Fractures in obese postmenopausal women may be associated with higher morbidity than in non-obese women. We aimed to compare healthcare utilization, functional status, and health-related quality of life (HRQL) in obese, non-obese and underweight women with fractures. Information from GLOW, started in 2006, was collected at baseline and at 1, 2 and 3 years. In this subanalysis, self-reported incident clinical fractures, healthcare utilization, HRQL and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 non-obese and 941 obese women with ≥1 incident clinical fracture during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities and fracture type, was significantly greater in obese than non-obese women (6 vs. 5 days, P = 0.017). Physical function and vitality score were significantly worse in obese than in non-obese women, both before and after fracture, but changes after fracture were similar across groups. Use of anti-osteoporosis medication was significantly lower in obese than in non-obese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than non-obese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.
Fractures; Healthcare utilization; Functional status; Quality of life; Obesity
We examined the distribution of quantitative heel ultrasound (QUS) parameters in population samples of European men, and looked at the influence of lifestyle factors on the occurrence of these parameters.
Men aged between 40 and 79 years were recruited from eight European centres and invited to attend for an interviewer-assisted questionnaire, assessment of physical performance and quantitative ultrasound (QUS) of the calcaneus (Hologic - SAHARA). The relationships between QUS parameters and lifestyle variables were assessed using linear regression with adjustments for age, centre and weight.
3,258 men, mean age 60.0 years were included in the analysis. A higher PASE score (upper vs lower tertile) was associated with higher BUA (β coefficient = 2.44 dB/Mhz), SOS (β coefficient = 6.83 m/s) and QUI (β coefficient = 3.87). Compared to those who were inactive, those who walked or cycled more than an hour per day had a higher BUA (β coeff =3.71 dB/Mhz), SOS (β coeff = 6.97 m/s) and QUI (β coeff = 4.50). A longer time to walk 50 feet was linked with lower BUA (β coeff = −0.62 dB/Mhz), SOS (β coeff = −1.06 m/s) and QUI (β coeff = −0.69). Smoking was associated with a reduction in BUA, SOS and QUI. There was a U shaped association with frequency of alcohol consumption.
Modification of lifestyle, including increasing physical activity and stopping smoking may help optimise bone strength and reduce the risk of fracture in middle aged and elderly European men.
Epidemiology; Ultrasound; Bone mineral density; Risk factors; Exercise
To test whether women age ≥ 55 years with increasing evidence of a frailty phenotype would have greater risk of fractures, disability, and recurrent falls, compared with women who were not frail, across geographic areas (Australia, Europe, and North America) and age groups.
Multinational, longitudinal, observational cohort study.
The Global Longitudinal Study of Osteoporosis in Women (GLOW).
Women (n=48,636) age ≥ 55 years enrolled at sites in Australia, Europe, and North America.
Components of frailty (slowness/weakness, poor endurance/exhaustion, physical activity, and unintentional weight loss) at baseline and report of fracture, disability, and recurrent falls at 1 year of follow-up were investigated. Women also reported health and demographic characteristics at baseline.
Among those age < 75 years, women from the United States were more likely to be prefrail and frail than women from Australia/Canada, and Europe. The distribution of frailty was similar by region for women age ≥ 75 years. Odds ratios from multivariable models for frailty versus non frailty were 1.23 (95% CI = 1.07–1.42) for fracture, 2.29 (95% CI = 2.09–2.51) for disability, and 1.68 (95% CI = 1.54–1.83) for recurrent falls. The associations for pre-frailty versus non frailty were weaker but still indicated statistically significant increased risk for each outcome. Overall, associations between frailty status and each outcome were similar across age and geographic region.
Increased evidence of a frailty phenotype is associated with increased risk for fracture, disability, and falls among women age ≥ 55 years in 10 countries, with similar patterns across age and geographic region.
falls; fracture; frailty; osteoporosis; postmenopausal; women
The aim of this study was to determine the influence of insulin-like growth factor binding proteins (IGFBP)-1 and IGFBP-3, and IGF-1 on calcaneal ultrasound parameters in middle-aged and elderly European men.
