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Objective To estimate the proportion of patients with very severe osteoporosis (those covered by the reimbursement criteria of the Italian National Health Service) experiencing new vertebral and non-vertebral fragility fractures in the first 24 months of a new anti-osteoporosis treatment. Methods Prospective observational study in men and post-menopausal women (aged > 21 years) initiating anti-osteoporosis treatment for very severe osteoporosis. Eligibility was based on teriparatide (TPD) reimbursement criteria in Italy: Incident of vertebral or hip fracture during anti-resorptive treatment (minimum 1 year), or at least three prevalent severe vertebral fractures, or two prevalent severe vertebral fractures and a historical proximal hip fracture. Incidence of new clinical vertebral and non-vertebral fractures was documented by original x-rays and/or radiological reports, and a post-hoc analysis compared data from the TPD monotherapy population versus the total treated group. Results Overall, 767 patients (mean age 72.8 years, 90.7% women) were enrolled in the study, of whom 628, 538, 419 and 424 attended visits at 6, 12, 18 and 24 months, respectively. The most commonly prescribed therapy was TPD (single-agent; 64.5%), then bisphosphonates and other anti-resorptives (33.3%). A combination of different oral treatments was given to 22.5% of the patients. Overall treatment adherence at 24 months was 65.7%. In a post-hoc analysis, the overall incidence of new clinical vertebral and non-vertebral fractures in the total treated population was, respectively, 4.7% and 2.3% in the first 6 months; 1.8% and 1.6% in the 6-12 month period; 2.9% and 1.4% in the 12-18 month period; and 2.2% and 1.0% in the 18-24 month period. Conclusion In patients with very severe osteoporosis, the risk of new vertebral and non-vertebral fractures declined after the first 6 months and remained low throughout the study. Objective To estimate the proportion of patients with very severe osteoporosis (those covered by the reimbursement criteria of the Italian National Health Service) experiencing new vertebral and non-vertebral fragility fractures in the first 24 months of a new anti-osteoporosis treatment. Methods Prospective observational study in men and post-menopausal women (aged > 21 years) initiating anti-osteoporosis treatment for very severe osteoporosis. Eligibility was based on teriparatide (TPD) reimbursement criteria in Italy: Incident of vertebral or hip fracture during anti-resorptive treatment (minimum 1 year), or at least three prevalent severe vertebral fractures, or two prevalent severe vertebral fractures and a historical proximal hip fracture. Incidence of new clinical vertebral and non-vertebral fractures was documented by original x-rays and/or radiological reports, and a post-hoc analysis compared data from the TPD monotherapy population versus the total treated group. Results Overall, 767 patients (mean age 72.8 years, 90.7% women) were enrolled in the study, of whom 628, 538, 419 and 424 attended visits at 6, 12, 18 and 24 months, respectively. The most commonly prescribed therapy was TPD (single-agent; 64.5%), then bisphosphonates and other anti-resorptives (33.3%). A combination of different oral treatments was given to 22.5% of the patients. Overall treatment adherence at 24 months was 65.7%. In a post-hoc analysis, the overall incidence of new clinical vertebral and non-vertebral fractures in the total treated population was, respectively, 4.7% and 2.3% in the first 6 months; 1.8% and 1.6% in the 6-12 month period; 2.9% and 1.4% in the 12-18 month period; and 2.2% and 1.0% in the 18-24 month period. Conclusion In patients with very severe osteoporosis, the risk of new vertebral and non-vertebral fractures declined after the first 6 months and remained low throughout the study.

Objective Baseline characteristics of the population enrolled in the ISSO study, designed to evaluate the incidence of vertebral and non-vertebral fractures in Italian patients with severe osteoporosis treated according to clinical practice over 24 months observation. Methods Prospective observational study in 783 post-menopausal women and men entering 18-month treatment with teriparatide in a community setting at 57 centres in Italy. Characterisation included demographics, fracture risk factors, hone mineral density, fracture status, Health-Related Quality of Life (HRQoL) measured by the European Quality of Life Questionnaire, EQ-5D, and back pain assessed by VAS. Results Most patients were elderly women (90.5%), mean age +/- SD was 72.9 +/- 8.8 years. Nearly all (91.3%) had experienced >= 1 vertebral fracture (mean +/- SD, 3.6 +/- 2.2 per patient), 37.5% had >= 1 non-vertebral fracture (mean +/- SD, 1.4 +/- 0.7 per patient). Nearly all patients were suffering from back pain (94.9%), which had significantly restricted their daily activities (51.7%) and had likely or very likely been caused by vertebral fractures (29.2% and 55.8%, respectively). Mean EuroQoL EQ-5D index value was 0.58 +/- 0.25 and VAS score 49.2 +/- 23.6. Non-vertebral fractures, back pain and multiple vertebral fractures were associated with lower HRQoL (EuroQoL-5D Index both p

