Margaret J. Henry

Serum leptin levels are associated with bone mass in nonobese women

Both serum leptin and bone mineral density are positively correlated with body fat, generating the hypothesis that leptin may be a systemic and/or local regulator of bone mass. We investigated 214 healthy, nonobese Australian women aged 20-91 yr. Bone mineral content, projected bone area, and body fat mass were measured by dual energy x-ray absorptiometry and fasting serum leptin levels by RIA. Associations between bone mineral content (adjusted for age, body weight, body fat mass, and bone area) and the natural logarithm of serum leptin concentrations were analyzed by multiple regression techniques. There was a significant positive association at the lateral spine, two proximal femur sites (Wards triangle and trochanter), and whole body (partial r(2) = 0.019 to 0.036; all P < 0.05). Similar trends were observed at the femoral neck and posterior-anterior-spine. With bone mineral density the dependent variable (adjusted for age, body weight, and body fat mass), the association with the natural logarithm of leptin remained significant at the lateral spine (partial r(2) = 0.030; P = 0.011), was of borderline significance at the proximal femur sites (partial r(2) = 0.012 to 0.017; P = 0.058 to 0.120), and was not significant at the other sites. Our results demonstrate an association between serum leptin levels and bone mass consistent with the hypothesis that circulating leptin may play a role in regulating bone mass.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or −4.0 to −1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies.

The population burden of fractures originates in women with osteopenia, not osteoporosis

IntroductionOsteoporosis is associated with increased risk for fracture. However, most postmenopausal women have bone mineral density (BMD) within the normal or osteopenic range. The aim of this study was to determine the proportion of the population burden of fragility fractures arising from women at modest risk for fracture.MethodsWe measured baseline BMD in a population-based random sample of 616 postmenopausal women aged 60–94 years and followed these individuals for a median of 5.6 years (IQR 3.9–6.5) to determine the incidence of fractures according to age, BMD and the presence of a prior fracture.ResultsBased on WHO criteria, 37.6% of the women had normal total hip BMD, 48.0% had osteopenia and 14.5% had osteoporosis. The incidence of fracture during follow-up was highest in women with osteoporosis, but only 26.9% of all fractures arose from this group; 73.1% occurred in women without osteoporosis (56.5% in women with osteopenia, 16.6% in women with normal BMD). Decreasing BMD, increasing age and prior fracture contributed independently to increased fracture risk; in a multivariate model, the relative risk for fracture increased 65% for each SD decrease in BMD (RR=1.65, 95%CI 1.32–2.05), increased 3% for every year of age (RR=1.03, 95%CI 1.01–1.06) and doubled with prevalent fracture (RR=2.01, 95% CI 1.40–2.88). A prevalent fracture increased the risk for fractures such that women with osteopenia and prevalent fracture had the same, if not greater, risk as women with osteoporosis alone.ConclusionsReducing the population burden of fractures requires attention to women with osteopenia, as well as osteoporosis, because over half of the fragility fractures in the population arise in these individuals, and women with osteopenia plus a prevalent fracture have the same fracture risk as women with osteoporosis.

Association of high-sensitivity C-reactive protein with de novo major depression

BACKGROUND Although there is cross-sectional evidence that changes in the immune system contribute to the pathophysiology of depression, longitudinal data capable of elucidating cause and effect relationships are lacking. AIMS We aimed to determine whether subclinical systemic inflammation, as measured by serum high-sensitivity C-reactive protein (hsCRP) concentration, is associated with an increased risk of de novo major depressive disorder. METHOD Major depressive disorder was diagnosed using a clinical interview (SCID-I/NP). This is a retrospective cohort study; from a population-based sample of 1494 randomly selected women recruited at baseline during the period 1994-7, 822 were followed for a decade and provided measures of both exposure and outcome. Of these women, 644 (aged 20-84 years) had no prior history of depression at baseline and were eligible for analysis. RESULTS During 5827 person-years of follow-up, 48 cases of de novo major depressive disorder were identified. The hazard ratio (HR) for depression increased by 44% for each standard deviation increase in log-transformed hsCRP (ln-hsCRP) (HR = 1.44, 95% CI 1.04-1.99), after adjusting for weight, smoking and use of non-steroidal anti-inflammatory drugs. Further adjustment for other lifestyle factors, medications and comorbidity failed to explain the observed increased risk for depression. CONCLUSIONS Serum hsCRP is an independent risk marker for de novo major depressive disorder in women. This supports an aetiological role for inflammatory activity in the pathophysiology of depression.

Seasonal Periodicity of Serum Vitamin D and Parathyroid Hormone, Bone Resorption, and Fractures: The Geelong Osteoporosis Study

In this population‐based study, seasonal periodicity was seen with reduced serum vitamin D, increased serum PTH, and increased bone resorption in winter. This was associated with an increased proportion of falls resulting in fracture and an increased risk of wrist and hip fractures.