Men aged 40 to 79 years were recruited from population registers for participation in the European Male Ageing Study (EMAS). Subjects were invited by letter to complete a postal questionnaire and to attend for an interviewer-assisted questionnaire, quantitative ultrasound (QUS) of the calcaneus and a fasting blood sample from which serum levels of IGFBP-1, IGFBP-3, IGF-1, oestradiol (E2) and SHBG were assayed. The questionnaires included the Physical Activity Scale for the Elderly (PASE) and questions about smoking and alcohol consumption. Estimated bone mineral density (eBMD) was derived as a function of the QUS parameters, speed of sound and broadband ultrasound attenuation. Height and weight were measured in all subjects.
3057 men, mean age 59.7 years (standard deviation [SD]=11.0) were included in the analysis. After adjusting for age, centre and BMI, higher levels of IGFBP-1 were associated with lower eBMD. Higher levels of both IGFBP-3 and IGF-1 were associated with higher eBMD. After further adjustment for PASE score, current smoking, alcohol consumption, free E2 and SHBG, IGFBP-3 and IGF-1, though not IGFBP-1, remained significantly associated with eBMD.
IGFBP-1 was associated with bone health though the effect could be explained by other factors. IGFBP-3 and IGF-1 were independent determinants of bone health in middle aged and elderly European men.
insulin-like growth factor binding protein 1; insulin-like growth factor binding protein 3; calcaneus quantitative ultrasound; population-based; men
Despite the growing demand for home care and preliminary evidence suggesting that the use of restraint is common practice in home care, research about restraint use in this setting is scarce.
To gain insight into the use of restraints in home care from the perspective of nurses, we conducted a qualitative explorative study. We conducted semi-structured face-to-face interviews of 14 nurses from Wit-Gele Kruis, a home-care organization in Flanders, Belgium. Interview transcripts were analyzed using the Qualitative Analysis Guide of Leuven.
Our findings revealed a lack of clarity among nurses about the concept of restraint in home care. Nurses reported that cognitively impaired older persons, who sometimes lived alone, were restrained or locked up without continuous follow-up. The interviews indicated that the patient’s family played a dominant role in the decision to use restraints. Reasons for using restraints included “providing relief to the family” and “keeping the patient at home as long as possible to avoid admission to a nursing home.” The nurses stated that general practitioners had no clear role in deciding whether to use restraints.
These findings suggest that the issue of restraint use in home care is even more complex than in long-term residential care settings and acute hospital settings. They raise questions about the ethical and legal responsibilities of home-care providers, nurses, and general practitioners. There is an urgent need for further research to carefully document the use of restraints in home care and to better understand it so that appropriate guidance can be provided to healthcare workers.
Home care; Physical restraints; Nursing
The reduced muscle mass and impaired muscle performance that defines sarcopenia in older individuals is associated with increased risk of physical limitation and a variety of chronic diseases. It may also contribute to clinical frailty.
A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities.
This review and report of an expert meeting, presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarises QoL concepts and specificities in older populations, examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability and argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade off study could be appropriate.
Age; aging; muscle weakness; quality of life; malnutrition
We review the various aspects of health technology assessment in osteoporosis, including epidemiology and burden of disease, and assessment of the cost-effectiveness of recent advances in the treatment of osteoporosis and the prevention of fracture, in the context of the allocation of healthcare resources by decision-makers in osteoporosis. This article was prepared on the basis of a symposium held by the Belgian Bone Club and the discussions surrounding that meeting, and is based on a review and critical appraisal of the literature. Epidemiological studies confirm the immense burden of osteoporotic fractures for patients and society with lifetime risks of any fracture of the hip, spine and forearm of around 40% for women and 13% for men. The economic impact is also large, for example, Europe’s six largest countries spent €31 billion on osteoporotic fractures in 2010. Moreover, the burden is expected to increase in the future with demographic changes and increasing life expectancy. Recent advances in the management of osteoporosis include novel treatments, better fracture risk assessment notably via fracture risk algorithms, and improved adherence to medication. Economic evaluation can inform decision-makers in healthcare on the cost-effectiveness of the various interventions. Cost-effectiveness analyses suggest that the recent advances in the prevention and treatment of osteoporosis may constitute an efficient basis for the allocation of scarce healthcare resources. In summary, health technology assessment is increasingly used in the field of osteoporosis and could be very useful to help decision-makers efficiently allocate healthcare resources.
Burden of disease; cost-effectiveness; economic evaluation; health technology assessment; osteoporosis
To examine when, where and how fractures occur in postmenopausal women.
We analyzed data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), including women aged ≥55 years from the United States of America, Canada, Australia and seven European countries. Women completed questionnaires including fracture data at baseline and years 1, 2 and 3.
Among 60,393 postmenopausal women, 4122 incident fractures were reported (86% non-hip, non-vertebral [NHNV], 8% presumably clinical vertebral and 6% hip). Hip fractures were more likely to occur in spring, with little seasonal variation for NHNV or spine fractures. Hip fractures occurred equally inside or outside the home, whereas 65% of NHNV fractures occurred outside and 61% of vertebral fractures occurred inside the home. Falls preceded 68–86% of NHNV and 68–83% of hip fractures among women aged ≤64 to ≥85 years, increasing with age. About 45% of vertebral fractures were associated with falls in all age groups except those ≥85 years, when only 24% occurred after falling.
In this multi-national cohort, fractures occurred throughout the year, with only hip fracture having a seasonal variation, with a higher proportion in spring. Hip fractures occurred equally within and outside the home, spine fractures more often in the home, and NHNV fractures outside the home. Falls were a proximate cause of most hip and NHNV fractures. Postmenopausal women at risk for fracture need counseling about reducing potentially modifiable fracture risk factors, particularly falls both inside and outside the home and during all seasons of the year.
For prevention and detection of falls, it is essential to unravel the way in which older people fall. This study aims to provide a description of video-based real-life fall events and to examine real-life falls using the classification system by Noury and colleagues, which divides a fall into four phases (the prefall, critical, postfall and recovery phase).
Observational study of three older persons at high risk for falls, residing in assisted living or residential care facilities: a camera system was installed in each participant’s room covering all areas, using a centralized PC platform in combination with standard Internet Protocol (IP) cameras. After a fall, two independent researchers analyzed recorded images using the camera position with the clearest viewpoint.
A total of 30 falls occurred of which 26 were recorded on camera over 17 months. Most falls happened in the morning or evening (62%), when no other persons were present (88%). Participants mainly fell backward (initial fall direction and landing configuration) on the pelvis or torso and none could get up unaided. In cases where a call alarm was used (54%), an average of 70 seconds (SD=64; range 15–224) was needed to call for help. Staff responded to the call after an average of eight minutes (SD=8.4; range 2–33). Mean time on the ground was 28 minutes (SD=25.4; range 2–59) without using a call alarm compared to 11 minutes (SD=9.2; range 3–38) when using a call alarm (p=0.445).
The real life falls were comparable with the prefall and recovery phase of Noury’s classification system. The critical phase, however, showed a prolonged duration in all falls. We suggest distinguishing two separate phases: a prolonged loss of balance phase and the actual descending phase after failure to recover balance, resulting in the impact of the body on the ground. In contrast to the theoretical description, the postfall phase was not typically characterized by inactivity; this depended on the individual.
This study contributes to a better understanding of the fall process in private areas of assisted living and residential care settings in older persons at high risk for falls.
Accidental falls; Detection; Fall characteristics; Older persons; Video-based; Classification system
The interRAI Acute Care instrument is a multidimensional geriatric assessment system intended to determine a hospitalized older persons’ medical, psychosocial and functional capacity and needs. Its objective is to develop an overall plan for treatment and long-term follow-up based on a common set of standardized items that can be used in various care settings. A Belgian web-based software system (BelRAI-software) was developed to enable clinicians to interpret the output and to communicate the patients’ data across wards and care organizations. The purpose of the study is to evaluate the (dis)advantages of the implementation of the interRAI Acute Care instrument as a comprehensive geriatric assessment instrument in an acute hospital context.
In a cross-sectional multicenter study on four geriatric wards in three acute hospitals, trained clinical staff (nurses, occupational therapists, social workers, and geriatricians) assessed 410 inpatients in routine clinical practice. The BelRAI-system was evaluated by focus groups, observations, and questionnaires. The Strengths, Weaknesses, Opportunities and Threats were mapped (SWOT-analysis) and validated by the participants.
The primary strengths of the BelRAI-system were a structured overview of the patients’ condition early after admission and the promotion of multidisciplinary assessment. Our study was a first attempt to transfer standardized data between home care organizations, nursing homes and hospitals and a way to centralize medical, allied health professionals and nursing data. With the BelRAI-software, privacy of data is guaranteed. Weaknesses are the time-consuming character of the process and the overlap with other assessment instruments or (electronic) registration forms. There is room for improving the user-friendliness and the efficiency of the software, which needs hospital-specific adaptations. Opportunities are a timely and systematic problem detection and continuity of care. An actual shortage of funding of personnel to coordinate the assessment process is the most important threat.
