Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism

Background Primary hyperparathyroidism (PHPT) is associated with reduced bone mineral density (BMD) mainly at sites rich in cortical bone. However, successful parathyroidectomy causes an increase in BMD especially at sites rich in trabecular bone. Plasma 25‐hydroxyvitamin D (25OHD) levels are typically reduced and plasma 1,25‐dihydroxyvitamin D [1,25(OH)₂D] slightly increased in PHPT. These variations in vitamin D metabolites may influence variations in BMD and fracture risk. Aim To investigate relations between preoperative vitamin D metabolites and skeletal consequences in patients with untreated PHPT and to appraise the influence of preoperative vitamin D metabolites on postoperative changes in BMD. Design Cross‐sectional and cohort study. Materials Two hundred and forty‐six consecutive Caucasian PHPT patients aged 19–91 years. (median 63, 87% females). Results BMD was reduced at the femoral neck (P < 0·001) and forearm (P < 0·001), but normal at the lumbar spine (P = 0·11). Levels of biochemical bone markers were associated with high plasma PTH, high plasma 1,25(OH)₂D and low plasma levels of 25OHD. Moreover, low plasma 25OHD was associated with low levels of BMD at the femoral neck (r_p = 0·23), the forearm (r_p = 0·19) and the whole body (r_p = 0·30), whereas plasma 1,25(OH)₂D was inversely associated with BMD at all regional sites and the whole body. Plasma PTH only showed an inverse association with BMD at the forearm (r_p = –0·21). No association was observed between biochemical variables and prevalent spinal fractures, all peripheral fractures or osteoporotic peripheral fractures. The annual increase in spinal BMD after surgery was positively associated with preoperative plasma PTH (r_p = 0·40), whereas the annual increase in whole body BMD was inversely associated with plasma 25OHD (r_p = –0·32). No change in BMD at the femoral neck and forearm was observed 1 year after surgery. Conclusion Low vitamin D status and high plasma 1,25(OH)₂D are associated with increased bone turnover and decreased BMD in patients with PHPT.     

Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease

Aim The aim of this study was to investigate the relationships between bone mineral density (BMD) vs insulin resistance and metabolic risk factors in obese adolescents with nonalcoholic fatty liver disease (NAFLD). Patients and methods Eighty‐two obese adolescents [45 girls and 37 boys, mean age: 12·3 ± 1·7 years, mean body mass index‐standard deviation score (BMI‐SDS): 1·9 ± 0·2] and 30 control subjects (15 girls and 15 boys, mean age: 12·3 ± 1·45 years, mean BMI‐SDS: 0·5 ± 0·7) were enrolled the study. The obese subjects were divided into two groups based on the presence or absence of liver steatosis with high transaminases (NAFLD group and non‐NAFLD group). Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR) from fasting samples. BMD was determined by dual‐energy X‐ray absorptiometry. Results Fasting insulin levels in the NAFLD group were significantly higher than in the non‐NAFLD obese (32·3 ± 24·0 vs 11·02 ± 2·95 mU/l, P < 0·001) and control groups (8·4 ± 2·4 mU/l, P< 0·001). The NAFLD group had higher values of HOMA‐IR than the non‐NAFLD obese (7·3 ± 0·1 vs 2·3 ± 0·7, P < 0·001) and control groups (1·8 ± 0·5, P < 0·001). BMD‐SDS measurements were lower in the NAFLD group than in the non‐NAFLD (0·56 ± 0·3 vs 1·02 ± 0·9, P < 0·001) and control groups (0·56 ± 0·3 vs 1·37 ± 1·04, P < 0·001). BMD‐SDS was positively correlated with BMI‐SDS (r = 0·530, P = 0·004) and negatively correlated with HOMA‐IR (r = ?0·628, P = 0·017) in the NAFLD obese group. Conclusion This study reports the association between BMD‐SDS and insulin resistance in obese adolescents both with and without NAFLD, although the NAFLD group had a lower BMD‐SDS than the non‐NAFLD group. We suggest that NAFLD has a detrimental effect on bone health in adolescents, and it is correlated with increased insulin resistance.     

