Amanda L. Stuart

Annual high-dose oral vitamin D and falls and fractures in older women: A randomized controlled trial

CONTEXT Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor. OBJECTIVE To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture. DESIGN, SETTING, AND PARTICIPANTS A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008. INTERVENTION 500,000 IU of cholecalciferol or placebo. MAIN OUTCOME MEASURES Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels. RESULTS Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing. CONCLUSION Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.

So depression is an inflammatory disease, but where does the inflammation come from?

BackgroundWe now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’DiscussionThis review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency.SummaryThe identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder.

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial

BACKGROUND Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking. AIMS To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health. METHOD A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D(3) (cholecalciferol) orally or placebo every autumn/winter for 3-5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression-Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants. RESULTS In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups. CONCLUSIONS The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3) is a practical intervention to prevent depressive symptoms in older community-dwelling women.

Validity of 12-month falls recall in community-dwelling older women participating in a clinical trial

Objectives. To compare 12-month falls recall with falls reported prospectively on daily falls calendars in a clinical trial of women aged ≥70 years. Methods. 2,096 community-dwelling women at high risk of falls and/or fracture completed a daily falls calendar and standardised interviews when falls were recorded, for 12 months. Data were compared to a 12-month falls recall question that categorised falls status as “no falls,” “a few times,” “several,” and “regular” falls. Results. 898 (43%) participants reported a fall on daily falls calendars of whom 692 (77%) recalled fall(s) at 12 months. Participants who did not recall a fall were older (median 79.3 years versus 77.8 years, P = 0.028). Smaller proportions of fallers who sustained an injury or accessed health care failed to recall a fall (all P < 0.04). Among participants who recalled “no fall,” 85% reported zero falls on daily calendars. Few women selected falls categories of “several times” or “regular” (4.1% and 0.4%, resp.) and the sensitivity of these categories was low (30% to 33%). Simply categorising participants into fallers or nonfallers had 77% sensitivity and 94% specificity. Conclusion. For studies where intensive ascertainment of falls is not feasible, 12-month falls recall questions with fewer responses may be an acceptable alternative.

Atopic disorders and depression: Findings from a large, population-based study

BACKGROUND Atopy, a common disorder characterized by a sensitivity to allergic reactions, affects a large proportion of the adult population and, as with depression, is associated with immune-inflammatory pathway changes. We sought to determine the role of atopic disorders in depression using data from a randomly-selected, population-based study of men and women. METHODS Cross-sectional data derived from the Geelong Osteoporosis Study for 942 males and 1085 females were analyzed. Depression [major depressive disorder (MDD), minor depression and dysthymia] was assessed using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition. Data on medical conditions, including atopic disorders (asthma, hay fever and eczema), smoking status, alcohol consumption, socioeconomic status, and physical activity were documented by self-report. Logistic regression modeling was used to explore the associations between atopic disorders and depression. RESULTS Atopic disorders were associated with a 59% increased likelihood of depression [gender and smoking-adjusted odds ratio (OR) 1:50, 95% CI 1.20-1.97]. Sub-group analyses revealed a similar pattern for those with MDD [gender and smoking-adjusted OR 1:54, 95% CI 1.22-1.94]. These associations were independent of socio-demographic characteristics, clinical and lifestyle factors. LIMITATIONS Reliance on self-report for allergic symptoms and cross-sectional nature of study. CONCLUSION This population-based study provides evidence of the potential contribution of allergic disorders to depression. Further research is required to elucidate the direction of this association and to further explicate its underlying physiology, including immune-inflammation markers.

Trials and tribulations of recruiting 2,000 older women onto a clinical trial investigating falls and fractures: Vital D study

BackgroundRandomised, placebo-controlled trials are needed to provide evidence demonstrating safe, effective interventions that reduce falls and fractures in the elderly. The quality of a clinical trial is dependent on successful recruitment of the target participant group. This paper documents the successes and failures of recruiting over 2,000 women aged at least 70 years and at higher risk of falls or fractures onto a placebo-controlled trial of six years duration. The characteristics of study participants at baseline are also described for this study.MethodsThe Vital D Study recruited older women identified at high risk of fracture through the use of an eligibility algorithm, adapted from identified risk factors for hip fracture. Participants were randomised to orally receive either 500,000 IU vitamin D3 (cholecalciferol) or placebo every autumn for five consecutive years. A variety of recruitment strategies were employed to attract potential participants.ResultsOf the 2,317 participants randomised onto the study, 74% (n = 1716/2317) were consented onto the study in the last five months of recruiting. This was largely due to the success of a targeted mail-out. Prior to this only 541 women were consented in the 18 months of recruiting. A total of 70% of all participants were recruited as a result of targeted mail-out. The response rate from the letters increased from 2 to 7% following revision of the material by a public relations company. Participant demographic or risk factor profile did not differ between those recruited by targeted mail-outs compared with other methods.ConclusionThe most successful recruitment strategy was the targeted mail-out and the response rate was no higher in the local region where the study had extensive exposure through other recruiting strategies. The strategies that were labour-intensive and did not result in successful recruitment include the activities directed towards the GP medical centres. Comprehensive recruitment programs employ overlapping strategies simultaneously with ongoing assessment of recruitment rates. In our experience, and others direct mail-outs work best although rights to privacy must be respected.Trial registrationISRCTN83409867 and ACTR12605000658617.

Comparison of self-report and structured clinical interview in the identification of depression.

