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Osteoporosis is a common skeletal disorder with a strong genetic component. In recent years, significant progress has been made in understanding the genetic basis of osteoporosis. Given the biological significance of signalling through steroid hormone receptors, bone biology and calcium homeostasis, alleles of steroid hormone receptor genes have been postulated to contribute to the well-documented genetic predisposition to osteoporosis; and in different studies, these alleles have been associated with variation in bone mass and fracture risk. Even though results are still conflicting and the molecular mechanisms by which these polymorphisms influence receptor activity remain, in part, to be investigated, an additional important issue is represented by potential pharmacogenomic (the investigation of variations of DNA or RNA characteristics as related to drug response) or pharmacogenetic (the influence of variations of DNA sequence on drug response) implications. In fact, steroid hormone receptors actually mediate the action of several compounds known to positively or negatively affect bone homeostasis, such as vitamin D, estrogen and glucocorticoids. This review analyses major pharmacogenetic studies of polymorphisms in steroid hormone receptor genes.

Osteoporosis is a common skeletal disorder characterized by compromised bone strength and increased fracture risk. It is becoming a growing health-economic problem worldwide. Over the past two decades, there has been considerable progress in the availability of compounds with antiresorptive or anabolic activity on bone. However, existing therapeutic strategies still have limitations.In this review, the authors summarize past and current approaches for the development of antiresorptive and anabolic agents for osteoporosis together with their mechanisms of action. They also provide discussion on the application of new technologies for novel osteoporosis drug discovery.Thanks to the recent advances in molecular biology over the past few years, novel therapeutic targets for antiresorptive or anabolic compounds have been discovered and several promising new drugs are in preclinical and clinical development. Despite these advances, the current understanding of the mechanisms regulating bone remodeling is far from complete, leaving significant drawbacks to the discovery and the clinical development of novel therapeutic agents. Hopefully, improvements in functional genomics and bioinformatics, along with new technological approaches such as RNA silencing, quantitative proteomics, metabolomics, and the use of mesenchymal stem cells, will address these issues and widen our options for treating several disorders of bone metabolism, including osteoporosis.

Patients with Paget's bone disease (PDB) have an increased risk of developing giant cell tumor (GCT). This study was performed to evaluate the clinical characteristics and evolution of GCT complicating PDB and to compare these clinical characteristics to those observed in two large PDB cohorts, the PDB Italian Registry and the United Kingdom's Multi-Centre Randomised Controlled Trial of Symptomatic Versus Intensive Bisphosphonate Therapy for Paget's Disease (PRISM) study. A systematic literature review identified 117 cases of PDB complicated by GCT (PDB-GCT), which involved the skeletal sites affected by PDB (110 patients) or the extraskeletal tissues adjacent to affected bones (7 patients). In contrast to what previously reported for GCT patients without GCT patients (83.2%) were white and one-fourth of them (24.8%) had multifocal GCTs. Compared to PDB patients without GCT, PDB-GCT patients showed a higher male/female ratio (2.1 versus 1.2) and more severe disease (age at PDB onset 52.1 +/- 12.1 versus 63.3 +/- 10.6 years; number of affected sites 6.1 +/- 2.9 versus 2.34 +/- 1.6; prevalence of polyostotic PDB 93.3% versus 60.6%). The mortality rate of PDB-GCT patients was higher than those occurring in GCT patients without PDB (about 50% versus 0% to 5% at 5 years) or in PDB patients without GCT (log rank=29.002). Moreover, up to 98% of PDB-GCT cases had elevated total alkaline phosphatase levels at neoplasm diagnosis, suggestive of active PDB. Importantly, PDB-GCT patients from Southern Italy (45.6% of all GCT patients) showed a higher prevalence of multifocal GCT (51.7%) and of positive familial history for PDB (70.8%) and GCT (65.0%). Finally, indirect evidence suggests a decline in the incidence of GCT in PDB patients. The occurrence of GCT in PDB patients is associated with severe disease and reduced life expectancy of affected patients. The increased prevalence of familial diseases in PDB-GCT patients from Southern Italy suggests a founder effect. The observed changes over time in the incidence of GCT in PDB patients could be related to improved clinical management and/or living conditions of patients. (c) 2014 American Society for Bone and Mineral Research.

Introduction: At this time, good quality randomized clinical trials assessing the effects of vitamin D supplementation on cardiometabolic outcomes are lacking in the international literature. Aim: To fill this gap, the Working Group on Vitamin D and Cardiorenal Disorders established jointly by the Italian Society of Hypertension (SIIA) and the Forum in Bone and Mineral Research conceived the HYPODD study (HYPOvitaminosis D and organ Damage). Methods: HYPODD is a no-profit multicenter 12-month parallel-group double-blind placebo controlled randomized trial aiming to assess the effects of cholecalciferol supplementation on blood pressure control, antihypertensive drugs consumption and progression of target organ damage in patients with essential hypertension and 25-hydroxyvitamin D serum level lower than 20 ng/ml (vitamin D deficiency). HYPODD is coordinated by the European Society Excellence Center of Hypertension of Federico II University, Naples, and involves 12 academic institutions in Italy (Ancona, Milan, Padua, Perugia, Rome, Siena, Trieste, Turin, Udine, Varese, and Verona). Results and conclusion: The HYPODD study has been registered at the Agenzia Italiana del Farmaco-Osservatorio sulla Sperimentazione Clinica del Farmaco (AIFA-OsSC) and EUDRACT sites (n° 2012-003514-14) and has been approved by the Ethical Committees of all the Centers involved in the study. The patients' recruitment is currently underway.

Imarker del turnover osseo rappresentano un mezzo di valutazione dinamica dello scheletro che aggiungono informazioni alla valutazione statica fornita dalla densitometria ossea. Numerosi studi hanno dimostrato che esiste un’associazione fra i marker ed il rischio di frattura, ma ancora e difficile trasferire questi dati nella gestione del singolo paziente. Probabilmente il maggior potenziale dei marker risiede nel loro utilizzo per il monitoraggio della terapia dell’osteoporosi, soprattutto quando vengono utilizzati farmaci antiriassorbitori, sia per la valutazione della compliance dei pazienti che per la valutazione dell’effetto terapeutico.