The relationship between PTH and 25-hydroxy vitamin D early in pregnancy

Objective Measure serum PTH and 25(OH)D in a cross‐sectional sample of pregnant women at 11th through 13th weeks’ gestation to examine vitamin D status and consider implications. Design Observational: we retrieved residual sera stored at ?20 °C after routine first trimester Down’s syndrome screening, distributed over 12 months. Patients 430 African American women and 586 Caucasian women. Measurements PTH and 25‐hydroxy vitamin D [25(OH)D] immunoassays. Results PTH medians were: 1·33 pmol/l (African American women); 1·20 pmol/l (Caucasian women) (t = 0·43, P = 0·7). Concentrations were highest in winter and decreased significantly in spring, fall, and summer. There was a direct PTH/weight relationship in Caucasian (t = 3·12, P < 0·002), but not African American women (t = 1·34, P = 0·18). Median 25(OH)D concentrations were 47·5 nmol/l (African American women) and 65 nmol/l (Caucasian women) (t = 13·7, P < 0·001). Concentrations were lowest in winter and rose significantly in spring, fall, and summer. Reciprocal 25(OH)D/weight relationships existed for both racial groups (t = ?4·31 P < 0·001; t = 4·54, P < 0·001, respectively). Among 68 Caucasian women who smoked, median PTH and 25(OH)D concentrations were somewhat lower (P = ns). In separate regression models with PTH and 25(OH)D [dependent variables] and season, weight and smoking [independent variables], the only qualifying interactive term was in the Caucasian PTH model (season*1/weight). A regression model applied to adjusted scatter plots of PTH vs 25(OH)D indicated a weak relationship. Conclusions The PTH/25(OH)D relationship is weaker during early pregnancy than in non‐pregnant adults, making it unreliable for estimating vitamin D sufficiency. A suitable reference point for sufficiency might be the maternal 25(OH)D level considered sufficient for adequate transfer to neonates.     

Bone mineral density and metabolism in premenopausal women taking l-thyroxine replacement therapy

BACKGROUND AND OBJECTIVE Excess endogenous thyroxine causes bone loss, but the effects of exogenous thyroxine are disputed. We report on bone mass and metabolism in women taking l -thyroxine therapy. DESIGN Cross-sectional and longitudinal studies. PATIENTS Cross-sectional study: 40 healthy premenopausal women with autoimmune thyroiditis taking either physiological (serum TSH usually normal, 0·35–3·3 mU/l) or suppressive (serum TSH usually < 0·35 mu/l) doses of l -thyroxine; patients were also compared with previously acquired age and weight matched premenopausal volunteers with no history of thyroid dysfunction. Longitudinal study: 28 patients were followed-up ≥ 1 year later. MEASUREMENTS In all subjects bone mineral density (BMD) was measured at the anteroposterior lumbar spine and left hip (femoral neck, greater trochanter and Ward's area) using dual-energy X-ray absorptiometry, and physical activity assessed using the Framingham physical activity index. Serum osteocalcin (OC), PTH and vitamin D, and urinary pyridinoline and deoxypyridinoline excretion were measured in patients. RESULTS Cross-sectional study: The patient groups were well matched for disease duration and physical activity although the suppressed group were slightly younger (mean 3·1 (SD 7·5) vs 43·3 (3·9) years, P < 0·05). BMD, serum OC, PTH and vitamin D, and urinary cross-link excretion did not differ significantly between the two groups. Multivariate analysis of the whole group suggested that BMD at the femoral neck and greater trochanter was related positively to weight and physical activity and negatively to thyroxine dose (μg/kg/day) and patient age. At the lumbar spine BMD was reduced non-specifically in the presence of thyroid disease and treatment, but this effect appeared to decline with increasing duration of therapy. A similar analysis of the patient group suggested that urinary cross-link excretion correlated positively with thyroxine dose, and negatively with duration of treatment. Longitudinal study: Annualized changes in BMD were inversely related to thyroxine dose (μg/kg/day) at all sites but achieved statistical significance only at the femoral neck and Ward's area. CONCLUSION We did not find any effect of persistent historical TSH suppression on current bone mass, and this might relate to the relative insensitivity of older TSH assays. However, the cross-sectional and longitudinal data suggest that high daily doses of thyroxine In relation to patient body weight might adversely affect bone mass, particularly at the hip. These findings support the contention that excess exogenous thyroxine might predominantly deplete skeletal sites, such as the femoral neck, rich in cortical bone.     

Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF)

Objective Reduced bone mineral density (BMD) and increased rates of atraumatic fracture are observed in cystic fibrosis (CF) patients, causing increasing morbidity as this population ages. The study aimed to assess the safety, tolerability and effect on BMD of intravenous zoledronate in adults with CF and osteopaenia. Design Randomized, double‐blind, placebo‐controlled clinical trial. Setting Adult CF outpatient clinics at two hospitals. Patients Twenty‐two non‐transplanted CF patients aged ≥ 18 years with a bone densitometry T‐score of < –1·5 at one of three sites (lumbar spine, femoral neck, distal forearm) were studied. Participants were randomized to receive either 2 mg zoledronate IV (n = 10) or normal saline (placebo, n = 12) every 3 months for 2 years (8 infusions). All participants received calcium and vitamin D supplements twice daily. Measurements Percentage change in areal BMD from baseline. Results Lumbar spine BMD increased from baseline more with zoledronate than placebo at 6 months (5·35 ± 0·76 vs. 1·19 ± 1·20%, P = 0·012), 12 months (6·6 ± 1·5 vs. 0·35 ± 1·55%, P = 0·011) and 24 months (6·14 ± 1·86 vs. 0·44 ± 0·10, P = 0·021). Femoral neck BMD increased more after zoledronate than placebo at 6 months (3·2 ± 1·6 vs.–1·43 ± 0·43%, P = 0·019), 12 months (4·12 ± 1·8 vs.–1·59 ± 1·4%, P = 0·024) and 24 months (4·23 ± 1·3 vs.–2·5 ± 1·41%, P = 0·0028). Forearm BMD did not change. Zoledronate was associated with flu‐like and musculoskeletal side effects, particularly after the first infusion. There were no fractures in either group. Conclusion Intravenous zoledronate was significantly more effective than placebo for increasing BMD in adults with CF and osteopaenia, but side effects limited its tolerability.     