The BelRAI-software allows standardized transmural information transfer and the centralization of medical, allied health professionals and nursing data. It is strictly secured and follows strict privacy regulations, allowing hospitals to optimize (transmural) communication and interaction. However, weaknesses and threats exist and must be tackled in order to promote large scale implementation.
Aged; Comprehensive geriatric assessment; Hospital; InterRAI Acute Care; Software; SWOT-analysis
Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post-hoc analysis assessed the time-to-onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis.
Data from 9355 women who were randomized in two placebo-controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio, 0.75; 95% confidence interval [CI], 0.61–0.92; p=0.0050) with significant reductions maintained at all subsequent timepoints. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR], 0.74, 95% CI, 0.60–0.91, p=0.0044; year 2: OR, 0.53, 95% CI, 0.42–0.66, p<0.0001; year 3: OR, 0.61, 95% CI, 0.48–0.77, p<0.0001). This antifracture effect was persistent over 3 years, with the reductions in year 2 and 3 slightly larger than in year 1 (p=0.097).
This analysis shows that zoledronic acid offers significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persist for at least 3 years.
fractures; postmenopausal osteoporosis; reaction time; zoledronic acid; bone mineral density
By the age of 80, approximately 80% of men will manifest some cancerous cells within their prostate, indicating that prostate cancer constitutes a major health burden. While this disease is clinically insignificant in most men, it can become lethal in others. The most challenging task for clinicians is developing a patient-tailored treatment in the knowledge that this disease is highly heterogeneous and that relatively little adequate prognostic tools are available to distinguish aggressive from indolent disease. Next-generation sequencing allows a description of the cancer at an unprecedented level of detail and at different levels, going from whole genome or exome sequencing to transcriptome analysis and methylation-specific immunoprecipitation, followed by sequencing. Integration of all these data is leading to a better understanding of the initiation, progression and metastatic processes of prostate cancer. Ultimately, these insights will result in a better and more personalized treatment of patients suffering from prostate cancer. The present review summarizes current knowledge on copy number changes, gene fusions, single nucleotide mutations and polymorphisms, methylation, microRNAs and long non-coding RNAs obtained from high-throughput studies.
prostate cancer; next-generation sequencing; copy number changes; gene fusions; long non-coding RNAs; methylation; microRNAs; single nucleotide polymorphisms; single nucleotide variants
To determine the efficacy of once-yearly intravenous zoledronic acid (ZOL) 5 mg in reducing risk of clinical vertebral, nonvertebral, and any clinical fractures in elderly osteoporotic postmenopausal women.
A post hoc subgroup analysis of pooled data from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly (HORIZON) Pivotal Fracture Trial and the HORIZON Recurrent Fracture Trial.
Multicenter, randomized, double-blind, placebo-controlled trials.
Postmenopausal women (aged ≥75) with documented osteoporosis (T-score ≤ −2.5 at femoral neck or ≥1 prevalent vertebral or hip fracture) or a recent hip fracture.
Patients were randomized to receive an intravenous infusion of ZOL 5 mg (n =1,961) or placebo (n =1,926) at baseline and 12 and 24 months.
Primary endpoints were incidence of clinical vertebral and nonvertebral and any clinical fracture after treatment.
At 3 years, incidence of any clinical, clinical vertebral, and nonvertebral fracture were significantly lower in the ZOL group than in the placebo group (10.8% vs 16.6%, 1.1% vs 3.7%, and 9.9% vs 13.7%, respectively) (hazard ratio (HR) =0.65, 95% confidence interval (CI) =0.54–0.78, P<.001; HR =0.34, 95% CI =0.21–0.55, P<.001; and HR =0.73, 95% CI =0.60–0.90, P =.002, respectively). The incidence of hip fracture was lower with ZOL but did not reach statistical significance. The incidence rate of postdose adverse events were higher with ZOL, although the rate of serious adverse events and deaths was comparable between the two groups.
Once-yearly intravenous ZOL 5 mg was associated with a significant reduction in the risk of new clinical fractures (vertebral and nonvertebral) in elderly postmenopausal women with osteroporosis.
elderly; postmenopausal women with osteoporosis; fractures; zoledronic acid
Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men.
Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes.
Design and Setting:
Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included.
Main Outcome Measures:
Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and ankle-brachial index.
Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient rS 0.53–0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, rS = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP.
Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.
We review the various aspects of health technology assessment in osteoporosis, including epidemiology and burden of disease, and assessment of the cost-effectiveness of recent advances in the treatment of osteoporosis and the prevention of fracture, in the context of the allocation of health-care resources by decision makers in osteoporosis. This article was prepared on the basis of a symposium held by the Belgian Bone Club and the discussions surrounding that meeting and is based on a review and critical appraisal of the literature. Epidemiological studies confirm the immense burden of osteoporotic fractures for patients and society, with lifetime risks of any fracture of the hip, spine, and forearm of around 40 % for women and 13 % for men. The economic impact is also large; for example, Europe’s six largest countries spent €31 billion on osteoporotic fractures in 2010. Moreover, the burden is expected to increase in the future with demographic changes and increasing life expectancy. Recent advances in the management of osteoporosis include novel treatments, better fracture-risk assessment notably via fracture risk algorithms, and improved adherence to medication. Economic evaluation can inform decision makers in health care on the cost-effectiveness of the various interventions. Cost-effectiveness analyses suggest that the recent advances in the prevention and treatment of osteoporosis may constitute an efficient basis for the allocation of scarce health-care resources. In summary, health technology assessment is increasingly used in the field of osteoporosis and could be very useful to help decision makers efficiently allocate health-care resources.
Burden of disease; Cost-effectiveness; Economic evaluation; Health technology assessment; Osteoporosis
Comprehensive geriatric assessment for older patients admitted to dedicated wards has proven to be beneficial, but the impact of comprehensive geriatric assessment delivered by mobile inpatient geriatric consultation teams remains unclear. This review and meta-analysis aims to determine the impact of inpatient geriatric consultation teams on clinical outcomes of interest in older adults.
An electronic search of Medline, CINAHL, EMBASE, Web of Science and Invert for English, French and Dutch articles was performed from inception to June 2012. Three independent reviewers selected prospective cohort studies assessing functional status, readmission rate, mortality or length of stay in adults aged 60 years or older. Twelve studies evaluating 4,546 participants in six countries were identified. Methodological quality of the included studies was assessed with the Methodological Index for Non-Randomized Studies.
The individual studies show that an inpatient geriatric consultation team intervention has favorable effects on functional status, readmission and mortality rate. None of the studies found an effect on the length of the hospital stay. The meta-analysis found a beneficial effect of the intervention with regard to mortality rate at 6 months (relative risk 0.66; 95% confidence interval 0.52 to 0.85) and 8 months (relative risk 0.51; confidence interval 0.31 to 0.85) after hospital discharge.
Inpatient geriatric consultation team interventions have a significant impact on mortality rate at 6 and 8 months postdischarge, but have no significant impact on functional status, readmission or length of stay. The reason for the lack of effect on these latter outcomes may be due to insufficient statistical power or the insensitivity of the measuring method for, for example, functional status. The questions of to whom IGCT intervention should be targeted and what can be achieved remain unanswered and require further research.
Trial registration: CRD42011001420 (http://www.crd.york.ac.uk/PROSPERO)
Acute care; functional status; geriatric consultation; meta-analysis; systematic review
Overt male hypogonadism induces not only osteoporosis but also unfavorable changes in body composition, which can be prevented by testosterone (T) replacement. In this preclinical study, the potential of synthetic androgen 7α-methyl-19-nortestosterone (MENT) as alternative treatment for male hypogonadism was evaluated in comparison with T.
11-month-old male rats were orchidectomized (orch) and left untreated for 2-months. Subsequently, the effects of 4-months MENT (12 µg/day) and T (72µg/day) treatment on bone, muscle and fat were analyzed by microcomputed tomography, dual-energy X-ray absorptiometry, dynamic bone histomorphometry and muscle fiber typing.
At the onset of treatment orch rats were clearly hypogonadal. This was evidenced by significant reductions of androgen-sensitive organ weight, lean mass, cortical thickness and trabecular bone volume compared with sham-operated aged-matched controls (sham). MENT and T restored weight of androgen-sensitive organs to a similar extent, with a superior anabolic action of MENT on levator ani muscle. Both androgens not only fully rescued hypogonadal loss of lean mass, but also restored muscle fiber type composition and trabecular bone volume. Cortical bone loss was similarly prevented by MENT and T, but without full recovery to sham. Both androgens stimulated periosteal bone formation, but with a stronger effect of T. In contrast, MENT more strongly suppressed endocortical bone formation and bone turnover rate and reduced fat mass and serum leptin to a greater extent than T.