Teriparatide has an anabolic effect on bone tissue, leading to an increase in bone strength with a reduction in the risk of fragility fractures in osteoporotic women. In the last ten years, many animal studies have been conducted to support the hypothesis that this anabolic effect of teriparatide may benefit fracture healing by reducing the time of callus formation and remodeling. Teriparatide also seems to have an effect in the early post-operative period after osteosynthesis or joint replacement, by stimulating new bone formation, increasing bone-implant contact as early as after 1 week, and enhancing the tensile strength of the bone-cement interface, thereby decreasing the risk of late aseptic loosening. Scientific evidence supports the hypothesis that teriparatide may represent a huge resource for wide applications in orthopedic surgery.

The patient, a 79-year-old woman with a history of osteoporosis, presented with acute back pain without trauma, three years ago. Spinal X rays showed a vertebral compression fracture at T7, and DXA indicated a T-score of -2.65 BMD at the total hip. The patient started treatment with alendronate 70 mg once a week, plus calcium and vitamin D supplementation. After two years, she presented new acute back pain, and spinal X-rays revealed new vertebral compression fractures at T8 and T11. In September 2004, she stopped alendronate therapy and began teriparatide 20 microg subcutaneously each day for 18 months, associated with a dose of 1200 mg/day of calcium and 880 IU/day of vitamin D. In July 2005, she fell and sustained a fracture of the left proximal humerus. She was treated with conservative therapy and continued teriparatide therapy. After 25 days of conservative management, left shoulder X-ray showed quick formation of fracture healing. In conclusion, although teriparatide is indicated for the treatment of severe osteoporosis and not to enhance fracture healing, there are many experimental data which indicate that it may be beneficial also in enhancing fracture healing. The patient, a 79-year-old woman with a history of osteoporosis, presented with acute back pain without trauma, three years ago. Spinal X rays showed a vertebral compression fracture at T7, and DXA indicated a T-score of -2.65 BMD at the total hip. The patient started treatment with alendronate 70 mg once a week, plus calcium and vitamin D supplementation. After two years, she presented new acute back pain, and spinal X-rays revealed new vertebral compression fractures at T8 and T11. In September 2004, she stopped alendronate therapy and began teriparatide 20 microg subcutaneously each day for 18 months, associated with a dose of 1200 mg/day of calcium and 880 IU/day of vitamin D. In July 2005, she fell and sustained a fracture of the left proximal humerus. She was treated with conservative therapy and continued teriparatide therapy. After 25 days of conservative management, left shoulder X-ray showed quick formation of fracture healing. In conclusion, although teriparatide is indicated for the treatment of severe osteoporosis and not to enhance fracture healing, there are many experimental data which indicate that it may be beneficial also in enhancing fracture healing.

The study was designed to assess the sensitivity of three commercial assays (which differ in methodology, standard and antibodies) for osteocalcin, used for detecting changes in osteocalcin secretion induced by calcitriol (1,25-dihydroxycholecalciferol) in vivo and in vitro. Osteocalcin levels were determined in serum samples of 10 osteoporotic women after short term calcitriol treatment, and in the culture medium of human osteoblast-like cells (n = 22) after 48 h calcitriol exposure. All assays displayed similar sensitivity in detecting osteocalcin production in vivo after a 1 microgram daily dose of calcitriol. A novel IRMA (CIS), claimed to detect intact osteocalcin, showed higher osteocalcin values than the other assays, and in vitro showed the best sensitivity; it provides an appropriate index of the osteocalcin synthetic activity of cultured human osteoblasts.

