Little is known about the acute effects of initiating a diuretic drug on risk of fracture. We evaluated the relationship between initiating a diuretic drug and the occurrence of hip fracture.
The study sample included 2, 118, 793 persons aged ≥ 50 years enrolled in The Health Improvement Network (THIN) between 1986–2010. The effect of a new start of a diuretic drug or comparator medication (ACE-Inhibitor) on risk of hip fracture was assessed using a case-crossover and case-control study during the 1–7, 8–14, 15–21, and 22–28 days following drug initiation.
Included were 28, 703 individuals with an incident hip fracture over a mean of 7.9 years follow-up. In the case-crossover study, the risk of experiencing a hip fracture was increased during the first 7 days following loop diuretic drug initiation (OR=1.8; 95% CI: 1.2, 2.7). The elevated risk did not continue during the 8–14, 15–21, or 22–28 days following drug initiation. For thiazide diuretics, the risk of hip fracture was elevated 8-14 days after drug initiation (OR=2.2; 95% CI: 1.2, 3.9). No such association was observed in the 1–7, 15–21, or 22–28 days following thiazide drug initiation. ACE-inhibitor initiation was not associated with a statistically significant increased risk of hip fracture. Similar results were observed using a case-control study.
The risk of hip fracture was transiently elevated around two-fold shortly after the new start of a loop or thiazide diuretic drug. Awareness of these short term risks may reduce hip fractures and other injurious falls in vulnerable adults.
loop diuretic; thiazide diuretic; hip fracture; acute risk
To compare characteristics of indoor and outdoor recurrent fallers and explore some implications for clinical practice, in which a fall risk assessment for all recurrent fallers has been recommended.
Prospective cohort study.
MOBILIZE Boston, a study of falls etiology among community-dwelling older individuals from randomly sampled households in the Boston MA area.
713 women and men, mainly of age 70 years and older, with at least one year of follow-up.
Data at baseline and an 18-month follow-up examination were collected by questionnaire and comprehensive clinic examination. During follow-up participants recorded falls on daily calendars. A telephone interview queried location and circumstances of each fall.
145 participants reported recurrent falls (≥ 2 falls) during the first year. Those who had fallen only outdoors had good health characteristics, whereas those who had fallen only indoors were generally in poor health. For instance, 25.5% of indoor-only recurrent fallers had gait speeds < 0.6 meters/second compared to 2.9% among outdoor-only recurrent fallers; the respective percentages were 44.7% and 8.8% for Berg balance score < 48. Recurrent indoor fallers generally had poor health characteristics regardless of their activity at the time of their falls, whereas recurrent outdoor fallers who fell during vigorous activity or walking were especially healthy. A report of any recurrent falls in the first year did not predict number of positive findings on either a comprehensive or abbreviated fall risk assessment at the 18-month follow-up examination.
Characteristics of community-dwelling older people with recurrent indoor and outdoor falls are very different. If confirmed, these results suggest that different types of fall risk assessment are needed for specific categories of recurrent fallers.
recurrent falls; risk factors; aging research; fall risk assessment
Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN-BMD) (n = 765); (2) 4-year change in FN-BMD (n = 556); and (3) hip fracture risk (n = 765) over 17-year follow-up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN-BMD over 4 years in women (p-trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN-BMD in women (p-trend = 0.02), and increased hip fracture risk in women and men (p-trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p-trend = 0.12 and p-trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN-BMD in men (p-trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN-BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk.
DOCOSAHEXAENOIC ACID; LINOLEIC ACID; ARACHIDONIC ACID; BMD; FRACTURE
Alternative methods of predicting hip fracture are needed since 50% of adults who fracture do not have osteoporosis by BMD measurements. One method, factor-of-risk (φ), computes the ratio of force on the hip in a fall, to femoral strength. We examined the relation between φ and hip fracture in 1,100 subjects from the Framingham Study with measured hip BMD, along with weight, height and age, collected in 1988-89.
We estimated both peak and attenuated force applied to the hip in a sideways fall from standing height, where attenuated force incorporated cushioning effects of trochanteric soft tissue. Femoral strength was estimated from femoral neck BMD, using cadaveric femoral strength data. Sex-specific, age-adjusted survival models were used to calculate hazard ratios (HR) and 95% confidence intervals for the relation between φpeak,φattenuated and their components, with hip fracture.