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.     

Impact of vitamin D-related serum PTH reference values on the diagnosis of mild primary hyperparathyroidism, using bivariate calcium/PTH reference regions

Background, objective An international consensus conference underlined the importance of defining upper parathyroid hormone (PTH) reference values based on 25‐OH‐vitamin D [25(OH)D] to diagnose mild primary hyperparathyroidism. We determined the importance of this factor in a Belgian population. Design, patients, methods Intact PTH and 25(OH)D were measured in 261 healthy controls (18–65 years, winter/summer). They were classified as 25(OH)D replete (50–153 nmol/l; n = 129) or deplete (8–50 nmol/l; n = 132). PTH was determined in 49 patients with surgically proven primary hyperparathyroidism. PTH thresholds for 95% specificities and corresponding sensitivities were computed from both 25(OH)D replete and deplete receiver operating characteristic (ROC) curves. The 95% bivariate reference ellipses, relating PTH to calcium for 25(OH)D replete and deplete controls, were compared to the PTH/calcium pairs of patients with primary hyperparathyroidism. Results Parathyroid hormone correlated with 25(OH)D (r = ?0·3232; P < 0·0001). PTH normative values were 20% lower in 25(OH)D replete than deplete controls (P < 0·0001). PTH thresholds, providing 95% specificities for primary hyperparathyroidism diagnosis, were 7·6 pmol/l and 5·8 pmol/l, using ROC curves derived from 25(OH)D deplete or replete controls, respectively. Corresponding sensitivities were of 56%vs 88%, respectively (P < 0·05). The 95% PTH/calcium bivariate reference ellipses for?deplete and replete 25(OH)D controls differed, but the PTH/calcium pairs of patients with primary hyperparathyroidism did not overlap these ellipses. Conclusion For a given specificity, primary hyperparathyroidism diagnostic parathyroid hormone thresholds were lower and sensitivities higher using ROC curves, derived from 25(OH)D replete vs deplete controls. The 25(OH)D status does not affect the efficiency of primary hyperparathyroidism diagnosis, using bivariate PTH/calcium reference density ellipses.     

Bone mineral density analysis in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1 after total parathyroidectomy

Objective Limited data have been reported on the effect of parathyroidectomy (PTx) on bone mineral density (BMD) in the setting of patients with hyperparathyroidism (HPT) associated with multiple endocrine neoplasia type 1 (MEN1). This study investigates the impact of total PTx on BMD in patients with HPT/MEN1. Design and patients A case series study was performed in a tertiary academic hospital. A total of 16 HPT/MEN1 patients from six families harbouring MEN1 germline mutations were subjected to total PTx followed by parathyroid auto‐implant in the forearm. Measurements Bone mineral density values were assessed using dual‐energy X‐ray absorptiometry. Results Before PTx, reduced BMD (Z‐score 2; +8·4%, P = 0·001), FN (from 0·745 to 0·798 g/cm²; +7·7%, P = 0·0001) and TF (from 0·818 to 0·874 g/cm²; +6·9%, P < 0·0001). No significant change was noticed in the 1/3 DR and UDR after PTx. Conclusions This data confirmed BMD recovery in the LS and FN after PTx in HPT/MEN1 patients. We also documented a significant BMD increase in the TF and no change in both the 1/3 DR and UDR BMD after PTx. Our data suggest that LS and proximal femur are the most informative sites to evaluate the short‐term BMD outcome after PTx in HPT/MEN1 subjects.     

