The association between hypoparathyroidism and cognitive impairment: a systematic review.

CONTEXT AND PURPOSE: Hypocalcemia and low parathyroid hormone levels have been commonly suggested as factors able to induce central nervous system disturbances. However, evidences on the occurrence of cognitive impairment are limited or underestimated. The aim of this review is, therefore, to systematically summarize the available evidence concerning the occurrence of cognitive impairment among subjects suffering from idiopathic or secondary hypoparathyroidism. METHODS: A systematic selection of the available literature was performed by searching the online databases PubMed, Scopus and Web of Knowledge. RESULTS: The present systematic review included sixteen case report articles and one cross-sectional controlled study. Case reports were the most representative literature sources and involved ten women and seven men. The presence of cognitive impairment was mostly discussed in association with idiopathic hypoparathyroidism (HPT); five articles described the occurrence of cognitive impairment following postsurgical HPT. The case-controlled study reported a significant presence of peculiar cognitive deficits (e.g. reduced inhibitory control, impairment in visuo-spatial functioning among, and psychomotor retardation) among HPT subjects compared to healthy controls, with serum total calcium and its product with phosphorus as independent predictors of neuropsychological dysfunctions. CONCLUSION: Even though mostly based on single case reports, the presence of neuropsychological dysfunctions in the context of HPT appears to be a consistent core finding.

Trabecular bone score and quantitative ultrasound measurements in the assessment of bone health in breast cancer survivors assuming aromatase inhibitors.

PURPOSE: Aromatase inhibitors (AIs) represent the first-line adjuvant therapy for hormone receptor-positive breast cancer (BC) women. AIs have been associated with an increased rate of fractures. The aim of our study was to investigate trabecular bone score (TBS) and bone quantitative ultrasound (QUS) measurements as bone quality surrogates in AIs users. METHODS: Sixty postmenopausal BC women starting AIs and forty-two controls (mean age 61.64 ± 8.33 years) were considered. Bone mineral density (BMD) at lumbar spine and femoral neck and TBS were measured by DXA; QUS-derived Amplitude-Dependent Speed of Sound (AD-SoS), Bone Transmission Time (BTT), and Ultrasound Bone Profile Index (UBPI) were assessed at phalangeal site; morphometric vertebral fractures (Vfx) by X-ray, serum bone-specific alkaline phosphatase (BSAP), and C-telopeptide of type 1 collagen (CTX) were also evaluated. RESULTS: After 18 months, changes of TBS vs baseline were significantly different between AIs group and controls [Δ TBS - 2.2% vs - 0.4%, respectively, p = 0.001]. AD-SoS, BTT and UBPI values decreased only in AIs' group (- 3.7%, - 6.45%, -8.5%, vs baseline, respectively, pall < 0.001). 3 Vfx occurred in AIs users and were associated with the greater TBS and AD-SoS modifications. In the AIs' group, ΔTBS was associated with ΔAD-SoS (r = 0.58, p < 0.001) and ΔUBPI (r = 0.415, p = 0.001), but not with ΔBMD. Moreover, ΔTBS was independently predicted by ΔAD-SoS, after correcting for BMD, CTX and BSAP level changes (ß = 0.37, SE = 2.44, p < 0.001). CONCLUSIONS: TBS and phalangeal QUS provide useful information related to bone quality in AI-treated BC survivors and could be considered for fracture risk evaluation.

Incidence of hypocalcemia and hypercalcemia in hospitalized patients: Is it changing?