In 425 men and 675 women (mean age 76 yrs), 136 hip fractures occurred over median follow-up of 11.3 yrs. φ was associated with increased age-adjusted risk for hip fracture. One standard deviation increase in φpeak and φattenuated was associated with HR of 1.88 and 1.78 in men and 1.23 and 1.41 in women, respectively. Examining components of φ, in women, we found fall force and soft tissue thickness were predictive of hip fracture independent of femoral strength, (was estimated from BMD).
Thus, both φpeak and φattenuated predict hip fracture in men and women. These findings suggest additional studies of φ predicting hip fracture using direct measurements of trochanteric soft tissue.
Hip fracture; Factor-of-Risk; bone strength; cohort study; fracture prediction; elderly
Adherences to treatments that require a behavioral action often rely on self-reported recall, yet it is vital to determine whether real time self reporting of adherence using a simple logbook accurately captures adherence. The purpose of this study was to determine whether real time self-reported adherence is an accurate measurement of device usage during a clinical trial by comparing it to electronic recording.
Using data collected from older adult men and women (N=135, mean age 82.3 yrs; range 66 to 98 yrs) participating in a clinical trial evaluating a vibrating platform for the treatment of osteoporosis, daily adherence to platform treatment was monitored using both self-reported written logs and electronically recorded radio-frequency identification card usage, enabling a direct comparison of the two methods over one year. Agreement between methods was also evaluated after stratification by age, gender, time in study, and cognition status.
The two methods were in high agreement (overall intraclass correlation coefficient = 0.96). The agreement between the two methods did not differ between age groups, sex, time in study and cognitive function.
Using a log book to report adherence to a daily intervention requiring a behavioral action in older adults is an accurate and simple approach to use in clinical trials, as evidenced by the high degree of concordance with an electronic monitor.
Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual common CNV regions (CNVR) for association with mortality. We observed that the burden of common but not of rare CNVs influences mortality. A higher burden of large (≥500 kb) common deletions associated with 4% higher mortality [hazard ratio (HR) per CNV 1.04, 95% confidence interval (CI) 1.02–1.07, P = 5.82 × 10−5] in the 11 442 participants of RS1, RS2 and FHS. In the analysis of 312 individual common CNVRs, we identified two regions (11p15.5; 14q21.3) that associated with higher mortality in these cohorts. The 11p15.5 region (combined HR 1.59, 95% CI 1.31–1.93, P = 2.87 × 10−6) encompasses 41 genes, of which some have previously been related to longevity, whereas the 14q21.3 region (combined HR 1.57, 95% CI 1.19–2.07, P = 1.53 × 10−3) does not encompass any genes. In conclusion, the burden of large common deletions, as well as common CNVs in 11p15.5 and 14q21.3 region, associate with higher mortality.
Although many studies have implicated antidepressants as a risk factor for falls, it is not clear if risk accrues with duration of use or if there are acute risks associated with initiation of the prescription. We conducted a case-crossover study of nursing home residents with a fall to determine the effect of an antidepressant change (defined as the new prescription of an antidepressant or increasing the dose of a previously used antidepressant) on fall risk.
Among 1,181 nursing home fallers, we compared the frequency of antidepressant changes during the hazard period (1–7 days before the fall) with the frequency of antidepressant changes during the control period (8–14 days before the fall). Odds ratios were estimated using conditional logistic regression models. Results were estimated for non-selective serotonin reuptake inhibitors (SSRI) and SSRI prescriptions, separately.
Mean age was 88 years, and 71% were females. Seventy participants experienced an antidepressant change during the hazard and/or control periods. The maximum effect of falling occurred within 2 days of a non-SSRI change (odds ratio: 4.7, 95% confidence interval, 1.3–16.2). The effect on falling was no longer significant at 5 days (odds ratio: 1.9, 95% confidence interval, 0.9–4.0). No association was found between SSRI changes and falls.
Nursing home residents are at high risk of falls during the days following a new prescription or increased dose of a non-SSRI antidepressant. Increased surveillance should occur, particularly during the first 48 hours, in an effort to decrease falls.
Antidepressant; Fall; Nursing home
Conflicting evidence exists on whether cholinesterase inhibitors and memantine increase the risk of falls, syncope, and related events, defined as fracture and accidental injury.
