Antidiabetic therapy effects on bone metabolism and fracture risk.

Patients with diabetes are at greater risk of fractures mostly due to not only to extraskeletal factors, such as propensity to fall, but also to bone quality alteration, which reduces bone strength. In people with diabetes, insulin deficiency and hyperglycaemia seem to play a role in determining bone formation alteration by advanced glycation end product (AGE) accumulation or AGE/RAGE (receptors for AGE) axis imbalance, which directly influence osteoblast activity. Moreover, hyperglycaemia and oxidative stress are able to negatively influence osteocalcin production and the Wnt signalling pathways with an imbalance of osteoblast/osteoclast activity leading to bone quality reduction as global effect. In addition, other factors such as insulin growth factors and peroxisome proliferator-activated receptor-γ pathways seem to have an important role in the pathophysiology of osteoporosis in diabetes. Although there are conflicting data in literature, adequate glycaemic control with hypoglycaemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 diabetes. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycaemic control. Finally, preliminary data on animals and in humans suggest the hypothesis that incretins and dipeptidyl peptidase-4 inhibitors could have a positive effect on bone metabolism by a direct effect on bone cells; however, such issue needs further investigations.

Diabetes and CoViD-19: Experience from the frontline of Internal Medicine wards in Italy.

Available data suggest that the issue of CoViD-19 is particularly critical in patients with diabetes. In Italy, Internal Medicine (IM) wards have played a pivotal role in contrasting the spread of SARS-Cov2. During this pandemic, FADOI submitted a brief questionnaire to a group of its members acting as Head of IM units. Considering 38 units, 58% of beds dedicated to CoViD patients in CoViD Hospitals were in charge of IM, and globally cared for 6650 patients during a six-week period. Of these patients, 1264 (19%) had diabetes. Mortality rate in CoViD patients with or without diabetes were 20.5% and 14%, respectively (p < 0.001). Our survey seems to confirm that diabetes is a major comorbidity of CoViD-19, but it does not support an increased incidence of CoViD-19 infection in people with diabetes, if compared with the figures of patients with diabetes and hospitalized before the outbreak. On the other side, patients with diabetes appeared at a significantly increased risk of worse outcome. This finding underlines the importance of paying special attention to this patient population and its management.

Hospitalization and mortality for acute exacerbation of chronic obstructive pulmonary disease (COPD): an Italian population-based study.

OBJECTIVE: Patients with acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD) have a significant mortality and morbidity. Previous studies have identified a number of independent prognostic factors. However, information on hospital admission databases is limited and data regarding short-term prognosis of these patients in Italian hospitals are lacking. Thus, we performed an epidemiological study on hospital admission for COPD acute exacerbation in Italy. PATIENTS AND METHODS: Patients were identified using clinical Modification (ICD-9-CM) codes. Information was collected on baseline characteristics, vital status at discharge, duration of hospitalization, and up to five secondary discharge diagnoses. Comorbidity was evaluated using the Charlson comorbidity index (CCI). RESULTS: During the observation period (2013-2014), 170,684 patients with COPD acute exacerbation were hospitalized. Mean length of hospitalization (LOH) was 9.95±8.69 days and mean in-hospital mortality was 5.30%. These data correspond to the 4.1% of all hospitalizations and to the 2.8% of all the days of hospitalization in Italy during the study period. In-hospital mortality and LOH varied among different regions (from 3.13 to 7.59% and from 8.22 to 11.28 days respectively). Old age, male gender, low discharge volume, previous hospitalization for COPD exacerbation and CCI resulted as significantly associated with higher in-hospital mortality. CONCLUSIONS: Hospitalization for COPD exacerbation is extremely frequent even in contemporary Italian population. COPD exacerbation is clinically demanding with a not negligible short-term mortality rate and a mean LOH approaching 10 days. These latter findings were quite variable in different regions but should be further analyzed to set up appropriate health-care policies on COPD patients.

Bone ultrasonography at phalanxes in patients with Rett syndrome: a 3-year longitudinal study.

Osteopenia is a frequent and early complication of Rett syndrome. This study aimed to evaluate the usefulness of Quantitative Ultrasonography (QUS) at phalanxes in the assessment and monitoring of bone status in Rett patients. We studied 109 girls (10.1+/-6.1 years; range 3-25 years) and 101 age-matched controls. Serum calcium (Ca), bone alkaline phosphatase (B-ALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD) and QUS parameters at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT) were measured. At baseline both QUS parameters and 25OHD levels were significantly lower in Rett patients than in controls. Serum 25OHD was inversely correlated with serum PTH and BTT Z-score and BTT Z-score was significantly lower (p<0.05) in the girls with a 25OHD serum levels

Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane.

Recently the third generation aromatase inhibitors have proved their efficacy and tolerability compared with tamoxifen in the adjuvant treatment of women with hormone responsive early breast cancer. However, there is some concern about the possible negative impact of these drugs on bone. The aim of the study was to evaluate the effects of the steroidal aromatase inactivator exemestane on bone turnover markers and on bone mineral density (BMD). Seventy postmenopausal women (62.0+/-8.9 years) with completely resected breast cancer and who were disease-free following 2-3 years on tamoxifen were randomly assigned to continue tamoxifen (n=36) or switch to exemestane (n=34). Sixty-one patients completed the 2-year study period. Bone alkaline phosphatase (B-ALP) and the carboxy-terminal telopeptide of type I collagen (CTX) were measured at baseline and after 3, 6, 9, 12, 18 and 24 months. BMD at lumbar spine (BMD-LS), at femoral neck (BMD-FN), at total hip (BMD-T) and at whole body (BMD-WB) were measured at 6-monthly intervals. Exemestane-treated women showed significant (p<0.01) increases with respect to baseline in both B-ALP and CTX. The difference between the 2 groups reached the statistical significance at month 6 for CTX (p<0.05) and at month 9 for B-ALP (p<0.01). Moreover, the exemestane-treated women showed an early decrease in PTH serum levels (-20.4%, p<0.01 at month 6). In the E group, the percentage changes were -2.37 (p<0.05) BMD-LS, -1.24 (p<0.05) BMD-FN, -1.1 (n.s.) BMD-T, -1.03 (n.s.) BMD-WB at month 12 and -2.99 (p<0.01) BMD-LS, -1.92 (p<0.01) BMD-FN, -2.01 (p<0.05) BMD-T, -1.3 (n.s.) BMD-WB at month 24. The tamoxifen group did not show significant changes in BMD. The differences between the two groups were significant at all skeletal sites except BMD-WB. Our data suggest that switching postmenopausal women from tamoxifen to exemestane causes a marked increase in bone turnover markers with a consequent reduction in BMD. These findings could be due to both the direct effect of exemestane and to the loss of the protective effect of tamoxifen. Therefore, the postmenopausal women switched from tamoxifen to exemestane should be monitored for bone loss especially if other risk factors for osteoporosis are present.

Vitamin D and estrogen receptor allelic variants in Italian postmenopausal women: evidence of multiple gene contribution to bone mineral density.

Bone mass and bone turnover are under genetic control. Restriction fragment length polymorphisms (RFLPs) at the vitamin D receptor (VDR) gene locus have been recently correlated to bone mineral density (BMD) and rate of bone loss. However, agreement on this relationship is not universal. The existence of ethnical and environmental differences between populations, a health-based selection bias in several previous studies, and the involvement of other genes could explain these discordant findings. In this study, we examined the relationship of VDR and estrogen receptor (ER) gene RFLPs with lumbar spine and upper femur BMD in 426 Italian postmenopausal women, 57.7 +/- 0.4 yr old (144 normal, 106 osteopenic, and 176 osteoporotic). VDR gene RFLPs for ApaI, Bsm I, and TaqI restriction endonucleases and ER RFLPs for PvuII and XbaI restriction endonucleases were assessed by Southern blotting analysis and were indicated, respectively, as A-a, B-b, T-t, P-p, and X-x (uppercase letters signifying the absence and lowercase letters the presence of the restriction site). After correcting for potential confounding factors (age, height, weight, age since menopause, osteophytosis, and facet joint osteoarthritis), a statistically significant VDR genotype effect on lumbar BMD (P = 0.01, analysis of covariance), but not on femoral BMD, was detected, with subjects in AABBtt genotype showing a 13% lower BMD than those with aabbTT genotype (P < 0.05, Tukey's test). Moreover, a statistically significant prevalence of AABBtt genotype in osteoporotics, and of AabbTT and aabbTT genotypes in nonosteoporotics, were detected. Conversely, there was no significant relationship of ER genotype to either lumbar or femoral BMD, even though a trend for higher BMD values in women with the ER PP genotype (with respect to those with ER pp genotype) was detected. When mean lumbar BMD was calculated for women grouped by ER and VDR genotype, we observed a significant difference between those within the 2 opposite associations AABBtt-PPXX and aabbTT-ppxx (0.71 +/- 0.05 vs. 0.97 +/- 0.03 g/cm2, P < 0.05 Tukey's test). These results are consistent with a segregation of the VDR AABBtt genotype with a higher risk of developing osteoporosis, in the Italian female population. The introduction of another variable, the ER genotype, in the analysis of VDR genetic determination of BMD, may represent a useful model in the identification of patients at risk of developing a multigenic disorder like osteoporosis.

Changes in serum HDL and LDL cholesterol in patients with Paget's bone disease treated with pamidronate.

Amino bisphosphonates represent one of the most important advances in the management of Paget's and other metabolic bone diseases. Although their mechanism of action has not yet been completely clarified, they seem to inhibit the mevalonate pathway and so they could interfere with cholesterol synthesis. The present study aimed to evaluate cholesterol and lipoprotein serum levels in patients with Paget's bone disease treated with intravenous pamidronate. The study included 20 consecutive patients (mean age, 67.6 +/- 11.0 years) with Paget's bone disease for at least 1 year, who needed intravenous amino bisphosphonate treatment; 12 patients with inactive Paget's bone disease served as controls. The patients with active Paget's bone disease underwent three cycles (every 3 months) of treatment with 60 mg of intravenous pamidronate. Controls were given a saline infusion following the same administration schedule. In all subjects total alkaline phosphatase (total ALP), bone alkaline phosphatase (bone ALP), total cholesterol (TC), tryglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) were measured before infusions (pamidronate or saline) at baseline and at 3-month intervals up to 9 months. In the control group no significant changes were observed through the study period for any of the biochemical parameters. In the pamidronate-treated patients, both bone ALP and total ALP significantly fell at the end of the study. In patients with active treatment, at the end of the study period HDL-C significantly (P < 0.05) increased by 10.3%, whereas LDL-C significantly (P < 0.05) decreased by 5.5%. In these patients TC showed a negative trend without reaching statistical significance, whereas the HDL-C/LDL-C ratio rose 16.2% above the basal value and TC/HDL-C decreased by 12.5%. In conclusion, pamidronate given intravenously seems to be able to induce a prolonged shifting in circulating cholesterol from the LDL-C to the HDL-C from associated with a weak decrease in total cholesterol, thus producing a possible improvement in the atherosclerotic risk index.

Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study.

Although several studies have reported a lower risk of osteoporotic fracture in hypercholesterolemic patients treated with statins, so far longitudinal studies on the effects of statins on bone are lacking. The aim of the present study was to evaluate bone mineral density (BMD) and bone turnover changes induced by 1-year simvastatin treatment on postmenopausal women. Thirty consecutive postmenopausal hypercholesterolemic women (61.2 +/- 4.9 years) were treated for 12 months with 40 mg/day simvastatin and 30 normocholesterolemic age-matched postmenopausal women provided control data. In all subjects, at baseline and at 3-month intervals, serum lipids, calcium, phosphate, total and bone alkaline phosphatase (Bone-ALP), and carboxy-terminal fragment of type I collagen (CTx) were measured in a fasting blood sample. At baseline and after 6 and 12 months BMD was measured at lumbar spine (BMD-LS) and at femur (BMD-Ftot) and at femoral neck (BMD-Fn) by DXA. In the simvastatin-treated group Bone-ALP showed a significant increase (P < 0.05) with respect to baseline from the sixth month, whereas serum CTx showed a weak and nonsignificant increase over the study period. In treated women BMD-LS, BMD-Fn, and BMD-Ftot increased respectively by 1.1, 0.9, and 0.4% at Month 6; and by 2.8, 1.0, and 0.8% at Month 12. In controls BMD-LS, BMD-Fn, and BMD-Ftot at the end of the study period decreased by 1.6, 1.4, and 1.2%, respectively. The difference between controls and simvastatin-treated patients was significant (P < 0.05) for both BMD-LS and BMD-Fn only at Month 12. In conclusion our results, although obtained from a small sample of postmenopausal hypercholesterolemic women, suggest a probable positive effect of simvastatin on bone formation and BMD.

Effects of pravastatin treatment on vitamin D metabolites.

Hyperlipidemias, and notably hypercholesterolemia, represent important risk factors for atherosclerotic vascular disease. The enzymatic inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a selective and specific key enzyme involved in endogenous cholesterol synthesis, cause a significant mean reduction in low-density lipoprotein (LDL) cholesterol, both in familial and nonfamilial hypercholesterolemic forms. It has been hypothesized that these compounds might interfere with vitamin D endogenous synthesis secondarily to their effects on cholesterol. To verify this hypothesis, we studied 14 hypercholesterolemic patients treated as follows: 4 weeks of low-lipid, fiber-rich diet followed by 8 weeks of pravastatin treatment at the oral evening dose of 20 mg/d and by a 1-month washout period. No significant changes in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were noticed; on the contrary, significant (P < 0.01) reductions in total cholesterol and LDL cholesterol and a significant (P < 0.05) increase in high-density lipoprotein cholesterol were observed. After the final 1-month washout period, all values returned to baseline levels. In conclusion, our study confirms the clinical efficacy of pravastatin on lipid fractions and demonstrates the absence of any interference on the circulating levels of the main vitamin D metabolites.

Acanthocytosis, retinitis pigmentosa, pallidal degeneration. Report of two cases without serum lipid abnormalities.

We describe two unrelated patients with Hallervorden-Spatz, disease characterized by prominent facio-bucco-lingual dyskinesia. Acanthocytosis and retinitis pigmentosa were additional findings. Brain MRI showed the typical 'tiger's eye' image of the globus pallidus. This phenotype closely resembled the so-called HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration), but extensive serum lipid study failed to demonstrate any lipoprotein abnormality. Our results raise the question whether HARP syndrome is an autonomous entity or a particular phenotype of Hallervorden-Spatz disease.

The combined use of ultrasound and densitometry in the prediction of vertebral fracture.

Measurement of ultrasonographic parameters provides information concerning not only bone density but also bone architecture. We investigated the usefulness of ultrasonographic parameters and bone mineral density for evaluating the probability of vertebral fracture. 397 postmenopausal women (59.1 +/- 6.0 years) with (n = 178) or without (n = 219) atraumatic vertebral fractures were studied. In all women, bone mineral density (BMD) of the lumbar spine was evaluated by dual X-ray absorptiometry (DXA) and speed of sound (SOS); broadband ultrasound attenuation (BUA) and Stiffness in the calcaneus were evaluated by an Achilles unit (Lunar Corporation). Ultrasonographic parameters and BMD were compared by examining the magnitude of the odds ratios, to determine which produces the highest estimate of the probability of odds of fracture, and by examining widths of the respective confidence intervals (CI) to show which estimate of odd ratio is the most precise. The relative risk of vertebral fracture, after adjusting for potential confounders, was 3.5 (CI 2.6-4.8) for BUA; 4.5 (CI 3.2-6.2) for SOS; 5.8 (CI 4.0-8.4) for Stiffness and 7.5 (CI 4.8-11.5) for BMD. Ultrasound (US) parameters were still significant independent predictors of vertebral fracture, even after adjusting for BMD. The relative risk of fracture for a simultaneous decrease by 1 SD of BMD and by 1 SD of each ultrasound parameter was 17.3 (CI 9.4-39.6) for BMD and SOS; 18.3 (CI 8.4-30.6) for BMD and BUA and 22.1 (CI 8.9-52.7) for BMD and Stiffness. Our data suggest that US and BMD provide complementary information which can be combined to improve estimates of vertebral fracture risk.

Usefulness of bone quantitative ultrasound in management of osteoporosis in men.

In order to evaluate the usefulness of QUS at the phalanx in the diagnosis of osteoporosis and in the prediction of fracture risk in males. The study consisted of 182 subjects (age 61.2 +/- 9.4 yr), of which 22 had had a previous nontraumatic bone fracture. In all subjects, bone mineral density (BMD) at the lumbar spine and femur was measured by DXA. Moreover, in the same subjects, QUS parameters, the amplitude-dependent speed of sound (AD-SOS), and the parameters characterizing the graphic trace (fast-wave amplitude, signal dynamic, and bone transmission time [BTT]) were assessed at the phalanxes using the DBM Sonic 1200 (IGEA). According to World Health Organization (WHO) criteria, all the patients were divided into two groups: 62 osteoporotic subjects and 120 nonosteoporotic subjects. All QUS parameters were significantly lower in osteoporotic than in nonosteoporotic patients. Receiver operating characteristic (ROC) analysis showed a moderate ability of AD-SOS, BTT, and ultrasound bone profile index (UBPI) in distinguishing between healthy and osteoporotic men. Among osteoporotic patients, BMD values were lower in patients with fracture than in those without fracture. AD-SOS and BTT were significantly reduced in men with fracture. Furthermore, in a regression analysis, only BTT and DXA parameters were predictive of fracture. Moreover, performing a multivariate regression analysis BTT entered before BMD at the lumbar spine and at Ward's triangle. In conclusion, our data show that QUS parameters are reduced in osteoporotic males; however, only BTT was comparable to DXA parameters in the prediction of fracture risk in men.

Quantitative ultrasound in the assessment of skeletal status in uremic patients.

Renal osteodystrophy (ROD) can be characterized by both high (HT) and low (LT) bone turnover states. Although bone biopsy remains the "gold standard" to diagnose ROD, noninvasive tools for the diagnosis and follow-up of such bone disease are desirable. Recently, ultrasound (US) techniques, proposed to assess skeletal status, have been shown to be correlated not only with bone density but also with bone quality. We have investigated 98 patients on chronic hemodyalisis (HD) and 98 healthy, sex- and age-matched subjects. Amplitude-dependent speed of sound (AD-SOS) and ultrasound bone profile score (UBPS) at phalanxes and speed of sound (SOS), broadband ultrasound attenuation (BUA), and a quantitative ultrasound index (QUI/stiffness) at the heel were performed in both groups. In all subjects intact parathyroid hormone (PTH), total alkaline phosphatase (T-ALP), bone isoenzyme alkaline phosphatase (B-ALP), and carboxy-terminal telopeptide of type I collagen (ICTP) were assessed. All US parameters were significantly lower in the hemodialysis group than in control subjects. Moreover, among US parameters only AD-SOS and UBPS showed a significant correlation with PTH, T-ALP, and B-ALP. Dialytic age showed a modest, but significant correlation only with US parameters at the phalanxes. On the basis of bone biochemical markers, we considered a group with high and a group with normal to low bone turnover. AD-SOS and UBPS, but not SOS, BUA, and stiffness were significantly (p < 0.01) lower in the high bone turnover than in low bone turnover group. Furthermore, in the high bone turnover group, parameters of the US phalanxes strongly correlated with B-ALP. Our results seem to demonstrate that US parameters are a useful tool in the assessment of skeletal status in patients on maintenance dialysis.

Ketoconazole treatment of chronic mucocutaneous candidiasis.

The authors report the results of treatment with ketoconazole in 8 patients with chronic mucocutaneous candidiasis (CMC). The drug, administered in the dose of 200 mg once a day orally for a period of time varying from 2 to 12 months, led to improvement in or elimination of clinical symptoms in all patients. One patient had a relapse on suspension of treatment, but this regressed rapidly on resumption of ketoconazole. In 7 cases there were no side-effects. In one case there was an increase in serum liver enzymes which disappeared spontaneously 7 days after suspension of treatment. These results appear encouraging in view of the difficulty of treating this disease, which is often resistant to conventional antifungal therapy.

Preliminary results of a clinical trial relative to the use of rifamycin SV in the treatment of herpes zoster.

In a controlled clinical trial undertaken in ten Italian centres, rifamycin SV was compared to associations of various drugs such as erythromycin, aureomycin, multivitamin preparations, etc, in the treatment of herpes zoster. Up to now 144 patients, suffering from herpes zoster at different localizations, were divided into three groups and randomly given either rifamycin SV by intramuscular injection and topically, or rifamycin SV by injection only, or the routine treatment used at the particular centre in question. To evaluate the effectiveness of the treatments, the presence of subjective and objective symptoms was determined before treatment started and daily thereafter. The duration, in days, of the most important symptoms, such as erythema, vesicles, scabs and pain, was considered for this partial evaluation. All the above-mentioned symptoms constantly showed a shorter duration in the two groups treated with rifamycin SV compared to the group treated with other therapies, with differences as significant on statistical calculation as they were important on the level of a clinical evaluation of the disease's course.

[Clinical and genetic study of a family with hereditary essential myoclonus]. / Etude clinique et génétique d'une famille atteinte de myoclonus essentiel héréditaire.

A large family with essential hereditary myoclonus is reported. Symptoms and signs, the age of clinical onset and the evolution are presented. The disease is autosomal dominant with complete penetrance.

[A family with the EEC syndrome (ectrodactily, ectodermal dysplasia clefting syndrome): clinical variability and genetic counseling]. / Une famille atteinte de EEC-syndrome (ectrodactily ectodermal-dysplasia clefting syndrome): variabilité clinique et conseil génétique.

In a family with segregation of EEC-Syndrome we observed five children--two girls and three males--(two of them dizygotic twins) affected by very various phenotypes of the syndrome. The ocular symptomatology was represented by agenesis or stenosis of lacrimal ducts: two children were operated, the other suffered from frequent inflammations. The study of the family suggest an autosomic dominant heredity with defect of penetrance on the father.