Bone mineral density and its determinants in diabetes: the Fremantle Diabetes Study

Aims/hypothesis We assessed the effects of type 1 and type 2 diabetes on bone density and metabolism.Materials and methods We analysed bone mineral density (BMD) measured at the hip, spine and forearm using dual energy X-ray absorptiometry in 34 patients with type 1 and 194 patients with type 2 diabetes. Patients were from the community-based Fremantle Diabetes Study, and findings for them were compared with those from normal age- and sex-matched control subjects from the local community. Biochemical and hormonal markers of bone metabolism were measured in a subset of 70 patients.Results After adjusting for age and BMI, there was a lower BMD at total hip (p<0.001) and femoral neck (p=0.012) in type 1 men vs control subjects, but type 1 women and matched controls had similar BMD at each site. There was a higher BMD at total hip (p=0.006), femoral neck (p=0.026) and forearm (p<0.001) in type 2 women vs control subjects, but diabetes status was not associated with BMD in type 2 men after adjustment for age and BMI. Serum oestradiol, BMI, C-terminal telopeptide of collagen type 1 and male sex were consistently and independently associated with BMD at forearm, hip and femoral neck and explained 61, 55 and 50% of the total variance in BMD, respectively, at these sites. Spine BMD was independently associated with BMI and ln(oestradiol).Conclusions/interpretation Men with type 1 diabetes may be at increased risk of osteoporosis, while type 2 women appear to be protected even after adjusting for BMI. Low serum oestradiol concentrations may predispose to diabetes-associated osteoporosis regardless of sex.     

THE EFFECT OF OESTROGEN PRETREATMENT ON SUBSEQUENT RESPONSE TO LUTEINIZING HORMONE RELEASING HORMONE IN NORMAL WOMEN

Twenty-two normal, regularly menstruating female subjects had an LHRH test performed before and after pretreatment with 0.5 mg, 1 mg or 2.5 mg of oestradiol benzoate during the follicular phase of their menstrual cycles (days 4–8). Two further women acted as controls and received no oestrogen; they showed identical responses for both LH and FSH release when LHRH tests were performed at intervals of 48 h. Oestrogen pretreatment induced a biphasic effect upon subsequent LHRH response. Four subjects retested 20 h after 0.5 mg oestradiol benzoate showed either no change or a slight suppression of LH and FSH release. Fifteen of the eighteen women pretreated with oestradiol benzoate and retested 44 h later showed significantly increased LH release and fourteen significantly increased FSH release when compared to their control responses. The responses appeared to be dose related with a positive correlation between sum of LH increments and basal oestradiol levels (r= 0.61; P<0.001) and a similar correlation (r= 0.67; P<0.001) between sum of FSH increments and basal oestradiol levels. The physiological significance of this biphasic action of oestrogen upon pituitary sensitivity is discussed in relation to the control of the menstrual cycle.     

Serum testosterone and its relation to bone mineral density and body composition in normal males

OBJECTIVE Bone mineral density (BMD) declines with age in both men and women, predisposing the elderly to osteoporosis and fractures. Although there are extensive data about post-menopausal osteoporosis, there is relatively little information concerning the decrease in BMD with age in normal men, particularly the contribution of declining gonadal function with age to BMD. In the present study, we investigated the effect of age on the pituitary-gonadal axis in normal males and its relation to BMD and body composition. SUBJECTS Ninety healthy Thai males in the Bangkok Metropolitan area without a history of smoking or significant alcohol consumption were studied. MEASUREMENTS Serum testosterone (T), free testosterone (FT), LH and FSH were measured by radioimmunoassay in fasting blood samples obtained In the morning between 0600 and 1000h. BMD at anteroposterior L2-L4, lateral L2-L4, femoral neck, femoral trochanter and Ward's triangle were determined by dual-energy X-ray absorptiometry. RESULTS There were significant declines with age in BMD at lateral L2-L4 (r= 0.37, P < 0.001), femoral neck (r=?0.49, P<0.0001), Ward's triangle (r=?0.54, P < 0.0001) but not at anteroposterior L2-L4 or femoral trochanter. Serum FT (r=?0.56, P < 0.0001) but not T (r=?0.19, P= 0.07) decreased with age. Serum LH (r= 0.27, P <0.001) and FSH (r= 0.4, P <0.0001) increased with age suggesting a defect in gonadal androgen synthesis or possibly a secretion of bioinactive LH. Serum FT concentrations were significantly correlated to lateral L2-L4 (r= 0.27, P<0.05), femoral neck (r= 0.48, P < 0.0001) and Ward's triangle (r= 0.50, P < 0.0001) BMD. After controlling for age, declining FT with age was still associated with a decrease In BMD in femoral neck (P < 0.05) and Ward's triangle (P < 0.05) but not in lateral L2-L4. The proportion of body fat increased with age (r= 0.3, P < 0.01). Decreased serum T, but not FT, was associated with increased body fat after age was taken into account (P < 0.0001). CONCLUSIONS There is a decline in serum free testosterone together with increases In LH and FSH with age In healthy males. The decrease in serum free testosterone Is partially associated with the age-related decline in bone mineral density added to the effect of age at the femoral neck and Ward's triangle. Testosterone but not free testosterone Is associated with age-related increase in body fat.     