Epidemiological studies of Paget's disease of bone (PDB) suggest a pronounced geographical variation in the prevalence of the disease and a decrease in prevalence and clinical severity over time. To analyze epidemiological and clinical features of PDB in Italy, we recently established a registry of Italian PDB cases and performed radiological, biochemical, and bone scan surveys in the towns of Siena and Turin. The overall prevalence of PDB in Italy varied between 0.7% and 2.4%. Prevalence rates increased with age and were higher in men than in women. We observed clinically confirmed familial aggregation in 15-26% of cases. Pedigree analysis indicated an autosomal dominant pattern of inheritance with variable penetrance. SQSTM1 gene analysis in two Italian studies revealed the presence of at least three different mutations accounting for both familial and sporadic cases. Interestingly, no decrease in the prevalence of PDB over time was observed, the opposite of what is described in populations of British descent. However, clinical severity of PDB cases included in the Registry in 2002-2004 seemed reduced with respect to that of PDB patients from the previous epidemiological studies, including a 1950-1956 Italian study. Of interest, a consistent association between PDB and animal-related factors and a significantly higher prevalence of the disease in rural than in urban districts were observed. These findings are in keeping with an important role of the environment in the pathogenesis of PDB, perhaps facilitating the expression of the disease in genetically susceptible subjects. Finally, there was also preliminary evidence indicating regional clustering of PDB in Italy, with a concentration of cases in rural districts of Campania and Tuscany. These districts may represent high prevalence areas of PDB in Italy, similar to what has been observed in other countries. Extrapolation estimates suggest that approximately 150,000-300,000 subjects may be affected with PDB in our country. These results confirm PDB to be the most common bone remodeling disorder in elderly people in Italy, excluding osteoporosis.

Sex steroid hormones play an important role in the maintenance of bone mass in males as well as in females. Even though androgens represent the major sex steroid class in men, their primacy in regulating male skeletal remodeling has been questioned increasingly as direct and indirect evidence has emerged suggesting that estrogens also play a major role in male skeletal health. This review summarizes clinical and experimental evidence that estrogens are essential for bone accrual in the growing skeleton, maintenance of bone mass and prevention of bone loss in men.

This study examined the characteristics of 147 PDB cases from Italy. Our data showed a reduced clinical severity of PDB with respect to other populations and provided further support of the importance of environmental factors (rural area of residence and animal contact) in the pathogenesis of PDB. Familial aggregation was observed in 15% of cases. Introduction: The etiology of Paget's disease of bone (PDB) remains unknown. Current evidence suggests that interactions among genetic or exogenous factors seem to be necessary for disease expression. Major epidemiological studies were performed in the United Kingdom and in other populations of British descent. To date, there are no reliable data on PDB characteristics among the Italian population, and its frequency in different areas of the country remains unknown. Materials and Methods: In an attempt to evaluate clinical characteristics, the proportion of familial cases and the influence of environmental features on the occurrence of the disease, we studied 147 consecutive PDB patients. For all subjects, a detailed medical history was obtained, and constitutional features were recorded. Characteristics of PDB patients were compared with those obtained from 323 consecutive non-Pagetic outpatient control subjects. Results and Conclusions: Of the 147 PDB patients, 22 (15%) had at least one other family member affected, 19 (13%) reported one family member with suspected features of PDB, and 106 (72%) were classified as sporadic PDB. Even though we observed a reduced clinical severity of PDB with respect to other populations (mean number of affected sites, 2.2 ± 1.6), we did not find any evidence of a decreased severity of the disease over time. We also found an association of PDB with animal contact (odds ratio [OR], 2.22; p < 0.0005) and a significant prevalence of PDB in rural versus urban districts (OR, 2.42; p < 0.0005). Osteoarthritis (45%), fractures (14%), hearing loss (14%), and valvular calcifications (15%) were the most observed complications. Interestingly, the geographical distribution of PDB showed a concentration of cases in rural areas of Campania and Tuscany. These areas may indicate local clustering of PDB cases in Italy, similar to that observed in other countries.

It is known that sex steroid hormones play an important role in the maintenance of bone mass in males as well as in females. Even though androgens are the major sex steroids in men, their primacy in regulating male skeletal remodeling has been increasingly questioned as direct and indirect evidence emerged suggesting that estrogens may also play a major role in male skeletal health. Recent data suggested that a threshold level of bioavailable estradiol is needed to prevent bone loss, and that with aging an increasing percentage of elderly men begin to fall below this level. The testes account for, at most, 15% of circulating estrogens in the male; the remaining 85% comes from peripheral aromatization of androgen precursors in different tissues, including bone. Human models of aromatase deficiency were the first to demonstrate the critical importance of the conversion of circulating androgens into estrogen in regulating male skeletal homeostasis. All four cases of aromatase-deficient men reported to date showed an identical skeletal phenotype, characterized by tall stature due to continued longitudinal growth, unfused epiphyses, high bone turnover, and osteopenia. Studies using knockout mice along with experimental observations in rats treated with an aromatase inhibitor provided useful information about the importance of aromatase in the male skeleton. Confirmatory evidence comes from recent interventional studies in adult men using aromatase inhibition, which confirmed that estrogens are critically important to the male skeleton by helping to control rates of bone remodeling. Intriguingly, common polymorphisms at the human aromatase (CYP19) gene have been associated with differences in aromatase activity, bone turnover, and rates of bone loss in elderly men, suggesting that variations in aromatase efficiency may also be relevant for skeletal homeostasis. Several additional mechanisms have been proposed in which aromatase activity could be modulated under certain circumstances in different tissues. Additional studies are needed to identify how these genetic, environmental, pathological, and pharmacological influences might modulate aromatase activity in vivo, increasing or reducing estrogen production in males and thereby affecting skeletal health.

The aim of our study was to evaluate the reproducibility and the diagnostic accuracy of a new device for the assessment of bone mineral density (BMD) of the heel, called dual X-ray and laser (DXL Calscan). This technique associates X-ray absorptiometry to the measure of heel thickness with a laser beam. The calcaneus BMD, calcaneus quantitative sonography (QUS), and lumbar spine and total-body BMD, were evaluated in 40 postmenopausal women. On the basis of the BMD T-score measured by dual-energy X-ray absorptiometry (DXA) of L2–L4, 20 women were classified as osteoporotic and 20 women were considered nonosteoporotic according to the WHO classification. The short-term coefficient of variation of the DXL was 2.4% and 1.7% in osteoporotic and nonosteoporotic women, respectively. The calcaneus BMD was lower in osteoporotic than in nonosteoporotic women. Among osteoporotic patients, 14 patients had a T-score lower than −2.5 at Calscan, whereas only 4 patients classified as nonosteoporotic based on the lumbar spine BMD were misclassified by Calscan. In these patients, the sensitivity and specificity of heel ultrasound measurements were 70% and 85%, respectively. The DXL BMD was highly correlated with the total-body BMD, Stiffness at the calcaneus, and the L2–L4 BMD. In conclusion, the new measuring device the Calscan DXL appeared easy to use, the time of examination was relatively short, and the reproducibility was sufficiently good; the diagnostic accuracy and relationships with other devices were good.