To evaluate the effect of cholinesterase inhibitors and memantine on the risk of falls, syncope, and related events
Design, Setting, Participants, and Intervention
Meta-analysis of 54 placebo-controlled randomized trials and extension studies of cholinesterase inhibitors and memantine that reported falls, syncope, and related events in cognitively impaired older adults. Trials were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (no language restriction, through July 2009), and manual search.
Falls, syncope, fracture, and accidental injury
Compared to placebo, cholinesterase inhibitor use was associated with an increased risk of syncope (odds ratio [95% confidence interval]: 1.53 [1.02-2.30]), but not with other events (falls: 0.88 [0.74-1.04]; fracture: 1.39 [0.75-2.56]; accidental injury: 1.13 [0.87-1.45]). Memantine use was associated with fewer fractures (0.21 [0.05-0.85]), but not with other events (fall: 0.92 [0.72-1.18]; syncope: 1.04 [0.35-3.04]; accidental injury: 0.80 [0.56-1.12]). There was no differential effect by type and severity of cognitive impairment, residential status, nor length of follow-up. However, due to underreporting and small number of events, a potential benefit or risk cannot be excluded.
Cholinesterase inhibitors may increase the risk of syncope, with no effects on falls, fracture, and accidental injury in cognitively impaired older adults. Memantine may have a favorable effect on fracture, with no effects on other events. More research is needed to confirm the reduction in fractures observed for memantine.
Cholinesterase Inhibitors; Memantine; Falls; Syncope; Dementia
The biomechanical mechanisms underlying sex-specific differences in age-related vertebral fracture rates are ill defined. To gain insight into this issue, we used finite element analysis of clinical computed tomography (CT) scans of the vertebral bodies of L3 and T10 of young and old men and women to assess age- and sex-related differences in the strength of the whole vertebra, the trabecular compartment, and the peripheral compartment (the outer 2 mm of vertebral bone, including the thin cortical shell). We sought to determine whether structural and geometric changes with age differ in men and women, making women more susceptible to vertebral fractures. As expected, we found that vertebral strength decreased with age 2-fold more in women than in men. The strength of the trabecular compartment declined significantly with age for both sexes, whereas the strength of the peripheral compartment decreased with age in women but was largely maintained in men. The proportion of mechanical strength attributable to the peripheral compartment increased with age in both sexes and at both vertebral levels. Taken together, these results indicate that men and women lose vertebral bone differently with age, particularly in the peripheral (cortical) compartment. This differential bone loss explains, in part, a greater decline in bone strength in women and may contribute to the higher incidence of vertebral fractures among women than men. © 2011 American Society for Bone and Mineral Research.
VERTEBRAL FRACTURE; FINITE ELEMENT ANALYSIS; QUANTITATIVE COMPUTED TOMOGRAPHY; BONE LOSS; VERTEBRAL STRENGTH; BONE STRENGTH; BIOMECHANICS
Apolipoprotein E (APOE) has been studied for its potential role in osteoporosis risk. It is hypothesized that genetic variation at APOE locus, known as E2, E3, and E4, may modulate bone mineral density (BMD) through its effects on lipoproteins and vitamin K transport. The purpose of this study was to determine the association of the APOE-E4 gene polymorphism with bone-related phenotypes.
We conducted a meta-analysis that combined newly-analyzed individual data from two community-based cohorts, the Framingham Offspring Study (N=1,495) and the Vitamin K Clinical Trial (N=377), with fifteen other eligible published reports. Bone phenotypes included BMD measurements of the hip (total hip and trochanteric and femoral neck sites) and lumbar spine (from the L2 to L4 vertebrae) and prevalence or incidence of vertebral, hip and other fractures.
In sex-pooled analyses, APOE4 carriers had a 0.018 g/cm2 lower weighted mean trochanteric BMD than non carriers (p=0.0002) with no evidence for between-study heterogeneity. A significant association was also detected with lumbar spine BMD (p=0.006); however, inter-study heterogeneity was observed. Associations with lumbar spine and trochanteric BMD were observed predominantly in women and became less significant in meta-regression (p=0.055 and 0.01, respectively). There were no consistent associations of APOE4 genotype with BMD at other skeletal sites or with fracture risk.
Based on these findings, there is insufficient evidence to support a strong and consistent association of the APOE genotype with BMD and fracture incidence.