Glucocorticoid replacement therapy is independently associated with reduced bone mineral density in women with hypopituitarism

Objective Patients with hypopituitarism have adverse cardiovascular morbidity and reduced bone mineral density (BMD). The objective of this study was to analyse the effects of glucocorticoid (GC) replacement on cardiovascular risk factors and BMD in patients with hypopituitarism. Design, patients and methods This was a cross‐sectional study on 365 patients with hypopituitarism. Two‐hundred and four patients (56%) were ACTH insufficient (ACTHins), receiving a mean ± SD hydrocortisone equivalent (HCeq) dose of 20·5 ± 5·8 mg/day. The difference in BMD and cardiovascular risk profile between ACTH sufficient (ACTHsuff) and ACTHins patients, before commencement of GH replacement, was analysed by multiple linear and logistic regression. Results ACTHins was independently associated with lower fasting glucose but not other cardiovascular risk factors. The mean HCeq dose per kg body weight was 15% higher in ACTHins women than in ACTHins men (P = 0·009). In women, ACTHins was independently associated with decreased BMD at the lumbar spine (P = 0·002) and femoral neck (P = 0·006) and the presence of osteopenia (P = 0·004). BMD was not different between ACTHins and ACTHsuff men. Conclusion The current average HCeq dose of approximately 20 mg per day is not associated with an adverse metabolic profile, as compared with ACTHsuff patients with hypopituitarism. GC replacement in ACTHins women is independently associated with reduced BMD and higher prevalence of osteopenia.     

Interindividual differences in the pituitary-thyroid axis influence the interpretation of thyroid function tests

OBJECTIVE The objective of this study was to investigate serial changes in the plasma concentration of inhibin in both the very early days of pregnancy following implantation and in late pregnancy. The timing of the changes in inhibin concentration relative to changes in the concentrations of other hormones of pregnancy was also investigated. DESIGN Serial observations of the peripheral concentrations of inhibin and other hormones in two groups of healthy volunteers in (a) early pregnancy and (b) late pregnancy. PATIENTS (a) Four healthy women recruited on cessation of contraception prior to conception. (b) Nine healthy women recruited at the antenatal clinic. MEASUREMENTS In the early pregnancy subjects, the concentrations of inhibin, progesterone, oestradiol and hCG were measured in plasma samples obtained three times per week from day 8 to day 10 of each menstrual cycle until 11 weeks after the last menstrual period in the conception cycle. In the late pregnancy subjects, plasma samples were obtained at 4-week intervals from 12 weeks until term. RESULTS The concentration of inhibin, progesterone and oestradiol in conception cycles were similar to those in the preceding cycles until the mid/ to late-luteal phase of the cycle when hCG was first measurable. By day 12 of the luteal phase the concentration of inhibin was significantly higher in the pregnancy cycle than in the non-pregnancy cycle (P > 0.05) and progressively increased after the time of the missed menstrual period. The concentration of inhibin reached a peak (513.0 U/I, CI 442.1–595.3) by day 47 when the concentration of hCG was maximal. In early pregnancy the concentration of inhibin was correlated with that of hCG (r= 0.361; P>0.01) as well as progesterone (r= 0.584, P>0.001) and oestradiol (r= 0.602. P>0.001). After 12 weeks there was no significant correlation between hCG and lnhibin although significant correlations persisted with progesterone (r= 0.553, P>0.001) and oestradiol (r= 0.361, P>0.01). CONCLUSIONS The corpus luteum makes a significant contribution to the production of inhibin in early pregnancy while after 12 weeks the placenta is the major source.     