Hypovitaminosis D is common in elderly women. Few data are available on vitamin D status and bone turnover in women with acute hip fracture. The aims of this study were to determine whether elderly Italian women with an acute hip fracture also had low vitamin D levels and an increase of bone turnover compared with elderly women with osteoporosis but without fractures. Seventy-four women with acute osteoporotic hip fracture and 73 women with postmenopausal osteoporosis were studied. All women were self-sufficient and had adequate sunlight exposure. To exclude the effect of trauma on serum 25-hydroxycolecalciferol levels and bone markers (bone alkaline phosphatase and C-terminal telopeptides of Type I collagen as indices of bone formation and bone resorption), blood samples were drawn within 24 hours of the fracture. Current data indicated that in our patients the prevalence of hypovitaminosis D is common although to a lesser extent than in women who are housebound. Women with acute hip fractures had a higher prevalence of vitamin deficiency defined as serum 25-hydroxycolecalciferol lower than 12 ng/mL, compared with women with osteoporosis. Moreover, the presence of fracture did not influence the rate of bone formation, whereas the increase in bone resorption could be attributed to an older age of women with acute hip fracture because of similar values of parathyroid hormone levels in the two groups.

This study was executed to evaluate left ventricular (LV) geometry, diastolic and systolic function assessed by B- and M-mode and pulsed Doppler echocardiography in a group of professional sprinter runners (group I), in young patients suffering from mild hypertension (group II) and in control young adults (group III). Twenty-one male sprinter runners were checked during a period of training and compared with 19 young patients suffering from mild hypertension and 15 healthy controls matched for gender and body size.LV septum thickness, LV posterior wall thickness, LV ejection fraction, LV shortening fraction, midwall fractional shortening and stroke volume were significantly higher in runners compared to hypertensive patients and controls (p0.001). A significant increase of diastolic function parameters of the early peak flow velocity, E, and the early/late diastolic wave ratio, E/A, and in the isovolumic relaxation time or in the E velocity deceleration time wave was observed in hypertensive patients when compared to runners and controls (p0.05). The study of the pulmonary venous flow revealed a significant increase in the early systolic flow velocity, S, in hypertensive patients compared to runners (p0.05); the late diastolic flow velocity, D, appeared to be similar in all groups, while atrial backward flow velocity, Ar, was higher in group I and II respect to control (p0.001).Our data indicate that LV concentric hypertrophy in sportsmen is associated with improvement of systolic and diastolic performance, whereas diastolic dysfunction can occurs even in the early stages of hypertension in young patients, in whom an alteration in the LV filling appears even in absence of systolic dysfunction and evident concentric myocardial hypertrophy.

Male osteoporosis is an increasingly important health problem. It is known that sex steroid hormones play an important role in regulating bone turnover and bone mass in males as well as in females. However, the exact mechanism of bone loss in men remains unknown. In the present study, 200 elderly men (age range, 55–85 yr) were followed for 4 yr to evaluate the relationships between hormone levels, bone turnover markers, bone mineral density, and rates of bone loss. Femoral and lumbar bone mineral density, bone ultrasound parameters at the os calcis, serum testosterone (T), serum estradiol (E2), SHBG levels, and bone turnover markers (urinary crosslaps and bone alkaline phosphatase) were evaluated for each man at enrollment and 4 yr afterward. The free androgen index (FAI) and free estrogen index (FEI) as well as measures of the bioavailable sex hormones [calculated bioavailable E2 (c-bioE2) and T (c-bioT)] were calculated from total hormone levels and SHBG. In the total population, T, c-bioT, c-bioE2, FAI, and FEI, but not E2, decreased significantly with age, whereas SHBG increased significantly. Subjects with FEI, c-bioE2, and E2 levels below the median showed higher rates of bone loss at the lumbar spine and the femoral neck as well as higher speed-of-sounds decrease at the calcaneus with respect to men with FEI, c-bioE2, and E2 levels above the median. Serum bone alkaline phosphatase and urinary crosslaps were significantly higher in men with FEI, c-bioE2, and E2 in the lower quartile than in men with FEI, c-bioE2, and E2 levels in the higher quartile. No statistically significant differences were observed in relation to T, c-bioT, or FAI levels. Finally, the ratio between E2 and T, an indirect measure for aromatase activity, increased significantly with age and was higher in normal than in osteoporotic subjects. In conclusion, results from the present study indicate an important role of estrogens, and particularly of the ability to aromatize T to E2, in the regulation of bone loss and bone metabolism in elderly men.

The possibility of using quantitative ultrasound (QUS) in monitoring the response to antiresorptive drugs has yet to be defined. The aim of the present study was to evaluate whether heel ultrasonography, considering its characteristics of long-term precision, is able to monitor osteoporotic patients treated with alendronate. We studied 150 postmenopausal osteoporotic women (age 59.6 +/- 5.3 years) treated with alendronate and calcium (n = 74) or with calcium alone (n = 76) for 4 years. At baseline and after 12, 24, 36 and 48 months, we measured bone mineral density (BMD) at the lumbar spine by dual-energy X-ray absorptiometry (DXA, Hologic 4500), and speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness at the calcaneus by Achilles plus. Moreover, the longitudinal precision of QUS parameters was assessed by measuring 10 subjects once a month for 1 year and, on the basis of the coefficients of variation we obtained, we calculated the Least Significant Change between two measurements. In the alendronate-treated patients, at year 1, BMD increased by 4.2%, SOS by 0.4%, BUA by 1.1% and Stiffness by 3.2%; at year 2, BMD increased by 5.0%, SOS by 0.7%, BUA by 1.4% and Stiffness by 5.7%. At year 3, BMD increased by 6.2%, SOS by 0.9%, BUA by 1.8% and Stiffness by 7.6%. At the end of the study period, BMD increased by 7.6%, SOS by 1.2%, BUA by 1.9% and Stiffness by 9.0%. The minimal significant difference between two measurements was 0.8% for SOS, 5.6% for BUA and 5.0% for Stiffness. Among the QUS parameters, Stiffness showed the greatest total treatment effect and a longitudinal sensitivity which was only slightly lower than BMD. The MTI, which represents the period between scans required to show that a 'true' change has occurred, was 1.8, 2.7, 11.9 and 2.2 years for BMD, SOS, BUA and Stiffness respectively. Therefore, although the spinal BMD remains the optimal method, QUS at the heel, and in particular Stiffness, seems to be a sensitive tool for monitoring the response to alendronate.

