Loran M. Salamone

The epidemiology of quantitative ultrasound : A review of the relationships with bone mass, osteoporosis and fracture risk

Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.

The association between vitamin D receptor gene polymorphisms and bone mineral density at the spine, hip and whole-body in premenopausal women.

The genetic influence on bone mineral density (BMD) is thought to be mediated in part by alleles at the vitamin D receptor (VDR) locus. In order to assess the effect of VDR on BMD in premenopausal women, we studied 470 healthy white subjects, aged 44–50 years, participating in the Womens Healthy Lifestyle Project. Each participant was genotyped for theBsmI polymorphism at the VDR gene locus. BMD at the lumbar spine, hip and whole-body, and the whole-body soft tissue composition, were measured cross-sectionally using a Hologic QDR 2000 densitometer. The presence of a polymorphic restriction site at the VDR gene locus was specified asb, whereas absence of this site wasB. The frequency distribution of the VDR genotype was:bb, 20.6%;Bb, 39.1%; andBB, 40.2%. Spinal BMD (mean±SD) was significantly lower in women with VDR genotypeBB (1.038±0.11 g/cm2) as compared with those with genotypebb (1.069±0.12 g/cm2,p<0.05). Trochanter BMD was 2.7% lower in those with genotypeBB versusbb (0.685±0.10 g/cm2 vs 0.708±0.09 g/cm2). A similar trend was shown at each subregion of the hip, but not at the whole-body. In premenopausal women, allelic status at the VDR locus contributed to variations in spinal and trochanteric BMDs, but the absolute difference in BMDs was small, amounting to 0.26 and 0.23 standard deviations, respectively. It is concluded that in this population of healthy premenopausal women there was a significant association between polymorphisms at the VDR gene locus and both spinal and trochanteric BMDs, yet no association was demonstrated for the whole-body BMD.

Apolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone loss.

The identification of genes that contribute to bone mineral density (BMD) and bone loss has widespread implications for the understanding and prevention of osteoporosis. The objective of this study was to examine the relationship between the presence and absence of the apolipoprotein E*4 (APOE*4) allele and both BMD and annualized percentage rate of change in BMD at the lumbar spine and hip in a population of 392 healthy, pre‐, peri‐, and postmenopausal white women participating in the Womens Healthy Lifestyle Project. APOE genotype was analyzed by restriction enzyme analysis from genomic DNA. BMD at the lumbar spine and hip was measured at baseline and after a mean of 2.5 years using dual‐energy X‐ray absorptiometry (DXA). In premenopausal women, there were no significant differences in BMD or in the annualized percentage rate of change in BMD at the spine or hip when comparing women with and without the APOE*4 allele. In contrast, spine bone loss was significantly greater in peri‐ and postmenopausal women having an APOE*4 allele than in women without this allele (−1.75 + 1.5% per year vs. −0.98 ± 1.4% per year, respectively, p = 0.018). Among peri‐ and postmenopausal women currently using hormone replacement therapy (HRT), there were no differences in the annualized percentage rate of change in spine BMD; whereas, among non‐HRT users, there was a 2‐fold higher rate of spine bone loss in women with an APOE*4 allele compared with women without this allele (−2.31 ± 1.5% per year vs. −1.27 ± 1.3% per year, respectively, p = 0.033; APOE*4 ×; HRT interaction, p = 0.076). In conclusion, this study shows the importance of APOE*4 allele in spine bone loss in peri‐ and postmenopausal women and, more importantly, it provides evidence for a genetic and lifestyle interaction in modulating spine bone loss. (J Bone Miner Res 2000;15:308–314)

Correlates of Quantitative Ultrasound in the Women’s Healthy Lifestyle Project

Abstract: Quantitative ultrasound (QUS) assessment of bone is a strong predictor of hip fractures and is currently an FDA-approved tool to identify women at risk of osteoporosis. However, few studies have investigated the lifestyle and genetic correlates of QUS in women. This study investigated the cross-sectional associates of several lifestyle, demographic and genetic factors with calcaneal QUS parameters (broadband ultrasound attenuation (BUA) and speed of sound (SOS)) in 393 women aged 45–53 years. Leisure-time and historical physical activity, dietary calcium and protein, body composition, vitamin D receptor genotypes, menopause status, other health behaviors, calcaneal QUS parameters and bone mineral density (BMD) were assessed at a single clinic visit. Lean mass, recent physical activity and African-American race were the strongest correlates of SOS whereas dietary protein, calcium and recent physical activity were the strongest correlates of BUA. These predictors explained 13% and 6% of the variance in SOS and BUA, respectively. Smoking, alcohol intake, education, hormone replacement therapy, calcium and vitamin D supplements, historical physical activity and vitamin D receptor genotypes were not significantly associated with BUA or SOS. Lean body mass and premenopausal status were the strongest correlates of lumbar BMD whereas lean body mass, physical activity, African-American race and body mass index were significantly related to femoral neck BMD. Physical activity remained predictive of SOS after controlling for lumbar BMD. The spectrum and magnitude of risk factors for SOS and BUA, including lean body mass, physical activity, race, protein and calcium intake, parallel previously observed predictors of BMD.