Bone mineral density in women with systemic lupus erythematosus

The aim of this cross-sectional study was to determine the prevalence of reduced bone mineral density (BMD) in a group of female SLE patients and to identify factors predictive of reduced BMD. Femoral neck (FN) and lumbar spine (LS) dual-energy X-ray absorptiometry results were evaluated in 79 pre- and postmenopausal women with SLE aged (mean, range) 49 (22–73) years). Variables evaluated were disease duration, SLEDAI, current and cumulative corticosteroid dose, Steinbrocker’s functional classification, use of immunosuppressive agents, and history of fracture due to minor trauma. A T-score of ≤1.0 was found in 61.9% at the LS and 48.3% at the FN, and 18 (23.7%) patients belonged to the category of osteoporosis at LS, compared to only three (5.4%) patients at FN. A statistical difference (P= 0.014) was found when comparing LS BMD in pre- and postmenopausal patients. LS BMD had a significant correlation with daily and cumulative steroid dose (P= 0.016 and 0.031, respectively). There was a significant difference in LS BMD between the daily steroid dose group receiving ≤7.5 and those receiving >7.5 mg/day (P= 0.008), and also in FN BMD comparing groups on 0 and >7.5 mg/day (P= 0.022). There was significant difference in LS and FN BMD between patients in Steinbrocker classes I and III (P= 0.016 and 0.005, respectively). No significant correlation was found in either subgroup between BMD and other studied parameters. We concluded that the prevalence of reduced bone mass at LS is pronounced among postmenopausal women with SLE, in those with a high Steinbrocker functional classification and those on a high daily steroid dose. Therefore, these patients should be considered as a high-risk group deserving regular spinal BMD scans and therapy in time to prevent vertebral fractures. Received: 26 March 2000 / Accepted: 18 September 2001     

Changes in dimeric inhibin A and B during normal early puberty in boys and girls

OBJECTIVE Although recently developed specific and sensitive assays of bioactive dimeric inhibin A and B have given new insights into the pituitary-gonadal axis in adult men and during the adult female menstrual cycle, there have been no reports on circulating inhibin A and B during normal human puberty. The aim of this study was to assess the relationship of dimeric inhibin A and B to pubertal stage, FSH and testosterone or oestradiol in late prepuberty and in early puberty. STUDY DESIGN AND SUBJECTS Serial samples were collected during a prospective longitudinal trial of GH treatment in short normal children. Seven boys were studied from late prepuberty to genital stage 3, and six pre-menarche girls from late prepuberty to breast stage 4. MEASUREMENTS Dimeric inhibin A (girls only) and inhibin B (boys and girls) were measured by highly specific and sensitive two-site ELISAs, FSH by IRMA, testosterone and oestradiol by RIA. RESULTS In boys, inhibin B increased progressively from pubertal stages 1 to 3 (ANOVA P<0.0001) and correlated strongly with mean testicular volume (r=0.72, P=0.0005). Prepubertal boys showed a positive correlation between inhibin B and FSH (r=0.65, P=0.056), whereas pubertal boys gave a strong negative correlation (r=0.75, P=0.012). In both prepubertal and pubertal boys positive correlations were observed between inhibin B (y) and testosterone (x) (r=0.81, P=0.008 and r=0.62, P=0.054 respectively), but the slope of the regression line between the two was much steeper before than after the onset of clinical puberty. In girls, both inhibin A and B increased through pubertal stages 1–4 (ANOVA P=0.01 and P=0.047 respectively). Both showed strong positive correlations with oestradiol (r=0.80 and 0.79, P=0.001) and with FSH (r=0.83, P=0.0004 and r=0.80, P=0.001). Inhibin A and B were also strongly correlated with each other (r=0.92, P=0.0001). CONCLUSIONS In boys, testicular production of inhibin B increases as puberty progresses. Our results show for the first time that the initiation of puberty is accompanied by a dramatic switch from a positive to a negative relation between inhibin B and FSH as inhibin B begins to exert the expected negative feedback on FSH. The results in girls suggest that, prior to menarche, the ovarian follicles produce inhibin A and B in strict proportion, and in progressively greater amounts as puberty proceeds. Measurement of dimeric inhibin A and B may provide a sensitive new tool for determining gonadal maturity in late prepuberty and early puberty.     