Disorders of calcium metabolism are frequently encountered in routine clinical practice. However limited data are available on the epidemiology of hypocalcemia and hypercalcemia in hospitalized patients. Our aim was to evaluate the frequency of hypocalcemia and hypercalcemia in hospitalized patients. This is a retrospective study based on the laboratory results of all hospitalized subjects (n = 12,334) whose calcemia was determined between January 1st, 2011 and December 31st, 2014. Measurements of serum calcium were carried out by a single centralized laboratory. Hypocalcemia was defined as serum calcium levels <8.2 mg/dl and hypercalcemia as serum calcium levels >10.4 mg/dl. Albumin correction was applied to adjust serum calcium values. Overall, hypocalcemia accounted for 27.72% (n = 3420) and hypercalcemia for 4.74% (n = 585) of the 12,334 inpatients. The highest prevalence of hypocalcemia was found in patients over 65 yr. (n = 2097, 61.31%) vs. younger subjects, while the highest prevalence of hypercalcemia was observed in patients aged 0-18 yr. (n = 380, 64.95%). Hypocalcemia was more often encountered in males (n = 1952, 57.07%) while no gender differences were found regarding hypercalcemia. Incidence of hypocalcemia changed over time varying from 35.42% (n = 1061) in 2011 to 21.93% (n = 672) in 2014 (r = -0.98; p = 0.01). Differently, incidence of hypercalcemia did not significantly increase significantly from 3.47% (n = 104) in 2011 to 6.92% (n = 211) in 2014 (r = 0.94; p = 0.052). Despite increased awareness about electrolytes disturbance, physicians should consider calcium levels because of life-threatening consequences associated to hypo- and hypercalcemia. Patient's gender and age could be associated to a different risk of calcium disturbance in hospitalized patients.

Quantitative ultrasound and DXA measurements in aromatase inhibitor-treated breast cancer women receiving denosumab.

PURPOSE: Denosumab has been proven to reduce fracture risk in breast cancer (BC) women under aromatase inhibitors (AIs). Quantitative ultrasound (QUS) provides information on the structure and elastic properties of bone. Our aim was to assess bone health by phalangeal QUS and by dual-energy X-ray absorptiometry (DXA), and to evaluate bone turnover in AIs-treated BC women receiving denosumab. METHODS: 35 Postmenopausal BC women on AIs were recruited (mean age 61.2 ± 4.5 years) and treated with denosumab 60 mg administered subcutaneously every 6 months. Phalangeal QUS parameters [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), Bone Transmission Time (BTT)] and DXA at lumbar spine and femoral neck were performed. Serum C-telopeptide of type 1 collagen (CTX) and bone-specific alkaline phosphatase (BSAP) were also measured. The main outcomes were compared with a control group not receiving denosumab (n = 39). RESULTS: In patients treated with denosumab, differently from controls, QUS and DXA measurements improved after 24 months, and a reduction of CTX and BSAP was detected at 12 and 24 months in comparison to baseline (P < 0.05). The percent changes (Δ) of QUS measurements were significantly associated with ΔBMD at femoral neck, and ΔCTX and ΔBSAP were associated with ΔBMD at lumbar spine (r = -0.39, P = 0.02; r = -0.49, P = 0.01, respectively). CONCLUSIONS: Denosumab preserves bone health as assessed by phalangeal QUS and DXA. Since inexpensive and radiation-free, phalangeal QUS may be considered in the follow-up of AIs-treated BC women receiving denosumab.

Effects of teriparatide on bone mineral density and quality of life in Duchenne muscular dystrophy related osteoporosis: a case report.

Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle disease characterized by secondary osteoporosis and increased fractures. We describe the case of a 20-year-old boy with DMD suffering from back pain due to multiple vertebral fractures who was treated with teriparatide. Improvement of bone density, pain, and quality of life was achieved. DMD is an X-linked recessive muscle disease with secondary osteoporosis and related frequently occurring fractures. To date, only bisphosphonates have been used to treat osteoporosis in DMD. Black bear parathyroid hormone has been previously reported to enhance bone mass in the dystrophin-deficient mouse. This study reports the positive effect of osteoanabolic treatment with once-daily recombinant human parathyroid hormone 1-34 (rhPTH 1-34, teriparatide) in a 20-year-old DMD boy suffering from multiple vertebral fractures causing back pain. Bone formation and resorption markers (osteocalcin and C-telopeptide of type I collagen, respectively), as expected, increased within 6 months and intensity of back pain early decreased, with no pain reported after 6 months at visual analog scale. Over a 18-month period of treatment with teriparatide, bone mineral density and quality of life, assessed by the 36-item short-form questionnaire, considerably improved and no side effects were reported. Further studies on large cohorts are warranted to test the efficacy of this promising treatment for DMD related osteoporosis.