Vitamin D, PTH and calcium levels in pregnant women and their neonates

Objectives To determine the prevalence of vitamin D deficiency in pregnant women and their neonates and to examine factors associated with vitamin D deficiency. Design and patients Population‐based study of pregnant women and their neonates from South‐eastern Sydney, Australia. Measurements Serum 25 hydroxy‐vitamin D (25‐OHD), PTH, calcium, albumin, phosphate and alkaline phosphatase were measured in women at 23–32 weeks gestation and on cord blood at delivery. Maternal skin phototype was recorded using the Fitzpatrick scale. Results Vitamin D deficiency (defined as 25‐OHD ≤ 25 nmol/l) was found in 144 of 971 (15%) women and 98 of 901 (11%) neonates. Median 25‐OHD was 52 nmol/l (range 17–174) in mothers and 60 nmol/l (17–245) in neonates. Maternal 25‐OHD levels varied by season, with lowest levels in late winter/early spring (P < 0·001). Factors associated with maternal vitamin D deficiency in multiple logistic regression were (OR, 95% CI): maternal birthplace outside Australia: 2·2 (1·4–3·5, P = 0·001), dark skin phototype: 2·7 (1·6–4·5, P < 0·001), wearing a veil: 21·7 (11·7–40·3, P < 0·001) and younger maternal age: 0·93 (0·89–0·97, P = 0·001). Maternal vitamin D deficiency increased the risk of neonatal vitamin D deficiency (OR 17·2, 95% CI 8·8–34·3) and birth weight was lower among infants of deficient vs. sufficient mothers: mean (SD) 3245 g (545) vs. 3453 g (555), P < 0·001. Conclusions Vitamin D deficiency is common among pregnant women; immigrant, veiled and dark skinned women are at greatest risk. Maternal vitamin D deficiency increases the risk of neonatal vitamin D deficiency and lower birth weight.     

Malignancy-associated hypercalcaemia: resolution of controversies over vitamin D metabolism by a pathophysiological approach to the syndrome

OBJECTIVE Parathyroid hormone-related protein (PTHrP) is recognized as a major pathogenetic factor of humoral hypercalcaemia of malignancy but Its action on vitamin D metabolism is controversial. Our aim was to study the relation between serum 1,25-dihydroxyvitamin D and humoral activity in malignancy-associated hypercalcaemia. DESIGN Prospective, cross-sectional, single-centre study of patients with documented solid malignancles, hypercalcaemia and suppressed plasma PTH concentrations. PATIENTS AND METHODS Vitamin D metabolites, PTH, nephrogenous cyclic AMP (N-CAMP), PTHrP and biochemical parameters of calcium and bone metabolism were measured in 39 patients with solid mallgnancles and hypercalcaemia and bone scans were performed. RESULTS In 27 patients plasma PTHrP levels were elevated (69%) and in 9 patients (23%) serum 1,25-(OH)₂D concentrations were not appropriately suppressed (>92pmol/l). Patients with plasma PTHrP levels below the upper limit of normal (< 1·6 pmol/l) had lower serum 1,25-(OH)₂,D concentrations than those with elevated levels (>1 6 pmol/l) (47±6 vs 70± 7 pmol/l, respectively; P < 0·04). Serum 1,25-(OH)₂D concentrations were higher in patients with negative bone scans than In those with metastatic bone disease (80 ± 9 vs 50 ± 5 pmol/l; P < 0·01) and similar levels of plasma PTHrP. In the patients with negative bone scans there was a significant relation between plasma PTHrP and serum 1,25(OH)₂,D (r= 0·51; P < 0·03) whereas there was no such correlation in those with a positive scan. CONCLUSION Contrary to current belief, serum 1,25-(OH)₂D concentrations are not generally suppressed in humoral hypercalcaemia of malignancy and PTHrP is a determinant of these levels in the absence of demonstrable bone metastases. These findings provide further Insights into the pathophysiology of malignancy-associated hypercalcaemia and may help in the clinical management of these patients.     

Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults*

OBJECTIVES The role of growth hormone in maintaining normal body composition and bone strength In adults has attracted much interest recently. We have assessed body composition and bone mass in GH deficient hypopituitary adults on conventional replacement therapy and compared them with matched controls. DESIGN AND SUBJECTS A cross-sectional Study Of 64 growth hormone deficient hypopituitary adults (29 males and 35 females) on conventional replacement therapy and a large number of healthy control subjects matched for age, sex and body mass index (BMI). MEASUREMENTS Skinfold thicknesses at two sites (triceps and subscapular), waist and hip girth circumferences were assessed by standard methods. Body composition was assessed using total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA). Bone mineral mass was assessed at the lumbar spine and the total body by DEXA. Not every patient and control participated In every measurement. RESULTS Obesity was common in the hypopituitary patients; BMI (mean±SD) was 27·5 ± 4·6 kg/m² and body weight was 111·8 ±185% of the maximal ideal for height (P< 0·001). The sum of subscapular and triceps skinfolds was significantly higher in hypopituitary patients than in controls (men 46+15 vs 37±14mm, P<0·05; women 55±13 vs 47±17mm, P<0·05). Waist to hip circumference ratio was significantly greater In female hypopituitary patients than in matched controls but was not significantly different in men (men 0·94± 0·07 vs 0·91 ± 0·07, NS; women 0·84±0·09 vs 0·77±0·05, P < 0·001). The difference between patients and controls in the sum of skinfolds and the waist to hip ratio were present In non-obese (BMI < 26 kg/m²) subjects (21 patients and 32 controls). TBK corrected for body weight was significantly lower In hypopituitary patients (n= 44) than in controls (n= 31) (men 43·±5.6 vs 50·1 ± 5·9 mmollkg, P < 0·003; women: 34·0 ± 3.2 vs 40·6 ± 5·3 mmol/kg, P < 0.0001). BIA-derived body water content (corrected for body weight) was significantly lower In hypopituitary patients (n= 56) than in controls (n= 57) (0·492 ± 0·064 vs 0·545 ± 0·067 1/kg, P < 0.0004). Percentage body fat derived from ail the three methods was significantly higher in hypopituitary patients than in normal controls In both sexes (from TBK men 34·7 ± 94 vs 28·8 ± 7·0%, P < 0·05; women 37·8 ± 8·7 vs 30·4 ± 9·7%, P < 0·01; from BIA men 29·3 ± 8·5 vs 23·2 ± 8·4%, P < 0·01; women 34·6 ± 8.1 vs 29·3 ± 9·1%P < 0·01; and from DEXA: men 24·8 ± 6·8 vs 20·4 ± 6·1 %, P < 0·05; women 38·9 ± 7·9 vs 32·5 ± 9·8%, P < 0·01). There was a significant difference between non-obese patients and controls in BIA-derived percentage fat in both sexes and in TBK-derived percentage fat In females only. Bone mineral density (BMD) of the lumbar spine in the L2-L4 region was lower in hypopituitary patients than in controls (men 1·116±0·129 vs 1·311 ± 0·131 g/cm², P <0·0001; women 1·001 ±0·122 vs 1·131 ±0·138g/cm², P < 0·001). Spine BMD was also reduced in hypopituitary patients compared to the young adult and age and weight matched reference data. Total body BMD was significantly lower in patients than In controls (men 1·186 ± 0·102 vs 1·250 ± 0·080 g/cm², P < 0·05; women 1·080 ± 0·077 vs 1·149 ± 0·073 g/cm², P < 0·005). CONCLUSIONS Hypopituitary adults on conventional therapy have abnormal body composition with increased fat content, reduced body water content and reduced bone mineral mass     

Bone mineral density and bone turnover in relation to serum leptin, α-ketoglutarate and sex steroids in overweight and obese postmenopausal women

Objective Recent studies have shown that parallel changes in body weight and bone mass can be partially mediated via circulating leptin. Therefore, among the hormones involved in bone and mineral metabolism, such as oestrogens, testosterone and parathormone, leptin has recently become a subject of considerable interest. The aim of this study was to assess associations between leptin, E₂, testosterone, dehydroepiandrosterone sulphate (DHEA‐S), SHBG, α‐ketoglutaric acid (AKG) and bone mineral density (BMD) and bone turnover markers in overweight and obese postmenopausal women. Design Eighty healthy, postmenopausal Caucasian women were studied. BMD of the lumbar spine (L₂–L₄) and femoral neck regions were examined using the dual X‐ray absorptiometry (DXA) method. Associations were evaluated in stepwise multiple regression analysis, including information on the possible confounders and effect modifiers, for example, age, years since menopause, height and weight. Results Femoral neck BMD was positively correlated with weight (r = 0·52, P < 0·000001), body mass index (BMI) (r = 0·48, P < 0·000006), hipline (r = 0·48, P < 0·00006), waistline (r = 0·45, P < 0·00002) and DHEA‐S (r = 0·36, P < 0·0008). Correlations of E₂, SHBG, testosterone and leptin, as well as biochemical markers of bone turnover with L₂–L₄ and femoral neck BMD were not found. In the whole study group, significant predictors of L₂–L₄ BMD were BMI (β = 0·35, P < 0·01) testosterone (β = 0·27, P < 0·05) and osteocalcin (OC) (β = 0·22, P < 0·05) (R² = 0·23), while predictors of femoral neck BMD were BMI (β = 0·42, P < 0·001), testosterone (β = 0·24, P < 0·05), E₂ (β = 0·19, P < 0·05), as well as osteocalcin (β = 0·20, P < 0·05) (R² = 0·41). In the subgroup with BMI 30–39·9, the significant predictors of both L₂–L₄ and femoral neck BMD were testosterone (β = 0·32, P < 0·05, R² = 0·19; β = 0·33, P < 0·05, R² = 0·29) and osteocalcin (β = 0·34, P < 0·05, R² = 0·19; β = 0·45, P < 0·01, R² = 0·29). In the subgroup with waist : hip ratio (WHR ≥ 0·85, the predictor of L₂–L₄ BMD was E₂ (β = 0·38, P < 0·05) (R² = 0·21), whereas the predictors of femoral neck BMD were BMI (β = 0·29, P < 0·05) and testosterone (β = 0·35, P < 0·01) (R² = 0·36). Conclusion The main endocrine variable predicting lumbar spine BMD in overweight and obese postmenopausal females was testosterone, while the main determinants of femoral neck BMD were both testosterone and E₂. No effect was found of serum leptin on examined indicators of bone status.     