Leptin is an independent determinant of bone mineral density in men with type 2 diabetes mellitus

To investigate the possible relationship of leptin to bone mineral density (BMD) in men with type 2 diabetes mellitus (T2DM), we screened 168 Belarusian men aged 45–65 years. Plasma total cholesterol (TC), high-density lipoprotein cholesterol, and triglyceride concentrations were assessed, and low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol (LDL-C) were calculated. Hemoglobin A_1c, immune-reactive insulin (IRI), serum total testosterone, and sex hormone-binding globulin were also evaluated. BMD was evaluated using dual-energy X-ray absorptiometry. By univariate linear regression analysis, BMD was significantly correlated with body mass index (r = 0.23, P = 0.002) and leptin (r = 0.21, P = 0.006). By multivariate regression analysis adjusting for confounding factors, log leptin was independently correlated with BMD (β = 0.058, P = 0.001). Our study revealed that leptin is an independent determinant of BMD in patients with T2DM. Further research is necessary to confirm this association and to develop ways to correct abnormalities of bone metabolism in patients with T2DM.     

The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B

Haemophilia A and B have been associated with increased prevalence of low bone mineral density (BMD). However, the utility of bone turnover markers (BTM) remains unknown. The aim of this study was to evaluate bone metabolism in men with haemophilia and to investigate associations between BTM and bone disease. Serum N‐ (NTX‐I), C‐terminal telopeptide of type I collagen (CTX‐I) and tartrate‐resistant acid phosphatase band‐5b (TRAP‐5b), as bone resorption markers, and osteocalcin (OC) and bone‐specific alkaline phosphatase (b‐ALP), as bone formation markers, were assessed. Seventy men with haemophilia A (n = 59) or B (n = 11) were studied. Patients with low BMD had significantly higher b‐ALP concentrations compared with those with normal BMD (12.8 ± 1.60 vs. 9.72 ± 0.58 μg/L, P = 0.009), without any differences in the other BTM. NTX‐I and CTX‐I concentrations were negatively associated with oestradiol levels and hip BMD and positively with human immunodeficiency virus infection, number of affected joints and arthropathy scores. B‐ALP and OC concentrations were negatively associated with hip BMD, severity of haemophilia and fracture history, and positively with the number of affected joints and testosterone concentrations. After multivariate analysis, NTX‐I levels remained negatively associated with oestradiol levels, whereas b‐ALP concentrations negatively correlated with the level of physical activity and positively with the number of affected joints. Increased bone metabolism exists in men with haemophilia and low BMD. Increased b‐ALP levels may identify patients at high risk for fracture. Increased number of target joints, low physical activity and low oestradiol concentrations are independently associated with increased bone metabolism.     

The gender differences in growth hormone-binding protein and leptin persist in 80-year-old men and women and is not caused by sex hormones

OBJECTIVE: Leptin and growth hormone-binding protein (GHBP) both show gender differences that might be explained by sex hormones. To study the potential relevance of oestradiol and testosterone, we have examined 80-year-old subjects in whom oestradiol is higher in men than in women. The interrelationships between leptin, insulin, GHBP and fat mass in this age group were also investigated. DESIGN AND SUBJECTS: Ninety-four subjects (55 females and 39 males), all 80 years old, were investigated in a community-based study. None of the investigated subjects was being treated for diabetes mellitus and none of the women had oestrogen replacement. METHODS: Levels of testosterone, oestradiol, SHBG, IGF-I, GHBP, glucose, insulin and leptin were analysed. Body composition was measured with bioimpedance analysis (BIA). RESULTS: As in younger age groups, serum leptin, the ratio leptin/kilogram fat mass and serum GHBP were higher in the women (all, P< or =0.007), although serum oestradiol was higher in the men (P<0.001). There were no significant associations between sex hormones and leptin or GHBP either in women or in men (all, r<0.13, P>0.1). Leptin correlated to kilogram fat mass in both women (r=0.55, P<0.001) and men (r=0.47, P=0.003), but in contrast, there were no significant correlations between GHBP and fat mass and GHBP and IGF-I, either in women or in men (all, r<0.24, P>0.2). Insulin and leptin were significantly associated with GHBP, both in women (r=0.48, P<0.001 and r=0.43, P=0.001, respectively) and in men (r=0.40, P=0.01 and r=0.34, P=0.03, respectively). CONCLUSIONS: Although the 80-year-old men had higher oestradiol levels than the women, the women had higher levels of leptin and GHBP. There were no correlations between sex hormones and leptin and GHBP, which indicates that the gender differences are not caused by sex hormones in old age. In contrast to studies in younger subjects, GHBP did not correlate to fat mass in the investigated 80-year-old men and women. In the older subjects investigated, as in younger subjects, GHBP was significantly correlated with leptin and insulin.     

Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover

Background The aim of this exploratory study was to establish whether we could improve skeletal health with a physiological regimen of SSR in young women with premature ovarian failure (POF). Patients and Methods In an open‐label randomized controlled crossover trial, 34 women with POF were randomized to 4‐week cycles of pSSR (transdermal oestradiol, 100 μg daily for week 1, 150 μg for weeks 2–4; vaginal progesterone, 200 mg twice daily for weeks 3–4) or standard hormone replacement treatment (sHRT) (oral ethinyloestradiol 30 μg and 1·5 mg norethisterone daily for weeks 1–3, week 4 ‘pill‐free’) for 12 months. Bone mineral density (BMD) was measured by DEXA at study entry and after each 12‐month treatment period. Blood samples for hormones and markers of bone formation (bone alkaline phosphatase, BALP and type I collagen N‐terminal propeptide, PINP) and bone resorption (CrossLaps) were collected pre‐/postwashout and after 3, 6 and 12 months of each treatment. Results Eighteen women, mean 27 (range 19–39) years, completed the study. Both regimens caused similar suppression of LH and FSH. Mean baseline lumbar spine BMD z‐score was ?0·89 (95% CI ?1·27 to ?0·51) and increased by +0·17 (CI +0·07 to +0·27) in response to pSSR (P = 0·003), compared with +0·07 (CI ?0·03 to +0·18) during standard HRT (P = 0·2). During pSSR, the increment in lumbar spine BMD z‐score was related positively to oestradiol (r = +0·49, P = 0·04) and inversely to FSH (r = ?0·65, P = 0·004). Bone formation markers, BALP and P1NP increased in the pSSR arm (anova P < 0·001) but decreased in the sHRT arm (P < 0·01). Both treatments suppressed the bone resorption marker, CrossLaps (P < 0·001). Conclusion We conclude that pSSR over 12 months has a beneficial affect on bone mass acquisition on the lumbar spine in women with POF, mediated by increased bone formation and decreased bone resorption.     

Relationship of sex steroid hormones with bone mineral density (BMD) in a nationally representative sample of men

Objective Sex steroid hormones influence bone mineral density (BMD) in women, but are less well‐studied in men. We evaluated the association of serum total and free sex steroid hormones and SHBG with osteopaenia in a nationally representative sample of men aged 20–90 years. Design BMD and sex steroid hormones were measured among participants in NHANES III, a cross‐sectional study of the US population. Population A total of 1185 adult men in morning examination session of Phase I of NHANES III (1988–91). Measurements Relation of oestradiol (E₂), testosterone, and SHBG concentrations with BMD. Osteopaenia was defined as 1–2·5   SD below the mean for white men aged 20–29 years. Results Men in the lowest quartile of free E₂ had 70% increased odds (OR = 1·69, 95% CI 0·95–2·98) of osteopaenia compared with men in the highest quartile. Men in the lowest quartile of free testosterone had nearly four times the odds of osteopaenia than those in the highest quartile (OR = 3·82, 95% CI 1·87–7·78). Lower concentrations of SHBG appeared protective against osteopaenia (P‐trend = 0·01). Neither total testosterone nor total E₂ was associated with BMD, although men with clinically low E₂ (< 20 ng/l) had lower BMD (0·930 g/cm², 95% CI 0·88–0·98) than men with normal‐range E₂ (1·024 g/cm², 95% CI 1·01–1·04; P = 0·004). Findings for free E₂ were most pronounced among elderly men, while the findings for free testosterone were most pronounced among younger men. Conclusions In this nationally representative study, men with lower free E₂, lower free testosterone, and higher SHBG concentrations in circulation were more likely to have low BMD.     