Are menopausal symptoms associated with bone mineral density and changes in bone mineral density in premenopausal women

BACKGROUND The relationship between menopausal symptoms and bone mineral density (BMD) was examined in 290 premenopausal women, ages 44-50 years, participating in a randomized clinical trial of a dietary and exercise intervention: The Womens Healthy Lifestyle Project. METHODS Information on hot flashes (presence, absence), menstrual cycles (irregular, regular) and menstrual flow per period (variable, same) over the past 6 months was collected at entry. Participants reporting at least one menopausal symptom were classified as symptomatic and compared to those having no symptoms. Bone mineral density (BMD) at the lumbar spine (L1-L4), total hip and whole-body were made at baseline and at 30 months using a dual-energy X-ray absorptiometer (Hologic QDR 2000 densitometer). RESULTS Baseline BMD at the spine, hip and whole-body were significantly reduced in women reporting menopausal symptoms compared to asymptomatic women, after adjustment for age, weight and intervention status (all p < 0.05). Women with irregular menstrual cycles had greater annualized rates of bone loss at the spine and hip than asymptomatic women (spine, -0.77 (1.6)% per year vs. -0.19 (1.0)% per year, p = 0.0043; hip, -0.37 (1.1)% per year vs. -0.04 (1.0)% per year, p = 0.061), after adjustments for age, percent change in weight, intervention status, and baseline BMD. Similar findings were not found for whole-body BMD. CONCLUSIONS These results suggest that menopausal symptoms are useful for the effective identification of premenopausal women at higher risk of low BMD and perhaps, of osteoporosis.

Risk Factors for Severity and Type of the Hip Fracture

More severe hip fractures such as displaced femoral neck (FN) fractures and unstable intertrochanteric (IT) fractures lead to poorer outcomes, but risk factors for severe fractures have not been studied. To identify risk factors for severe types of hip fracture, we performed a prospective cohort study and obtained preoperative hip radiographs from women who sustained an incident hip fracture (excluding traumatic fractures). A single radiologist scored the severity of FN fractures by the Garden System: grades I and II, undisplaced; grades III and IV, displaced. The severity of IT hip fractures was rated by the Kyle System: grades I and II, stable; grades III and IV, unstable. A total of 249 women had FN fractures: 75 (30%) were undisplaced. A total of 213 women had IT fractures: 59 (28%) were stable. Both types of hip fracture increased with age, but older age was even more strongly associated with more severe hip fractures. Low BMD was more strongly related to undisplaced FN fractures (p interaction BMD × FN type, p = 0.0008) and stable IT fractures (p interaction BMD × IT type, p = 0.04). Similar findings were observed for estimated volumetric BMD and hip geometric parameters. Corticosteroid use was only associated with displaced FN fractures, and Parkinsons disease was only associated with stable IT fractures. Little difference was reported in the self‐reported circumstances surrounding each type of fracture. In conclusion, the lower the BMD, the greater the likelihood of experiencing a hip fracture that is less displaced and more stable.

Postmenopausal Endogenous and Exogenous Hormones, Degree of Obesity, Thiazide Diuretics, and Risk of Osteoporosis

Publisher Summary This chapter reviews the relationship among thiazide diuretics, estrogen, both endogenous and exogenous, and the degree of obesity with bone mass and fractures among postmenopausal women. All of these factors may be interrelated to each other. Obese women have higher levels of circulating estrogens, reflecting the aromatization of androstenedione to estrone in fat tissue. When evaluating these relationships to bone mass and fracture risk, it is critical to consider the underlying factor of obesity. Thiazide diuretics may prevent hip fractures, but the underlying mechanisms for this effect are not known. More data are needed in normotensives before thiazide diuretics can be advocated for the prevention of osteoporotic fractures. Not only data on the efficacy of thiazide diuretics on fracture but also careful documentation of the risks and side effects of this therapy are needed. Obesity may be in the causal pathway among endogenous estrogens, bone mass, and fractures. In addition, there are other mechanisms for an effect of obesity on osteoporotic risk. Future research needs to identify this causal pathway to improve our understanding of the etiology of osteoporotic risk.

COHORT STUDIES AND RANDOMIZED CONTROLLED STUDIES IN ENDOCRINOLOGY

This article describes the basic skills for the design, implementation, and interpretation of randomized controlled studies. Strengths and limitations of each study design are discussed. Epidemiologic issues in the analysis and interpretation of studies, such as loss to follow-up and biases, are included. Numerous clinical examples are provided to better illustrate the epidemiologic methodology.