Oxidative Stress and Natural Antioxidants in Osteoporosis: Novel Preventive and Therapeutic Approaches.

This review reports in detail the cellular and molecular mechanisms which regulate the bone remodeling process in relation to oxidative stress (OS), inflammatory factors, and estrogen deficiency. OS is considered an important pathogenic factor of osteoporosis, inducing osteocyte apoptosis and varying levels of specific factors, such as receptor activator κB ligand (RANKL), sclerostin, and, according to recent evidence, fibroblast growth factor 23, with consequent impairment of bone remodeling and high bone resorption. Bone loss increases the risk of fragility fractures, and the most commonly used treatments are antiresorptive drugs, followed by anabolic drugs or those with a double effect. In addition, recent data show that natural antioxidants contained in the diet are efficient in preventing and reducing the negative effects of OS on bone remodeling and osteocytes through the involvement of sirtuin type 1 enzyme. Indeed, osteocytes and some of their molecular factors are considered potential biological targets on which antioxidants can act to prevent and reduce bone loss, as well as to promote bone anabolic and regenerative processes by restoring physiological bone remodeling. Several data suggest including antioxidants in novel therapeutic approaches to develop better management strategies for the prevention and treatment of osteoporosis and OS-related bone diseases. In particular, anthocyanins, as well as resveratrol, lycopene, oleuropein, some vitamins, and thiol antioxidants, could have protective and therapeutic anti-osteoporotic effects.

Skeletal and extraskeletal disorders of biomineralization.

The physiological process of biomineralization is complex and deviation from it leads to a variety of diseases. Progress in the past 10 years has enhanced understanding of the genetic, molecular and cellular pathophysiology underlying these disorders; sometimes, this knowledge has both facilitated restoration of health and clarified the very nature of biomineralization as it occurs in humans. In this Review, we consider the principal regulators of mineralization and crystallization, and how dysregulation of these processes can lead to human disease. The knowledge acquired to date and gaps still to be filled are highlighted. The disorders of mineralization discussed comprise a broad spectrum of conditions that encompass bone disorders associated with alterations of mineral quantity and quality, as well as disorders of extraskeletal mineralization (hyperphosphataemic familial tumoural calcinosis). Included are disorders of alkaline phosphatase (hypophosphatasia) and phosphate homeostasis (X-linked hypophosphataemic rickets, fluorosis, rickets and osteomalacia). Furthermore, crystallopathies are covered as well as arterial and renal calcification. This Review discusses the current knowledge of biomineralization derived from basic and clinical research and points to future studies that will lead to new therapeutic approaches for biomineralization disorders.

Effect of Oxidative Stress-Induced Apoptosis on Active FGF23 Levels in MLO-Y4 Cells: The Protective Role of 17-ß-Estradiol.

The discovery that osteocytes secrete phosphaturic fibroblast growth factor 23 (FGF23) has defined bone as an endocrine organ. However, the autocrine and paracrine functions of FGF23 are still unknown. The present study focuses on the cellular and molecular mechanisms involved in the complex control of FGF23 production and local bone remodeling functions. FGF23 was assayed using ELISA kit in the presence or absence of 17ß-estradiol in starved MLO-Y4 osteocytes. In these cells, a relationship between oxidative stress-induced apoptosis and up-regulation of active FGF23 levels due to MAP Kinases activation with involvement of the transcriptional factor (NF-kB) has been demonstrated. The active FGF23 increase can be due to up-regulation of its expression and post-transcriptional modifications. 17ß-estradiol prevents the increase of FGF23 by inhibiting JNK and NF-kB activation, osteocyte apoptosis and by the down-regulation of osteoclastogenic factors, such as sclerostin. No alteration in the levels of dentin matrix protein 1, a FGF23 negative regulator, has been determined. The results of this study identify biological targets on which drugs and estrogen may act to control active FGF23 levels in oxidative stress-related bone and non-bone inflammatory diseases.

ALPL Genotypes in Patients With Atypical Femur Fractures or Other Biochemical and Clinical Signs of Hypophosphatasia.