Tobacco smoking as a risk factor for major depressive disorder: Population-based study

BACKGROUND Smoking is disproportionately prevalent among people with psychiatric illness. AIMS To investigate smoking as a risk factor for major depressive disorder. METHOD A population-based sample of women was studied using case-control and retrospective cohort study designs. Exposure to smoking was self-reported, and major depressive disorder diagnosed using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP). RESULTS Among 165 people with major depressive disorder and 806 controls, smoking was associated with increased odds for major depressive disorder (age-adjusted odds ratio (OR)=1.46, 95% CI 1.03-2.07). Compared with non-smokers, odds for major depressive disorder more than doubled for heavy smokers (>20 cigarettes/day). Among 671 women with no history of major depressive disorder at baseline, 13 of 87 smokers and 38 of 584 non-smokers developed de novo major depressive disorder during a decade of follow-up. Smoking increased major depressive disorder risk by 93% (hazard ratio (HR)=1.93, 95% CI 1.02-3.69); this was not explained by physical activity or alcohol consumption. CONCLUSIONS Evidence from cross-sectional and longitudinal data suggests that smoking increases the risk of major depressive disorder in women.

Prevalence of osteoporosis in Australian women - Geelong Osteoporosis study

To evaluate the prevalence of osteoporosis at various sites among Australian women, cross-sectional bone mineral density (BMD) data for adult females was obtained from an age-stratified population-based sample (n = 1494; 20-94 yr) drawn at random from the Barwon Statistical Division, a population characteristic of Australia. Age- and weight- (and for three sites, height) matched reference ranges for BMD at the lumbar spine, proximal femur, forearm, and total body were developed using regression techniques. The cutoff BMD level for osteoporosis at the PA spine was 0. 917g/cm(2) and 0.713 g/cm(2) at the femoral neck according to the World Health Organization (WHO) guidelines. The upper cutoff level for osteopenia was 1.128 g/cm(2) at the PA spine and 0.913g/cm(2) for the femoral neck. The proportion of Australian women categorized as having osteoporosis at the PA spine, femoral neck, or midforearm ranged from 0.9% among those aged 40-44 yr to 87.0% for those older than 79 yr. This study provides reference data representative of the Australian female population. A large proportion of elderly Australian women has osteoporosis according to the WHO guidelines.

Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression.

Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for depression. They have been reported to regulate serotonin signalling in bone cells and may influence bone metabolism. This study aimed to investigate the effect of SSRIs on bone mineral density (BMD) in a sample of women with a lifetime history of depression. In this community-based study of 607 women, a history of depression was ascertained using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR research version, non-patient edition. BMD was measured at the posterior–anterior (PA) spine, hip, total body and forearm using dual energy absorptiometry, and medication use and lifestyle factors were self-reported. Among 177 women with a lifetime history of depression, current users of bisphosphonates, glucocorticoids, hormone therapy and antidepressants other than SSRIs were excluded. Of the remaining 128 (median age 51.5 years, range 30–74), 26 (20.3%) reported current SSRI use. After controlling for age, weight, height and smoking history, BMD among SSRI users was 5.6% lower at the femoral neck (P=0.03), 6.2% lower at the trochanter (P=0.04) and 4.4% lower at the mid-forearm (P=0.03) than nonusers. No differences in BMD were detected at other sites. Although the mechanism remains unclear, these observations are consistent with a role for the serotonergic system in regulating bone metabolism.

Habitual physical activity and the risk for depressive and anxiety disorders among older men and women

BACKGROUND Regular physical activity is generally associated with psychological well-being, although there are relatively few prospective studies in older adults. We investigated habitual physical activity as a risk factor for de novo depressive and anxiety disorders in older men and women from the general population. METHODS In this nested case-control study, subjects aged 60 years or more were identified from randomly selected cohorts being followed prospectively in the Geelong Osteoporosis Study. Cases were individuals with incident depressive or anxiety disorders, diagnosed using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP); controls had no history of these disorders. Habitual physical activity, measured using a validated questionnaire, and other exposures were documented at baseline, approximately four years prior to psychiatric interviews. Those with depressive or anxiety disorders that pre-dated baseline were excluded. RESULTS Of 547 eligible subjects, 14 developed de novo depressive or anxiety disorders and were classified as cases; 533 controls remained free of disease. Physical activity was protective against the likelihood of depressive and anxiety disorders; OR = 0.55 (95% CI 0.32-0.94), p = 0.03; each standard deviation increase in the transformed physical activity score was associated with an approximate halving in the likelihood of developing depressive or anxiety disorders. Leisure-time physical activity contributed substantially to the overall physical activity score. Age, gender, smoking, alcohol consumption, weight and socioeconomic status did not substantially confound the association. CONCLUSION This study provides evidence consistent with the notion that higher levels of habitual physical activity are protective against the subsequent risk of development of de novo depressive and anxiety disorders.

Risk Factors for Mycobacterium ulcerans Infection, Southeastern Australia

Epidemiologic evidence shows that mosquitoes play a role in transmission to humans.