László B. Tankó

Relationship Between Osteoporosis and Cardiovascular Disease in Postmenopausal Women

In the placebo group of the MORE study, including 2576 postmenopausal women (mean age, 66.5 years), the authors describe a strong linear association between the severity grade of osteoporosis (from low BMD to presence of severe vertebral fractures) and the future risk of cardiovascular events. Accordingly, treatment of postmenopausal osteoporosis should include consideration of measures to prevent adverse cardiovascular outcomes.

Peripheral Adiposity Exhibits an Independent Dominant Antiatherogenic Effect in Elderly Women

Background—Although several lines of evidence point to an atherogenic role of central fat mass (CFM), few data are available to address the specific role played by peripheral fat mass (PFM). Methods and Results—This study was a cross-sectional analysis of 1356 women aged 60 to 85 years. Study variables were physical measures, CFM and PFM measured by DEXA, aortic calcification (AC) graded on lateral radiographs, lipid and glucose metabolites, blood pressure, and information on lifestyle factors and coronary disease. Peripheral fat mass showed independent negative correlation with both atherogenic metabolic risk factors and AC (P <0.001). The most severe insulin resistance-dyslipidemic syndrome and AC (score 5.10±0.76) was found in women with high central fat percentage (CF%, 21.7±0.2%) and low peripheral fat percentage (PF%, 18.3±0.2%, n=48). The least severe AC (score 2.45±0.31) was found in obese women with high CF% (21.6±0.1%) and high PF% (27.3±0.14%, n=112). The insulin resistance-dyslipidemic syndrome was also less severe compared with those with the same CF% but low PF%. The most favorable metabolic profile characterized women with low CF% (11.56±0.16%) and high PF% (26.86±0.33%, n=44). In women with a history of myocardial infarct (18.41±0.55%, n=45), CF% was significantly higher compared with women with no manifest coronary disease (16.48±0.12%, n=1210) without differences in PF%. Conclusions—In elderly women, localization of fat mass is apparently more important for atherosclerosis than obesity per se; although CFM is associated with atherogenic tendencies, PFM seems to exhibit an independent dominant antiatherogenic effect.

Low bone mineral density in the hip as a marker of advanced atherosclerosis in elderly women.

Previous studies indicate that low bone mineral density (BMD) in the hip is a useful predictor of cardiovascular mortality among the elderly. The objective of this study was to investigate whether low hip BMD is directly associated with the severity of atherosclerosis. The per-protocol population consisted of 963 women aged 60-85 years. Study variables were aortic calcification (AC) graded on lateral lumbar radiographs, BMD at various anatomic sites (distal radius, lumbar spine, proximal femur) measured by DXA, information on various risk factors, and medical history. After adjustment for age, BMD at the proximal femur, but not at the radius or spine BMD, showed statistically significant association with the severity of AC (r = −0.12−17, P < 0.001). Age, years since menopause, BMI, level of education, current and previous smoking, and weekly fitness activity were significant common risk factors (all P < 0.05) with contrasting influence on AC and hip BMD. In a multiple regression model, AC contributed significantly and independently to the variation in hip BMD (β = −0.10, P = 0.004). Impaired blood flow represented by 40 women with documented history of intermittent claudication was not an independent contributor and did not alter the association between AC and hip BMD. However, AC and demineralization in the hip was particularly severe in women with intermittent claudication accompanied by a higher prevalence of coronary heart disease compared with age-matched controls (all P < 0.001). In conclusion, severe osteoporosis in the hip may indicate advanced atherosclerosis and thereby an increased risk for not only hip fractures but also for coronary heart disease. The results further emphasize that osteoporosis in the hip and peripheral vascular disease are linked by common risk factors and pathomechanisms.

Enlarged Waist Combined With Elevated Triglycerides Is a Strong Predictor of Accelerated Atherogenesis and Related Cardiovascular Mortality in Postmenopausal Women

Background—Upward trends of obesity urge more effective identification of those at cardiovascular risk. A simple dichotomous indicator, enlarged waist (≥88 cm) combined with elevated triglycerides (≥1.45 mmol/L) (EWET), was shown to offer advantages in identifying individuals with atherogenic “lipid overaccumulation” compared with other indicators, including the metabolic syndrome defined by the National Cholesterol Education Program (MS-NCEP). Whether EWET offers superior disease and event prediction in postmenopausal women, however, remains unknown. Methods and Results—A community-based sample of 557 women (48 to 76 years of age) were followed up for 8.5±0.3 years to assess the utility of EWET and MS-NCEP in estimating the risk of all-cause and cardiovascular mortality and the annual progression rate of aortic calcification. At baseline, 15.8% of women had EWET and 17.6% had MS-NCEP. All-cause mortality and cardiovascular mortality were increased in carriers of the dichotomous indicators (P<0.001). After adjustment for age, smoking, and LDL cholesterol, presence of EWET was associated with a 4.7-fold (95% CI, 2.2 to 9.8; P<0.001) increased risk and presence of MS-NCEP was associated with a 3.2-fold (95% CI, 1.5 to 6.5; P<0.001) increased risk for fatal cardiovascular events. Exclusion of women with prevalent diabetes did not change these trends; respective hazard ratios were 4.2 (95% CI, 1.9 to 9.3; P<0.001) and 2.5 (95% CI, 1.1 to 5.5; P<0.05). Among those who were discordant for EWET and MS-NCEP at baseline, those who had EWET alone (n=21) had a higher annual progression rate of aortic calcification compared with those who had MS-NCEP alone (n=31; P<0.05). Conclusions—The combined presence of EWET may be the best indicator of cardiovascular risk in postmenopausal women. Other components of the MS-NCEP add little medical value to screening in general practices.

Early postmenopausal hormone therapy may prevent cognitive impairment later in life.

Objective: Estrogen deficiency has been implicated as a risk factor for cognitive impairment in elderly women, yet the role of hormone therapy (HT) to prevent this event remains controversial. The aim of this study was to investigate the impact of administration of HT for 2 to 3 years in the early postmenopausal years on the risk of cognitive impairment 5 to 15 years later. Design: We followed a group of 343 women who had received HT in randomized, placebo-controlled trials and were reexamined 5, 11, or 15 years after completion of therapy. Of these women, 261 received either HT or placebo for 2 to 3 years during the trials with no further hormone treatment until follow-up, and the remaining 82 women reported either prolonged or current use of HT at reexamination. Outcome of the study was cognitive function assessed by the short Blessed test that includes tests of orientation, concentration, and memory function on a scale of 0 to 28 (score ≥6 indicates cognitive impairment). Results: The mean age of participants at follow-up was 65 ± 3 years. There was no difference in the mean cognitive scores between ever HT users and never users. For women who received 2 to 3 years of HT, the risk of cognitive impairment (cognitive score ≥6) was decreased by 64% (odds ratio [OR]: 0.36, 95% CI: 0.15-0.90; P = 0.03). A similar OR was found in long-term/current HT users. Adjustment for age, alcohol intake, current smoking, and education did not alter the results. Conclusion: The results of the present study suggest that previous short-term HT administered in the early phase of the menopause may provide a long-term protection against cognitive impairment.

Cartilage turnover assessed with a newly developed assay measuring collagen type II degradation products: influence of age, sex, menopause, hormone replacement therapy, and body mass index

Background: Cartilage normally has a slow turnover but in arthritis increased metabolism results in degradation of the tissue. Objective: To assess cartilage turnover in a sample of the general population by an assay measuring cartilage derived urinary collagen type II (CTX-II) C-telopeptide degradation products. Methods: CTX-II concentrations were measured in urine samples from 615 healthy men and women aged 20–87 years, and the influence of age, sex, menopause, hormone replacement therapy (HRT), and body mass index (BMI) was assessed. Results: CTX-II concentrations showed age dependent variations, with notable differences between men and women. Mean (SD) CTX-II concentration in postmenopausal women (220 (118) ng/mmol, n=25) was significantly higher than in an age matched group of premenopausal women (112 (79) ng/mmol, n=26, p<0.001). CTX-II concentration in women using HRT (118 (57) ng/mmol, n=50) was significantly lower than in an age and BMI matched group of women not receiving HRT (215 (99) ng/mmol, n=50, p<0.001). In subjects with a BMI ≥25 kg/m2, CTX-II concentrations were significantly higher than in those with a BMI <25 kg/m2 (185 (114) v 148 (91) ng/mmol, p<0.001). Conclusions: Cartilage turnover, as assessed by measuring urinary degradation products of CTX-II varies considerably with age, and significant differences between CTX-II levels in men and women as well as in pre- and postmenopausal women are found. Further studies are required to validate the marker for assessing cartilage degradation in arthritis.

An update on the antiestrogenic effect of smoking: a literature review with implications for researchers and practitioners.

Objective To draw attention to the implications of smoking in the pathogenesis of osteoporosis and for the effectiveness and safety of hormone therapy. Design Summary of own research and a MEDLINE search of English-language literature on the antiestrogenic effect of smoking in pre- and postmenopausal women published during the past two decades. Results Numerous observations suggest that part of the detrimental effect of smoking on bone metabolism is mediated by an adverse influence on sex-steroid metabolism, and in particular by an estrogen-lowering effect. Furthermore, in smokers, serum concentrations of estradiol and estrone during oral, but not parenteral, hormone therapy (HT) reach only half the concentrations of nonsmokers. Thus, cigarette smoking may reduce the favorable effects of HT significantly and may even negate the protective effects. In such cases, the failure of preventive therapy is a failure of dosing rather than of HT per se. Conclusions We urge colleagues to take the antiestrogenic effect of smoking into account when drawing conclusions from population-based trials, as well as when prescribing HT to their patients for the prevention of menopause-related health problems.

Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases

Numerous experimental and clinical observations suggest that overall changes in bone resorption during menopause or treatment with hormone replacement therapy (HRT) are combined effects of changes in osteoclast number and function. Moreover, due to a coupling between osteoclastic bone resorption and osteoblastic bone formation, pronounced alteration of osteoclast number will eventually lead to alteration of osteoblastic bone formation. Fragments of type I collagen, such as the C- and N-terminal telopeptides of collagen type I (CTX and NTX, respectively), are generated during bone resorption and hence can be used as surrogate markers of osteoclast function. Circulating levels of different enzymes in the serum, such as TRAP 5b and cathepsin K are proportional to the number of osteoclasts, and hence can be used as surrogate markers of osteoclast number. Since antiresorptive effects can be obtained in different ways, we felt it was timely to discuss the different scenarios, highlight differences specific to different pharmacological interventions with different mechanisms of action, and discuss how these bone markers can assist us in a deeper analysis of the pharmacodynamics and safety profile of existing and upcoming drug candidates.

Novel associations between bioavailable estradiol and adipokines in elderly women with different phenotypes of obesity. Implications for atherogenesis

Background—Peripheral adiposity confers protection against diabetes and atherosclerosis in elderly women. The underlying mechanisms, however, remain to be elucidated. Methods and Results—On the basis on dual-energy X-ray absorptiometry measurements of central fat mass (CFM) and peripheral fat mass (PFM), we identified 290 elderly women with distinct forms of body fat distribution (lean, peripheral obesity, central obesity, or general obesity). Study parameters were plasma tumor necrosis factor-&agr;, interleukin (IL)-6, adiponectin, estradiol, sex hormone–binding globulin, insulin resistance, and aortic calcification, graded on lateral radiography. In peripherally and generally obese women, plasma estradiol and insulin resistance were significantly lower, whereas sex hormone–binding globulin and adiponectin were significantly higher compared with centrally obese women independent of age, body mass index, total fat mass, and smoking habits (all P<0.05). After adjustment for these confounders, IL-6 in centrally obese women was comparable with that seen in generally obese (similar high CFM%) but significantly higher than in peripherally obese women and lean women (low CFM%). Atherosclerosis was less severe in generally obese (2.5±0.3) compared with centrally obese women (5.0±0.7, P=0.001). In multiple regression analysis, total fat mass, body fat distribution, insulin resistance, estradiol, current smoking, treated hyperlipidemia, and treated hypertension contributed independently to the variation of aortic calcification (R=0.55, SEE=3.60, P<0.001). Conclusions—Abundant presence of PFM in generally obese women is associated with increased plasma adiponectin and higher insulin sensitivity, which could explain the apparent protection against the atherogenic effects of IL-6 derived from CFM. Low peripheral exposure to estradiol appears to be a sine qua non of maintained adiponectin secretion from PFM.

The Relative Use of Eight Collagenous and Noncollagenous Markers for Diagnosis of Skeletal Metastases in Breast, Prostate, or Lung Cancer Patients

The present study was sought to assess the relative use of eight biomarkers for the detection of bone metastases in cancer forms frequently spreading to the skeleton. Participants were 161 patients with either breast, prostate, or lung cancer. The presence and extent of bone metastases was assessed by imaging techniques (computer tomography and/or magnetic resonance imaging) and Technetium-99m scintigraphy. Serum or urinary level of the bone resorption markers (ααCTX, ββCTX, NTX, and ICTP), formation marker (BSAP), and osteoclastogenesis markers (osteoprotegerin, RANKL, and TRAP5b) was measured by commercially available immunoassays. When assessed on a group basis, all biomarkers, except for osteoprotegerin and RANKL, were significantly elevated in patients compared with those without bone metastases (P < 0.05). Biomarkers had greater diagnostic value in breast and prostate cancer patients, yet ααCTX, NTx, and ICTP were able to discriminate lung cancer patients with or without bone metastases (P < 0.05). Strong linear associations were seen between the extent of skeletal infiltration and levels of the different biomarkers, except for osteoprotegerin and RANKL. Furthermore, all biomarkers (except for osteoprotegerin and RANKL) were indicative at the early stage of skeletal involvement (one to five metastases). When expressing sensitivity as the percentage increase in biomarker level relative to patients without bone metastases, ααCTX showed the largest relative increases at each stage of the metastatic disease. These results suggest that closer monitoring of cancer patients with serial measures of biomarkers might facilitate the timely diagnosis of skeletal metastases. (Cancer Epidemiol Biomarkers Prev 2006;15(1)32–8)