CONTEXT: Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue nonspecific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the administration of contraindicated antiresorptive drugs that, in patients with HPP, substantially increase the risk of atypical femur fractures (AFFs) and worsen the fracture healing process that is usually already compromised in these patients. OBJECTIVE: Performing ALPL genetic testing to identify rare variants in suspected adult patients with HPP. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP. METHODS: Patients with suspected adult HPP were retrospectively selected for the genetic testing of the ALPL gene. Patients included were from 3 main European Bone Units (Florence, Naples, and Geneva); 106 patients with biochemical and/or clinical signs suggestive of a mild form of HPP were included. RESULTS: Genetic testing led to the identification of a heterozygote rare variant in 2.8% of cases who were initially referred as suspected osteoporosis. The analysis of frequencies of ALPL common variants showed a high prevalence (30.8%) of homozygosity in subjects who developed an AFF, in association with normal serum total ALP activity. CONCLUSION: The results suggest homozygosity of common ALPL variants as a possible genetic mark of risk for these fractures.

In Vitro Non-Genomic Effects of Calcifediol on Human Preosteoblastic Cells.

Several recent studies have demonstrated that the direct precursor of vitamin D3, the calcifediol [25(OH)D3], through the binding to the nuclear vitamin D receptor (VDR), is able to regulate the expression of many genes involved in several cellular processes. Considering that itself may function as a VDR ligand, although with a lower affinity, respect than the active form of vitamin D, we have assumed that 25(OH)D3 by binding the VDR could have a vitamin's D3 activity such as activating non-genomic pathways, and in particular we selected mesenchymal stem cells derived from human adipose tissue (hADMSCs) for the in vitro assessment of the intracellular Ca2+ mobilization in response to 25(OH)D3. Our result reveals the ability of 25(OH)D3 to activate rapid, non-genomic pathways, such as an increase of intracellular Ca2+ levels, similar to what observed with the biologically active form of vitamin D3. hADMSCs loaded with Fluo-4 AM exhibited a rapid and sustained increase in intracellular Ca2+ concentration as a result of exposure to 10-5 M of 25(OH)D3. In this work, we show for the first time the in vitro ability of 25(OH)D3 to induce a rapid increase of intracellular Ca2+ levels in hADMSCs. These findings represent an important step to better understand the non-genomic effects of vitamin D3 and its role in endocrine system.

Hypoparathyroidism and pseudohypoparathyroidism in pregnancy: an Italian retrospective observational study.

BACKGROUND: Hypoparathyroidism (HypoPT) or pseudo-hypoparathyroidism (pseudo-HypoPT) during pregnancy may cause maternal and fetal/neonatal complications. In this regard, only a few case reports or case series of pregnant or lactating women have been published. The purpose of this study was to describe clinical and biochemical course, pharmacological management, and potential adverse events during pregnancy and post-partum in pregnant women with HypoPT or pseudo-HypoPT. This was a retrospective, observational, multicenter, study involving nine Italian referral centers for endocrine diseases affiliated with the Italian Society of Endocrinology and involved in "Hypoparathyroidism Working Group". RESULTS: This study identified a cohort of 28 women (followed between 2005 and 2018) with HypoPT (n = 25, 84% postsurgical, 16% idiopathic/autoimmune) and pseudo-HypoPT (n = 3). In HypoPT women, the mean calcium carbonate dose tended to increase gradually from the first to third trimester (+ 12.6%) in pregnancy. This average increase in the third trimester was significantly greater compared to the pre-pregnancy period (p value = 0.03). However, analyzing the individual cases, in 44% the mean calcium dosage remained unchanged throughout gestation. Mean calcitriol doses tended to increase during pregnancy, with a statistically significant increase between the third trimester and the pre-pregnancy period (p value = 0.02). Nevertheless, analyzing the individual cases, in the third trimester most women with HypoPT (64%) maintained the same dosage of calcitriol compared to the first trimester. Both mean calcium carbonate and calcitriol doses tended to decrease from the third trimester to the post-partum six months. Most identified women (~ 70%) did not display maternal complications and (~ 90%) maintained mean serum albumin-corrected total calcium levels within the low-to-mid normal reference range (8.5 ± 0.8 mg/dl) during pregnancy. The main complications related to pregnancy period included: preterm birth (n = 3 HypoPT women), and history of miscarriages (n = 6 HypoPT women and n = 2 pseudo-HypoPT women). CONCLUSION: This study shows that mean serum albumin-corrected total calcium levels were carefully monitored during pregnancy and post-pregnancy, with limited evaluation of other biochemical parameters, such as serum phosphate, 24 h urinary calcium, 25-OH vitamin D, and creatinine clearance. To avoid complications in mothers affected by (HypoPT) or (pseudo-HypoPT) and offspring, intense biochemical, clinical and pharmacological monitoring during pregnancy and breastfeeding is highly recommended.

Chronic hypoparathyroidism and treatment with teriparatide.

