Nancy Morabito

Neridronate Prevents Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

Today, androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, although it presents important complications such as osteoporosis. Neridronate, a relatively new bisphosphonate, is able to prevent bone loss in patients with prostate cancer during androgen ablation.

Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus

BACKGROUNDnSclerostin is an osteocyte-derived inhibitor of the Wnt/β-catenin signaling pathway, which acts as a negative regulator of bone formation. Published data on sclerostin levels in type 1 diabetes mellitus (T1DM) are few.nnnOBJECTIVEnTo evaluate gender differences in sclerostin serum levels and the association among sclerostin, bone mass, bone metabolism, and the main clinical characteristics of subjects with T1DM.nnnDESIGN AND METHODSnA total of 69 patients with T1DM (mean age, 33.7±8.1; 49% males) were enrolled in this cross-sectional study in a clinical research center. Bone mineral density was measured by phalangeal quantitative ultrasound (QUS); bone turnover markers (urinary pyridinoline, deoxypyridinoline (D-PYR), and urine hydroxyproline (OH-PRO) to evaluate bone resorption; serum bone alkaline phosphatase and BGP to evaluate bone formation) and sclerostin were assessed.nnnRESULTSnD-PYR and sclerostin were significantly higher in women when compared with men (P=0.04). A disease duration >15 years was associated with higher sclerostin levels (P=0.03). Bone turnover markers and QUS parameters were not correlated with sclerostin. A significant negative correlation was observed among QUS parameters, BMI, and OH-PRO. Sclerostin serum levels were correlated with homocysteine (r=-0.34, P=0.005) and vitamin B12 (r=-0.31, P=0.02). Generalized linear model showed that macroangiopathy was the only predictor of sclerostin serum levels (β=-11.8, 95% CI from -21.9 to -1.7; P=0.02).nnnCONCLUSIONSnOur data demonstrate that women with T1DM exhibit higher sclerostin levels than men and that circulating sclerostin is not associated with bone turnover markers and phalangeal QUS measurements. Macroangiopathy was associated with sclerostin levels.

Effect of long-term treatment with raloxifene on mammary density in postmenopausal women.

Objective: To evaluate in a group of postmenopausal women the effects of long-term raloxifene treatment on breast density using a digitized analysis of mammograms and on insulinlike growth factor-1 (IGF-1), insulinlike growth factor binding protein-3 (IGFBP-3), and sex hormone-binding globulin (SHBG) plasma levels. Design: Seventy healthy postmenopausal women with normal body weight were enrolled in this study and were divided into two groups based on their bone status, evaluated by dual-energy x-ray at the lumbar spine (L2-4). Fifty women (chronological age 52.4 ± 4.1 y, menopausal age 42.1 ± 3.9 y), in whom the L2-4 T score was less than −2.5 SD, were treated with raloxifene HCl 60 mg/day orally for 2 years. The other 20 women (chronological age 53.6 ± 3.5 y, age at menopause 43.1 ± 3.6 y), in whom the L2-4 T score ranged between −1 and −2.5 SD, were enrolled as controls. All 70 women received calcium (1 g/d orally) and cholecalciferol (880 UI/d orally) supplementation. Moreover, all women followed a normocaloric and personalized diet. All women had mammography at baseline and after 2 years of therapy. The mammographic images on traditional support (radiography) were acquired by using a film scanner and were then elaborated by means of ad hoc software. Moreover, assessments of IGF-1, IGFBP-3, and SHBG plasma levels were obtained at baseline and after 24 months. Results: After 24 months of therapy, there was a significant variation in the raloxifene-treated group with respect to baseline in the distribution of gray classes of radiographic images. In particular, an attenuation of graphic trace with a reduction of the areas with the lowest and most elevated gray classes was observed. In the control group, no significant variations of graphic traces were observed. Moreover, raloxifene treatment significantly reduced IGF-1 and increased IGFBP-3 and SHBG plasma levels at 24 months. During follow-up, IGF-1, IGFPB-3, and SHBG levels did not change significantly in the control group. Conclusions: Long-term treatment with raloxifene in a population of postmenopausal women is able to reduce breast density. Such an effect could perhaps explain the reduction in the incidence of mammary carcinoma observed in the Multiple Outcomes of Raloxifene Evaluation study probably due to the direct antiestrogenic activity of raloxifene on mammalian tissue and/or its indirect activity increasing SHBG levels or modifying the IGF-1/IGFBP-3 ratio.

