identifying the prevalence and the main clinical risk factors (CRF) associated with osteoporotic fracture in our population. A total of 2,420 individuals (women, 70%) from 150 different cities in the five geographic regions in Brazil, and all different socio-economical classes were selected to participate in the present survey. Anthropometrical data as well as life habits, fracture history, food intake, physical activity, falls and quality of life were determined by individual quantitative interviews. The representative sampling was based on Brazilian National data provided by the 2000 and 2003 census. Low trauma fracture was defined as that resulting of a fall from standing height or less in individuals 50 years or older at specific skeletal sites: forearm, femur, ribs, vertebra and humerus. Sampling error was 2.2% with 95% confidence intervals. Logistic regression analysis models were designed having the fragility fracture as the dependent variable and all other parameters as the independent variable. Significance level was set as p < 0.05. The average of age, height and weight for men and women were 58.4 +/- 12.8 and 60.1 +/- 13.7 years, 1.67 +/- 0.08 and 1.56 +/- 0.07 m and 73.3 +/- 14.7 and 64.7 +/- 13.7 kg, respectively. About 15.1% of the women and 12.8% of the men reported fragility fractures. In the women, the main CRF associated with fractures were advanced age (OR = 1.6; 95% CI 1.06-2.4), family history of hip fracture (OR = 1.7; 95% CI 1.1-2.8), early menopause (OR = 1.7; 95% CI 1.02-2.9), sedentary lifestyle (OR = 1.6; 95% CI 1.02-2.7), poor quality of life (OR = 1.9; 95% CI 1.2-2.9), higher intake of phosphorus (OR = 1.9; 95% CI 1.2-2.9), diabetes mellitus (OR = 2.8; 95% CI 1.01-8.2), use of benzodiazepine drugs (OR = 2.0; 95% CI 1.1-3.6) and recurrent falls (OR = 2.4; 95% CI 1.2-5.0). In the men, the main CRF were poor quality of life (OR = 3.2; 95% CI 1.7-6.1), current smoking (OR = 3.5; 95% CI 1.28-9.77), diabetes mellitus (OR = 4.2; 95% CI 1.27-13.7) and sedentary lifestyle (OR = 6.3; 95% CI 1.1-36.1). Our findings suggest that CRF may contribute as an important tool to identify men and women with higher risk of osteoporotic fractures and that interventions aiming at specific risk factors (quit smoking, regular physical activity, prevention of falls) may help to manage patients to reduce their risk of fracture.

Screening for Osteoporosis in Men: A Systematic Review for an American College of Physicians Guideline

Screening for low bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is the primary way to identify asymptomatic men who might benefit from osteoporosis treatment. Identifying men at risk for low BMD and fracture can help clinicians determine which men should be tested. To identify which asymptomatic men should receive DXA BMD testing, this systematic review evaluates 1) risk factors for osteoporotic fracture in men that may be mediated through low BMD and 2) the performance of non-DXA tests in identifying men with low BMD. Studies identified through the MEDLINE database (1990 to July 2007). Articles that assessed risk factors for osteoporotic fracture in men or evaluated a non-DXA screening test against a gold standard of DXA. Researchers performed independent dual abstractions for each article, determined performance characteristics of screening tests, and assessed the quality of included articles. A published meta-analysis of 167 studies evaluating risk factors for low BMD-related fracture in men and women found high-risk factors to be increased age (>70 years), low body weight (body mass index <20 to 25 kg/m2), weight loss (>10%), physical inactivity, prolonged corticosteroid use, and previous osteoporotic fracture. An additional 102 studies assessing 15 other proposed risk factors were reviewed; most had insufficient evidence in men to draw conclusions. Twenty diagnostic study articles were reviewed. At a T-score threshold of -1.0, calcaneal ultrasonography had a sensitivity of 75% and specificity of 66% for identifying DXA-determined osteoporosis (DXA T-score, -2.5). At a risk score threshold of -1, the Osteoporosis Self-Assessment Screening Tool had a sensitivity of 81% and specificity of 68% to identify DXA-determined osteoporosis. Data on other screening tests, including radiography, and bone geometry variables, were sparse. Key risk factors for low BMD-mediated fracture include increased age, low body weight, weight loss, physical inactivity, prolonged corticosteroid use, previous osteoporotic fracture, and androgen deprivation therapy. Non-DXA tests either are too insensitive or have insufficient data to reach conclusions.

Association Between Alcohol Consumption and Both Osteoporotic Fracture and Bone Density

Objective Alcoholism is a risk factor for osteoporotic fractures and low bone density, but the effects of moderate alcohol consumption on bone are unknown. We performed a systematic review and meta-analysis to assess the associations between alcohol consumption and osteoporotic fractures, bone density and bone density loss over time, bone response to estrogen replacement, and bone remodeling. Methods MEDLINE, Current Contents, PsychINFO, and Cochrane Libraries were searched for studies published before May 14, 2007. We assessed quality using the internal validity criteria of the US Preventive Services Task Force. Results We pooled effect sizes for 2 specific outcomes (hip fracture and bone density) and synthesized data qualitatively for 4 outcomes (non-hip fracture, bone density loss over time, bone response to estrogen replacement, and bone remodeling). Compared with abstainers, persons consuming from more than 0.5 to 1.0 drinks per day had lower hip fracture risk (relative risk = 0.80 [95% confidence interval, 0.71-0.91]), and persons consuming more than 2 drinks per day had higher risk (relative risk = 1.39 [95% confidence interval, 1.08-1.79]). A linear relationship existed between femoral neck bone density and alcohol consumption. Because studies often combined moderate and heavier drinkers in a single category, we could not assess relative associations between alcohol consumption and bone density in moderate compared with heavy drinkers. Conclusion Compared with abstainers and heavier drinkers, persons who consume 0.5 to 1.0 drink per day have a lower risk of hip fracture. Although available evidence suggests a favorable effect of alcohol consumption on bone density, a precise range of beneficial alcohol consumption cannot be determined.

Plasma B Vitamins, Homocysteine, and Their Relation with Bone Loss and Hip Fracture in Elderly Men and Women

Elevated homocysteine is a strong risk factor for osteoporotic fractures among elders, yet it may be a marker for low B-vitamin status. Our objective was to examine the associations of plasma concentrations of folate, vitamin B12, vitamin B6, and homocysteine with bone loss and hip fracture risk in elderly men and women. This was a longitudinal follow-up study of the Framingham Osteoporosis Study. Community dwelling residents of Framingham, MA, were included in the study. A total of 1002 men and women (mean age 75 yr) was included in the study. Baseline (1987-1989) blood samples were used to categorize participants into plasma B-vitamin (normal, low, deficient) and homocysteine (normal, high) groups. Femoral neck bone mineral density (BMD) measured at baseline and 4-yr follow-up was used to calculate annual percent BMD change. Incident hip fracture was assessed from baseline through 2003. Multivariable-adjusted mean bone loss was inversely associated with vitamin B6 (P for trend 0.01). Vitamins B12 and B6 were inversely associated with hip fracture risk (all P for trend < 0.05), yet associations were somewhat attenuated and not significant after controlling for baseline BMD, serum vitamin D, and homocysteine. Participants with high homocysteine (>14 micromol/liter) had approximately 70% higher hip fracture risk after adjusting for folate and vitamin B6, but this association was attenuated after controlling for vitamin B12 (hazard ratio = 1.49; 95% confidence interval 0.91, 2.46). Low B-vitamin concentration may be a risk factor for decreased bone health, yet does not fully explain the relation between elevated homocysteine and hip fracture. Thus, homocysteine is not merely a marker for low B-vitamin status.

Does homocysteine contribute to bone disease in hyperparathyroidism?

Background Osteoporosis is a complication of hyperparathyroidism (HPT). Hyperhomocysteinemia (HHCy) is an independent risk factor for osteoporotic fractures. We hypothesize that HHCy correlates with bone disease in HPT. Methods A prospectively collected database of 250 patients treated for HPT was reviewed. Patients were categorized into 3 groups: group I, normal renal function; group 2, mild renal insufficiency; and group 3, secondary HPT with end-stage renal disease on dialysis. Serum homocysteine levels, markers of bone metabolism, and bone density studies were examined. Results The prevalence of HHCy in group 1 (208 patients) was 5%, in group 2 (23 patients), 82%, and in group 3 (19 patients), 78%. Mean (±SD) preoperative homocysteinemia (HCy) levels in groups 1, 2, and 3 were 9.3 ± 4.0, 20 ± 10.2, and 20.6 ± 12.3 μmol/L, respectively. Elevated serum markers of bone metabolism increased significantly with decreasing renal function. Conclusions Prevalence of HHCy is low in HPT patients with normal renal function. It is significantly greater in those with dialysis-independent and -dependent renal insufficiency. HHCy correlates with other serum markers of bone metabolism in HPT and may be useful for monitoring progression or improvement.

