Metabolite Profiling of Osteoporosis and Atherosclerosis in Postmenopausal Women: A Cross-Sectional Study.

PURPOSE: Atherosclerosis (AS) and osteoporosis (OP) are common causes of morbidity and mortality in postmenopausal women and are connected via an unknown mechanistic link. Metabolite profiling of blood samples may allow the identification of new biomarkers and pathways for this enigmatic association. PATIENTS AND METHODS: We studied the difference in 148 metabolite levels from serum samples in postmenopausal women with AS and OP compared with those in healthy participants in this cross-sectional study. Quantitative AS was assessed by carotid artery intima-media thickness (cIMT) and carotid artery calcifications (CACs) by ultrasound, as well as OP by femoral neck (FN) bone mineral density (BMD) and 148 metabolic measures with high-throughput proton (1H) nuclear magnetic resonance (NMR) in serum samples from 280 postmenopausal (PM) women. Subjects were a randomly selected subsample from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The final study population included the following groups: OP with CAC (n=16, group I), non-OP with no CAC (n=59, group II), high cIMT tertile with OP (n=11, group III) and low cIMT tertile without OP (n=48, group IV). RESULTS: There were differences in several metabolite levels between groups I and II. The acetate level was lower in group I compared to that in group II (group I mean ± SD: 0.033 ± 0.0070; group II: 0.041 ± 0.014, CI95%: 0.018‒0.15, p=0.014). The result was similar with diacylglycerol (p=0.002), leucine (p=0.031), valine (p=0.022) and several very low-density lipoprotein (VLDL) metabolite levels, which were lower in group I compared to those in group II. However, no associations were found in adjusted analyses with total body (TB) fat mass (FM), age and statin use (p>0.05). CONCLUSION: Our novel study found differences in the metabolite profiling of altered amino acid and lipoprotein metabolism in participants with OP and AS compared with those in healthy women. The causative mechanisms remain unknown and further studies are needed.

Corrigendum to "Mikkeli Osteoporosis Index Identifies Fracture Risk Factors and Osteoporosis and Intervention Thresholds Parallel with FRAX".

[This corrects the article DOI: 10.4061/2011/732560.].

Effects of antidepressants on postmenopausal bone loss - A 5-year longitudinal study from the OSTPRE cohort.

BACKGROUND: Osteoporosis and depression are major health problems worldwide. The association between antidepressants, a treatment for depression, and bone health needs more detailed exploration. OBJECTIVE: The present study investigates antidepressant medication use and postmenopausal bone loss over time. METHODS: A total of 1988 women (aged 57-67) participating in the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) cohort responded to a postal enquiry and had their femoral neck bone mineral density (BMD) measured in 1999 and again in 2004. Data on antidepressant use was obtained from the National Prescription Register. Multiple regression techniques were used to test the associations, before and after adjustment for anthropometric, medical, physical and lifestyle factors. RESULTS: Over the five years of follow-up, 319 (16.0%) women purchased antidepressants. Mean baseline femoral neck BMD for the entire study group was 881mg/cm(2) (SD 123) and mean 5-year bone loss was 6.0mg/cm(2) (SD 4.7). After adjustments, users of tricyclic antidepressants (TCA) had greater annual BMD loss than non-users (-3.6mg/cm(2) vs. -1.1mg/cm(2); P=0.031). Accelerated bone loss was also associated with selective serotonin reuptake inhibitor's (SSRI) use (P=0.001) and use of other antidepressants in a dose-response way, with the latter only among women of low-weight and normal-weight women who had lost weight over the study period. CONCLUSIONS: In conclusion, the use of SSRIs seems to accelerate postmenopausal bone loss in a dose-response manner. Associations between TCA and other antidepressant use and bone loss may also exist. Thus, the possibility of increased risk of osteoporosis should be considered when prescribing antidepressants for postmenopausal women.

Life satisfaction and bone mineral density among postmenopausal women: cross-sectional and longitudinal associations.