BACKGROUND A self-report method seeking a binary response for assessing depression is a cost-effective and time-efficient way to obtain a psychiatric history, yet the reliability of this method is largely unknown. The aim of the study was to compare and assess the validity of two methods for identifying a past history of depression in a population-based study. METHODS This study examined data collected from 891 men and 1086 women participating in the Geelong Osteoporosis Study. Self-reports of depression were compared with results obtained using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). RESULTS Using the SCID-I/NP, 146 (16.4%) men and 285 (26.2%) women met criteria for a lifetime depression. Of those participants, 61.0% (n=263) self-reported a history of depression. The level of agreement between self-reporting depression and the SCID-I/NP depression module was reasonably high; 61% sensitivity, 89.5% specificity and the overall level of agreement (kappa) was 0.5. LIMITATIONS Results may not be generalizable to other self-report instruments or be suitable for use in clinical samples. CONCLUSION The SCID-I/NP remains the gold standard for identifying depression; however, given the moderate level of agreement between the self-report questionnaire and SCID-I/NP in our current study, we conclude that simple self-report methods can be used to identify depression with some degree of confidence.

Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women

We investigated the association between undercarboxylated osteocalcin (ucOC) and lower-limb muscle strength in women over the age of 70years. The study also aims to confirm the association between bone turnover markers and heel ultrasound measures. A post-hoc analysis using data collected as part of a randomized placebo-controlled trial of vitamin D supplementation. An immunoassay was used to quantify total OC (tOC), with hydroxyapatite pre-treatment for ucOC. We determined associations of absolute and relative (ucOC/tOC; ucOC%) measures of ucOC with lower-limb muscle strength, heel ultrasound measures of speed of sound (SOS) and broadband ultrasound attenuation (BUA), bone turnover markers (BTMs; P1NP and CTx) and the acute phase protein alpha-1-antichymotrypsin (α-ACT). ucOC%, but not absolute ucOC concentration, was positively associated with hip flexor, hip abductor and quadriceps muscle strength (all p<0.05). ucOC% was negatively associated with α-ACT (β-coefficient=-0.24, p=0.02). tOC was positively associated with both P1NP and CTx (p<0.001). For each per unit increase in tOC (μg/L) there was a corresponding lower BUA, SOS and SI (β-coefficient = -0.28; -0.23 and -0.23, respectively; all p<0.04). In conclusion, ucOC% is positively associated with muscle strength and negatively associated with α-ACT. These data support a role for ucOC in musculoskeletal interactions in humans. Whilst tOC is associated with bone health, ucOC% and ucOC may also be linked to falls and fracture risk by influencing muscle function.

Investigating the predictive ability of gait speed and quadriceps strength for incident falls in community-dwelling older women at high risk of fracture

Gait speed is a recommended geriatric assessment of physical performance, but may not be regularly examined in clinical settings. We aimed to investigate whether quadriceps strength tests demonstrate similar predictive ability for incident falls as gait speed in older women. We investigated 135 female volunteers aged mean±SD 76.7±5.0 years (range 70-92) at high risk of fracture. Participants completed gait speed assessments using the GAITRite Electronic Walkway System, and quadriceps strength assessments using a hand-held dynamometer (HHD). Participants reported incident falls monthly for 3.7±1.2 years. N=99 (73%) participants fell 355 times during the follow-up period (mean fall rate 83 per 100 person years). We observed a reduced odds ratio for multiple falls (0.83, 95% CI 0.70-0.98) and a reduced hazard ratio for time to first fall (0.90, 95% CI 0.83-0.98), according to quadriceps strength. There was also a significantly shorter time to first fall for those with low quadriceps strength (<7.0 kg; lowest tertile) compared with those with normal quadriceps strength (estimated means [95% CI] 1.54 [1.02, 2.06] vs. 2.23 [1.82, 2.64] years; P=0.019), but not for those with low (<1.0 m/s) vs. normal gait speed (P=0.15). Quadriceps strength is a significant predictor of incident falls over three years amongst community-dwelling older women at high risk of fracture. Quadriceps strength tests may be an acceptable alternative to gait speed for geriatric assessments of falls risk.

Physical comorbidities in men with mood and anxiety disorders: a population-based study

BackgroundThe mind-body nexus has been a topic of growing interest. Further data are however required to understand the specific relationship between mood and anxiety disorders and individual physical health conditions, and to verify whether these psychiatric disorders are linked to overall medical burden.MethodsThis study examined data collected from 942 men, 20 to 97 years old, participating in the Geelong Osteoporosis Study. A lifetime history of mood and anxiety disorders was identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). The presence of medical conditions (lifetime) was self-reported and confirmed by medical records, medication use or clinical data. Anthropometric measurements and socioeconomic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Logistic regression models were used to test the associations.ResultsAfter adjustment for age, socioeconomic status, and health risk factors (body mass index, physical activity and smoking), mood disorders were associated with gastro oesophageal reflux disease (GORD), recurrent headaches, blackouts and/or epilepsy, liver disorders and pulmonary disease in older people, whilst anxiety disorders were significantly associated with thyroid, GORD and other gastrointestinal disorders, and psoriasis. Increased odds of high medical burden were associated with both mood and anxiety disorders.ConclusionsOur study provides further population-based evidence supporting the link between mental and physical illness in men. Understanding these associations is not only necessary for individual management, but also to inform the delivery of health promotion messages and health care.