Vitamin D and bone mineral density changes in postmenopausal women treated with strontium ranelate.

OBJECTIVE: Vitamin D deficiency is widespread and often reported in subjects treated for osteoporosis. Optimal vitamin D repletion was previously shown to maximize the efficacy of anti-resorptive agents. To date, no information exists about the role of vitamin D in the response to strontium ranelate (SrR) treatment. The aim of our study was to investigate the BMD response to SrR in accordance with change of vitamin D status. METHODS: A retrospective analysis of 108 women receiving SrR for postmenopausal osteoporosis was carried out. Women were treated with SrR (2 g/day), with cholecalciferol (25,000 IU biweekly) and calcium carbonate as appropriate. Lumbar spine and femoral neck BMD, bone formation markers (BGP, ALP), resorption marker (OH-PRO) and serum 25(OH)D were measured at baseline after 18-months. All participants were divided into two groups according to the median variation of 25(OH)D over the observation period. RESULTS: SrR was associated with improvement of BMD at lumbar spine (p < 0.0001) and to a non significant variation at femoral neck (p = 0.2). Only subjects with Δ25(OH)D > 6.14 %, reported a significant BMD gain at femoral neck (p = 0.03). Change of BMD at femoral neck was positively associated with modification of ALP (r = 0.28, p = 0.01). This association was not maintained when considering only women with Δ25(OH)D < 6.14 % (r = 0.28, p = 0.09). At a multiple regression analysis, ALP change was the only predictor of femoral neck BMD modification (ß 0.13; SE 0.05; p = 0.01). CONCLUSION: Improvement of vitamin D status was associated with enhancement of BMD response to SrR in women with postmenopausal osteoporosis, in particular, at femoral neck.

Phalangeal quantitative ultrasound and metabolic control in pre-menopausal women with type 1 diabetes mellitus.

BACKGROUND: Several studies have reported increased fracture risk in Type 1 diabetes mellitus (T1DM). Quantitative Ultrasound (QUS) provides information on the structure and elastic properties of bone, which are important determinants of fracture risk, along with bone mineral density. AIM: To study phalangeal sites by QUS, examine bone turnover markers and analyze association between these factors with metabolic control in a population of pre-menopausal women with T1DM. MATERIAL AND METHODS: Thirty-five T1DM pre-menopausal women (mean age 34.5 ± 6.8 yr) attending the Diabetic Outpatients Clinic in the Department of Internal Medicine, University of Messina, were consecutively enrolled and divided into two groups, taking into account the mean value of glycated hemoglobin in the last three years. Twenty healthy age-matched women served as controls. Phalangeal ultrasound measurements [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), TScore, Z-Score] were performed using a DBM Sonic Bone Profiler. Osteocalcin and deoxypyridinoline served as markers of bone formation and bone resorption, respectively. RESULTS: T1DM women with poor metabolic control showed lower phalangeal QUS values compared to healthy controls (p<0.01) and T1DM women with good metabolic control (p<0.05). No significant differences in QUS measurements were detected between T1DM women with good metabolic control and healthy controls. Lower bone formation and increased bone resorption, although not statistically significant, were observed in patients with poor metabolic control in comparison to patients with good metabolic control. CONCLUSIONS: Poor metabolic control may worsen the quality of bone in T1DM. Phalangeal QUS could be considered as a tool to screen T1DM women for osteoporosis in pre-menopausal age.

Adrenal effects of teriparatide in the treatment of severe postmenopausal osteoporosis.