OBJECTIVE: The purpose of this study was to determine whether and how global life satisfaction is associated with bone mineral density (BMD) and bone loss. METHODS: A total of 2167 women from a cohort of Finnish women born in 1932 to 1941 were included in the cross-sectional and 1147 women in the 10-year longitudinal part of the present study. Participants responded to a postal enquiry and underwent femoral BMD densitometry in 1999 (baseline) and 2009 (follow-up). During the follow-up, their life satisfaction was repeatedly measured using a four-item scale. Self-reported data on health, life-style, and medication were used to adjust the multivariate linear regression models. RESULTS: Mean (standard deviation) femoral BMD decreased over the 10-year follow-up from 880 (125) to 846 (122) mg/cm. In the multivariate model, life satisfaction (p = .028) and its improvement (p = .001) predicted reduced bone loss, whereas hospitalization due to depression predicted increased bone loss (B = -0.523 annual % change, standard error = 0.212, p = .014). These effects were independent of each other. CONCLUSIONS: Easily assessed global life satisfaction should be taken into account when effects of aging and prevention of osteoporosis as well as health promotion in postmenopausal women are considered.

Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women-the OSTPRE-BBA study.

OBJECTIVES: Atherosclerosis (AS) and osteoporosis are common diseases in elderly people and may be metabolically related. The aim of this cross-sectional population-based study was to explore the association between common carotid artery intima-media thickness (cIMT), carotid artery calcification (CAC), and BMD in postmenopausal women. In addition, the association of postmenopausal hormone therapy (HT) and selected diseases with cIMT and carotid calcification was studied. STUDY DESIGN: The 290 women (mean age 73.6 years) included in this Bone Brain Atherosclerosis study (OSTPRE-BBA) were randomly selected from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort, Finland. MAIN OUTCOME MEASURES: For this cross-sectional study, cIMT was measured with B-mode ultrasound; femoral neck and total body BMD were measured with dual-energy X-ray absorptiometry. RESULTS: There were no statistically significant associations between mean cIMT and femoral neck T-score (p>0.05). However, an increased maximum cIMT was significantly associated with low femoral neck T-score. In the osteoporotic group (T-score <-2.5, n=20), the maximum cIMT was 2.51±0.88mm (mean±SD); in the normal BMD group (T-score >-1, n=122), it was 1.93±0.64mm (p=0.001). The odds of having CAC were approximately four-fold higher in the osteoporotic group compared with the group with a normal femoral neck T-score (odds ratio [OR]=4.2, p=0.038). The maximum cIMT was smaller in HT users (1.98±0.56mm, n=190) than in non-users (2.16±0.74mm, n=156, p=0.036). CONCLUSIONS: The results of our population-based study suggest that BMD is related to AS, at least in carotid arteries. They indirectly support the hypothesis of partially shared pathophysiological mechanisms between these two disorders.

The relationship between self-reported and registry-based data on use of psychoactive medications in postmenopausal women.

BACKGROUND: Self-report is commonly used as a source of information on the use of medicine. The aim of this study was to investigate the relationship between self-reported and register-based information on the use of psychoactive medication, especially in respect to antidepressants, and reasons of non-reporting. METHODS: Study subjects (n = 11,031) originated from a population-based cohort of postmenopausal women born in 1932-41 from Eastern Finland who responded to a postal enquiry in 1999. Self-reported currently used prescribed medications were compared to the National prescription register data. Diuretics served as a reference for psychoactive medications. RESULTS: Only 44% out of 1,638 women reported their use of psychoactive medication when compared to the prescription register within a 4-month time window preceding their response to enquiry. Altogether, 55% out of 777 women reported their use of antidepressants and 29% out of 861 reported their use of other psychoactive medications. In comparison 83% reported their use of diuretics. After excluding the occasional use, an increase in sensitivity by approximately 10 percentage points was seen regardless of the group of psychoactive medication. High use and history of work disability pension due to psychiatric cause were associated with a much higher likelihood of reporting psychoactive medication use (for antidepressants 70% and 81%, respectively). CONCLUSIONS: For research purposes, self-reported current use of psychoactive medication seems to be a sufficient indicator for regular use of antidepressants or in respect of use of any psychoactive medication, for subjects with severe psychiatric disease.

Validation of a semi-quantitative FFQ using food records as a reference in older women in the Kuopio Fracture Prevention Study (OSTPRE-FPS).

OBJECTIVE: To validate an eighty-nine-item semi-quantitative FFQ for measurement of nutrient intakes in elderly women. DESIGN: FFQ and 3 d food records were filled in by women participating in the Kuopio Fracture Prevention Study (OSTPRE-FPS). Data on intakes of energy, fat, protein, carbohydrate, fibre, Ca, Fe, P, K, Mg, folic acid, vitamin B12, vitamin C, vitamin D and vitamin K from ninety-nine women were available to assess the agreement of the two methods. Validity was assessed using correlation coefficients, cross-classification into quintile categories and Bland-Altman plots. Nutrients relevant to bone health were assessed. SETTING: OSTPRE-FPS in Finland. SUBJECTS: Elderly women with a mean age 71·3 years. RESULTS: The FFQ overestimated energy and nutrient intakes as compared with food records by 30-50%. The highest correlation coefficients of the energy-adjusted nutrient intakes between the methods were observed for fibre (0·60), Mg (0·56) and folic acid (0·49) and the lowest for protein and vitamin D (both 0·19). The cross-classification of energy-adjusted nutrient intakes showed that on average 68% of the participants (range 62-78%) were classified into the same or an adjacent quintile category. CONCLUSIONS: The validity of energy and nutrient intakes measured with the FFQ was moderate as compared with 3 d food records in elderly women. The FFQ is a useful tool for the nutrient assessment of elderly women in epidemiological research.

Mikkeli Osteoporosis Index Identifies Fracture Risk Factors and Osteoporosis and Intervention Thresholds Parallel with FRAX.

Osteoporosis Index (MOI) was developed from Fracture Index (FI), a validated fracture risk score, to identify also osteoporosis. MOI risk factors are age, weight, previous fracture, family history of hip fracture or spinal osteoporosis, smoking, shortening of the stature, and use of arms to rise from a chair. The association of these risk factors with BMD was examined in development cohorts of 300 Finnish postmenopausal women with a fracture and in a population control of 434 women aged 65-72. Validation cohorts included 200 fracture patients and a population control of 943 women aged 58-69. MOI identified femoral neck osteoporosis in these cohorts as well as the Osteoporosis Self-Assessment Tool (OST). In the pooled fracture cohort, the association of BMI-based FRAX fracture risk with MOI was good. After BMD measurement, MOI identified well FRAX hip fracture risk-based Intervention Thresholds (ITs) (AUC 0.74-0.90).

Use of calcium supplements and the risk of coronary heart disease in 52-62-year-old women: The Kuopio Osteoporosis Risk Factor and Prevention Study.

BACKGROUND: To analyse prospectively the effect of calcium or calcium+D supplementation on coronary heart disease (CHD) in 52-62-year-old women. METHODS AND RESULTS: 10,555 52-62-year-old women from the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) who did not have CHD at baseline were followed for nearly 7 years in 1994-2001. Information about use of calcium supplements and health events was obtained from two repeated questionnaires in 1989 and 1994. Information about causes of death during the follow-up was obtained from the Statistics Finland. Information about CHD and other disease morbidity before and during the follow-up was obtained from the Registry of Specially Refunded Drugs of the Finnish Social Insurance Institution (SII). Cox's proportional-hazards models were used to estimate the risk of CHD morbidity related to the use of calcium supplements. At baseline, 2723 women reported current use of calcium or calcium+D supplementation. During the follow-up, CHD was diagnosed in 513 women. Compared to non-users of calcium/calcium+D supplements, the multivariate adjusted hazard ratio (HR) of CHD was 1.24 (95% CI 1.02-1.52) in women who used these supplements. The multivariate adjusted HR for CHD morbidity in postmenopausal women who used calcium/calcium+D supplements was 1.26 (95% CI 1.01-1.57). CONCLUSIONS: Calcium or calcium+D supplementation appears to increase the risk of CHD among women before old age.

Hormone therapy protects from diabetes: the Kuopio osteoporosis risk factor and prevention study.