Giovanni Iolascon,1 Alessandro de Sire,1– 3 Dario Calafiore,1,4 Maria Grazia Benedetti,5 Carlo Cisari,2,6 Giulia Letizia Mauro,7 Silvia Migliaccio,8 Ranuccio Nuti,9 Giuseppina Resmini,10 Stefano Gonnelli,9 Antimo Moretti1 1Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples, Italy; 2Physical and Rehabilitative Medicine, Department of Health Sciences, University of Eastern Piedmont “A. Avogadro”, Novara, Italy; 3Rehabilitation Unit, “Mons L. Novarese” Hospital, Vercelli, Moncrivello, Italy; 4Section of Neuromotor Rehabilitation, Department of Neuroscience, ASST Carlo Poma, Mantova, Italy; 5Physical Medicine and Rehabilitation Unit, IRCCS-Istituto Ortopedico Rizzoli, Bologna, Italy; 6Physical Medicine and Rehabilitation Unit, University Hospital “Maggiore della Carità”, Novara, Italy; 7Department of Surgical and Oncology Sciences, University of Palermo, Palermo, Italy; 8Department of Movement, Human and Health Sciences, Section of Health Sciences, University of Rome, Foro Italico, Rome, Italy; 9Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy; 10Section of Orthopaedics and Traumatology, Treviglio-Caravaggio Hospital, Treviglio, Bergamo, ItalyCorrespondence: Alessandro de SirePhysical and Rehabilitative Medicine, Department of Health Sciences, University of Eastern Piedmont “A. Avogadro”, Viale Piazza D’Armi 1, Novara 28100, ItalyTel +3903213734800Email alessandro.desire@gmail.comObjective: To assess physical performance, number of falls, previous fragility fractures, and ongoing pharmacological therapy in a cohort of post-menopausal women, according to their risk of falling.Methods: In this multicenter cross-sectional study, we recruited in a 3-year period (May 2016 to April 2019), women aged > 60 years referred to seven Osteoporosis and Bone Metabolism Outpatient Services of the Italian Group for the Study of Metabolic Bone Diseases. The study population was divided into three groups according to the risk of falling, assessed through the Elderly Fall Screening Test (EFST): low risk (EFST score=0– 1); moderate risk (EFST=2– 3); high risk (EFST=4– 5). Outcome measures were: 4-meter gait speed (4MGS); unipedal stance time (UST); number of falls in the previous year; previous fragility fractures; ongoing pharmacological therapy.Results: We analyzed 753 women (mean aged 70.1± 9.2 years): 378 (50.2%) at low risk of falling, 247 (32.8%) at moderate risk, and 128 (17.0%) at high risk. 4MGS and UST resulted as pathological in the 93.9% and 99.2%, respectively, of women at high risk. There were significant differences among groups for both outcomes (p< 0.001). There was also a significant difference among groups (p< 0.001) in terms of previous falls and fragility fractures. Lastly, there were significant differences (p< 0.05) among groups in using antihypertensive drugs, antiplatelet agents, anticoagulants, antidepressants, anti-osteoporotic drugs, and vitamin D, and/or calcium supplementation.Conclusion: Physical performance, prevalence of falls and fragility fractures, and an assessment of pharmacological therapy should be investigated in post-menopausal women because of their significant correlation with risk of falling.Keywords: accidental falls, osteoporosis, walking speed, fractures, bone, rehabilitation

Background: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. Aim: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. Material/subjects and methods: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia ® ) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. Results: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m 2 . At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was −2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was −2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. Conclusions: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures. Background: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. Aim: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. Material/subjects and methods: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia®) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. Results: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was −2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was −2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. Conclusions: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures.

Background Hypoxia is a common feature of many congenital heart defects (CHDs) and significantly contributes to their pathophysiology. Thus, understanding the mechanism underlying cell response to hypoxia is vital for the development of novel therapeutic strategies. Certainly, the hypoxia inducible factor (HIF) has been extensively investigated and it is now recognized as the master regulator of cell defense machinery counteracting hypoxic stress. Along this line, we recently discovered and reported a novel mechanism of HIF activation, which is mediated by sialidase NEU3. Thus, aim of this study was to test whether NEU3 played any role in the cardiac cell response to chronic hypoxia in congenital cyanotic patients. Methods Right atrial appendage biopsies were obtained from pediatric patients with cyanotic/non-cyanotic CHDs and processed to obtain mRNA and proteins. Real-Time PCR and Western Blot were performed to analyze HIF-1α and its downstream targets expression, NEU3 expression, and the NEU3 mediated effects on the EGFR signaling cascade. Results Cyanotic patients showed increased levels of HIF-1α, NEU3, EGFR and their downstream targets, as compared to acyanotic controls. The same patients were also characterized by increased phosphorylation of the EGFR signaling cascade proteins. Moreover, we found that HIF-1α expression levels positively correlated with those recorded for NEU3 in both cyanotic and control patients. Conclusions Sialidase NEU3 plays a central role in activating cell response to chronic hypoxia inducing the up-regulation of HIF-1α, and this represent a possible novel tool to treat several CHD pathologies.

Cancer cells secrete proteins that modify the extracellular environment acting as autocrine and paracrine stimulatory factors and have a relevant role in cancer progression. The HMGA1 oncofetal protein has a prominent role in controlling the expression of an articulated set of genes involved in various aspect of cancer cell transformation. However, little is known about its role in influencing the secretome of cancer cells. Performing an iTRAQ LC–MS/MS screening for the identification of secreted proteins, in an inducible model of HMGA1 silencing in breast cancer cells, we found that HMGA1 has a profound impact on cancer cell secretome. We demonstrated that the pool of HMGA1–linked secreted proteins has pro–migratory and pro-invasive stimulatory roles. From an inspection of the HMGA1–dependent secreted factors it turned out that HMGA1 influences the presence in the extra cellular milieu of key components of the Plasminogen activation system (PLAU, SERPINE1, and PLAUR) that has a prominent role in promoting metastasis, and that HMGA1 has a direct role in regulating the transcription of two of them, i.e. PLAU and SERPINE1. The ability of HMGA1 to regulate the plasminogen activator system may constitute an important mechanism by which HMGA1 promotes cancer progression.