Influence of recombinant erythropoietin on the production of endothelin-1 from human umbilical artery.

Prof. Michele Buemi, MD, Via Oddo delle Colonne 16, I-98100 Messina (Italy) Dear Sir, Induced hypertension due to treatments with recombinant erythropoietin (rHuEPO) is with no doubt the most frequent and important side effect of this hormone therapy, capable of conditioning the therapeutic success in subjects affected by anemia from renal failure. Although different factors, among which the increase in hematic viscosity, are recognized as possibly responsible for the pressure rise which often goes along with rHuEPO treatment, up to now a reliable explanation of the pathogenetic mechanisms of hypertension induced by erythropoietin [1] is still missing. In previous investigations, through the evaluation of the changes brought about by the intravenous administration of rHuEPO on the pretibial flux by means of the Xenon 133 clearance, we showed the existence of a direct vasoconstric-tive action exerted by erythropoietin on the compliance vasa [2]. The presence of endothe-lial receptors for the erythropoietin could give account of such action [3]. Furthermore, in our previous investigations as well as in other investigations [4], it was shown how the intravenous chronic treatment was able to change the plasma levels of endothel·in-1, a substance produced by the endothelium, able to induce a high vasoconstriction. Yet, the plasma dosage of endothelin does not seem to correspond to the real activity of the vasal endothelium. Therefore, we wanted to use an experimental model based on the umbilical arteries, where the receptors for endothelin are to be found [5]. The arteries were quickly Fig. 1. Production of immunoreactive endothelin-1 (ir ET-1) in the umbilical artery: electrolytic solution (I); rHuEPO solvent (II); 30 U of rHuEPO (III). 20 μl of solvent. Then, the 3 umbilical artery segments were kept for 10 min at 37 °C, were weighed and the corresponding supernatant frozen at -30 °C, the endothelin-1 was dosed with the RIA method (Amersham, UK). The results obtained from 25 umbilical arteries showed the presence of a significant increase in the concentration of endothelin-1 from the medium to

Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis.

CONTEXTnSclerostin is a circulating inhibitor of the Wnt-signaling pathway produced by osteocytes, which acts as a negative regulator of bone formation. Effects of zoledronic acid on sclerostin serum levels in postmenopausal osteoporosis are unknown.nnnOBJECTIVEnThe purpose of this study was to evaluate sclerostin serum levels after zoledronic acid administration and correlate variations with bone turnover markers.nnnDESIGN AND SETTINGnWe conducted a prospective intervention study in an ambulatory care setting.nnnPARTICIPANTS AND INTERVENTIONnForty women (mean age 62.6 ± 4.9 years) with postmenopausal osteoporosis were enrolled in this study and randomized into 2 groups to receive zoledronic acid (5 mg) or placebo.nnnMAIN OUTCOMES MEASURESnAt baseline and then at 2, 7, 30, and 360 days after zoledronic acid or placebo administration, serum levels of sclerostin, bone-specific alkaline phosphatase (BSAP), as a bone formation marker, and serum C-telopeptide of type 1 collagen (CTX), as a bone resorption marker, were measured.nnnRESULTSnSclerostin serum levels increased by day 2, reached a peak at day 7 (3-fold baseline, P < .001), and then decreased at day 30 and returned near to baseline after 360 days in the zoledronic acid group. Both CTX and BSAP were reduced, and a significant negative correlation was observed between the percentage changes of sclerostin and the variation in BSAP and CTX at all time points in the zoledronic acid group (P < .05). No changes were observed in the placebo group.nnnCONCLUSIONSnOur data demonstrate that zoledronic acid increases sclerostin serum levels and that sclerostin could play a role in coupling bone resorption to bone formation.

Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis.