OBJECTIVES: The purpose of this population-based prospective cohort study was to examine the effect of hormone therapy (HT) on incidence of diabetes mellitus (DM). DESIGN AND METHODS: Eight thousand four hundred and eighty-three DM-free post-menopausal women aged 52-62 from the population-based Kuopio osteoporosis risk factor and prevention study were followed for 5 years from 1994-1999. Information about the use of HT and health events was obtained from three repeated questionnaires in 1989, 1994, and 1999. DM morbidity before and during the follow-up was obtained from the Registry of Specially Refunded Drugs of the Finnish Social Insurance Institution. Kaplan-Meyer survival curves and Cox's proportional-hazards models were used to estimate the risk of incident DM in relation to the use of HT. RESULTS: During the follow-up, 40.8% DM-free post-menopausal women had never used HT, 27.3% women were HT past users and 31.9% women had used HT presently during the follow-up. During the follow-up, 162 incident DM cases were recorded. Compared with never users of HT, the adjusted hazard ratio of DM was 0.81 (95% confidence interval (CI) 0.57-1.16) for only past users, 0.53 (95% CI 0.24-1.15) in part-time (during the follow-up <2.5 years) users and 0.31 (95% CI 0.16-0.60) in continuous (during the follow-up 2.5-5.0 years) users of HT. CONCLUSIONS: HT use decreases the incidence of DM in post-menopausal women.

HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial.

OBJECTIVES: We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS: A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth year); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS: Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS: This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.

Hormone replacement therapy and mortality in 52- to 70-year-old women: the Kuopio Osteoporosis Risk Factor and Prevention Study.

OBJECTIVES: To analyze prospectively the association between hormone replacement therapy (HRT) and mortality in women before old age. DESIGN AND METHODS: A group of 11,667 women (91% of the age cohort of the area) aged 52-62 years from the population-based Kuopio Osteoporosis Risk Factor and Prevention Study were followed for 7 years in 1994-2001. Information about HRT use and health events was obtained from two repeated questionnaires in 1989 and 1994. Information about deaths and causes of death from the follow-up period was obtained from the Statistics Finland. Cox's proportional-hazards models were used to calculate risk of death related to the use of HRT. RESULTS: At the start of follow-up, 2203 women had used HRT > 5 years, 3945 women < or = 5 years and 5519 women had never used it. During the follow-up, 361 deaths occurred. Compared with non-users of HRT, the adjusted hazard ratio (HR) of death from any cause was 1.05 (95% confidence interval (CI) 0.80-1.36) in women who used HRT < or = 5 years and 1.06 (95% CI 0.78-1.46) in women who used HRT > 5 years. The adjusted HR for coronary heart disease (CHD) mortality in women who used HRT < or = 5 years was 0.79 (95% CI 0.36-1.73), and in women who used HRT > 5 years, 2.16 (95% CI 0.93-4.98). For breast cancer mortality the adjusted HR for < or = 5 years of HRT use was 0.96 (95% CI 0.32-2.82) and 2.62 (95% CI 0.98-7.00) for > 5 years of HRT use. CONCLUSIONS: History of HRT use does not affect overall or CHD mortality in women. More than 5 years of HRT use may increase the risk of breast cancer mortality.

Fracture risk and bone density of peri- and early postmenopausal women with uterine leiomyomas.

OBJECTIVES: Fracture risk and bone mineral density (BMD) among peri- and early postmenopausal women with leiomyomas requiring hysterectomy was evaluated. METHODS: We counted fractures among women with or without leiomyomas using data from the Kuopio Osteoporosis Study. The study population consisted of 6086 women aged 47-56 years with never-use of hormone replacement therapy (HRT) responding to the baseline and 5-year follow-up inquiries. Part of the sample (n=1271) underwent bone densitometry. RESULTS: Hysterectomy was carried out in 927 women, and 59% reported that this was attributable to leiomyomas. The hazard ratio (HR) was 0.68 (95% CI 0.49-0.94) for any and 0.73 (95% CI 0.43-1.26) for distal forearm fracture among women with leiomyomas compared to those without any. Among women postmenopausal at baseline, the corresponding HRs were 0.62 (95% CI 0.44-0.87) and 0.54 (95% CI 0.31-0.96); after adjusting for age, time since menopause weight, height and previous fracture 0.69 (95% CI 0.49-0.97) and 0.63 (95% CI 0.35-1.11). The baseline BMDs were 1.15 g/cm2 among hysterectomized leiomyoma and 1.12 g/cm2 (ns) among non-hysterectomized women at lumbar (L2-L4), and 0.94 and 0.93 g/cm2 (ns) at femoral sites. The follow-up lumbar BMDs were 1.13 and 1.09 g/cm2 (p<0.001) and the corresponding femoral values were 0.90 and 0.89 g/cm2 (ns), respectively. Among postmenopausal women, the corresponding baseline lumbar BMDs were 1.15 and 1.08 g/cm2 (p<0.001), femoral 0.93 and 0.90 g/cm2 (p=0.003); the follow-up lumbar BMDs 1.13 g/cm2 versus 1.07 g/cm2 (p<0.001); femoral BMDs 0.89 versus 0.87 (ns). CONCLUSIONS: Peri- and early postmenopausal women with a history of leiomyomas seem to have better BMD and less fractures compared with those without leiomyomas. This may be mediated through higher estrogen levels leading to higher BMD and the growth of leiomyomas.

Leucine7 to proline7 polymorphism in prepro-NPY gene and femoral neck bone mineral density in postmenopausal women.

Neuropeptide Y (NPY) is a versatile neurotransmitter that has recently been shown to regulate bone metabolism in animal and in vitro studies. We studied the influence of leucine7-to-proline7 (Leu7/Pro7) polymorphism of the NPY signal peptide gene on bone mineral density (BMD) before and after a 5-year hormone replacement therapy (HRT) in 316 early postmenopausal women participating in a randomized controlled trial nested in the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study. The participants were randomized into two treatment groups: the HRT group (n = 146) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate and calcium lactate, 500 mg/day (equal to 93 mg Ca2+) alone or in combination with vitamin D3, 100-300 IU/day. The non-HRT group (n = 170) received calcium lactate, 500 mg alone or in combination with vitamin D3, 100-300 IU/day. BMDs of the lumbar spine (L2-4) and proximal femur were measured by using dual X-ray absorptiometry (DXA). The frequency of Leu7/Pro7 polymorphism was 15.2%. At baseline, there were no significant differences in the lumbar or femoral neck BMD between the subjects who had Leu7Pro7 polymorphism and the normal subjects. After 5 years, the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7% in the HRT group, whereas both BMDs were decreased by 4-5% in the non-HRT group. After 5 years, the femoral neck BMD was significantly lower in those with the wild-type NPY polymorphism than in those with Leu7/Pro7 polymorphism (P = 0.040) in the non-HRT group. In the HRT group, the changes in BMD were quite modest and not significantly modified by Leu7/Pro7 genotype. We conclude that the Leu7/Pro7 polymorphism in NPY signal gene may favorably affect femoral neck BMD in postmenopausal women.

Factors affecting bone loss around menopause in women without HRT: a prospective study.

OBJECTIVES: The present study evaluated the effects of menopause and other putative bone loss modifying factors on bone mineral density (BMD) change. METHODS: The study population, 396 healthy women aged 48-59 years with no history of hormone replacement therapy (HRT) use or any bone affecting disease or medications, was selected from a random sample (n=2025) of the OSTPRE-study cohort (n=13100) in Kuopio, Finland. BMD at lumbar spine (LS) and three areas of proximal femur (femoral neck (FN), Ward's triangle (W), trochanter (T)) was measured with dual X-ray absorptiometry at baseline in 1989-1991 and at 5 years in 1994-1997. RESULTS: 116 women who reported the beginning of menopause during the follow-up (perimenopausal) had the greatest mean annual bone loss (-1.22%/year (LS), -0.87% year (FN), -1.14%/year (W), -0.36%/year (T)). In women under 5 years postmenopausal at baseline (early postmenopausal, n=172) bone loss rate was significantly lower than in perimenopausal women. In women over 5 years postmenopausal at baseline (late postmenopausal, n=108) bone loss rate was significantly further decreased only at lumbar spine. In peri- and postmenopausal women the annual BMD change was best described as a trinomial function of the duration of menopause at all sites (P<0.03). Of the life-style factors studied protective effects were found in weight increase in both spinal and femoral bone (P=0.010/P<0.001), high baseline weight in spine (P<0.001) and high grip strength in femoral neck (P=0.002). CONCLUSION: The beginning of menopause is accompanied by significant bone loss, which decreases in later menopause. Few other physiological and life-style factors were found to significantly contribute to this phenomenon.