Disproportional geometry of the proximal femur in patients with Turner syndrome: a cross-sectional study

Objective Patients with Turner syndrome (TS) have altered growth and increased risk of osteoporosis due to oestrogen deficiency and possibly a host of other factors. Thus, TS patients have a 4·9‐fold increased risk of femoral neck fractures. Most patients are treated with oestrogen during puberty and adolescence to facilitate pubertal development and prevent secondary osteoporosis. The geometry of the hip is a predictor for hip fractures independent of bone mineral density (BMD). The purpose of the present study was to investigate the variation of the geometry of the hip in patients with TS in comparison with healthy controls. Patients The study population comprised 58 patients with TS (aged 22–67 years) and 60 age‐matched healthy women (aged 21–65 years). Measurements Hip axis length (HAL), neck width (NW), neck shaft angle (NSA), and femoral head‐radius (HR) on dual‐energy X‐ray absorptiometry (DXA) screen images. These parameters related to age of oestrogen supplementation, menarche, and duration of oestrogen exposure. Results Height was 146·6 ± 6·9 cm and 167·1 ± 6·2 cm (P < 0·1) and weight 57·4 ± 13·9 kg and 62·3 ± 8·3 kg (P < 0·001) in patients and controls, respectively. After adjustment for differences in height, HAL was not significantly different (9·4 ± 0·5 vs. 9·5 ± 0·5 cm; NS) in TS compared with controls while NW was significantly increased (3·5 ± 0·4 cm vs. 3·3 ± 0·2 cm, P < 0·001), NSA was similar (129 ± 4°vs. 130 ± 4°, NS), and HR was significantly decreased (4·1 ± 0·4 vs. 4·5 ± 0·3 cm, P < 0·001). The duration of oestrogen exposure was significantly shorter among TS, but did not correlate significantly with the geometrical parameters in either TS or controls. Conclusion Our data demonstrates that hip geometry is disproportionate in TS compared with normal controls. The altered hip geometry, however, cannot explain the increased risk of hip fracture in TS.     

Plasma visfatin concentrations increase in both hyper and hypothyroid subjects after normalization of thyroid function and are not related to insulin resistance, anthropometric or inflammatory parameters

Objective The objective of this study was to evaluate plasma visfatin levels in thyroid dysfunction and its relationship with inflammatory, anthropometric and insulin resistance parameters. Design and patients Twenty‐four hyperthyroid and 27 hypothyroid patients were studied before and after treatment. Forty‐five euthyroid subjects were used as control group. Measurements Fasting plasma visfatin, IL‐6, C reactive protein, adiponectin, thyroid hormones, waist‐to‐hip ratio, BMI, percentage of body fat and homeostasis model insulin resistance index (HOMA‐IR) were measured. Results Hyperthyroid patients showed increased insulin resistance, IL‐6 and visfatin levels compared with controls (3·21 ± 3·0 vs. 1·67 ± 0·75, P = 0·022; 3·35 ± 0·41 vs. 2·10 ± 0·25 pg/ml, P = 0·016; and 37·4 ± 5·81 vs. 23·79 ± 4·2 ng/ml, P = 0·061 respectively). After normalization of thyroid function, IL‐6 levels and HOMA‐IR decreased (2·35 ± 0·37 vs. 2·10 ± 0·25 pg/ml, P = 0·045 and 3·21 ± 0·60 vs. 2·28 ± 0·38, P = 0·032 respectively), while body weight, adiposity and visfatin levels increased (26·1 ± 1·2 vs. 26·7 ± 1·2 kg/m², P = 0·049; 30·9 ± 1·6 vs. 32·2 ± 1·6%, P = 0·007; and 37·4 ± 5·81 vs. 63·13 ± 8·72 ng/ml, P = 0·047 respectively). C reactive protein and adiponectin levels were similar to those of the control group. Hypothyroid patients showed high visfatin levels (40·59 ± 3·07 vs. 29·34 ± 4·9 ng/ml, P = 0·049) that increased after treatment (81·4 ± 9·2 ng/ml, P = 0·001) without changes in anthropometric or insulin resistance parameters. C reactive protein, IL‐6 and adiponectin levels were similar to those of the control group. No correlations between visfatin and any analysed parameter were found in either hyper‐ or hypothyroidism. Conclusion Visfatin exhibits a marked increase after normalization of thyroid function in both hyper and hypothyroid patients. We suggest that visfatin may play a role in the hormone stabilization process independent of anthropometric, inflammatory or insulin resistance variables.     