Apolipoprotein E; BMD; Fracture; meta-analysis; polymorphism
Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.
To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
Design and Setting
Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
Main Outcome Measures
Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) 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.
Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Skeletal loads are dominated by muscle action. Recently, it has become clear that bone and muscle share genetic determinants. Involution of the musculoskeletal system manifests as bone loss (osteoporosis) and muscle wasting (sarcopenia). Therefore, the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. This Perspective will provide the evidence for a shared genetic influence on bone and muscle. We will start with an overview of accumulating evidence that physical exercise produces effects on the adult skeleton, seeking to unravel some of the contradictory findings published thus far. We will provide indications that there are pleiotropic relationships between bone structure/mass and muscle mass/function. Finally, we will offer some insights and practical recommendations as to the value of studying shared genetic factors and will explore possible directions for future research. We consider several related questions that together comprise the general paradigm of bone responses to mechanical loading and the relationship between muscle strength and bone parameters, including the genetic factors that modulate these responses. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both conditions and may translate into new approaches to reduce the burdens of both conditions through improved diagnosis, prevention, and early targeted treatment.
genetics; pleiotropy; osteoporosis; sarcopenia; development; aging
Tai Chi (TC) is a mind-body exercise that shows potential as an effective and safe intervention for preventing fall-related fractures in the elderly. Few randomized trials have simultaneously evaluated TC's potential to reduce bone loss and improve fall-predictive balance parameters in osteopenic women.
In a pragmatic randomized trial, 86 post-menopausal osteopenic women, aged 45-70, were recruited from community clinics. Women were assigned to either nine months of TC training plus usual care (UC) vs. UC alone. Primary outcomes were changes between baseline and nine months of bone mineral density (BMD) of the proximal femur and lumbar spine (dual-energy X-ray absorptiometry) and serum markers of bone resorption and formation. Secondary outcomes included quality of life. In a subsample (n = 16), quiet standing fall-predictive sway parameters and clinical balance tests were also assessed. Both intent-to-treat and per-protocol analyses were employed.
For BMD, no intent-to-treat analyses were statistically significant; however, per protocol analyses (i.e., only including TC participants who completed ≥ 75% training requirements) of femoral neck BMD changes were significantly different between TC and UC (+0.04 vs. -0.98%; P = 0.05). Changes in bone formation markers and physical domains of quality of life were also more favorable in per protocol TC vs. UC (P = 0.05). Changes in sway parameters were significantly improved by TC vs. UC (average sway velocity, P = 0.027; anterior-posterior sway range, P = 0.014). Clinical measures of balance and function showed non-significant trends in favor of TC.
TC training offered through existing community-based programs is a safe, feasible, and promising intervention for reducing multiple fracture risks. Our results affirm the value of a more definitive, longer-term trial of TC for osteopenic women, adequately powered to detect clinically relevant effects of TC on attenuation of BMD loss and reduction of fall risk in this population.
Whether certain types of footwear, such as slippers, socks without shoes, and going barefoot, increase the risk for falls among the elderly is uncertain. Our purpose was to examine the relationship between footwear and falls within the home in MOBILIZE Boston, a prospective cohort study of falls etiology among non-institutionalized women and men, mainly aged 70 years and older, from the Boston MA, USA area.
The 765 participants were from households randomly selected from town lists. They were followed for a median of 27.5 months. At baseline, participants were administered a questionnaire that included questions on footwear usually worn, and were given a comprehensive examination that included measurement of many risk factors for falls. During follow-up participants were asked to record each day whether they had fallen; those reporting falls were asked about their footwear when they fell.
At the time of in-home falls, 51.9% of people were barefoot, wearing socks without shoes, or wearing slippers; 10.1% of people reported that their usual footwear was one of these types. Among those who fell in their own home, the adjusted odds ratio for a serious injury among those who were shoeless or wearing slippers compared to those who were wearing other shoes at the time of the fall was 2.27 (95% confidence interval 1.21–4.24).
It may be advisable for older individuals to wear shoes in their home whenever possible to minimize the risk of falling. Further research is needed to identify optimal footwear for falls prevention.