An imbalance of the remodeling process for bone resorption leads to a loss of tissue with consequent microarchitectural damage, evident in conditions such as osteoporosis and related fragility fractures. Currently, pharmacological therapies are able to prevent or slow down bone resorption by inhibiting osteoclast activity. An innovative and targeted anti-resorptive approach is represented by the inhibition of RANK ligand (RANK-L), essential for the proliferation and activity of osteoclastic cells. The human monoclonal antibody against RANK-L (denosumab) has been approved for the treatment of osteoporosis. In clinical trials of patients with osteoporosis, inhibition of RANK-L has reduced bone loss and damage to the microarchitecture and was associated with an increase in mass and resistance at different skeletal sites, with most significant effects than those demonstrated by any other antiresorptive drugs. In addition, after 3 years of treatment, it showed a reduction in vertebral and non-vertebral fracture risk. Denosumab treatment also has not revealed any alteration in the physiological processes of fracture repair, showing no increase in the onset of complications 3 years after the fracture. The data show that denosumab offers an effective alternative therapeutic approach for the treatment of severe osteoporosis, with positive effects on BMD and reduction of fragility fractures risk. So, promising results in terms of therapeutic efficacy and reliability make desirable the wide clinical use of denosumab for the treatment of osteoporotic fractures in the near future. © 2013 Springer International Publishing Switzerland. An imbalance of the remodeling process for bone resorption leads to a loss of tissue with consequent microarchitectural damage, evident in conditions such as osteoporosis and related fragility fractures. Currently, pharmacological therapies are able to prevent or slow down bone resorption by inhibiting osteoclast activity. An innovative and targeted anti-resorptive approach is represented by the inhibition of RANK ligand (RANK-L), essential for the proliferation and activity of osteoclastic cells. The human monoclonal antibody against RANK-L (denosumab) has been approved for the treatment of osteoporosis. In clinical trials of patients with osteoporosis, inhibition of RANK-L has reduced bone loss and damage to the microarchitecture and was associated with an increase in mass and resistance at different skeletal sites, with most significant effects than those demonstrated by any other antiresorptive drugs. In addition, after 3 years of treatment, it showed a reduction in vertebral and non-vertebral fracture risk. Denosumab treatment also has not revealed any alteration in the physiological processes of fracture repair, showing no increase in the onset of complications 3 years after the fracture. The data show that denosumab offers an effective alternative therapeutic approach for the treatment of severe osteoporosis, with positive effects on BMD and reduction of fragility fractures risk. So, promising results in terms of therapeutic efficacy and reliability make desirable the wide clinical use of denosumab for the treatment of osteoporotic fractures in the near future. © 2013 Springer International Publishing Switzerland.

The major role of vitamin D in humans is to increase the absorption of calcium and phosphatase for the mineralization of the skeleton. The synthesis of vitamin D3 in the skin under influence of UV light decreases with aging due to insufficient sunlight exposure, and a decreased functional capacity of the skin. Deficiency in vitamin D causes secondary hyperparathyroidism, high bone turnover, bone loss, mineralization defects, proximal myopathy, falls and hip and other fractures. The goal of therapy of hypovitaminosis D is to restore normal serum and deposits of 25 (OH) D. The daily supplementation of vitamin D indicated is about 800-1,000 IU/day but may increase up to a maximum dose of 2,000 IU/day in conditions of severe vitamin D deficiency with a concomitant reduced or no sun exposure, reduced dietary intake and reduced calcium absorption. © 2013 Springer International Publishing Switzerland.

Background and aims: Bone density and quality alterations worsen the ability of osteoporotic bone to support prosthetic implants. The aim of our study was to evaluate potential differences in bone quality and bone turnover markers in aged individuals undergoing surgery for hip fragility fracture or hip osteoarthritis. Methods: Eighteen subjects with hip fragility fractures (Hip Fracture Group), 35 subjects with osteoarthritis of the hip (Hip Osteoarthritis Group) and 19 subjects with normal femoral bone mineral density (Control Group) were evaluated. Serum and urinary bone markers were assayed preoperatively in all surgical patients, and within 48 hours after fracture in the Hip Fracture, Osteoarthritis and Control groups. Histomorphometric analysis was performed on surgical samples. Results: A significant alteration in calcium and PTH serum levels with hyperparathyroidism was observed in the Hip Fracture Group compared with Hip Osteoarthritis and Control Groups. C-Terminal telopeptides of type I-collagen (CTx) and tartrate resistant-acid phosphatase (TRAP), markers of bone resorption, were increased in the Hip Fracture Group compared with both Osteoarthritis and Control Groups (CTx: p