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Background and Objectives : Sport-related musculoskeletal injuries (MSK-Is) are a common health issue in athletes that can lead to reduced performance. The aim of this scoping review was to synthetize available evidence on injury incidence rates (IIRs), types, and sites that affect the musculoskeletal (MSK) system of adult athletes. Materials and Methods : We performed a scoping review on the Pubmed database limiting our search to 33 Olympic sports. Results : We identified a total of 1022 papers, and of these 162 were examined in full for the purpose of this review. Archery was the sport with the highest risk of injuries to the upper extremities, marathons for the lower extremities, and triathlon and weightlifting for the body bust. In the majority of the sports examined, muscle/tendon strain and ligament sprain were the most common MSK-Is diagnoses, while athletics, karate, and football were the sports with the highest IIRs, depending on the methods used for their calculations. Conclusions : Our scoping review highlighted the general lack and dishomogeneity in the collection of data on MSK-Is in athletes.

Herein we unveil that Hypoxia-inducible factor-1α (HIF-1α) directly regulates WNT7A expression during myogenesis. In fact, chromatin immunoprecipitation (ChiP) and site-directed mutagenesis experiments revealed two distinct hypoxia response elements (HREs) that are specific HIF-1α binding sites on the WNT7A promoter. Remarkably, a pharmacological activation of HIF-1α induced WNT7A expression and enhanced muscle differentiation. On the other hand, silencing of WNT7A using CRISPR/Cas9 genome editing blocked the effects of HIF-1α activation on myogenesis. Finally, treatment with prolyl hydroxylases (PHDs) inhibitors improved muscle regeneration in vitro and in vivo in a cardiotoxin (CTX)-induced muscle injury mouse model, paving the way for further studies to test its efficacy on acute and chronic muscular pathologies., (Copyright © 2020 Cirillo, Resmini, Angelino, Ferrara, Tarantino, Piccoli, Rota, Ghiroldi, Monasky, Ciconte, Pappone, Graziani and Anastasia.)

Background: The Italian Society for Orthopaedics and Traumatology conceived this guidance-which is primarily addressed to Italian orthopedic surgeons, but should also prove useful to other bone specialists and to general practitioners-in order to improve the diagnosis, prevention, and treatment of osteoporosis and its consequences., Materials and Methods: Literature reviews by a multidisciplinary team., Results: The following topics are covered: the role of instrumental, metabolic, and genetic evaluations in the diagnosis of osteoporosis; appraisal of the risk of fracture and thresholds for intervention; general strategies for the prevention and treatment of osteoporosis (primary and secondary prevention); the pharmacologic treatment of osteoporosis; the setting and implementation of fracture liaison services for tertiary prevention. Grade A, B, and C recommendations are provided based on the main levels of evidence (1-3). Toolboxes for everyday clinical practice are provided., Conclusions: The first up-to-date Italian guidelines for the primary, secondary, and tertiary prevention of osteoporosis and osteoporotic fractures are presented.

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.

Regeneration of skeletal muscle is a complex process that requires the activation of quiescent adult stem cells, called satellite cells, which are resident in hypoxic niches in the tissue. Hypoxia has been recognized as a key factor to maintain stem cells in an undifferentiated state. Herein we report that hypoxia plays a fundamental role also in activating myogenesis. In particular, we found that the activation of the hypoxia-inducible factor (HIF)-1α under hypoxia, in murine skeletal myoblasts, leads to activation of MyoD through the noncanonical Wnt/β-catenin pathway. Moreover, chemical inhibition of HIF-1α activity significantly reduces differentiation, thus confirming its crucial role in the process. Furthermore, hypoxia-preconditioned myoblasts, once induced to differentiate under normoxic conditions, tend to form hypertrophic myotubes. These results support the notion that hypoxia plays a pivotal role in activating the regeneration process by directly inducing myogenesis through HIF-1α. Although preliminary, these findings may suggest new perspective for novel therapeutic targets in the treatment of several muscle diseases.-Cirillo, F., Resmini, G., Ghiroldi, A., Piccoli, M., Bergante, S., Tettamanti, G., Anastasia, L. Activation of the hypoxia-inducible factor 1α promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes., (© FASEB.)