The acute-phase response (APR) is a frequent occurrence after infusion of zoledronic acid and is caused by activation of γδ T cells. Vitamin D receptor is expressed in immune cells, and vitamin D has immunomodulatory properties. The aim of this prospective study was to test the effect of vitamin D (cholecalciferol) on the incidence of APR and intensity of pain in women undergoing infusion of zoledronic acid for postmenopausal osteoporosis. 60 women were enrolled and randomized into two groups. At baseline, 30 women received an oral bolus of cholecalciferol (300,000xa0IU), while another 30 women received placebo. On day 5 both groups were treated with a single infusion of zoledronic acid (5xa0mg) and received a daily supplementation of calcium (1,000xa0mg) and vitamin D (800xa0IU). Patients were clinically evaluated and inflammatory markers were assayed before zoledronic acid administration and every 24xa0h for the following 2xa0days. The onset of APR has been defined by the occurrence of fever or at least one of the typical symptoms, such as musculoskeletal pain after zoledronic acid infusion. Intensity of pain was measured by a one-dimensional scale (0xa0=xa0no pain, 10xa0=xa0unbearable pain). APR developed in 66.6% of patients, with no significant difference between groups. The vitamin group experienced less musculoskeletal pain [median 1 (0–4) vs. 2 (1–8), Pxa0<xa00.05] and exhibited lower inflammatory markers (Pxa0<xa00.005 vs. placebo). Our data demonstrate that cholecalciferol at a dose of 300,000xa0IU reduces the intensity of musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis.

Pharmacological management of severe postmenopausal osteoporosis.

The most devastating consequence of osteoporosis is bone fracture, particularly at the vertebral or femoral level. As defined by the WHO, patients with osteoporosis who have had one or more fragility fractures have severe osteoporosis. Those who sustain a vertebral fracture represent a particularly vulnerable group whose risk of another vertebral fracture within the following year is increased by a factor of 3–5. In addition, the presence of a vertebral fracture is associated with an increased risk of hip fracture. In light of these data, treatment of established osteoporosis is extremely important to prevent other fragility fractures. This review examines the therapies approved by the US FDA for the treatment of osteoporosis that have been shown to reduce the incidence of new fractures in patients with established osteoporosis. We evaluated the mechanisms of action, available formulations, efficacy in preventing fractures and increasing bone mineral density (BMD), duration of treatment, adverse effects and contraindications to use of alendronic acid (alendronate), risedronic acid (risedronate), calcitonin, raloxifene and teriparatide. All these drugs are able to prevent new vertebral fractures in patients with established osteoporosis. Only alendronic acid and risedronic acid have also been shown to reduce the risk of fracture at the femoral level, but they are contraindicated in patients with upper gastrointestinal diseases. Calcitonin is a good option in subjects with back pain because of its analgesic effect. Raloxifene is useful when patients have high plasma lipid levels or a family history of breast cancer. Teriparatide is indicated in subjects with very low BMD and multiple vertebral fractures. Patient characteristics should determine selection of therapy but the decision is always difficult and fraught with uncertainty.

Iron Burden and Liver Fibrosis Decrease During a Long-Term Phlebotomy Program and Iron Chelating Treatment After Bone Marrow Transplantation

In this retrospective study, we report the results of the association of a combined phlebotomy program and chelation in hereditary sideroblastic anemia (HSA) to reduce iron overload after bone marrow transplantation (BMT). A male HSA patient, not responding to pyridoxine treatment, was submitted to successful allogeneic BMT. As there was a persistence of a tissue iron overload, a regular phlebotomy program was started followed by chelation. A significant decrease of iron burden was obtained using a combined treatment with deferoxamine (DFO) and deferiprone (L1) in addition to the phlebotomy program. A 10-year follow-up shows a marked decrease in the concentration of serum ferritin, non-transferrin-bound iron (NTBI), liver iron and normal hemoglobin (Hb), which allows the patient to reach and maintain a good quality of life.

Role of genetic pattern on bone mineral density in thalassemic patients.

OBJECTIVESnTo evaluate the role of genetic background in osteoporosis/osteopenia development in beta-Thalassemia Major patients.nnnDESIGN AND METHODSnThe influence of VDR (FokI, BsmI) as well as COLIA1 (Sp1) gene polymorphisms on BMD was investigated in 40 patients.nnnRESULTSnAlthough the examined gene polymorphisms did not significantly affect BMD variations in our population, BsmI was found to display beneficial effects on patient response to alendronate therapy.nnnCONCLUSIONnGenetic factors retain a potential role for improvement of osteoporosis management in thalassemic patients.

Impact of diabetes on cognitive impairment and disability in elderly hospitalized patients with heart failure

Heart failure (HF) and diabetes mellitus (DM) are each associated with cognitive impairment and disability. The aim of the present study was to evaluate the impact of DM on cognitive impairment and functional status in elderly hospitalized patients affected by HF.