Osteoporosis is a common skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. In the past years, twin and family study have shown that this disease recognizes a strong genetic component and that genetic factors play an important role in regulating bone mineral density (BMD). While in few isolate conditions osteoporosis can be inherited in a simple Mendelian pattern, due to single gene mutations, in the majority of cases has to be considered a multifactorial polygenic disease in which genetic determinants are modulated by hormonal, environmental and nutritional factors. Given the important role that steroid hormones play in bone cell development and in the maintenance of normal bone architecture, polymorphisms at receptor of the steroid/thyroid hormone receptor superfamily, such as estrogen receptor alpha (ERalpha) and Vitamin D receptor (VDR) have been thoroughly investigated in the last years and appeared to represent important candidate genes. The individual contribution of these genetic polymorphisms to the pathogenesis of osteoporosis remains to be universally confirmed and an important aim in future work will be to define their functional molecular consequences and how these polymorphisms interact with each other and with the environment to cause the osteoporotic phenotype. A further promising application of genetic studies in osteoporosis comes from their pharmacogenomic implications, with the possibility to give a better guidance for therapeutic agents commonly used to treat this invalidating disorder or to identify target molecules for new therapeutic agents.

The role of H. pylori infection in increasing the risk of ischemic heart diseases (IHD) is still debated. We determined serologically the prevalence of overall H. pylori and CagA-positive H. pylori infection in 63 consecutive patients with IHD and 189 gender- and age-matched controls. We also determined in patients the influence of the infection and the CagA serological status on the results of an exercise ECG test and other parameters considered possible variables that may enhance the risk of IHD. The prevalence of H. pylori infection in patients and controls was 79.3% and 73.0%, respectively (P = 0.403) and that of CagA-positive H. pylori infection was 69.8% and 42.3%, respectively (P = 0.0002). The scores of the ECG S-T segment and T-wave abnormalities in the course of an exercise ECG in uninfected patients and in patients infected by CagA-negative and CagA-positive H. pylori strains were (mean +/- SD): 1.59 +/- 0.67, 1.92 +/- 0.64, and 2.19 +/- 0.70, respectively; (P = 0.011, 95% confidence limits of difference 0.15-1.07, CagA-positive infected vs uninfected patients). There was no intergroup difference in the levels of peripheral white blood cells, glucose, cholesterol, triglycerides, creatinine, and systolic and diastolic pressure. In conclusion, genetic heterogeneity of H. pylori could possibly explain some conflicting results concerning the association of H. pylori infection with IHD. Coronary vessels of IHD patients infected by CagA-positive H. pylori strains may be damaged more severely than those of uninfected patients.

Paget's disease of bone (PDB) is a chronic disorder of bone metabolism, which typically results in enlarged and deformed bones in one or more regions of the skeleton. The aetiology of PDB has remained unknown for several decades, but either environmental or genetic factors have been implicated. The former mainly concern the presence of a slow-acting viral infection, a condition that may be present for many years before symptoms appear. However, there are also several data supporting a hereditary hypothesis, since in up to 40% of patients the disease may appear in more than one family member. The genetic architecture of PDB is incompletely understood, but recent evidence suggests that the disease may be caused by a combination of rare variants in genes such as SQSTM1 (detected in up to 50% of familial cases of PDB) and more common variants (i.e. polymorphisms) in genes such as CSF1, TNFRSF11A, OPTN and TM7SF4. Key Concepts: Paget's disease of bone (PDB) is a focal disorder of bone metabolism characterised by enlarged and deformed bones in one (monostotic form) or more regions (polyostotic form) of the skeleton. Over the last two decades there have been major advances in our understanding of the genetic basis of the disorder. Mutations in 3 genes have been detected in rare syndromes related to PDB and mutations in SQSTM1 gene have been associated with the classical form of PDB in up to 50% of familial cases. SQSTM1 gene encodes for the p62/sequestosome 1 protein, which acts as a scaffold protein in the NFκB pathway as well as an intermediate protein in the proteosomal degradation of polyubiquitinated proteins. To date the exact molecular mechanisms leading to the development of pagetic lesions in SQSTM1 mutation carriers remain to be defined. Indeed, recent experimental evidence suggests that additional contribution from environmental factors (i.e. a viral infection with paramyxovirus) or other genetic factors (i.e. polymorphisms) may be required to induce the full pagetic phenotype in the presence of SQSTM1 mutation. The genetic cause of PDB in familial cases negative for SQSTM1 mutations remains to be determined in more detail. Keywords: Paget's disease of bone; p62/sequestosome; bone metabolism; genetics; NFκB signalling

Osteoporosis, a multifactorial systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to increased bone fragility, is a worldwide public health problem. Vertebral fractures affect approximately 20% of postmenopausal women and are a hallmark of osteoporosis, but they may pass unnoticed, although they may lead to long-term immobility and disability.The aims of the present study were (1) to determine the prevalence and the severity of vertebral fractures in a large cohort of Italian women aged 60 years or older with reduced values of quantitative ultrasound parameters; and (2) to assess whether vertebral fractures and other variables may be associated with health-related quality of life.A total of 2450 women without back pain aged 60 years or older, after the completion of the Quality of Life Questionnaire of the European Foundation for Osteoporosis QUALEFFO, underwent quantitative ultrasound evaluation of the calcaneus; in those with a stiffness t-score of ≤ -2 (n = 1194), radiographic evaluation of the thoracic and lumbar spine was carried out and then quantitative morphometry was performed by dedicated software (MorphoXpress). The radiographic analysis was carried out on 885 women who presented films of adequate quality. Multivariate regression was used to adjust for confounding variables.Of those who underwent radiographic analysis, 681 had no vertebral fractures, and 204 women (23.1%) had one or more previously undiagnosed vertebral fractures. The prevalence of previously undiagnosed vertebral fractures increased with advancing age with more than 30% of women older than 75 years having at least one fracture. Older age, body mass index, and severe vertebral fractures were independently associated with a worse total QUALEFFO score.We found that approximately one in four women showed evidence of undiagnosed vertebral fractures, and there was a strong age effect trend. Moreover, the severity grade of vertebral fractures, more than the number of fractures, was associated with a worsening of health-related quality of life as assessed by QUALEFFO. These findings confirm the clinical relevance of an early diagnosis of vertebral fractures and seem to support the usefulness of quantitative ultrasound measurements in the stratification of postmenopausal women at increased fracture risk.Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Introduction: Paget’s disease of bone (PDB) is a chronic disorder of bone turnover, characterized by increased osteoclast-mediated bone resorption and subsequent compensatory increase in new bone formation, resulting in a disorganized mosaic of woven and lamellar bone at the affected skeletal sites. As a result, bone pain, osteoarthritis, noticeable deformities, nerve compression syndromes, fractures and, less frequently, neoplastic degeneration can occur. Areas covered: The published literature has been critically appraised, focusing on three main areas: epidemiology, pathogenesis (particularly regarding SQSTM1 mutations and other genetic aspects) and treatment of PDB. Expert opinion: Over the last two decades, there have been major advances in our understanding of pathogenesis and management of PDB. Mutations in SQSTM1 gene (encoding p62) have been identified in a consistent proportion of familial cases and treatment opportunities have been recently improved with the use of intravenous aminobisphosphona...