UNLABELLED: The aim of our study was to investigate the effects of teriparatide on the hypophysis-adrenal axis in postmenopausal women. Treatment with teriparatide increased plasmatic and urinary levels of cortisol after 6 and 12 months. Our paper demonstrates a possible direct secretagogue effect of teriparatide on adrenals in osteoporotic postmenopausal women. INTRODUCTION: Teriparatide, recombinant human parathyroid hormone (1-34) (rhPTH [1-34]), is approved for the treatment of osteoporosis in men and postmenopausal women at high risk for fracture. In literature, data regarding the secretagogue effect of PTH on adrenocortical cells are present on in vitro, but not on in vivo, studies. The aim of our study was to investigate the effects of teriparatide on the hypophysis-adrenal axis in postmenopausal women. METHODS: Twenty postmenopausal women with severe osteoporosis were treated with teriparatide in a regimen of 20 µg daily, self-administered injections at bedtime for 12 months and a calcium and vitamin D supplementation. At the same time, 20 osteopenic women matched for age and body mass index with the patients were enrolled and treated only with calcium and vitamin D. In all subjects, calcium, adrenocorticotropic hormone (ACTH), and plasmatic and urinary cortisol were evaluated at baseline and after 6 and 12 months. RESULTS: Treatment with teriparatide increased plasmatic and urinary levels of cortisol after 6 and 12 months, reaching statistical significance only after 1 year. Plasmatic levels of ACTH did not change significantly. CONCLUSIONS: Our paper, for the first time, demonstrates a possible direct secretagogue effect of teriparatide on adrenals in osteoporotic postmenopausal women.

Haemostatic effects of phytoestrogen genistein in postmenopausal women.

INTRODUCTION: Genistein is an isoflavone phytoestrogen derived from the soybean which acts as natural selective estrogen receptor modulator. Various studies have pointed out its cardioprotective role. The aim of the study was to evaluate the haemostatic effects of genistein in postmenopausal women. MATERIAL AND METHODS: In this double-blind placebo-controlled trial we enrolled 104 healthy postmenopausal women with osteopenia. 53 patients (mean age 54.9+/-4.2 yr; BMI 23.4+/-3.2 Kg/m(2)) received genistein (54 mg/day) and 51 patients (mean age 55.4+/-4.3 yr; BMI 23.6+/-3.6 Kg/m(2)) received an identical placebo-tablet. Both groups received a calcium and vitamin D supplement. Plasma levels of D-dimer (DD), plasminogen activator inhibitor-1 (PAI-1) and prothrombin fragment 1+2 (F1+2) were measured at baseline and after 6 and 12 months of treatment. RESULTS: Baseline characteristics of the two groups were similar. Compared with placebo, genistein decreased significantly DD (p<0.001), but did not affect PAI-1 and F 1+2 plasma levels. CONCLUSION: The results of our study do not confirm effects of genistein on activation of the haemostatic system, but on the contrary the significant decrease of DD could indicate a possible cardioprotective role of genistein in postmenopausal women.

Bisphosphonates in the treatment of thalassemia-associated osteoporosis.

Thalassemia major is a common cause of skeletal morbidity, as shown by the increased fracture risk in thalassemic patients. The etiology of this bone disease is multifactorial and culminates in a state of increased bone turnover with excessive bone resorption and remodeling. Despite hormonal replacement therapy, calcium and vitamin D administration, effective iron chelation, and normalization of hemoglobin levels, patients with thalassemia major continue to lose bone mass. The increased bone turnover rate observed in thalassemic patients justifies the use of powerful anti-resorption drugs, such as bisphosphonates. To date, alendronate, pamidronate, and zoledronate seem to be effective in increasing bone mineral density and normalizing bone turnover, but more trials are necessary to evaluate their efficacy in reducing fracture risks in larger thalassemic populations.

Hepatic osteodystrophy: does the osteoprotegerin/receptor activator of nuclear factor-kB ligand system play a role?

Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease (CLD). Recently, two new cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor-kB ligand (RANKL), have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases. Therefore, the aim of our study was to evaluate bone metabolism, bone mineral density (BMD) and OPG/RANKL system in 65 male patients with CLD and in 65 healthy controls. Our patients showed lower BMD values than controls both at lumbar and femoral levels. Moreover, they had an unbalanced bone turnover with an increased resorption phase, as shown by high levels of urinary deoxypyridinoline and a decreased formation phase, as shown by the slightly, but significant, low levels of bone-alkaline phosphatase. Patients showed lower plasma levels of free-testosterone than controls and higher - although not significantly so - plasma levels of 17 beta-estradiol. Furthermore, patients with CLD had higher levels of sex hormone-binding globulin and OPG, and lower levels of 25-hydroxyvitamin D (25-HOD) and IGF-I than the control group, while RANKL levels were similar in the two groups. In conclusion, our data do not confirm the hypothesis that the OPG/RANKL system could exert a key role in the pathogenesis of hepatic osteodystrophy, but rather that the observed increase in OPG levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption.