Elderly; Falls; Footwear; Shoes; Population-based study; Cohort study
The effect of protein on bone is controversial, and calcium intake may modify protein's effect on bone. We evaluated associations of energy-adjusted tertiles of protein intake (ie, total, animal, plant, animal/plant ratio) with incident hip fracture and whether total calcium intake modified these associations in the Framingham Offspring Study. A total of 1752 men and 1972 women completed a baseline food frequency questionnaire (1991–1995 or 1995–1998) and were followed for hip fracture until 2005. Hazard ratios (HRs) were estimated using Cox proportional hazards regression adjusting for confounders. Baseline mean age was 55 years (SD 9.9 years, range 26 to 86 years). Forty-four hip fractures occurred over 12 years of follow-up. Owing to significant interaction between protein (total, animal, animal/plant ratio) and calcium intake (p interaction range = .03 to .04), stratified results are presented. Among those with calcium intakes less than 800 mg/day, the highest tertile (T3) of animal protein intake had 2.8 times the risk of hip fracture [HR = 2.84, 95% confidence interval (CI) 1.20–6.74, p = .02] versus the lowest tertile (T1, p trend = .02). In the 800 mg/day or more group, T3 of animal protein had an 85% reduced hip fracture risk (HR = 0.15, 95% CI 0.02–0.92, p = .04) versus T1 (p trend = .04). Total protein intake and the animal/plant ratio were not significantly associated with hip fracture (p range = .12 to .65). Our results from middle-aged men and women show that higher animal protein intake coupled with calcium intake of 800 mg/day or more may protect against hip fracture, whereas the effect appears reversed for those with lower calcium intake. Calcium intake modifies the association of protein intake and the risk of hip fracture in this cohort and may explain the lack of concordance seen in previous studies. © 2010 American Society for Bone and Mineral Research.
NUTRITION; PROTEIN INTAKE; HIP FRACTURE; CALCIUM; COHORT STUDY
To identify risk factors for indoor and outdoor falls.
Prospective cohort study.
MOBILIZE Boston, a study of falls etiology among community-dwelling older individuals.
765 women and men, mainly of age 70 years and older, from randomly sampled households in the Boston MA area.
Baseline data were collected by questionnaire and comprehensive clinic examination. During follow-up participants recorded falls on daily calendars. A telephone interview queried the location and circumstances of each fall.
598 indoor and 524 outdoor falls were reported over a median follow-up of 21.7 months. Risk factors for indoor falls included older age, being female, and various indicators of poor health. Risk factors for outdoor falls included younger age, being male, and being relatively physically active and healthy. For instance, the age- and gender-adjusted rate ratio (and 95% confidence interval) for having much difficulty or inability to perform activities of daily living relative to no difficulty was 2.57 (1.69–3.90) for indoor falls, but 0.27 (0.13–0.56) for outdoor falls. The rate ratio for gait speed of <0.68 m/sec relative to a speed of >1.33 m/sec was 1.48 (0.81–2.68) for indoor falls, but 0.27 (0.15–0.50) for outdoor falls.
Risk factors for indoor and outdoor falls differ. Combining these falls, as is done in many studies, masks important information. Prevention recommendations for non-institutionalized older people should be more effective if targeted differently for frail, inactive older people at high risk for indoor falls and relatively active, healthy people at high risk for outdoor falls.
falls; risk factors; elders; aging research; population-based; epidemiology; aged; cohort studies
Osteoporosis is a common complication of aging. Alternatives to pharmacologic treatment are needed for older adults. Non-pharmacologic treatment with low magnitude, high frequency mechanical stimulation has been shown to prevent bone loss in animal and human studies.
The VIBES (Vibration to Improve Bone Density in Elderly Subjects) study is a randomized, double-blind, sham-controlled trial of the efficacy of low magnitude, high frequency mechanical stimulation in 200 men and women aged 60 years and older with bone mineral density T-scores by dual-x-ray absorptiometry between –1 and –2.5 at entry. Participants are healthy, cognitively intact residents of independent living communities in the Boston area who receive free calcium and Vitamin D supplements. They are randomly assigned to active or sham treatment and stand on their assigned platform once daily for 10 minutes. All platforms have adherence data collection software downloadable to a laptop computer. Adverse events are closely monitored. 174 participants were randomized and will be followed for two years. Almost all active subjects have attained one year of follow-up. Bone mineral density is measured by both dual x-ray absorptiometry and quantitative computed tomography at baseline and annually. The main analysis will compare mean changes from baseline in volumetric bone density by quantitative computed tomography in active and sham groups. Adherence and treatment effect magnitude will also be evaluated. Secondary analyses will compare changes in three biochemical markers of bone turnover as well as longitudinal comparisons of muscle and balance endpoints.