SQSTM1 mutations are common in patients with Paget disease of bone (PDB), with most affecting the C-terminal ubiquitin-associated (UBA) domain of the SQSTM1 protein. We performed structural and functional analyses of two UBA domain mutations, an I424S mutation relatively common in UK PDB patients, and an A427D mutation associated with a severe phenotype in Southern Italian patients. Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and resulted in activation of basal NF-κB signalling, compared to wild-type, in reporter assays. We found evidence for a relationship between the ability of different UBA domain mutants to activate NF-κB signalling in vitro and number of affected sites in vivo in 1152 PDB patients from the UK and Italy, with A427D-SQSTM1 producing the greatest level of activation (relative to wild-type) of all PDB mutants tested to date. NMR and isothermal titration calorimetry studies were able to demonstrate that I424S is associated with global structural changes in the UBA domain, resulting in 10-fold weaker UBA dimer stability than wild-type and reduced ubiquitin-binding affinity of the UBA monomer. Our observations provide insights into the role of SQSTM1-mediated NF-κB signalling in PDB aetiology, and demonstrate that different mutations in close proximity within loop 2/helix 3 of the SQSTM1 UBA domain exert distinct effects on protein structure and stability, including indirect effects at the UBA/ubiquitin-binding interface., Highlights • The I424S and A427D SQSTM1 mutations affect ubiquitin-binding and NF-κB signalling. • Mutant SQSTM1's ability to activate NF-κB signalling may be related to disease extent in PDB. • A427D-SQSTM1 produces the greatest activation (relative to wild-type) of all PDB mutants. • The I424S mutant destabilises the UBA dimer causing unfolding of the monomer. • UBA domain mutations of SQSTM1 exert distinct effects on protein structure and stability.

This study evaluated bone status and bone turnover in 82 females (ages 2-21 years) with the Rett Syndrome (RS) and 82 age-matched controls. Bone mineral density (BMD) by dual X-ray absorptiometry (DXA) at the ultradistal and proximal radius and ultrasonographic (QUS) parameters at the calcaneus [speed of sound(SOS), broadband ultrasound attenuation(BUA), and stiffness] and at the phalanxes (amplitude dependent speed of sound: AD-SOS) were measured. We also measured serum calcium, phosphate, 25-hydroxyvitamin D, and biochemical markers of bone turnover. DXA and QUS parameters were significantly lower in patients with RS compared with controls and, among RS alone, in those treated with anticonvulsants and in those who are nonambulatory. Ambulatory RS patients showed QUS and DXA parameters significantly greater than nonambulatory patients but significantly lower than controls. Patients with RS treated with anticonvulsants presented QUS and DXA parameters lower than those of other RS. In RS patients, walking significantly influences BMD-UD, BMD-P, SOS. BUA. and Stiffness. Serum 25-hydroxyvitamin D was significantly lower in RS than in controls. These results suggest that ambulatory status, to a major extent, and anticonvulsant therapy certainly play an important role in the reduction of bone mass and bone quality, but they cannot completely explain the altered bone status. Whatever the cause, girls with RS present abnormal bone status with an increase in the risk of fracture.

Conversion of C19 steroids to estrogens is catalyzed by the aromatase enzyme. Inactivating mutations of the aromatase gene are associated with decreased bone mineral density in both men and women. Genetic studies suggest that several genes contribute to the regulation of bone mass via interaction with the modeling and remodeling processes. Among these genes, the aromatase gene is a potential candidate to be evaluated for segregation with bone metabolism and bone mass. A tetranucleotide simple tandem repeat polymorphism in intron 4 at the human aromatase cytochrome P-450 gene has been recently described. In the present study we evaluated the distribution of this polymorphism in a cohort of Italian postmenopausal women, both normal and osteoporotic. We observed that the NN genotype was significantly more frequent in nonosteoporotic women than in osteoporotic women (72.7% vs. 27.2%), whereas the DN genotype was significantly more represented in osteoporotic women (90.48% vs. 9.5%; Pearson’s χ2 test = 42.8; d...

Background: The effect of pulsed electromagnetic fields (PEMFs) on bone formation and remodeling has been evaluated in several studies in the last 30 years, but the results of these studies have been equivocal. Objective: The aim of this study was to investigate the effects of PEMFs on bone mineral density (BMD) and the biochemical markers of bone turnover in patients with postmenopausal osteoporosis. Methods: In this single-blind, randomized study, 40 outpatients were exposed to 100-Hz PEMFs (n = 20) or to a placebo electromagnetic field (n = 20) for 60 minutes per day, 3 times a week for 3 months. BMD was measured at baseline and at the end of treatment, and biochemical markers of bone metabolism were measured at baseline, after 3 months' treatment, and 1 month after treatment cessation. Results: Treatment with PEMFs did not cause a significant increase in BMD in either group. However, in the group treated with 100-Hz PEMFs, a significant increase in serum osteocalcin and serum procollagen type I C-terminal propeptide was observed during treatment ( P Conclusions: These findings suggest that PEMFs may stimulate osteogenesis, possibly by increasing osteoblastic activity, in postmenopausal women with osteoporosis.

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component. The discovery that inactivation of estrogen receptor alpha (ERalpha) gene is associated with low BMD indicated ERalpha as a candidate gene for osteoporosis. We have investigated the role of three ERalpha gene polymorphisms [intron 1 PVU:II and XBA:I RFLPs and TA dinucleotide repeat polymorphism 5' upstream of exon 1] in 610 postmenopausal women. There was a strong linkage disequilibrium between intron 1 polymorphic sites and also between these sites and the microsatellite (TA)(n) dinucleotide polymorphism, with a high degree of coincidence of the short TA alleles and the presence of PVU:II and XBA:I restriction sites. No significant relationship between intron 1 RFLPs and BMD was observed. A statistically significant correlation between (TA)(n) repeat allelic variants and lumbar BMD was observed (P = 0.04, ANCOVA), with subjects with a low number of repeats (TA15) showing the lowest BMD values. We observed a statistically significant difference in the mean +/- SD number of TA repeats between analyzed women with a vertebral fracture (n = 73) and the non-fracture group, equivalent to 2.9 (95% CI 1.56-5.72) increased fracture risk in women with a low number of repeats (TA15). We conclude that in this large population sample the (TA)(n) dinucleotide repeat polymorphism at the 5' end of the ERalpha gene accounts for part of the heritable component of BMD and might prove useful in the prediction of vertebral fracture risk in postmenopausal osteoporosis.