Effects of a long-term treatment with raloxifene on insulin sensitivity in postmenopausal women.

AIMS/HYPOTHESIS: Our aim was to investigate the effect of long-term administration of raloxifene, a selective estrogen receptor modulator, on insulin sensitivity, glucose tolerance and plasma lipid concentrations in a group of postmenopausal women. METHODS: A total of 24 women with postmenopausal osteoporosis were consecutively enrolled and randomly assigned to take raloxifene, 60 mg/day for 12 months or placebo. At baseline and after 6 and 12 months, in each subject insulin sensitivity (M-index) was assessed by means of an euglycaemic hyperinsulinaemic clamp. Plasma concentrations of total cholesterol, triglycerides and HDL-cholesterol were also measured and glucose tolerance was evaluated. RESULTS: In the raloxifene-treated group, the M index decreased after 6 and 12 months with respect to the placebo group (-21%, p=0.042 and -23%, p=0.018, respectively). Neither fasting plasma glucose nor glucose tolerance changed in the raloxifene-treated group, compared to the placebo group. Low density lipoprotein cholesterol concentrations decreased at 12 months (-13%, p=0.047). CONCLUSION/INTERPRETATION: A long-term treatment with raloxifene in osteoporotic, otherwise healthy post-menopausal women can reduce insulin sensitivity without affecting glucose tolerance.

Three-year effectiveness of intravenous pamidronate versus pamidronate plus slow-release sodium fluoride for postmenopausal osteoporosis.

All currently available and approved therapies for osteoporosis inhibit bone resorption. But, despite their great value, antiresorptive agents are generally not associated with dramatic increases in bone mass. In light of these data, the aim of our prospective, placebo-controlled, randomized clinical trial, with a 3-year follow up, was to examine the effects of cyclic intravenous pamidronate and fluoride in combination, versus pamidronate alone, on bone mineral density (BMD) at vertebral and femoral levels, biochemical markers of bone turnover, IGF-1 serum levels, and safety and tolerability in 40 postmenopausal women with osteoporosis. During the treatment period, pamidronate alone reduced both markers of bone formation and bone resorption, resulting in an increase of BMD, after 3 years, of 7.07% at the lumbar level and of 6.76% at the femoral level. In the group treated with pamidronate and fluoride, markers of bone turnover had a different trend: after 3 years, there was a lower reduction of bone resorption and an increase of bone formation markers, with a concomitant increase in IGF-1 levels. This resulted, after 3 years of treatment, in a marked variation of BMD at the lumbar level (+12.74%) and a reduced, but still significant, increase at the femoral level (3.89%). Spine radiography and clinical evaluation did not reveal any vertebral fractures in either treatment group. In conclusion, the combined use of pamidronate and fluoride produced somewhat larger, continuous increases in BMD, at the lumbar level, than pamidronate alone.

Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women.