The VIBES trial has completed its first year of data collection and encountered multiple challenges leading to valuable lessons learned about the areas of recruitment from independent living communities, deployment of multi-user mechanical devices using radio frequency identification cards and electronic adherence monitoring, organization of transportation for imaging at a central site, and the expansion of study aims to include additional musculoskeletal outcomes.
These lessons will guide future investigations in studies of individuals of advanced age.
osteoporosis; BMD; balance; muscle mass; fractures; vibration; falls; bone; DXA; QCT
Genome-wide association studies offer an unbiased approach to identify new candidate genes for osteoporosis. We examined the Affymetrix 500K + 50K SNP GeneChip marker sets for associations with multiple osteoporosis-related traits at various skeletal sites, including bone mineral density (BMD, hip and spine), heel ultrasound, and hip geometric indices in the Framingham Osteoporosis Study. We evaluated 433,510 single-nucleotide polymorphisms (SNPs) in 2073 women (mean age 65 years), members of two-generational families. Variance components analysis was performed to estimate phenotypic, genetic, and environmental correlations (ρP, ρG, and ρE) among bone traits. Linear mixed-effects models were used to test associations between SNPs and multivariable-adjusted trait values. We evaluated the proportion of SNPs associated with pairs of the traits at a nominal significance threshold α = 0.01. We found substantial correlation between the proportion of associated SNPs and the ρP and ρG (r = 0.91 and 0.84, respectively) but much lower with ρE (r = 0.38). Thus, for example, hip and spine BMD had 6.8% associated SNPs in common, corresponding to ρP = 0.55 and ρG = 0.66 between them. Fewer SNPs were associated with both BMD and any of the hip geometric traits (eg, femoral neck and shaft width, section moduli, neck shaft angle, and neck length); ρG between BMD and geometric traits ranged from −0.24 to +0.40. In conclusion, we examined relationships between osteoporosis-related traits based on genome-wide associations. Most of the similarity between the quantitative bone phenotypes may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in defining the best phenotypes to be used in genetic studies of osteoporosis. © 2010 American Society for Bone and Mineral Research.
bone mineral density; quantitative ultrasound; femoral geometry; genome-wide association; single-nucleotide polymorphisms; genetic correlations; pleiotropy
Poor medication adherence is associated with negative health outcomes. We investigated whether poor medication adherence increases the rate of falls as part of Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly of Boston (MOBILIZE Boston), a prospective, community-based cohort recruited for the purpose of studying novel risk factors for falls.
A total of 246 men and 408 women (mean age, 78 years) were followed for the occurrence of falls (median follow-up, 1.8 years). Adherence was assessed by the Morisky scale based on the following four questions: whether an individual ever forgets, is careless at times, stops taking medications when feels better, or stops taking medications when feels worse. Low adherence was defined as a “yes” answer to one or more questions. High adherence was defined as a “no” answer to every question.
Forty-eight percent of subjects were classified as having low medication adherence. The rate of falls in the low adherence group was 1.1 falls/person-year (95% confidence interval [CI]: 1.0–1.3) compared with 0.7 falls/person-year (95% CI: 0.6–0.8) in the high adherence group. After adjusting for age, sex, race/ethnicity, education, alcohol use, cognitive measures, functional status, depression, and number of medications, low medication adherence was associated with a 50% increased rate of falls compared with high medication adherence (rate ratio = 1.5, 95% CI: 1.2–1.9; p < .001).
Low medication adherence may be associated with an increased rate of falls among older adults. Future studies should confirm this association and explore whether interventions to improve medication adherence might decrease the frequency of falls and other serious health-related outcomes.
Falls; Community; Medication adherence
Tracking falls among elders is challenging. In this reliability study, which took place between October 2007 and February 2008, the authors compared participants’ daily recordings of falls on calendars with a telephone survey of recall of falls over the previous 3 months within the population-based MOBILIZE Boston Study cohort, a cohort of 765 elders. From the cohort, 218 participants were randomly selected. Falls were tracked prospectively on daily calendars (mailed back monthly). Telephone recalls of falls over the previous 3 months were conducted in January and February 2008. Agreement, sensitivity, and specificity were calculated to compare the occurrence of falls as determined by 3-month recall with falls recorded by daily calendar (gold standard) during the same 3-month period. Results showed good agreement between recall and calendars: 27 persons reported a fall by both methods. However, while the 3-month recall correctly classified persons who did not fall (164 persons by both methods), it missed 25% of participants who fell (of 36 participants with a calendar-reported fall, 9 did not report a fall by telephone recall). Kappa was 0.74 (95% confidence interval: 0.68, 0.80), sensitivity was 75%, and specificity was 96%. Retrospective 3-month recall of falls resulted in underreporting of falls by as much as 25% compared with daily calendars. Calendars should be considered the preferred method of ascertaining falls in longitudinal studies.
accidental falls; aged; cohort studies; data collection; epidemiologic methods; frail elderly; mental recall; reproducibility of results
Genome-wide association studies (GWAS) using high-density array of single-nucleotide polymorphisms (SNPs) offer an unbiased strategy to identify new candidate genes for osteoporosis.
We used a subset of autosomal SNPs from the Affymetrix 500K+50K SNP GeneChip marker set to examine genetic linkage with multiple highly heritable osteoporosis-related traits, including BMD of the hip and spine, heel ultrasound (attenuation and speed of sound), and geometric indices of the hip, in two generations from the Framingham Osteoporosis Study. Variance component linkage analysis was performed using normalized residuals (adjusted for age, height, BMI, and estrogen status in women).
Multipoint linkage analyses produced LOD scores ≥ 3.0 for BMD on chromosomes (chr.) 9 and 11, and for ultrasound speed of sound on chr. 5. Hip geometric traits were linked with higher LOD scores, such as with Shaft Width on chr. 4 (LOD = 3.9) and chr. 16 (LOD = 3.8), and with Shaft section modulus on chr. 22 (LOD = 4.0). LOD score ≥ 5.0 was obtained for femoral Neck Width on chr. 7.
In conclusion, with a SNP-based linkage approach, we identified several novel potential QTLs and confirmed previously identified chromosomal regions linked to bone mass and geometry. Subsequent focus on the spectrum of genetic polymorphisms in these refined regions may contribute to finding variants predisposing to osteoporosis.
quantitative trait loci; BMD; bone geometry; osteoporosis; SNP array
New technology introduced over time results in changes in densitometers during longitudinal studies of bone mineral density (BMD). This requires that a cross-calibration process be completed to translate measurements from the old densitometer to the new one. Previously described cross-calibration methods for research settings have collected single measures on each densitometer and used linear regression to estimate cross-calibration corrections. Thus, these methods may produce corrections that have limited precision and underestimate the variability in converted BMD values. Furthermore, most prior studies have included small samples recruited from specialized populations. Increasing the sample size, obtaining multiple measures on each machine, and utilizing linear mixed models to account for between- and within-subject variability may improve cross-calibration estimates. The purpose of this study was to conduct an in vivo cross-calibration of a Lunar DPX-L with a Lunar Prodigy densitometer using a sample of 249 healthy volunteers who were scanned twice on each densitometer, without repositioning, at both the femur and spine. Scans were analyzed using both automated and manual placement of regions of interest. Wilcoxon rank-sum tests and Bland-Altman plots were used to examine possible differences between repeat scans within and across densitometers. We used linear mixed models to determine the cross-calibration equations for the femoral neck, trochanter, total hip and lumbar spine (L2-L4) regions. Results using automated and manual placement of the regions of interest did not differ significantly The DPX–L exhibited larger median absolute differences in repeat scans for femoral neck [0.016 vs. 0.012, p=0.1] and trochanter [0.011 vs. 0.009, p=0.06] BMD values compared to the Prodigy. The Bland-Altman plots revealed no statistically significant linear relation between the difference in paired measures between machines and mean BMD. In our large sample of healthy volunteers we did detect systematic differences between the DPX-L and Prodigy densitometers. Our proposed cross-calibration method, which includes acquiring multiple measures and using linear mixed models, provides researchers with a more realistic estimate of the variance of cross-calibrated BMD measures, potentially reducing the chance of making a type I error in longitudinal studies of changes in BMD.
cross-calibration; densitometer; bone mineral density; DXA; mixed models; Framingham Osteoporosis Study
Determine nursing home characteristics related to adherence to use of a hip protector (HP) to prevent fracture; also describe adherence and related resident characteristics.
A multi-center, randomized controlled trial of a HP in which adherence to wearing the HP was monitored by research staff three times a week for up to 21 months; data were collected by interviews and chart review.
Thirty-five nursing homes in Boston, St. Louis, and Baltimore.
A total of 797 eligible residents, 633 (79%) of whom passed the run-in period, 397 (63%) of whom remained in the study until the end of follow-up.
Residents wore a single HP on their right or left side.
In addition to regular monitoring of adherence, data were collected regarding facility characteristics, staffing, policies and procedures, perception of HPs and related experience, and research staff ratings of environmental and overall quality; and also resident demographic characteristics, and function, health, and psychosocial status.
Facility characteristics related to more adherence were not being chain-affiliated; less Medicaid case-mix; fewer residents wearing HPs; more paraprofessional staff training; more rotating workers; and having administrators who were less involved in meetings.
Efforts to increase adherence to the use of HPs should focus on facilities with more Medicaid case-mix to reduce disparities in care, and those that have less of a culture of training. Staff may need support to increase adherence, and when adherence cannot be maintained, HP use should be targeted to those who remain adherent.
hip fracture; nursing homes; compliance
To examine potential risk factors for hallux valgus in community-dwelling elders.
Data from 600 MOBILIZE Boston Study participants (386 women and 214 men) were analyzed. Hallux valgus was defined as > 15 degrees angular deviation of the hallux with respect to the first metatarsal bone toward the lesser toes. Associations of hallux valgus with age, body mass index (BMI), race, education, pes planus, foot pain, and in women, history of high heel shoe use, were assessed using sex-specific Poisson regression with robust variance estimation for risk ratios (RR) and 95% confidence intervals (CI).
Hallux valgus was present in 58% of women and 25% of men. Higher BMI was inversely associated with presence of hallux valgus in women (p trend = 0.001), with the strongest inverse association observed in those with BMI of 30.0 or more compared to those with normal BMI (RR=0.7, 95% CI: 0.5, 0.9). Women, who usually wore high-heeled shoes during ages 20 to 64 years compared to those who did not, had increased likelihood of hallux valgus (RR=1.2, 95% CI: 1.0, 1.5). Among men, those with BMI between 25.0 and 29.9 had increased likelihood of hallux valgus compared to those with normal BMI (RR=1.9, 95% CI: 1.0, 3.5). Men with pes planus were more likely to have hallux valgus (RR=2.1, 95% CI: 1.3, 3.3) compared to men without pes planus.
In women, hallux valgus was associated with lower BMI and high heel use during ages 20 to 64, while in men, associations were observed with higher BMI and pes planus. Our results suggest that the etiologic mechanisms for hallux valgus may differ between men and women.
hallux valgus; pes planus; foot pain; BMI; high-heeled shoes; population-based cohort study
Little is known about the public health impact of the National Osteoporosis Foundation (NOF) Guidelines. Therefore, we determined the proportion of U.S. Caucasians recommended for treatment of osteoporosis according to NOF Guidelines (2003 & 2008).
1,946 postmenopausal women and 1,681 men ≥ age 50 years from the Framingham Study with information on BMD (1987-2001). Information on clinical predictors was used to estimate the 10-year probability of hip and major osteoporotic fracture by FRAX® (version 3.0).
Overall proportion of women meeting treatment criterion was less when the 2008 NOF Guidelines were applied (41.1%) compared with 2003 Guidelines (47.8%). The proportion of women < age 65 years meeting treatment criterion was much less when applying 2008 Guidelines (23.1% in 2003, 8.3% in 2008), whereas the proportion of women > age 75 years increased slightly (78.3% in 2003, 86.0% in 2008). 17.0% of men ≥ age 50 years met treatment criterion (2.5% aged 50-64 years, 49.8% > age 75 years).
Nearly one-half of Caucasian post-menopausal women and one-sixth of men aged 50 years and older would be recommended for osteoporosis treatment according to 2008 NOF Guidelines. Given the high proportion of persons recommended for treatment, NOF Guidelines may need to be re-evaluated with respect to budget impact.
osteoporosis; treatment; FRAX®; NOF guidelines