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: In the pathogenesis of hip fracture, proximal femur geometry plays a key role as well as decreased bone density. The hip structural analysis (HSA) processes dual energy X-ray absorptiometry (DXA) images containing information on the geometry closely related to the strength of the proximal femur. The objective of this study was to investigate bone mineral density (BMD) and mechanical properties of the proximal femur in a group of women with a previous contralateral hip fragility fracture compared to women without history of hip fracture., Materials and Methods: In a population of postmenopausal women, we evaluated bone density by DXA and bone geometry using the HSA parameters (femoral strength index, cross-sectional moment of inertia, cross-sectional area, section modulus, and buckling ratio) including hip axis length (HAL) and neck shaft angle., Results: Of a total of 62 postmenopausal women, twenty-six with a history of hip fracture had a mean femoral neck BMD significantly lower in comparison with 36 women in the control group (0.703 versus 0.768 g/cm(2), p = 0.0347). There was a statistically significant difference between groups also for HAL (106.75 mm in fracture group versus 100.93 mm in control group, p = 0.0015)., Discussion and Conclusions: Our results demonstrated that all the geometrical parameters resulted worst into the group of patients with history of hip fracture, even though only the HAL was significantly lower in control subjects. In our opinion HSA is useful to characterize the risk of hip fracture in postmenopausal women, providing additional data on the spatial distribution of bone mass strongly related to bone strength.

Complex Regional Pain Syndrome (CRPS) is a chronic pain condition that occurs after a tissue injury (fractures, sprain, surgery) of the upper or lower extremities. A clear pathophysiological mechanism has not been established yet and different patterns are considered to play a role in the genesis of the disease. The diagnosis is made by different diagnosis criteria and a gold standard has not been established yet. Incidence of CRPS is unclear and large prospective studies on the incidence and prevalence of CRPS are scarce. The aim of this review is to give an overview on the prevalent data regarding this chronic syndrome.

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.

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.

Introduction: Osteoporosis is a chronic condition leading to an increased risk of developing fractures, with high morbidity and mortality in aging population. Efficacy of anti-osteoporotic treatment is based on drug potency but also on compliance and persistence to treatment regimen, which is very low, as already described for other diseases. Teriparatide (TPTD) is the first anabolic agent developed for the treatment of osteoporosis. Since it appears that persistence to Teriparatide declines over time, aim of this pilot multicenter observational study was to evaluate persistence and adherence to TPTD (20 μg daily injection regimen for 18 months) treatment (PATT) in patients affected by severe osteoporosis in an every day clinical practice., Methods: Patients affected by severe osteoporosis were selected among those who referred to 5 different specialized centers for osteoporosis in North, Center and South of Italy. A sample of 475 women with severe postmenopausal osteoporosis treated with TPTD in accordance to the Italian osteoporosis guidelines was included. At the beginning of TPTD treatment patients were instructed on the use of the device by the referring specialist of the center, a resident fellow or a nurse. Bone biochemical markers were evaluated the same morning and after 1, 3, 6, 12 and 18 months. Patients were visited at time 0 and after 6, 12 and 18 months for clinical follow up., Results: The results included observations of 441/475 patients (98% women) who completed the 18 months treatment; mean age for women was 73±8 and for men 65±9. After 6 months of TPTD treatment persistence was of 89,79%, 87,75% after 12 months and 86,85% after 18 months. Adherence was of 100% at 6,12 and 18 months. Total dropouts were 13,15% (71/441), which was usually higher within the first 6 months of TPTD treatment. Most common adverse events (arthralgies 2,7%, dizziness 1,8%, migraine 1,8%, depression 1,6%, hypertension 1,1%) were reported in 62/441 patients (14%) of patients, but were not reason for stopping treatment., Conclusions: The persistence and adherence to TPTD treatment obtained in this multicenter observational real life study was very high as compared to studies performed by others. These encouraging results suggest that different key factors such quality of information, frequency of visits, motivations given to patients, opportunity to call the doctor might play a pivotal role in the high persistence and adherence to TPTD treatment obtained in our study and need to be carefully considered before prescribing chronic anti-osteoporotic therapy.