OBJECTIVE: To evaluate the effects of a 6 month administration of raloxifene hydrochloride, a selective estrogen receptor modulator which was recently approved for the prevention of osteoporosis, on serum gonadotropin and prolactin (PRL) levels and on TRH-stimulated PRL responsiveness in postmenopausal women who have not undergone estrogen replacement therapy. DESIGN AND METHODS: Sixteen healthy postmenopausal women were divided into two groups on the basis of their bone status, evaluated by dual energy X-ray absorptiometry at the lumbar level. Eight women (chronological age 52.4+/-4.1 (s.d.) years, menopausal age 42.4+/-3.9 years), in whom T-score L2-L4 was less than -2.5 s.d., were treated with raloxifene (60 mg p.o.) administered daily for 6 months (group 1), while the other eight women (chronological age 52.6+/-2.5 years, menopausal age 42.1+/-3.6 years), in whom the T-score L2-L4 ranged between -1 and -2.5 s.d., were used as a control group (group 2). Serum PRL, FSH, LH and 17beta-estradiol (E2) levels were evaluated at baseline and after 3 and 6 months of treatment. In all subjects, PRL responsiveness to TRH (200 microg i.v.) administration was evaluated at baseline and at the end of the study. RESULTS: At baseline, mean PRL, LH and FSH levels were not significantly different in the two groups (PRL 133.6+/-21.7 vs 136.7+/-28.1 mIU/l (NS), LH 25.1+/-6.8 vs 24.4+/-6.7 mIU/ml (NS), FSH 74.4+/-25.0 vs 71.1+/-24.1 mIU/ml (NS), in group 1 and group 2 respectively). No significant variations in serum FSH and LH values, in either group, or in serum PRL levels in group 2, were observed at the 3 and 6 month examinations. On the contrary, serum PRL values decreased significantly in group 1 after 3 months (100.1+/-47.7 mIU/l, P<0.05) and 6 months (81.5+/-30.2 mIU/l, P<0.001). At baseline, no significant differences were observed in the TRH-stimulated serum PRL peak between the groups (1015.4+/-30.5 vs 1030.2+/-25.7 mIU/l in group 1 and in group 2 respectively), while it decreased significantly at the 6 month examination in group 1 (770.5+/-47.4 mIU/l, P<0.001) and it was significantly lower than in group 2 (1068.1+/-301.8 mIU/l, P=0.02). Serum E2 was not detected at baseline and at each examination, in all patients. CONCLUSIONS: The decrease of PRL values induced by long-term raloxifene administration in postmenopausal women could be explained by a direct antiestrogenic effect of raloxifene on lactotrope cells or by the recently suggested increase of opiatergic tone on the hypothalamic-pituitary region.

Bisphosphonates in the treatment of thalassemia-induced osteoporosis.

The aim of our randomized, placebo-controlled study was to investigate the effects of 2 years' daily oral administration of alendronate or intramuscular administration of clodronate every 10 days, on bone remodeling parameters and bone mineral density (BMD), safety and tolerability in a group of osteoporotic thalassemic patients. Twenty-five young patients (mean age 26.6 +/- 7.1 years) with beta-thalassemia major were randomly divided to receive placebo or 100 mg of clodronate intramuscularly every 10 days or 10 mg of alendronate per os daily. All patients took 500 mg of elemental calcium and 400 IU cholecalciferol in the evening at meal time. After 2 years, pyridinium crosslinks, which are bone resorption markers, did not differ significantly from baseline values in the placebo group, whereas they had decreased significantly in the clodronate and alendronate groups. Osteocalcin, a bone formation marker, did not change significantly in the placebo group, whereas it decreased slightly, but not significantly, in the clodronate and alendronate groups after 12 and 24 months. At the end of the study, the lumbar spine BMD had decreased significantly in the placebo group; it did not change significantly in the clodronate group; in the alendronate group it had increased but not significantly, whereas the increase was significant with respect to the placebo group. Femoral neck BMD decreased significantly in the placebo group; it did not change significantly in the clodronate group, but increased significantly in the alendronate group. No relevant side effects were recorded during our study. In conclusion, in patients with thalassemia-induced osteoporosis, the daily administration of alendronate significantly increases BMD, the most important predictor of the risk of fracture at several sites. Clodronate treatment at our dosage is ineffective in this pathology in spite of the good compliance of patients.

Osteoporosis and beta-thalassemia major: role of the IGF-I/IGFBP-III axis.