Hip, Osteoporosis: New Paradigm.

Osteoporosis is the most common metabolic bone disease. Recently, the paradigm for diagnosis and treatment of osteoporosis has undergone changes due to new findings on this disease. With the arrival of densitometers that could measure BMD we started using medications that block further degradation of density and repair the densitometric results. More recent findings, however, suggest that the BMD value influences the predicted success of future fracture prevention in less than 50%. The remainder is attributed to bone quality. There are a number of risk factors for osteoporotic fractures, some of greater and some of lesser significance. A small external force is necessary to cause an osteoporotic fracture; otherwise, the osteoporotic bone still does not break. The dominant factor in a fracture is therefore the fall of the elderly patient. Falls are preventable, although most are benign and injury free. Only in the recent decade have we started paying attention to the fall phenomenon, which does not only involve accidents, but is also a consequence of the normal aging process. Incidence of falls and hip fractures in residential elderly patients can be reduced with a multifactorial interdisciplinary prevention program (MIPP):• Staff training • Adaptation of environment • Gait and mobility exercise • Technical accessories • Revision of pharmacotherapy (psychotropics) • Hip protectors • Post-fall problem-solving conferences. Mobility exercise is useful in elderly groups; however, the maintenance of mobility is not linked to a reduction of fall risk. Hip protectors are protective pads designed to cover the greater trochanter and attenuate or disperse the force of fall sufficiently to prevent a hip fracture. A number of cost-benefit studies on residential elderly patients between 2004 and 2006 proved the efficacy of MIPP and hip protectors, and some studies did so also on those patients living independently. Unfortunately, as much as 75% of women and 90% ofmen at high risk in nursing homes are not investigated, and 75% of those affected are not treated.

Epistatic effects contribute to variation in BMD in Fischer 344 x Lewis F2 rats.

To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F(2) progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an alpha level of 0.01. Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture.

Low Dietary Riboflavin but Not Folate Predicts Increased Fracture Risk in Postmenopausal Women Homozygous for the MTHFR 677 T Allele

The MTHFR C677T polymorphism is associated with mildly elevated homocysteine levels when folate and/or riboflavin status is low. Furthermore, a mildly elevated homocysteine level is a risk factor for osteoporotic fractures. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T variant on fracture risk in 5,035 men and women from the Rotterdam Study. We found that the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women. The MTHFR C677T polymorphism is associated with mildly elevated homocysteine (Hcy) levels in the presence of low folate and/or riboflavin status. A mildly elevated Hcy level was recently identified as a modifiable risk factor for osteoporotic fracture. We studied whether dietary intake of riboflavin and folate modifies the effects of the MTHFR C677T polymorphism on BMD and fracture risk. We studied 5,035 individuals from the Rotterdam Study, >or=55 yr of age, who had data available on MTHFR, nutrient intake, and fracture risk. We performed analysis on Hcy levels in a total of 666 individuals, whereas BMD data were present for 4,646 individuals (2,692 women). In the total population, neither the MTHFR C677T polymorphism nor low riboflavin intake was associated with fracture risk and BMD. However, in the lowest quartile of riboflavin intake, female 677-T homozygotes had a 1.8 (95% CI: 1.1-2.9, p = 0.01) times higher risk for incident osteoporotic fractures and a 2.6 (95% CI: 1.3-5.1, p = 0.01) times higher risk for fragility fractures compared with the 677-CC genotype (interaction, p = 0.0002). This effect was not seen for baseline BMD in both men and women. No significant influence was found for dietary folate intake on the association between the MTHFR C677T genotype and fracture risk or BMD. In the lowest quartile of dietary riboflavin intake, T-homozygous individuals (men and women combined) had higher (22.5%) Hcy levels compared with C-homozygotes (mean difference = 3.44 microM, p = 0. 01; trend, p = 0.02). In this cohort of elderly whites, the MTHFR C677T variant interacts with dietary riboflavin intake to influence fracture risk in women.