Vitamin D levels: its relationship to bone mineral density response and disease activity in premenopausal Malaysian systemic lupus erythematosus patients on corticosteroids

Aim: To determine if baseline vitamin D levels would influence the gain in bone mineral density (BMD) in female systemic lupus erythematosus (SLE) patients on corticosteroids (CS) taking bone‐active medication. Method: Premenopausal SLE patients participating in a trial assessing the efficacy of calcium alone, calcitriol and calcium, and alendronate and calcium, on BMD in patients on CS, were studied. Patients were randomly allocated to the treatment groups at the start of the study and followed up for 2 years. Serum 25‐hydroxy vitamin D [25(OH)D] was measured at baseline. Results: Thirty‐eight patients were studied. One (2%) patient had osteoporosis, nine (24%) had osteopenia and all others had normal BMD. The mean baseline 25(OH)D levels were 21.6 ± 4.6 ng/mL (± 1 SD). Twelve (32%) patients had vitamin D deficiency [25(OH)D < 20 ng/mL]. There was a significant negative correlation between SLEDAI scores and 25(OH)D levels, that is, patients with high SLEDAI scores had significantly lower 25(OH)D levels (P = 0.033). Left femoral neck BMD was significantly lower in the deficient compared to insufficient group (P = 0.042). There was a trend toward better BMD gain at 2 years in the vitamin D insufficient compared to the deficient group, which did not reach statistical significance. Conclusion: This study showed that in female SLE patients, low vitamin D levels are associated with higher disease activity and suggests that patients who have higher vitamin D levels have a better BMD response during treatment with bone‐active agents.     

Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency

objective To investigate the role of IGF‐1 on intima–media thickness (IMT) at common carotid arteries by Doppler ultrasonography. subjects Thirty‐nine patients (17 women, 22 men, aged 25–70 years) with severe GH deficiency (GHD), 19 with normal and 20 with low IGF‐1 levels, and 39 sex‐, age‐ and body mass index (BMI)‐matched healthy controls. results Patients with GHD showed abnormalities in lipid profile, and increased fibrinogen levels, mean IMT (0·88 ± 0·26 vs. 0·69 ± 0·14 mm, P < 0·001), and systolic and diastolic peak velocity (P < 0·001) compared to controls. Eight patients (18%) and one control (2·1%, P = 0·04) had well‐defined plaques. In controls, but not in patients with GHD, mean carotid IMT was correlated with age (r = 0·78, P < 0·001). In both controls (r = ?0·82; P < 0·0001) and patients with GHD (r = ?0·84, P < 0·0001), serum IGF‐1 levels were inversely correlated with mean IMT at common carotid arteries. At the stepwise multiple regression, the variables most significantly related to IMT in GH‐deficient patients were total cholesterol levels (t = 5·2, P < 0·001), followed by disease duration (t = 2·4, P = 0·02), while in controls the variables most significantly related to IMT were IGF‐1 levels (t = ?9·9, P < 0·001), followed by low density lipoprotein (LDL)‐cholesterol levels (t = ?2·3, P = 0·02). Compared to patients with normal IGF‐1 levels, those with low IGF‐1 levels had lower high density lipoprotein (HDL)‐cholesterol levels (1·0 ± 0·2 vs. 1·3 ± 0·2 mmol/l, P = 0·0002), and higher glucose (54·3 ± 6·1 vs. 48·9 ± 5·9 mmol/l, P = 0·008), insulin (25·2 ± 6·8 vs. 18·8 ± 6·0 mUl/l, P = 0·004), total cholesterol (7·1 ± 1·1 vs. 4·9 ± 0·6 mmol/l, P < 0·0001), total/HDL‐cholesterol ratio (7·2 ± 1·8 vs. 3·9 ± 0·7, P < 0·0001), fibrinogen levels (319·8 ± 56·9 vs. 241·8 ± 53·0 mg/dl, P < 0·0001) and mean IMT at common carotid arteries (1·05 ± 0·25 vs. 0·69 ± 0·07 mm, P < 0·0001). Atherosclerotic plaques were found only in GH‐deficient patients with low IGF‐1 levels. conclusions GH‐deficient patients have alterations in lipid profile with an increase in the total/HDL‐cholesterol ratio, which is an index of increased cardiovascular risk, but only patients with IGF‐1 deficiency have increased IMT.     

The impact of clothing style on bone mineral density among women in Turkey

To investigate the effect of veiled clothing style on bone mineral density (BMD). The BMD measurements were performed on the femoral neck and the lumbar spines of adult female population with two different types of clothing taking calcium daily in the normal range according to the proper technique utilizing dual energy X-ray absorptiometry (DEXA). In the lumbar spine measurements, the BMD was measured 1.0020 ± 0.177 gr/cm² in cases with veiled clothing style while it was measured 1.0793 ± 0.169 gr/cm² in cases with unveiled clothing style (P = 0.049, t = 1.98). In the femoral neck measurements, the BMD was measured 0.8428 ± 0.146 gr/cm² in cases with veiled clothing style while it was measured 0.8532 ± 0.177 in cases with unveiled clothing style (P = 0.548, t = 0.457). Although a decrease in BMD values was observed in both regions with veiled clothing style, only the change in the lumbar spine BMD measurements was statistically significant. These findings suggest that the veiled clothing style may have an adverse effect on BMD by interfering with the sun exposure which is believed to have a key role in bone strength.     