Patients with beta-thalassaemia major are susceptible to osteopenia due to several factors which interfere with bone remodeling. It is known that bone metabolism and skeletal consolidation result from a complex sequence of hormonal changes, where the concerted actions of GH, IGF-I and sex hormones and their receptors, are responsible for the timing and attainment of skeletal consolidation. IGF-I and the corresponding binding protein (IGFBP-III), markers of bone metabolism and lumbar and femoral neck BMD were measured in 28 adult patients, undergoing hormonal replacement and chelation therapy and a hypertransfusion program, with beta-thalassaemia major (12 males with mean age 22.5+/-3.1 and 16 females with mean age 27.5+/-8.2), and in 28 healthy volunteers matched for age, anthropometric features and sex to the patients. BMD values, both at lumbar and femoral neck level were significantly lower (p<0.001 and p<0.05) by 18.7 and 4.2% respectively, in patients than in the controls. Markers of bone resorption [pyridinoline (Pyr) 78.1+/-15.7 vs 47.5+/-11.2 pmol/pmol urinary creatinine, p<0.001 and deoxypyridinoline (D-Pyr) 21.9+/-3.5 vs 14.5+/-5.4 pmol/ micromol urinary creatinine, p<0.001] were higher in patients than in controls, whereas the marker of bone formation was slightly lower [osteocalcin (BGP) 3.8+/-0.6 vs 4.6+/-1.7 pmol/ml, p<0.05]. Plasma levels of IGF-I (21.07+/-5.12 vs 35.25+/-8.33 nmol/ml, p<0.001) and IGF binding protein III (IGFBP-III) (1.9+/-0.4 vs 2.5+/-0.1 mg/ml, p<0.001) were lower in patients than in controls and positively correlated with BMD L2-L4 (r=0.57, p<0.05 and r=0.47, p<0.05 respectively), BMD neck (r=0.40, p<0.05 and r=0.34, p<0.05 respectively) and BGP (r=0.52, p<0.05 and r=0.34, p<0.05 respectively). Our beta-thalassaemic patients, in spite of normalizing hemoglobin levels, adequate hormone replacement and chelation therapies, showed osteopenia and an unbalanced bone turnover with an increased resorptive phase and a decreased formation phase probably correlated to low levels of IGF-I and IGFBP-III observed in our study.

Metabolic effects of dehydroepiandrosterone replacement therapy in postmenopausal women.

OBJECTIVE: To investigate whether long-term treatment with dehydroepiandrosterone (DHEA) in postmenopausal women can modify insulin sensitivity and plasma lipid profile. DESIGN AND METHODS: Twenty healthy postmenopausal women with serum dehydroepiandrosterone sulfate (DHEA-S) concentrations <2.5 micromol/l were enrolled and randomly assigned to two different treatment groups: group 1 were treated with micronized DHEA, 25 mg/day at 0800 h for 12 months; group 2 were treated with an identical placebo tablet. At the beginning and at the end of the study, plasma lipid profile, glucose tolerance (oral glucose tolerance test) and insulin sensitivity (euglycemic hyperinsulinemic clamp: M index) were assessed. RESULTS: After 12 months, the group treated with DHEA showed a considerable improvement of insulin sensitivity (M index +29.55%, P=0.01) and lipid pattern (high-density lipoprotein cholesterol +11.61%, P=0.03; low-density lipoprotein cholesterol -11.07%, P=0.04; triglycerides -19.60%, P=0.03), but glucose tolerance did not change. No modifications were observed in the placebo group. CONCLUSIONS: Long-term treatment with DHEA ameliorates some metabolic parameters that are linked to increased cardiovascular risk and, consequently, this seems to be an interesting therapeutic tool in the management of the postmenopausal syndrome.

Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women.

The endothelium is thought to play an important role in the genesis of atherosclerosis, and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events. Estrogen has direct effects on the blood vessel wall, indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium-dependent vasodilatation in postmenopausal women. Healthy postmenopausal women (n=90) were enrolled in a double-blind, randomized, placebo-controlled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 mg 17beta-estradiol combined with 0.5 mg norethisterone acetate), raloxifene (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothelin levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5+/-10.7 micromol/L and increased to 36.3+/-11.4 micromol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3+/-8.9 pg/mL and decreased to 11.5+/-2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3+/-2.1% at baseline and increased to 12.3+/-2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the participants treated with placebo. We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation is warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality.