Carla Caffarelli

Alendronate Treatment in Men With Primary Osteoporosis: A Three-Year Longitudinal Study

Bisphosphonates have been widely used in the treatment of osteoporosis in women, whereas until now there have been few data on their use in men. The aim of this study was to evaluate the effect of a 3-year alendronate treatment on bone mineral density (BMD) and quantitative ultrasound (QUS) in men with primary osteoporosis. We studied 77 osteoporotic men (aged 57.1 ± 10.8 yrs) who completed a 3-year treatment with alendronate (10 mg/day) plus calcium (1000 mg/day) (n = 39), or calcium alone (n = 38). At baseline and at a 12-month interval, we measured BMD at the lumbar spine and femur (femoral neck and total hip) by DXA (Hologic) and speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness (S) at the os calcis by Achilles plus (Lunar). Alendronate treatment had significantly increased lumbar spine BMD by 4.2% at year 1, by 6.3% at year 2, and 8.8% at year 3. BMD at the femoral neck and total hip had increased by 2.1% and 1.6% at year 1, by 3.2% and 2.9% at year 2, and by 4.2% and 3.9% at year 3, respectively. BUA and Stiffness showed a significant increase in the alendronate-treated group at year 2 (3.2% and 4.9%, respectively) and at year 3 (3.8% and 6%, respectively). BMD at the lumbar spine showed the best longitudinal sensitivity whereas longitudinal sensitivity of both QUS at the heel and femur BMD were similar. In conclusion, this study confirms that alendronate represents an important therapeutic advance in the management of male osteoporosis. BMD at the lumbar spine appears to be the best method for monitoring the effect of alendronate on bone mass in osteoporotic men.

Quantitative ultrasound and dual-energy X-ray absorptiometry in the prediction of fragility fracture in men

Fragility fractures in men represent a major health problem, and this prompts a necessity for reliable tools for the identification of men at risk of fracture. In order to assess the ability of dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in the prediction of fracture risk in men and whether their combination might be useful in a clinical setting, we studied 401 men (age range 45–82 years, mean 60.3±12.5), of whom 133 had osteoporotic fractures and 268 did not. In all subjects we measured bone mineral density at the lumbar spine (BMD-LS) and at the femur, calculating thereafter the standard femoral subregions: neck (BMD-FN), total hip (BMD-T), trochanter (BMD-TR), intertrochanter (BMD-ITR), and Ward’s triangle (BMD-W), by DXA. We also performed ultrasound parameters at the calcaneus: speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness, by Achilles plus, and at the phalanxes: amplitude dependent speed of sound (AD-SoS) and the parameters of the graphic trace: bone transmission time (BTT), fast wave amplitude (FWA), signal dynamic (SDy) and ultrasound bone profile index (UBPI), by Bone Profiler. All DXA and QUS parameters, apart from FWA, were significantly (P<0.001) lower in patients with a history of fracture. BMD at the proximal femur showed the best ability in discriminating men with or without fractures. QUS at the heel showed discriminatory ability significantly better than QUS at the fingers. By logistic regression analysis, adjusted for age and BMI, BMD-T showed the best association with fragility fracture [odds ratio (OR)=3.43, 95% confidence interval (CI)=2.47–4.77]. Among QUS parameters, the highest value of the OR was shown by stiffness (OR=3.18, CI=2.27–4.48). FWA and SDy were not associated with fragility fractures in men. If DXA and QUS were combined, the prediction of the OR of fragility fracture events in men increases; in fact Stiffness was able to increase the OR when added to BMD-LS (OR=5.44, CI=3.16–10.13) and BMD-T (OR=6.08, CI=2.63–14.27). SOS and BUA showed a similar pattern. AD-SoS improved the prediction of fracture only when combined with BMD-LS (OR=4.36, CI=1.99–9.57). If BMD-LS and BMD-FN or BMD-T were combined, the value of the OR increases (OR=4.59, CI=2.27–9.25 and OR=4.68, CI=2.24–9.76), respectively. Our study supports the effectiveness of QUS in the identification of osteoporotic fractures in men. QUS seems to play an independent and complementary role, with respect to DXA, in order to enhance the power for predicting osteoporotic fractures in men.

Obesity and fracture risk.

Obesity and osteoporosis are two common diseases with an increasing prevalence and a high impact on morbidity and mortality. Obese women have always been considered protected against osteoporosis and osteoporotic fractures. However, several recent studies have challenged the widespread belief that obesity is protective against fracture and have suggested that obesity is a risk factor for certain fractures. Fat and bone are linked by many pathways, which ultimately serve the function of providing a skeleton appropriate to the mass of adipose tissue it is carrying. Leptin, adiponectin, adipocytic estrogens and insulin/amylin are involved in this connection. However, excessive body fat, and particularly abdominal fat, produces inflammatory cytokines which may stimulate bone resorption and reduce bone strength. This review aimed to examine the literature data on the relationships of BMI and fat mass with factures in adult and elderly subjects. Even though the more recent studies have shown conflicting results, there is growing evidence that obesity, and particularly severe obesity, may be related to an increased risk of fracture at different skeletal sites which is partially independent from BMD. Moreover, the relationship between obesity and fracture appears to be markedly influenced by ethnicity, gender and fat distribution. Even though the incidence and the pathogenesis of fracture in obese individuals has not yet been clearly defined, the growing evidence that obesity may be related to an increased risk of fracture has important public health implications and emphasizes the need to develop effective strategies to reduce fracture risk in obese subjects.

Divergent effects of obesity on fragility fractures.

Obesity was commonly thought to be advantageous for maintaining healthy bones due to the higher bone mineral density observed in overweight individuals. However, several recent studies have challenged the widespread belief that obesity is protective against fracture and have suggested that obesity is a risk factor for certain fractures. The effect of obesity on fracture risk is site-dependent, the risk being increased for some fractures (humerus, ankle, upper arm) and decreased for others (hip, pelvis, wrist). Moreover, the relationship between obesity and fracture may also vary by sex, age, and ethnicity. Risk factors for fracture in obese individuals appear to be similar to those in nonobese populations, although patterns of falling are particularly important in the obese. Research is needed to determine if and how visceral fat and metabolic complications of obesity (type 2 diabetes mellitus, insulin resistance, chronic inflammation, etc) are causally associated with bone status and fragility fracture risk. Vitamin D deficiency and hypogonadism may also influence fracture risk in obese individuals. Fracture algorithms such as FRAX® might be expected to underestimate fracture probability. Studies specifically designed to evaluate the antifracture efficacy of different drugs in obese patients are not available; however, literature data may suggest that in obese patients higher doses of the bisphosphonates might be required in order to maintain efficacy against nonvertebral fractures. Therefore, the search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with obesity might be considered a clinical priority which could improve the prevention of fracture in obese individuals.

Osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANK-L) serum levels in patients on chronic hemodialysis

The mechanisms underlying the skeletal resistance to PTH in patients on chronic hemodialysis (CHD) are not yet fully clarified. Osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANK-L) modulate the genesis and activity of osteoclasts, however their role in renal osteodystrophy pathogenesis has not been clarified so far. The present study aimed to evaluate OPG and RANK-L serum levels in hemodialysis patients and whether OPG/RANK-L system could have a role in the skeletal resistance to PTH. In fasting blood samples obtainedfrom 60 patients (36 males and 24 females) on CHD for at least 2 yr and from 40 healthy subjects of similar age and gender distribution as controls (CTRs), we measured serum OPG, RANK-L, bone alkaline phosphatase (B-ALP), N-terminal telopeptide of type I collagen (NTx), PTH(1–84), calcium and phosphate. In 30 of 60 hemodialysis patients, a blood sample was also drawn soon after the dialytic session. Serum levels of RANK-L, but not OPG, showed a slight but significant (p<0.05) decrease after the dialytic session. OPG resulted being about six times higher in CHD patients than in CTRs (38.7±16.2 vs 6.3±0.17 pg/ml), whereas RANK-L serum levels were only slightly increased with respect to controls (0.88±0.47 vs 0.64±0.38 pmol/l). CHD patients showed serum PTH(1–84) and bone turnover higher than in CTRs. No correlation was found between OPG/RANK-L system and PTH or bone turnover markers. Instead, in the patients with high osteoclast activity (no.=21) OPG/RANK-L ratio was correlated (r=−0.41, p<0.01) with NTx serum levels, whereas in patients with decreased osteoclast activity (no.=39) no relationship was found. In conclusion, our findings showed that, although both OPG and RANK-L are accumulated in hemodialysis patients, only RANK-L and the balance between OPG and RANK-L seem to be related to osteoclast activity.

The Associations of Body Composition and Fat Distribution With Bone Mineral Density in Elderly Italian Men and Women

This study aimed to investigate the associations of body composition and fat distribution with bone mineral density (BMD) in elderly Italian subjects. In 866 women (age 64.2±6.5yr) and 168 men (age 65.1±6.1yr), we measured BMD at lumbar spine, at femur, at the total body, and at the right hand. In all subjects, we also measured sex hormones, 25-hydroxyvitamin D, bone markers, and calcium intake. In both men and women, all body composition parameters had significant positive correlations with BMD at all sites after adjusting for age only; after adjusting also for body weight only lean mass (LM) remained positively associated with BMD at all sites except BMD at lumbar spine. In males, LM was associated with BMD at all sites, whereas android fat was associated with BMD at lumbar spine, at femur, and at whole body. In females, fat mass (FM) was positively and age inversely associated with BMD at all sites, whereas gynoid fat and alkaline phosphatase were inversely associated with BMD at lumbar spine and at femur. In conclusion, the role of LM seems more important in males, whereas in women the role of FM prevails with negative associations between gynoid fat and BMD.

Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: effects of omega-3 polyunsaturated fatty acid supplementation.

This study mainly aims at examining the erythrocyte membrane fatty acid (FAs) profile in Rett syndrome (RTT), a genetically determined neurodevelopmental disease. Early reports suggest a beneficial effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on disease severity in RTT. A total of 24 RTT patients were assigned to ω-3 PUFAs-containing fish oil for 12 months in a randomized controlled study (average DHA and EPA doses of 72.9, and 117.1mg/kgb.w./day, respectively). A distinctly altered FAs profile was detectable in RTT, with deficient ω-6 PUFAs, increased saturated FAs and reduced trans 20:4 FAs. FAs changes were found to be related to redox imbalance, subclinical inflammation, and decreased bone density. Supplementation with ω-3 PUFAs led to improved ω-6/ω-3 ratio and serum plasma lipid profile, decreased PUFAs peroxidation end-products, normalization of biochemical markers of inflammation, and reduction of bone hypodensity as compared to the untreated RTT group. Our data indicate that a significant FAs abnormality is detectable in the RTT erythrocyte membranes and is partially rescued by ω-3 PUFAs.

Efficacy and Tolerability of a Nutraceutical Combination (Red Yeast Rice, Policosanols, and Berberine) in Patients with Low-Moderate Risk Hypercholesterolemia: A Double-Blind, Placebo-Controlled Study

Background Statins are at the forefront of strategies to manage hypercholesterolemia. However 10% to 15% of patients are intolerant to any statin drugs, even at low daily doses and almost one-third of statin users discontinue therapy within 1 year. Some nutraceuticals are prescribed as lipid-lowering substances, but doubts remain about their efficacy and tolerability. Objectives We aimed to investigate the efficacy and the safety of a nutraceutical combination consisting mainly of 200 mg red yeast rice extract (equivalent to 3 mg monacolins), 500 mg berberine, and 10 mg policosanols (MBP-NC) in patients with low-moderate risk hypercholesterolemia. Methods In this single centre, randomized, double-blind, placebo-controlled study 60 consecutive outpatients (29 men and 31 women; age range = 18–60 years), with newly diagnosed primary hypercholesterolemia not previously treated, after a run-in period of 3 weeks on a stable hypolipidic diet, were randomized to receive a pill of MBP-NC (n = 30) or placebo (n = 30) once a day after dinner, in addition to the hypolipidic diet. The efficacy and the tolerability of the proposed nutraceutical treatment were fully assessed after 4, 12, and 24 weeks of treatment. Results In the MBP-NC group both total cholesterol and LDL-C already showed a significant reduction at Week 4 (–30.3% ± 33.9% and –29.4% ± 35.3%, respectively) that remained substantially unchanged at Week 12 (–26.7% ± 33.1% and –25.6% ± 31.5%, respectively) and at Week 24 (–24.6% ± 32.1% and –23.7% ± 32.6%, respectively). The between-groups differences were significant at all time points for both total cholesterol and LDL-C. There were no significant changes in HDL-C, fasting glucose, and triglyceride serum levels in either group. MBP-NC was also safe and well tolerated. Conclusions In patients with low- to moderate-risk hypercholesterolemia a nutraceutical combination in association with a hypolipidic diet significantly reduced total cholesterol and LDL-C levels and may favor the reaching the recommended cholesterol targets. ClinicalTrials.gov identifier: NCT02078167.

The effects on lipid serum levels of a 2-year adjuvant treatment with exemestane after tamoxifen in postmenopausal women with early breast cancer.

BACKGROUND The third-generation aromatase inhibitor exemestane represents a new development in the treatment of estrogen-positive breast cancer. The aim of this study was to evaluate the effects on lipid profile and body composition of the shift from tamoxifen to exemestane. METHODS After 2-3 years of tamoxifen adjuvant treatment, 68 postmenopausal women were randomly assigned to either continue tamoxifen 20 mg/day (n = 35) or to switch to exemestane 25 mg/day (n = 33). RESULTS No significant changes in lipid profile were found in patients continuing on tamoxifen. In the exemestane group, serum HDL-cholesterol (HDL-C) and triglycerides (TG) decreased significantly (p < 0.01) and serum LDL-cholesterol (LDL-C) increased significantly (p < 0.05) with respect to baseline. The difference between the two groups was significant. Moreover, in the exemestane group, fat mass (FM) and fat-free mass (FFM) showed an opposite trend, which determined a progressive and significant increase in the FFM/FM ratio. CONCLUSION This study shows that the choice of first-line treatment or adjuvant therapy for breast cancer should also take the individual lipid and body composition profile into account.

Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability.

BACKGROUND Nicolaides-Baraitser and Coffin-Siris syndromes are emerging conditions with overlapping clinical features including intellectual disability and typical somatic characteristics, especially sparse hair, low frontal hairline, large mouth with thick and everted lips, and hands and feet anomalies. Since 2012, mutations in genes encoding six proteins of the BAF complex were identified in both conditions. METHODS AND RESULTS We have clinically evaluated a cohort of 1161 patients with intellectual disability from three different Italian centers. A strong clinical suspicion of either Nicolaides-Baraitser syndrome or Coffin-Siris syndrome was proposed in 11 cases who were then molecularly confirmed: 8 having de novo missense mutations in SMARCA2, two frame-shift mutations in ARID1B and one missense mutation in SMARCB1. Given the high frequency of the condition we set up a one-step deep sequencing test for all 6 genes of the BAF complex. CONCLUSIONS These results prove that the frequency of these conditions may be as high as the most common syndromes with intellectual deficit (about 1%). Clinical geneticists should be well aware of this group of disorders in the clinical setting when ascertaining patients with intellectual deficit, the specific facial features being the major diagnostic handle. Finally, this work adds information on the clinical differences of the two conditions and presents a fast and sensitive test for the molecular diagnosis.