Cardiac flow velocity in women with the polycystic ovary syndrome

OBJECTIVE Women with the polycystic ovary syndrome (PCOS) often have several of the known risk factors for cardiovascular disease, including hyperinsulinaemia. We have therefore investigated variables of cardiac flow in young women with PCOS and related them to blood levels of reproductive hormones (LH, FSH, oestradiol and testosterone) and also of insulin. DESIGN A prospective study. PATIENTS Twenty-six young women with PCOS (mean age 22.8 ± 0.9 years; mean BMI 23.0 ± 0.8) and 11 healthy age matched women with regular ovulatory cycles (mean age 26.3 ± 1.7 years; mean BMI 22.9 ± 0.9). MEASUREMENTS Cardiac flow was measured by pulsed wave Doppler echocardiography in the follicular phase of the cycle in controls and oligomenorrhoeic women; there was no special timing for amenorrhoeic women. The indicators assessed were: ejection fraction (EF), pre-ejection time (PEP), ejection time (ET), peak systolic flow velocity (PFV), acceleration time (AT), flow velocity integral (FVI), mean acceleration (MA), diastolic time (DT), early diastolic filling time (EI), atrial filling time interval (AI), peak velocity of the early diastolic filling (PE) and peak velocity of the atrial filling (PA). Serum LH, FSH, oestradiol, testosterone, SHBG and insulin concentrations were analysed by standard RIA. RESULTS Significantly lower PFV (1.055 ± 0.025 vs 1.242 ± 0.054, P= 0.0006) and MA (17.06 ± 0.57 vs 23.00 ± 1.49, P= 0.0001) and longer AT (0.063 ± 0.001 vs 0.056 ± 0.004, P= 0.026) were found in women with PCOS as compared to age matched controls. Significant negative correlation between serum fasting insulin concentration and EF (r=-0.725, P= 0.002), PFV (r=?0.719, P= 0.0025), FVI (r=?0.654, P= 0.003) and MA (r=?0.757, P= 0.001) was observed In the 15 women with PCOS in whom insulin was measured. CONCLUSION An inverse relation between serum fasting insulin level and left ventricular systolic outflow parameters suggests that insulin is associated with the decreased systolic flow velocity observed in women with PCOS.     

Reduced bone mineral density in Japanese premenopausal women with systemic lupus erythematosus treated with glucocorticoids

We evaluated bone mineral density (BMD) in Japanese female patients with systemic lupus erythematosus (SLE) and assessed the influence of the use of glucocorticoids. Lumbar BMD was measured by dual x-ray absorptiometry (DXA) in 60 premenopausal females who previously had been receiving glucocorticoid therapy. Therapeutic- and disease-related variables for SLE were analyzed and bone resorption or formation markers were measured. Osteoporosis was defined as a T-score below 2.5 SD by DXA; 12 patients (20%) showed osteoporosis, and 30 (50%) had osteopenia. Compared with the nonosteoporotic group (n = 48), the osteoporotic group (n = 12) had a significantly longer duration of glucocorticoid treatment (P = 0.01), a cumulative prednisolone dose (P = 0.002), and an SLE damage index (SLICC/ACR). There was no difference in the incidence of osteoporosis either with or without the previous use of methyl-prednisolone pulse or immunosuppressive drugs. There was a significant positive correlation between urinary type I collagen cross-linked N-telopeptides (NTx) and serum bone-specific alkaline phosphatase (BAP) (r = 0.404, P = 0.002), but these bone metabolic markers showed no difference between the osteoporotic and nonosteoporotic groups. A good significant negative correlation was shown between BMD and the cumulative glucocorticoid dose (r = −0.351, P = 0.007). Stepwise logistic regression analysis showed that the cumulative glucocorticoid intake was independently associated with osteoporosis. Glucocorticoid-induced osteoporosis was frequently observed in Japanese SLE patients, as in Caucasian populations. The cumulative glucocorticoid dose was associated with an increased risk for osteoporosis. Bone metabolic markers such as NTx and BAP were not influenced by glucocorticoid treatment and could not predict current osteoporosis in SLE patients. Received: October 18, 2001 / Accepted: April 8, 2002 Correspondence to:S. Banno     

Relationships between muscle strength and bone mineral density of three body regions in sedentary postmenopausal women