Bone Mineral Density Is Negatively Associated With Arterial Stiffness in Men With Hypertension

Hypertension (HTN) and osteoporosis are associated with the development and progress of atherosclerosis. However, little research has been conducted to examine the relationship between arterial stiffness and bone mineral density (BMD) in men with HTN. This cross‐sectional study recruited 355 men with HTN and 353 control patients without HTN. Brachial‐ankle pulse wave velocity (baPWV) and BMD measurements were performed. BMD was decreased and baPWV was elevated in patients with HTN compared with control patients (femoral neck [FN] BMD in the HTN and control groups were 0.662±0.195 g/cm² and 0.713±0.204 g/cm², respectively [P=.001], and baPWV in the HTN and control groups were 1403.3±156.8 cm/s and 1354.8±136.0 cm/s, respectively [P<.001]). Multiple linear regression analysis demonstrated that FN BMD was negatively associated with increased baPWV in HTN. Reduced FN BMD may be an independent factor for baPWV in patients with HTN.     

In vivo imaging studies of the effect of recipient conditioning,donor cell phenotype and antigen disparity on homing of haematopoietic cells to the bone marrow

Summary. Homing of transplanted bone marrow cells (BMC) to the host bone marrow (BM) is the first step of engraftment towards durable multilineage haematopoietic reconstitution. We used an in vivo assay to track PKH‐labelled cells in the BM of mice after transplantation, using fluorescence microscopy through an optical window placed over the distal femoral epiphysis. Within hours after intravenous injection, the cells moved in and out the femur, and were mobile within the marrow space. One hour after injection of whole BMC into non‐conditioned syngeneic and allogeneic recipients, the homing efficiencies (HE) were 1·23 ± 0·14% and 0·12 ± 0·02% respectively (P < 0·001). Irrespective of antigen disparity, the number of PKH‐labelled cells in the femur decreased by 30% and 50% after 1 and 3 d respectively (P < 0·001). Similar HE of naïve and irradiated cells suggested that the majority of cells (> 80%) were quiescent in the BM during the first 3 d. HE were twofold higher in busulphan‐myeloablated recipients (P < 0·001 vs non‐conditioned), and allogeneic transplantation resulted in 84 ± 9% donor chimaerism at 4 weeks. The HE of lin^– cells was 16‐fold higher than that of lin⁺ cells (P < 0·001), and the subset of lin^– SCA‐1⁺ cells was 4·6‐fold higher in the BM‐homed cell population (P < 0·001 vs lin^– cells). Approximately 1500 of the BM‐homed cells rescued 62–71% secondary syngeneic and allogeneic myeloablated recipients. Strikingly, the HE could be predicted during the first 3 d after transplantation by correcting the measurements performed in vivo for the enrichment of progenitors in donor inoculum, donor‐recipient antigen disparity and myeloablative conditioning.     

THE EFFECT OF OESTROGENS ON HUMAN CALCITONIN SECRETION AFTER CALCIUM INFUSION IN ELDERLY FEMALE SUBJECTS

The effect of oestrogen administration (4–6 weeks) on the response of human calcitonin (hCT) secretion to 5 min calcium infusions was studied in ten elderly women. There was no significant difference in mean basal plasma hCT levels before and after oestrogen administration. However, the mean increment in plasma hCT in response to calcium infusion (ΔhCT) increased significantly (P < 0·001) from 21·9±6·6 (mean ±SE) before treatment, to 79·6±15·5 ng/l after oestrogen administration. Mean serum calcium levels decreased significantly (P < 0·001) from 2·42 ±0·06 before to 2·19·0±07 mmol/l after oestrogen treatment. Mean plasma immunoreactive PTH (iPTH) levels increased significantly (P < 0·05) from 521·41 before to 696·96 ng/l after oestrogen treatment. To exclude out the possibility that the decreased serum calcium level itself might have influenced ΔhCT, 1α-hydroxycholecalciferol (1α-OH-D₃) was administered with oestrogens. While this resulted in a slight increase in serum calcium level, there was no significant difference in ΔhCT in response to calcium infusion following oestrogen treatment alone, and after combination therapy of oestrogen and 1 α-OH-D₃. The primary action of administered oestrogen may be in stimulating hCT secretion which results in a decrease in plasma calcium concentration and an increase in plasma iPTH level.