The aim of this study was to assess the pattern of ultrasound (QUS) parameters and bone mineral density at different skeletal sites in patients with primary hyperparathyroidism (PHPT) before and after surgical treatment. In 22 patients (age range 28–74 years) with PHPT we measured speed of sound (SOS), attenuation (BUA) and Stiffness at the calcaneus, amplitude-dependent speed of sound (AD-SoS) at proximal phalanges, and bone mineral density at lumbar spine (BMD-LS) and at the mid-radius (BMD-MR) and ultradistal radius (BMD-UDR) before, 1 and 2 years after surgical operation. Twenty-two age- and sex-matched healthy subjects provided control data. Before surgery, all parameters apart from SOS were significantly lower in PHPT patients than in controls. At the end of the study period, BMD-LS increased by 7.0%, BMD-UDR by 7.4% and BMD-MR by 11.0%. The changes in ultrasound parameters after surgery were lower (0.44% for SOS, 2.2% for BUA, 3.3% for Stiffness and 2.6% for AD-SoS); however, the increase was statistically significant (p

Telomerase results to be active in human germ, stem cells, several malignant cell tumors and in immortalized cell lines. In order to investigate if molecular mechanisms other than Rb gene inactivation can be helpful to diagnose malignancy of parathyroid tumors, we decided to investigate the presence of active telomerase in homogenates from different pathological parathyroid tissues (hyperplastic, adenomatous, carcinomatous, and normal) and primary cell cultures. The TRAP assay was performed to detect this activity in histologically characterized normal, hyperplastic, adenomatous, and carcinomatous human parathyroid tissues, primary cell lines, and one metastatic tissue from parathyroid carcinoma. Only malignant parathyroid glands and the metastatic tissue were TRAP positive. Our findings suggest that telomerase expression could represent an important molecular mechanism underlying the acquisition and progression of an aggressive phenotype of epithelial parathyroid cells and it may help to predict their malignant potential. The TRAP assay is easy to perform and it could become an additional tool to be included in the harmamentarium for the molecular diagnosis of parathyroid carcinoma.

A novel T/C polymorphism (ATG to ACG) at the translation initiation site of the vitamin D receptor (VDR) gene, defined by FokI restriction endonuclease, has been recently associated with variation in bone mineral density (BMD) and rates of bone loss in a group of postmenopausal Mexican-American women. The presence of the restriction site, designated as f, allows protein translation to initiate from the first ATG, while the allele lacking the site, indicated as F, initiates translation at a second ATG. In this study, we investigated the role of FokI polymorphism in a group of 400 postmenopausal women of Italian descent stratified for BMD into osteoporotic (n = 164), osteopenic (n = 117), and normal (n = 119) groups. There were 159 (41%) FF homozygotes, 55 (14%) ff homozygotes, and 186 (45%) Ff heterozygotes. In the whole population, we observed a weak association between FokI polymorphism and lumbar BMD (p = 0.06, analysis of covariance [ANCOVA]) but not with femoral neck BMD (p = 0.5, ANCOVA). Interestingly, the effect of FokI genotypes on lumbar BMD was influenced by the years since menopause such that differences in BMD related to different VDR allelic variants were greater among women in the first 5 years of menopause (p = 0.04, ANCOVA), progressively declining afterward. In addition, a significantly higher prevalence of ff genotype in osteoporotic than in osteopenic and normal women was observed (p = 0.04, Chi-square test). Finally, ff genotype resulted significantly over-represented in the group of women with a vertebral fracture as compared with controls (p = 0.003, Chi-square test), equivalent to a relative risk of 2.58 (95% confidence intervals 1.36-4.91). We conclude that in this population, FokI polymorphism at the VDR gene locus accounts for a part of the heritable component of BMD at the lumbar spine.

Although about 25% of all hip fractures occur in men, little is known about the pattern of their age-related bone loss and its main determinants. The aim of this cross-sectional study was to evaluate the age-related changes of intestinal calcium absorption, bone mass, and bone turnover in normal men. In 70 normal males (age 17-91 years), we measured spinal and forearm bone density (FBD) (by DXA), fractional intestinal calcium absorption (by oral test), serum immunoreactive parathyroid hormone (PTH), dietary calcium intake (diet records), biochemical markers of bone turnover (serum alkaline phosphatase (ALP), osteocalcin, urine calcium, creatinine, and hydroxyproline), and 1,25(OH)2D3 serum levels. Vertebral bone density (VBD) showed a modest decline before age 50 and a greater decline after age 50, whereas FBD presented a significant decrease with advancing age starting at age 40, suggesting a predominant age-related cortical bone loss. Intestinal calcium absorption (47CaFA) and serum 1,25(OH)2D3 also presented an age-related decline similar to FBD. Simple correlation analysis revealed that age was significantly related to 47CaFA (r = 0.60), calcium intake (r = 0.32), VBD and FBD (r = 0.79 and 0.63, respectively), serum 1,25(OH)2D3 (r = 0.69), and serum iPTH (r = 0.72). No significant correlation was found between age and biochemical markers of bone remodeling. Partial correlation and stepwise variable selection analyses, using 47CaFA and bone mass as dependent variables, showed that in normal males, serum 1,25(OH)2D3 and dietary calcium intake were the main contributors (64%) to 47CaFA variability, whereas only age accounted for 63% of VBD and age and dietary calcium accounted for 45% of FBD variability. These results indicate that bone loss in men accelerates after age 50 years and that among other factors, intestinal calcium malabsorption and 1,25(OH)2D3 serum levels play a role.

Recognition of a major genetic component in bone mass determination represented the basis for studies aiming to the identification of underlying major and minor genes. Bone mineral density (BMD) represents the continuous trait to be quantified in order to evaluate segregation of candidate genes with risk of osteoporosis. Polymorphisms at the vitamin D receptor (VDR), estrogen receptor, (ER), collagen type I, and interleukin 6 (IL6) gene loci have been correlated to BMD. However, in a polygenic disorder, such as osteoporosis, the number of genes expected to influence BMD is very large. In the present study we examined the presence of restriction fragment length polymorphisms (RFLPs) for the calcitonin receptor (CTR) gene in postmenopausal women. We identified a polymorphic (Tt) site at the CTR gene locus using the Taq I restriction fragment enzyme. Three genotypes were observed, whose Tt was the most frequent in our population (49.7%). In addition, Ancova analysis and Tukey's test showed that women with tt genotype had significantly lower lumbar BMD in comparison with Tt genotype (Tukey's test: p = 0.005). In conclusion, evidence of RFLPs at the CTR gene locus in Caucasian postmenopausal women of Italian origin made it possible to identify the involvement of another gene, the CTR gene, in the determination of bone mass.