This cross-sectional study was designed to investigate correlations between muscle strength and regional bone mineral density (BMD) in sedentary postmenopausal women. Sixty-two women who ranged in age from 41 to 76 years were investigated. Hip and trunk muscle strength was measured by isokinetic dynamometry. Grip strength of the nondominant hand was measured using a hand-held dynamometer. Bone mineral density of the lumbar spine, femur, and distal radius was measured by dual-energy X-ray absorptiometry. Only the correlation between hip abductor strength and femoral BMD was significant (P=0.009, r=0.327). There was no correlation between trunk muscle strength and lumbar vertebral BMD or between grip strength and distal radius BMD. Subjects with osteoporosis (T score <–2.5) or osteopenia T (–2.5 to –1) and normal subjects (T>–1) exhibited similar isokinetic hip and trunk muscle strength. Women with osteoporotic distal radii had significantly lower grip strength than subjects who were osteopenic or normal at this site, but the osteoporotic group was also significantly older. In conclusion, our results indicate that the isokinetic strength of hip abductors weakly correlates with femoral BMD in postmenopausal women with and without osteoporosis. Trunk muscle strength did not correlate with lumbar vertebral BMD in either of these groups. The weaker handgrip we observed in the women with osteoporotic radii may be attributed to older age.     

Serum fasting cortisol in relation to bone, and the role of genetic variations in the glucocorticoid receptor

Objective To examine the relationship between endogenous cortisol and bone, and the role of genetic variations in the glucocorticoid receptor (GR). Design and patients The Longitudinal Ageing Study Amsterdam (LASA), a population‐based cohort study in older men and women. Measurements Serum fasting cortisol was assessed by competitive immunoassay (n = 1214); bone mineral density (BMD) by dual X‐ray absorptiometry (DXA) (n = 502); broadband ultrasound attenuation (BUA) by ultrasound (n = 1209); fractures by self‐report (n = 1211); and GR gene polymorphisms (ER22/23EK, N363S, 9beta, BclI) were genotyped by Taqman (n = 858). Results Higher serum fasting cortisol was significantly associated with lower BMD at all sites and BUA at the heel in women, although most relationships were attenuated by age and body mass index (BMI). The effect on femoral neck BMD remained statistically significant in the fully adjusted model (r = –0·135, P = 0·04). No significant associations in men were found. Female 9beta G‐allele carriers had 50·2 nmol/l lower cortisol and 1·2 lower free cortisol levels than AA homozygotes [P = 0·01 for (free) cortisol]. Furthermore, female BclI GG homozygotes had 54·8 nmol/l higher cortisol levels than C‐carriers (P = 0·03). In the total population, BclI GG homozygotes had 0·05 g/cm² lower trochanteric region BMD (P = 0·03). For the other GR gene polymorphisms, no significant associations were found. Conclusions Higher cortisol levels are associated with lower femoral neck BMD in elderly women. The G allele of the 9beta polymorphism was associated with lower serum cortisol levels in women. Female BclI GG homozygotes had higher serum cortisol levels, and BclI GG homozygotes had lower trochanteric region BMD in the total population.     

The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis

The objective of this study is to investigate the relationship between soluble components of the interleukin 6 (IL-6) system mediating and modifying IL-6 trans-signaling and the RANKL–RANK–osteoprotegerin system in postmenopausal women with rheumatoid arthritis (RA). The following parameters were investigated in 126 postmenopausal women with RA: IL-6, soluble IL-6-receptor (sIL-6R), soluble glycoprotein 130 (sgp130), sRANKL, osteoprotegerin (OPG), osteocalcin, erythrocyte sedimentation rate and C-reactive protein in sera, pyridinolin and desoxypyridinolin crosslinks in the morning urine. Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN). Predictors of RANKL/OPG ratio and BMD were evaluated by multiple linear regression analysis. The following determinants of the RANKL/OPG ratio were identified: sIL-6R/sgp130 ratio and daily glucocorticoid (GC) dose as positive determinants in the whole group (R ² = 0.56; P = 0.001), sIL-6R/sgp130 ratio as the exclusive positive determinant in patients with GC therapy (R ² = 0.48; P = 0.001) and sgp130 as negative determinant in patients without GC (R ² = 0.42; P = 0.031). Sgp130 was highly significantly positively correlated with OPG in the whole group (P < 0.001) as well as in patients with (n = 70; P < 0.05) and without GC therapy (n = 56; P < 0.01). sIL-6R was the main negative predictor of BMD-LS (R ² = 0.41; P = 0.019). High sIL-6R/sgp130 ratio and/or low sgp130 are associated with a high sRANKL/OPG ratio in sera of postmenopausal women with RA indicating the critical significance of IL-6 trans-signaling for an increase in the RANKL/OPG ratio and of bone resorption. Inhibition of IL-6 trans-signaling may be an effective bone-protecting principle in postmenopausal women with RA.     