MENT and T are both effective replacement therapies to stimulate bone and muscle in hypogonadal rats, with stronger lipolytic action of MENT.
7α-methyl-19-nortestosterone (MENT); testosterone; hypogonadal osteoporosis; bone; muscle; fat
High homocysteine (HCY) levels are a risk factor for osteoporotic fracture. Furthermore, bone quality and strength are compromised by elevated HCY due to its negative impact on collagen maturation. HCY is cleared by cystathionine β-synthase (CBS), the first enzyme in the transsulfuration pathway. CBS converts HCY to cystathionine, thereby committing it to cysteine synthesis. A microarray experiment on MC3T3-E1 murine pre-osteoblasts treated with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] revealed a cluster of genes including the cbs gene, of which the transcription was rapidly and strongly induced by 1,25(OH)2D3. Quantitative real-time PCR and Western blot analysis confirmed higher levels of cbs mRNA and protein after 1,25(OH)2D3 treatment in murine and human cells. Moreover, measurement of CBS enzyme activity and quantitative measurements of HCY, cystathionine and cysteine concentrations were consistent with elevated transsulfuration activity in 1,25(OH)2D3-treated cells. The importance of a functional vitamin D receptor (VDR) for transcriptional regulation of cbs was shown in primary murine VDR knock-out osteoblasts, in which up-regulation of cbs in response to 1,25(OH)2D3 was abolished. Chromatin immunoprecipitation on chip and transfection studies revealed a functional vitamin D response element in the second intron of cbs. To further explore the potential clinical relevance of our ex vivo findings, human data from the Longitudinal Aging Study Amsterdam suggested a correlation between vitamin D status [25(OH)D3 levels] and HCY levels. In conclusion, this study demonstrated that cbs is a primary 1,25(OH)2D3 target gene which renders HCY metabolism responsive to 1,25(OH)2D3.
1,25(OH)2D3; homocysteine (HCY); cystathionine β-synthase (CBS); vitamin D receptor (VDR); osteoporosis
The interRAI Suite contains comprehensive geriatric assessment tools designed for various healthcare settings. Although each instrument is developed for a particular population, together they form an integrated health evaluation system. The interRAI Acute Care Minimum Data Set (interRAI AC) is tailored for hospitalized older persons. Our aim in this study was to translate and adapt the interRAI AC to the Belgian hospital context, where it can be used together with the interRAI Home Care (HC) and the interRAI Long Term Care Facility (LTCF).
A systematic, comprehensive, and rigorous 10-step approach was used to adapt the interRAI AC to local requirements. After linguistic translation by an official translator, five researchers assessed the translation for appropriate hospital jargon. Three researchers double-checked for translation accuracy and proposed additional items. A provisional version was converted into the three official languages of Belgium—Flemish, French, and German. Next, a multidisciplinary panel of nine experts judged item relevance to the Belgian care context and advised which country-specific items should be added. After these suggestions were incorporated into the interRAI AC, hospital staff from nine Flemish hospitals field-tested the tool in their practice. After evaluating field-test results, we compared the interRAI AC with Belgian versions of the interRAI HC and interRAI LTCF. Next, the Flemish, French, and German versions of the Belgian interRAI portfolio were harmonized. Finally, we submitted the Belgian interRAI AC to the interRAI organization for ratification.
Eighteen administrative items of the interRAI AC were adapted to the Belgian healthcare context (e.g., usual residence, formal community services prior to admission). Fourteen items assessing the ‘informal caregiver’, and 17 items, including country-specific items, were added (e.g., advanced directive for euthanasia).
The interRAI AC was adapted to local requirements using a meticulous and recursive 10-step approach. As use of the interRAI Suite continues to grow worldwide and as it continues to expand to other care settings and populations, this procedure can guide future translations. This procedure might also be used by others facing similar challenges of complex translation and adaptation situations, where multidimensional instruments are used across multiple care settings in multiple languages.