Introduction: Vertebral fractures have been associated with back pain, functional limitations and reduced health-related quality of life (HRQoL). Teriparatide is the first effective anabolic agent that demonstrated to significantly reduce the risk of vertebral fracture by 65%, as compared to placebo. The aims of this study were to evaluate the effectiveness of teriparatide treatment on back pain-related functional limitations and to investigate on patients HRQoL., Materials and Methods: In this prospective observational pilot study osteoporotic patients, who were prescribed teriparatide therapy and a supplementation of calcium and vitamin D, were asked to answer to two self-administered questionnaires: the Spine Pain Index (SPI) and the SF-12 (at the recruitment, after 6, 12, and 18 months)., Results: Fifty-two women were evaluated (mean age of 70.58 yrs). The mean SPI score passed from 50.01 at baseline to 32.20 at 18 months. The mean SF-12 PCS score passed from 30.00 at baseline to 36.79 at 18 months, while the mean SF-12 MCS score was already within the normality range at baseline, constantly improving during the 18 months., Conclusion: In conclusion, 18 months of treatment with teriparatide has to be considered an effective therapeutic option for women with severe osteoporosis and vertebral fractures, in a real-life clinical setting, to improve both back pain related disability and quality of life.

The rapid onset of the Domino Effect following the first Vertebral Compression Fracture is a direct consequence of the mechanical variations that affect the spine when physiological curves are modified. The degree of kyphosis influences the intensity of the Flexor Moment; this is greater on vertebrae D7, D8 and on vertebrae D12, L1 when the spine flexes. Fractures of D7, D8, D12 and L1 are, by far, the most frequent and also the main cause of the mechanical alterations that can trigger the Domino Effect. For these considerations vertebrae D7, D8, D12 and L1 have to be taken in consideration as "critical". In the case of critical clinical vertebral fractures it is useful to provide an indication for minimally invasive surgical reduction or intrasomatic stabilization. When occurs a fracture of a "critical vertebra", prompt restoration of the heights leads to a reduction in the Kyphosis Index and therefore in the Flexor Moment, not only of the fractured vertebra but also, in turn, of all the other metameres which, even if morphologically still intact, are structurally fragile; so, through the restoration of the mechanical vertebral proprieties, we can reduce the risk of the Domino Effect. At the same time the prompt implementation of osteoinductive therapy is indispensable in order to achieve rapid and intense reconstruction of the trabecular bone, the strength of which increases significantly in a short period of time. Clinical studies are necessary to confirm the reduction of the domino effect following a fragility fracture of "critical vertebrae" with the restoration of the mechanical properties together with anabolic therapy.

Parathyroid hormone (PTH) is secreted by the parathyroid glands and is an important regulator of blood calcium concentrations. Synthesis and secretion of PTH are stimulated by a decrease in blood calcium. PTH has three actions: 1) to increase the release of calcium from bone, 2) to reduce renal clearance of calcium, and 3) to stimulate the production of 1,25 (OH)2D3. Human parathyroid hormone is a single chain polypeptide with 84 amino acids and a molecular weight of 9425 Da. The N-terminal region, 1-34, is biologically active and sufficient for regulation of mineral ion homeostasis (1). Recombinant teriparatide {human PTH(1-34) [hPTH (1-34)]}, currently the only bone-forming osteoporosis drug available for clinical use, increases bone turnover with a greater stimulation of formation than resorption (2). Bone turnover markers also rise during treatment with teriparatide (TPTD), with markers of bone formation rising early and rapidly, followed by rises in bone resorption markers.

The severity of osteoporosis depends not only on densitometric data but implies the occurrence of at least one of the following conditions: increased risk of mortality, worsening of quality of life and significant disability in the performance of activities of daily living, presence of comorbidities that increase the risk of falls, the presence of at least one fragility fracture.