THE CONTROL OF GONADOTROPHIN RELEASE IN WOMEN WITH HYPERPROLACTINAEMIC AMENORRHOEA: EFFECT OF OESTROGEN AND PROGESTERONE ON THE LH AND FSH RESPONSE TO LHRH

The effect of the administration of oestradiol benzoate and of progesterone on the subsequent response to LHRH has been investigated in women with hyperprolactinaemia. There was an amplification in the release of LH in four out of ten patients and of FSH in one out of ten patients at 44 h after the administration of 2·5 mg oestradiol benzoate. The average amount of LH released before and after oestrogen did not change, but there was a significant decrease in the amount of FSH released. There was no correlation between the LH released and the oestradiol concentration in serum at the time of the LHRH tests but there was a negative correlation between the FSH released and the oestradiol concentration (r= 0.507; P < 0.05). These results contrast with those obtained in normal subjects in the follicular phase of the cycle when there is a positive correlation of oestrogen concentrations and the amount of LH and FSH released. As in normal subjects, bowever, a significant suppression of basal FSH concentrations, persisting until 44 h, was produced by the oestrogen (P < 0.01). Seven out of eleven patients showed an amplification of LH response and six out of eleven an FSH response 20 h after the administration of 25 mg progesterone. The mean amplifications are not significantly different from those of normal subjects tested in the early follicular phase of the cycle, but are significantly less than those tested in the mid follicular phase of the cycle (LH P < 0.001; FSH P < 0.01). This may be related to the serum concentrations of oestradiol which in patients with hyperprolactinaemia are significantly less than those found in the mid follicular phase of the cycle (P < 0.05). These results indicate that in women with hyperprolactinaemia oestrogen negative feedback, necessary for cycle initiation, is normal: failure of ovulation may be related to failure of positive feedback to oestrogen. Oestrogen-negative feedback is unopposed and this may explain the follicullar development and lack of oestrogen in the mid-follicular phase.     

Continuous combined oestrogen/progestin therapy is well tolerated and increases bone density at the hip and spine in post-menopausal osteoporosis

OBJECTIVES Although oestrogen/progestin therapy is effective prophylaxis against post-menopausal osteoporosis, its efficacy in the treatment of established disease is uncertain. In addition, cyclical oestrogen/progestin regimens are associated with low rates of patient acceptance. The present study assesses the acceptability of, and skeletal response to, continuous combined hormone replacement therapy in osteoporotic late post-menopausal women. DESIGN Retrospective, controlled study. PATIENTS One hundred and four osteoporotic late postmenopausal women treated with continuous combined hormone replacement therapy (5 mg medroxyprogester-one acetate daily and either 0·625 mg oral conjugated oestrogens or 50 μg transdermal oestradiol daily) were followed for an average of 1 year (range 2–38 months). Control subjects were 19 healthy normal women matched for menopausal age and weight. MEASUREMENTS Adverse effects and compliance rate were monitored. Baseline and 1-year measurements of lumbar spine bone mineral density (BMD) were performed using dual-energy X-ray absorptiometry in 51 women, 22 of whom also had measurements at 2 years. Twenty-eight women had proximal femur scans at baseline and 1 year. RESULTS Eighty-six per cent of women continued to take continuous combined hormone replacement therapy at the end of follow-up. Mastalgia (44%) and vaginal bleeding (29%), the most common side-effects, were minor and self-limiting in virtually all women. Spinal BMD increased by 7·1 ± 0·8% (mean±SEM P < 0·001) at 1 year and by 8·9 ± 1·5% (P < 0·001) at 2 years. In the proximal femur, BMD increased by 2·9 ± 0·9% at the femoral neck (P= 0·01) and by 2·5±0·9% (P= 0·001) at the trochanter at 1 year. BMD tended to decline in the control group. Among the women taking hormone replacement therapy, the increase in spinal BMD was similar in those treated with 0·3–0·44 mg/day of conjugated equine oestrogens to those receiving 0·45–0·625 mg/day. CONCLUSION Continuous combined hormone replacement therapy is an acceptable therapy to osteoporotic late post-menopausal women and produces substantial increases in lumbar spine and proximal femoral bone mineral density.