Over the last decade, the increasingly significant problem of osteoporosis in men has begun to receive much more attention than in the past. In particular, recent observations from large scale population studies in males led to an advance in the understanding of morphologic basis of growth, maintenance and loss of bone in men, as well as new insights about the pathophysiology and treatment of this disorder. While fracture risk consistently increases after age 65 in men (with up to 50 % of cases due to secondary etiologies), osteoporosis and fractures may also occur in young or middle aged males in the absence of an identifiable etiology. For this category (so called idiopathic osteoporosis), there are still major gaps in knowledge, particularly concerning the etiology and the clinical management. This article provides a summary of recent developments in the acquisition and maintenance of bone strength in men, as well as new insights about the pathogenesis, diagnosis, and treatment of idiopathic osteoporosis.

Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree. © 2013 American Society for Bone and Mineral Research.

Besides functional estrogen receptors, the presence of signalling cell surface binding sites for 17beta-estradiol (17betaE2) has been reported in osteoblast- and osteoclast-like cells, suggesting that 17betaE2 may influence bone remodelling by a dual mechanism of action: to affect gene expression mediated by the nuclear activity of the steroid-receptor complex, and to initiate rapid responses triggered by a signal-generating receptor on the cell surface. Recently, we demonstrated that the human pre-osteoclastic cell line FLG 29.1 bears functional estrogen receptors. In this study we examined FLG 29.1 cells for the presence of cell surface binding sites for 17betaE2, and whether 17betaE2 could elicit cell signalling. Using a cell-impermeant and fluorescent estrogen conjugate, 17beta-estradiol-6-carboxymethyloxime-bovine serum albumin-fluorescein isothiocyanate, we demonstrated the presence of specific plasma membrane binding sites for 17betaE2. Stimulation of FLG 29.1 cells with low (1 nM) and high (1 microM) doses of 17betaE2 induced a prompt and significant (P0.05) increase of cellular pH, as measured in single cells using an image analysis system. In addition, both cAMP and cGMP were significantly increased by 17betaE2 with a dose-dependent response. Finally, a rapid increase of intracellular calcium ion concentration [Ca2+] was also induced by 1 nM 17betaE2, as measured in single cells using an image analysis system. Our findings strongly suggest a non-genomic action of 17betaE2 on osteoclast precursors.

Parathyroid hormone-related protein (PTHrP) is involved in the hypercalcemia of malignancy and expressed by a number of tumours. It is also produced by normal tissues (such heart, brain, kidney, and vascular smooth cells). It has been demonstrated that PTHrP like parathyroid hormone (PTH) induces vasodilation and positive chronotropic and inotropic action in the rat, and an involvement of the adrenergic and RAA system has been postulated. Therefore, the aim of the study was to evaluate serum middle molecular immunoreactive PTH (iPTH-MM), intact [1–84] iPTH, iPTHrP levels and PRA in supine and standing position, and daily urinary catecholamine (Ur.Tot.CAT) excretion in 17 essential hypertensive patients and in 15 sex- and age-matched normotensive control subjects.

We investigated the associations of body composition and sex hormones with quantitative ultrasound (QUS) parameters carried out at different skeletal sites. In 897 postmenopausal women (64.1 ± 6.6 years) we measured QUS at the calcaneus (stiffness) by Achilles-GE and at phalanxes (amplitude-dependent speed of sound [AD-SOS], bone transmission time [BTT], and ultrasound bone profile index [UBPI]) by Bone Profiler-IGEA. In all subjects we measured fat mass (FM), lean mass (LM), android fat, and gynoid fat by DXA. In all subjects we also assessed serum testosterone (T), estradiol (E(2)), sex-hormone binding globulin, free estrogen index (FEI), free androgen index, 25-hydroxyvitamin D (25OHD), bone alkaline phosphatase (B-ALP), and type I collagen β carboxy telopeptide. Both E(2) and FEI showed weak but significant correlations with stiffness and QUS parameters at phalanxes. No significant relationships were found between T and QUS. BMI and LM were positively correlated with stiffness (r = 0.14 and r = 0.17, respectively), whereas BMI and FM showed negative correlations with AD-SOS, BTT, and UBPI. 25OHD showed positive relationships with stiffness and QUS at phalanxes. In multivariate models LM and age were associated with stiffness whereas E(2) and age were significant predictors of BTT. AD-SOS was negatively associated with FM, B-ALP, and age but positively with E(2) and 25OHD. In postmenopausal women QUS parameters at the calcaneus and at phalanxes are significantly, but diversely, associated with body composition, sex hormones, 25OHD, and bone turnover markers.

Aromatase is a specific component of the cytochrome P450 enzyme system responsible for the transformation of androgen precursors into estrogens. This enzyme is encoded by theCYP19A1gene located at chromosome 15q21.2, that is, expressed in ovary and testis, but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The activity of aromatase regulates the concentrations of estrogens with endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen in men. Clinical and experimental evidences clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, the attainment of peak bone mass, pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity may significantly affect bone loss and fracture risk in men.

Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone remodeling. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors for PDB by genome-wide association study(1). Here we extended this study, identified three new loci and confirmed their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from seven independent populations. The new associations were with rs5742915 within PML on 15q24 (odds ratio (OR) = 1.34, P = 1.6 x 10(-14)), rs10498635 within RIN3 on 14q32 (OR = 1.44, P = 2.55 x 10(-11)) and rs4294134 within NUP205 on 7q33 (OR = 1.45, P = 8.45 x 10(-10)). Our data also confirmed the association of TM7SF4 (rs2458413, OR = 1.40, P = 7.38 x 10(-17)) with PDB. These seven loci explained similar to 13% of the familial risk of PDB. These studies provide new insights into the genetic architecture and pathophysiology of PDB., This work was supported by grants from the ‘Fonds voor Wetenschappelijk onderzoek’ (FWO, G.0065.10N) and a network of excellence grant (EuroBoNeT) from the European Union (FP6) to W.V.H.

Aromatase is a specific component of the cytochrome P450 enzyme system that is responsible for the transformation of C19 androgen precursors into C18 estrogenic compounds. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is expressed in ovary and testis not only but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The regulation of the level and activity of aromatase determines the levels of estrogens that have endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen not only in men (since only 15% of circulating estradiol is released directly by the testis) but also in women after the menopause. Several lines of clinical and experimental evidence now clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity and thus in estrogen levels may significantly affect bone loss and fracture risk in both genders.

Aminobisphosphonates actually represent the most common treatment for Paget disease of bone (PDB). In a previous study we demonstrated that either zoledronic acid (4 mg) or neridronate (200 mg) given as a single intravenous infusion showed a similar short-term efficacy in achieving biochemical remission in up to 90% of patient nonresponders to pamidronate. In this study we compared the long-term (36 months) effects of a same neridronate dose (200 mg) given as an intravenous (100-mg infusion for 2 consecutive days) or intramuscular (25-mg injection weekly for 2 months) regimen in 56 patients with active PDB. All patients were advised to receive calcium plus vitamin D supplementation throughout the study period. At 6 months, 92.6% and 96.5% of patients receiving intravenous and intramuscular neridronate, respectively, achieved a therapeutic response [defined as normalization of alkaline phosphatase (ALP) levels or a reduction of at least 75% in total ALP excess]. The response to treatment was significantly correlated with baseline ALP and 25-hydroxyvitamin D [25(OH)D] levels at 6 months. The decrease in ALP levels was highest in patients with higher baseline total or bone-specific ALP levels and with higher 25(OH)D levels at 6 months. Response rates were maintained at 12 months but decreased progressively at 24 and 36 months without significant differences between the two neridronate regimens. Both regimens were well tolerated. The only relevant side effect was an acute-phase response occurring in 14% of the patients. In conclusion, these results indicate that a 200-mg intramuscular neridronate course has a similar efficacy as an intravenous infusion of the same dose for the treatment of PDB and might be of particular value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusions.

Aromatase is a specific component of the cytochrome P450 enzyme system that is responsible for the transformation of C19 androgen precursors into C18 estrogenic compounds. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is expressed in ovary and testis not only but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The regulation of the level and activity of aromatase determines the levels of estrogens that have endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen not only in men (since only 15% of circulating estradiol is released directly by the testis) but also in women after the menopause. Several lines of clinical and experimental evidence now clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity and thus in estrogen levels may significantly affect bone loss and fracture risk in both genders.

Estrogen replacement is traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women as well as for the management of menopausal symptoms. However, estrogen may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter is considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remains uncertain. Hence, there is a need for additional effective medications to prevent fractures in postmenopausal women that provide additional benefits.This article reviews lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis and urogenital atrophy. The medical literature is reviewed for articles containing the terms 'lasofoxifene' and 'SERMs'. The manuscript reviews the discovery strategies and preclinical development of lasofoxifene as well as its clinical development.Recent evidence suggests that the ideal SERM profile for one patient may be far from ideal for another. Thus, it could be favorable that different SERMs may be available in the future, each with a somewhat different profile that may be rationally applied to various patients with a spectrum of needs. In this context, lasofoxifene, while retaining some of the adverse effects of other SERMs (i.e., hot flushes and risk of venous thromboembolic events), may offer an improved skeletal efficacy over raloxifene, addressing other postmenopausal conditions, including reduction in breast cancer risk and treatment of vaginal atrophy.

Osteoporosis in men is an increasingly important clinical issue, that actually remains under-recognized and undertreated. Moreover there is no validated strategy for a systematic osteoporosis screening in men and decisions regarding treatment should be based on the absolute risk of fracture. Among the different treatment options, bisphosphonate therapy is becoming a mainstay in the treatment of male osteoporosis, even though evidence for the long-term efficacy and safety of therapies for osteoporosis in men remains limited. In this review, we report the current evidence on the use of zoledronic acid, a potent aminobisphosphonate that can be administered intravenously, for the prevention and treatment of osteoporosis in men.

Pharmacogenomics and pharmacogenetics are emerging interdisciplinary areas recently defined, respectively as “the investigation of variations of DNA and RNA characteristics as related to drug response”, and the study of “the influence of variations in DNA sequence on drug efficacy and toxicity”. A major challenge of future genetic studies in complex disorders such as osteoporosis is the development of specific genetic tests to identify responders from non-responders as well as to identify patients at higher risk to develop adverse reactions. Even though the knowledge of the genetic determinants of bone fragility and fracture risk has consistently increased over the past decade and despite the parallel development of multiple drugs with antiresorptive or anabolic activity in bone, there is still relatively little known about pharmacogenomics and pharmacogenetics of osteoporosis. This review provides an overview of available information and identifies potential targets for future studies in this field.

BACKGROUND: The prevalence of Paget's disease of bone (PDB) is unknown in peninsular Southern Italy, although an elevated clinical severity of the disease was reported in patients from Campania. AIM: This study was performed to evaluate the epidemiological and genetic characteristics of PDB in a rural area of Calabria, the southernmost region in the Italian peninsula. SUBJECTS AND METHODS: We examined 1068 consecutive pelvic radiographs of patients older than 40 yr referred for any reason to the "Spinelli" Hospital, Belvedere Marittimo, from January 1st 2004 to December 31st 2006. In subjects with radiological findings of pelvic PDB, a 99m Technetium methylene diphosphonate bone scan and the sequence analysis of the sequestosome 1 (SQSTM1) gene were subsequently performed. RESULTS: In the examined geographic area, the crude radiographic prevalence of pelvic PDB was 0.74% (8/1068; male:female 5:3, mean age 71.6 ± 13.1 yr) whereas the estimated overall prevalence of PDB between 0.82% and 1.21%. PDB patients from Calabria showed clinical characteristics similar to those reported in patients from Campania. The disease was also frequently complicated by osteoarthritis and the right side of the body was more affected than the left. The SQSTM1 gene analysis revealed the presence of a novel missense mutation (M401V) in exon 8 in one subject with a familial and aggressive form of PDB. CONCLUSION: The study results confirmed that patients with PDB from rural districts of Southern Italy show an earlier onset and an increased clinical severity of the disease that appears mostly independent from the presence of germinal SQSTM1 mutations.

Publisher Summary Genetic factors play a key role in the pathogenesis of skeletal fragility and osteoporosis in both genders. Several studies using twin pairs or parent–offspring models have shown high levels of heritability of bone mineral density (BMD), the most commonly used skeletal trait to evaluate the genetic basis of bone strength and, ultimately, osteoporotic fractures. Theoretically, inheritance could affect bone strength and fracture risk in at least two ways. Genetic factors could influence skeletal growth and the amount of bone mass attained in early adulthood (peak bone mass) and subjects with genetically determined low bone mass might be more susceptible to develop osteoporosis with subsequent aging. Alternatively, or in conjunction with the above, genetic factors could influence the rate of age-related bone loss. To date, twin and family studies have shown a predominant genetic effect on peak bone mineral mass acquisition rather than on age-related bone loss. In fact, both male and female offspring of subjects with osteoporosis have reduced bone mass well before age-related or postmenopausal bone loss, suggesting the expression of inherited determinants of osteoporotic risk from an early age.