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<0.0007 and p<0.0039 respectively; TRAP: p<0.002 and p<0.0007). All subjects were vitamin D3-deficient, but no differences were found among the different groups. In addition, histomorphometric data showed better maintained connectivity in the Osteoarthritis Group compared with the Hip Fracture Group (p<0.0001)., Conclusions: Our data show significant differences in bone turnover markers in patients undergoing hip prosthesis for fragility fractures, compared with patients operated for hip osteoarthritis.

Cortical and trabecular bone undergo a continuous and balanced remodeling process, consisting of an osteoclast-mediated bone-resorption phase and an osteoblast- mediated bone-formation phase. An imbalance in this process, which favours bone resorption, results in bone loss and in damage to the skeletal microarchitecture. A new targeted anti-resorptive approach is represented by the inhibition of RANK ligand (RANKL), which is one of the primary mediators of osteoclast activity, essential for osteoclast formation, function and survival.

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.

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 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.

This study was designed to test the hypothesis that a short treatment course of 1,25(OH)2D3 elicits a stimulation of osteoblast activity without any action on the osteoclast. To test this, oral daily doses of 0.5 microgram or 1 microgram of 1,25(OH)2D3 were administered for 7 days to two groups (n = 5 and n = 7, respectively) of postmenopausal women with low bone mineral density. Markers of osteoblast activity, i.e. osteocalcin (BGP), total alkaline phosphatase activity (ALP) and bone alkaline phosphatase activity (BALP), and markers of osteoclast activity, i.e. hydroxylysyl-pyridinoline (Pyr), lysyl-pyridinoline (D-Pyr), and galactosyl-hydroxylysine (GHyl) were measured in plasma and in fasting urinary samples, respectively, at sequential times during and after 1,25(OH)2D3 administration. It resulted that short term 1 microgram 1,25(OH)2D3 oral administration induced a significant (P < 0.05) rise of BGP serum level without any associated increase of D-Pyr and GHyl, the latter also expressed as GHyl to GGHyl ratio. Urinary Pyr increased significantly after 1 microgram daily doses of 1,25(OH)2D3. Thus, a short course of 1 microgram daily doses of 1,25(OH)2D3 elicits a stimulation of osteoblast activity without any enhancement of D-Pyr, the most specific marker of osteoclast activity. The enhancement of Pyr after 1 microgram daily doses of 1,25(OH)2D3 might be due to the activation of extraosseous metabolic pathways rather than to the activation of osteoclast.

The purpose of this study was to verify if a decreased inhibition of PTH secretion (abnormal suppressibility) in response to physiological increment of plasma calcium is present in patients with osteoporosis. The plasma concentration curve of intact PTH 1-84 following an oral calcium load (Pak) has been calculated in a selected population of 38 osteopenic patients (16 males and 22 females) and in a control group of 9 young healthy adults. All the patients included in this study a) had no past or present diseases and medications of potential influence on calcium homeostasis, b) showed a maximal calcemic response to the oral calcium load equal to that of the control group. PTH suppressibility was significantly smaller in the osteoporotic patients (-42% in males and -32% in females) than in the control group (-76%). This abnormal suppressibility of PTH is independent on sex and, in the females, also on postmenopausal estrogen deficiency. These results support the hypothesis that osteoporosis is associated to an altered secretory response of parathyroid glands maybe due to reduced sensitivity of the parathyroid cells to extracellular calcium.

The oral calcium load test, originally proposed for evaluating the intestinal calcium absorption and the renal calcium leak triggers some endocrine and metabolic responses addressed to correct the "calcemic error" induced by the load. Besides the increased plasma calcium there are: plasma PTH drop, increment in the urinary calcium excretion and in the threshold of tubular phosphate reabsorption. These responses have been measured and reciprocally correlated in 9 young adults at different times after the oral calcium load. The responses can be assessed with high precision in clinical practice and are in agreement with the known physiological models. The oral calcium load test is proposed as a tool for studying in the osteopenic population in the individual's capacity of correcting the calcemic error induced by the load.