Aged; Geriatric assessment; Inpatient; interRAI Acute Care; Minimum Data Set; Validation studies; Instrument translation
Proximal femur fracture (PFF) is associated with considerable morbidity and mortality. The European Quality of Care Pathway (EQCP) study on PFF (NCT00962910) was designed to determine how care pathways (CP) for hospital treatment of PFF affect consistency of care, adherence to evidence-based key interventions, and clinical outcome.
An international cluster-randomized controlled trial (cRCT) will be performed in Belgium, Ireland, Italy and Portugal. Based on power analyses, a sample of 44 hospital teams and 437 patients per arm will be included in the study. In the control arm, usual care will be provided. Experimental teams will implement a care pathway which will include three active components: a formative evaluation of quality and organization of the care setting, a set of evidence-based key interventions, and support of the development and implementation of the CP. Main outcome will be the six-month mortality rate.
The EQCP study constitutes the first international cRCT on care pathways. The EQCP project was designed as both a research and a quality improvement project and will provide a real-world framework for process evaluation to improve our understanding of why and when CP can really work.
Trial registration number
Clinical trial participants may be temporarily absent or withdraw from trials, leading to missing data. In intention-to-treat (ITT) analyses, several approaches are used for handling the missing information - complete case (CC) analysis, mixed-effects model (MM) analysis, last observation carried forward (LOCF) and multiple imputation (MI). This report discusses the consequences of applying the CC, LOCF and MI for the ITT analysis of published data (analysed using the MM method) from the Fracture Reduction Evaluation (FREE) trial.
The FREE trial was a randomised, non-blinded study comparing balloon kyphoplasty with non-surgical care for the treatment of patients with acute painful vertebral fractures. Patients were randomised to treatment (1:1 ratio), and stratified for gender, fracture aetiology, use of bisphosphonates and use of systemic steroids at the time of enrolment. Six outcome measures - Short-form 36 physical component summary (SF-36 PCS) scale, EuroQol 5-Dimension Questionnaire (EQ-5D), Roland-Morris Disability (RMD) score, back pain, number of days with restricted activity in last 2 weeks, and number of days in bed in last 2 weeks - were analysed using four methods for dealing with missing data: CC, LOCF, MM and MI analyses.
There were no missing data in baseline covariates values, and only a few missing baseline values in outcome variables. The overall missing-response level increased during follow-up (1 month: 14.5%; 24 months: 28%), corresponding to a mean of 19% missing data during the entire period. Overall patterns of missing response across time were similar for each treatment group. Almost half of all randomised patients were not available for a CC analysis, a maximum of 4% were not included in the LOCF analysis, and all randomised patients were included in the MM and MI analyses. Improved estimates of treatment effect were observed with LOCF, MM and MI compared with CC; only MM provided improved estimates across all six outcomes considered.
The FREE trial results are robust as the alternative methods used for substituting missing data produced similar results. The MM method showed the highest statistical precision suggesting it is the most appropriate method to use for analysing the FREE trial data.
This trial is registered with ClinicalTrials.gov (number NCT00211211).
In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-κB cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover.
Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r2≥0.8) within MAP3K14 (±10 kb) were genotyped in 2359 men aged 40–79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS). Measurement of bone turnover markers (PINP and CTX-I) in the serum and quantitative ultrasound (QUS) at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA), at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT), at the distal and midshaft radius, were performed in a subsample (2 centres). Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre.
We validated the associations between SNPs in GPR177 and BMDa previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMDa, increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMDa, vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS.
Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-κB signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.
Our purpose was to characterize the risks of osteoporosis-related subtrochanteric fractures in bisphosphonate-naive individuals. Baseline characteristics of patients enrolled in the HORIZON-Recurrent Fracture Trial with a study-qualifying hip fracture were examined, comparing those who sustained incident subtrochanteric fractures with those sustaining other hip fractures. Subjects were bisphosphonate-naive or had a bisphosphonate washout period of 6–24 months and subsequently received an annual infusion of zoledronic acid 5 mg or placebo after low-trauma hip-fracture repair. In total, 2,127 men and women were included. Of the qualifying hip fractures, 5.2% were subtrochanteric, 54.8% femoral neck, 33.0% intertrochanteric, and 7.1% other (generally complex fractures of mixed type). Significant baseline (pre-hip fracture) differences were seen between index hip-fracture types, with the percentage of patients with extreme mobility problems being twofold higher in patients with index subtrochanteric fracture (9.9%) compared to other patients. The distribution of hip-fracture types was similar between the treatment groups at baseline. No patients with index subtrochanteric fractures and six patients with other qualifying hip fractures reported prior bisphosphonate use. Only one further subtrochanteric fracture occurred in each treatment group over an average 2-year patient follow-up. Subtrochanteric fractures are not uncommon in bisphosphonate-naive patients. Extreme difficulties with mobility may be a unique risk factor predisposing to development of incident subtrochanteric fractures rather than other types of hip fracture. In patients with recent hip fracture who received zoledronic acid therapy, the incidence of new subtrochanteric fractures was too small to draw any meaningful conclusions.
Bisphosphonate; Hip fracture; Osteoporosis; Subtrochanteric; Zoledronic acid
We sought to determine the influence of single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG on volumetric bone mineral density (vBMD) and bone geometry at the radius in men. Pairwise tag SNPs (r2 ≥ 0.8) for RANKL (n = 8), RANK (n = 44), and OPG (n = 22) and five SNPs near RANKL and OPG strongly associated with areal BMD in genomewide association studies were previously genotyped in men aged 40–79 years in the European Male Ageing Study (EMAS). Here, these SNPs were analyzed in a subsample of men (n = 589) who had peripheral quantitative computed tomography (pQCT) performed at the distal (4%) and mid-shaft (50%) radius. Estimated parameters were total and trabecular vBMD (mg/mm3) and cross-sectional area (mm2) at the 4% site and cortical vBMD (mg/mm3); total, cortical, and medullary area (mm2); cortical thickness (mm); and stress strain index (SSI) (mm3) at the 50% site. We identified 12 OPG SNPs associated with vBMD and/or geometric parameters, including rs10505348 associated with total vBMD (β [95% CI] = 9.35 [2.12–16.58], P = 0.011), cortical vBMD (β [95% CI] = 5.62 [2.10–9.14], P = 0.002), cortical thickness (β [95% CI] = 0.08 [0.03–0.13], P = 0.002), and medullary area (β [95% CI] = −2.90 [−4.94 to −0.86], P = 0.005) and rs2073618 associated with cortical vBMD (β [95% CI] = −4.30 [−7.78 to −0.82], P = 0.015) and cortical thickness (β [95% CI] = −0.08 [−0.13 to −0.03], P = 0.001). Three RANK SNPs were associated with vBMD, including rs12956925 associated with trabecular vBMD (β [95% CI] = −7.58 [−14.01 to −1.15], P = 0.021). There were five RANK SNPs associated with geometric parameters, including rs8083511 associated with distal radius cross-sectional area (β [95% CI] = 8.90 [0.92–16.88], P = 0.029). No significant association was observed between RANKL SNPs and pQCT parameters. Our findings suggest that genetic variation in OPG and RANK influences radius vBMD and geometry in men.
Electronic supplementary material
The online version of this article (doi:10.1007/s00223-011-9532-y) contains supplementary material, which is available to authorized users.
Osteoporosis; Genetic association; Genetic polymorphism; Male; QCT
Testosterone is an important hormone for both bone gain and maintenance in men. Hypogonadal men have accelerated bone turnover and increased fracture risk. In these men, administration of testosterone inhibits bone resorption and maintains bone mass. Testosterone, however, is converted into estradiol via aromatization in many tissues including male bone. The importance of estrogen receptor alpha activation as well of aromatization of androgens into estrogens was highlighted by a number of cases of men suffering from an inactivating mutation in the estrogen receptor alpha or in the aromatase enzyme. All these men typically had low bone mass, high bone turnover and open epiphyses. In line with these findings, cohort studies have confirmed that estradiol contributes to the maintenance of bone mass after reaching peak bone mass, with an association between estradiol and fractures in elderly men. Recent studies in knock-out mice have increased our understanding of the role of androgens and estrogens in different bone compartments. Estrogen receptor activation, but not androgen receptor activation, is involved in the regulation of male longitudinal appendicular skeletal growth in mice. Both the androgen and the estrogen receptor can independently mediate the cancellous bone-sparing effects of sex steroids in male mice. Selective KO studies of the androgen receptor in osteoblasts in male mice suggest that the osteoblast in the target cell for androgen receptor mediated maintenance of trabecular bone volume and coordination of bone matrix synthesis and mineralization. Taken together, both human and animal studies suggest that testosterone has a dual mode of action on different bone surfaces with involvement of both the androgen and estrogen receptor.