PURPOSE: Chronic hypoparathyroidism is usually treated with calcium and active vitamin D metabolites or analogs, despite the fact that their chronic use can lead to long-term complications. The use of hormone replacement therapy with PTH peptides [teriparatide and rhPTH (1-84)] has therefore been proposed. The main purpose of this study was to investigate the efficacy of teriparatide dose at 20 µg once or twice daily, in order to maintain normocalcemia reducing standard treatment, in adult patients with chronic hypoparathyroidism not well controlled with conventional treatment. METHODS: The study was a Phase III, open-label, non-comparative, clinical investigation (study period: 3 months), at a tertiary care clinical research center. Thirty patients with chronic hypoparathyroidism were screened, and 12 started teriparatide. After the optimization phase (0-4 weeks), calcium and calcitriol supplements were progressively reduced, while teriparatide 20 µg once daily was administered (5-7 weeks), and then could be titrated up to 20 µg twice daily (7-17 weeks). The main outcome measures included serum and urinary biochemical exams and Rand 36-Item Short Form Health Survey. RESULTS: This study showed that teriparatide 20 µg once daily was insufficient to discontinue calcium and calcitriol supplements to maintain normal serum calcium concentrations. Conversely, for more than half of patients treated with teriparatide 20 µg twice daily, calcium and calcitriol administration was avoidable, but in some cases at the expense of serum calcium and phosphate oscillations. CONCLUSIONS: Since intervention trials evaluating the efficacy and safety of teriparatide in hypoparathyroid patients are not yet available, the routine use of this molecule poses some doubts.

Congenital Conditions of Hypophosphatemia Expressed in Adults.

The main congenital conditions of hypophosphatemia expressed in adulthood include several forms of hereditary hypophosphatemic rickets and a congenital disorder of vitamin D metabolism characterized by osteomalacia and hypophosphatemia in adult patients. Hypophosphatemia in adults is defined as serum phosphate concentration < 0.80 mmol/L. The principal regulators of phosphate homeostasis, as is well known, are parathyroid hormone (PTH), activated vitamin D, and Fibroblast Growth Factor 23 (FGF23). Differential diagnosis of hypophosphatemia is based on the evaluation of mechanisms leading to this alteration, such as high PTH activity, inadequate phosphate absorption from the gut, or renal phosphate wasting, either due to primary tubular defects or high FGF23 levels. The most common inherited form associated to hypophosphatemia is X-linked hypophosphatemic rickets (XLH), caused by PHEX gene mutations with enhanced secretion of the FGF23. Until now, the management of hypophosphatemia in adulthood has been poorly investigated. It is widely debated whether adult patients benefit from the conventional treatments normally used for pediatric patients. The new treatment for XLH with burosumab, a recombinant human IgG1 monoclonal antibody that binds to FGF23, blocking its activity, may change the pharmacological management of adult subjects with hypophosphatemia associated to FGF23-dependent mechanisms.

Blueberry Juice Antioxidants Protect Osteogenic Activity against Oxidative Stress and Improve Long-Term Activation of the Mineralization Process in Human Osteoblast-Like SaOS-2 Cells: Involvement of SIRT1.

Diets rich in fruits and vegetables with many antioxidants can be very important in the prevention and treatment of osteoporosis. Studies show that oxidative stress, often due to lack of antioxidants, is involved in alteration of bone remodeling and reduction in bone density. This study demonstrates in human osteoblast-like SaOS-2 cells that blueberry juice (BJ), containing 7.5 or 15 µg∙mL-1 total soluble polyphenols (TSP), is able to prevent the inhibition of osteogenic differentiation and the mineralization process due to oxidative stress induced by glutathione depletion. This situation mimics a metabolic condition of oxidative stress that may occur during estrogen deficiency. The effect of BJ phytochemicals occurs through redox- and non-redox-regulated mechanisms. BJ protects from oxidative damage factors related to bone remodeling and bone formation, such as alkaline phosphatase and Runt-related transcription factor 2. It upregulates these factors by activation of sirtuin type 1 deacetylase expression, a possible molecular target for anti-osteoporotic drugs. Quantitative analysis of TSP in BJ shows high levels of anthocyanins with high antioxidant capacity and bioavailability. These novel data may be important to elucidate the molecular and cellular beneficial effects of blueberry polyphenols on bone regeneration, and they suggest their use as a dietary supplement for osteoporosis prevention and therapies.

Blueberry juice protects osteocytes and bone precursor cells against oxidative stress partly through SIRT1.

Oxidative stress and abnormal osteocyte apoptosis are often related to dysregulation of bone turnover and chronic bone loss, and so fruit and vegetables with high antioxidant potential may play an important role in the prevention and/or management of osteoporosis. Osteocytes are the main regulators of bone remodelling. For the first time, we demonstrate here that blueberry juice (BJ), obtained from Vaccinium myrtillus, rich in polyphenols, shows antioxidant and antiosteoclastogenic properties in MLO-Y4 osteocytes. We report that BJ prevents oxidative stress-induced apoptosis and reverses the increase in receptor activator of nuclear factor κB ligand and sclerostin expression, crucial factors for osteoclast activation and bone resorption. BJ is also able to prevent oxidative stress-induced cell cytotoxicity in bone marrow mesenchymal stromal cells (MSCs), which are considered to be an important tool for cell therapy in bone disorders. No significant difference in preventing these events was observed between BJ and blueberry dry extract containing equal amounts of total soluble polyphenols. We have also shown that blueberry acts as both an antioxidant and an activator of sirtuin type 1, a class III histone deacetylase involved in cell death regulation and considered a molecular target for blocking bone resorption without affecting osteoclast survival. Overall, these novel data obtained in osteocytes and MSCs may help us clarify the mechanisms by which blueberry counteracts oxidative stress-induced damage in bone remodelling and osteogenesis at the cellular and molecular level. Our findings are consistent with the reported beneficial effects of blueberry on bone tissue reported in animal studies, which suggest that blueberry may be a useful supplement for the prevention and/or management of osteoporosis and osteogenic process.

A New Era for Chronic Management of Hypoparathyroidism: Parathyroid Hormone Peptides.

Several studies have investigated replacement therapy with recombinant human parathyroid hormone [rhPTH(1-84)] for patients affected by chronic hypoparathyroidism who are not adequately controlled with standard treatment. In 2015, the Food and Drug Administration (FDA) in the USA approved rhPTH(1-84), named Natpara®, for the pharmacological management of hypoparathyroidism. In Europe, in February 2017, the European Medicines Agency (EMA) recommended granting a conditional marketing authorization in the European Union for rhPTH(1-84). Here we review the studies conducted with rhPTH(1-84) and PTH(1-34) in patients with chronic hypoparathyroidism. The research done in this field has shown that replacement treatment with rhPTH(1-84) is an important therapeutic option for subjects with chronic hypoparathyroidism who are not well controlled with conventional treatment. However, further long-term investigations are needed.

Conventional Treatment of Hypoparathyroidism.

The treatment of hypoparathyroidism depends on the severity of hypocalcemia, how rapidly the hypocalcemia developed, and the symptomatology. Chronic hypoparathyroidism is usually treated with oral supplementations, including calcium, calcitriol, or other active vitamin D analogs, and at times, thiazide diuretics. Although the standard therapy can adequately control patients with this disease, sometimes very high doses are required to maintain serum calcium levels in the normal range, with poor compliance and risk of long-term complications.

Calcium Intake in Bone Health: A Focus on Calcium-Rich Mineral Waters.

Calcium is an essential element that plays numerous biological functions in the human body, of which one of the most important is skeleton mineralization. Bone is a mineralized connective tissue in which calcium represents the major component, conferring bone strength and structure. Proper dietary calcium intake is important for bone development and metabolism, and its requirement can vary throughout life. The mineral composition of drinking water is becoming relevant in the modulation of calcium homeostasis. In fact, calcium present in mineral drinking waters is an important quantitative source of calcium intake. This, together with its excellent bioavailability, contributes to the maintenance of the bone health. This article aims to examine studies that assessed the bioavailability of the calcium contained in calcium-rich mineral waters and their impact on bone health, including original data collected in a recent study in humans.

HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.

Prevalence of Chronic Hypoparathyroidism in a Mediterranean Region as Estimated by the Analysis of Anonymous Healthcare Database.

Epidemiological data on prevalence and incidence of chronic hypoparathyroidism are still scarce. This study aimed to establish prevalence of chronic hypoparathyroidism and incidence of surgical hypoparathyroidism using the analysis of electronic anonymous public health care database. Data referred to a 5-year period (2009-2013, Region of Tuscany, Italy, as a sample representative of the whole Mediterranean/European population, estimated mean population: 3,750,000 inhabitants) were retrieved by the analysis of pharmaceutical distribution dataset, containing data related to drugs reimbursed by public health system, hospital discharge and procedures codes, and ICD9 exemption codes for chronic diseases. The application of a specific algorithm was applied to indirectly identify people with chronic hypoparathyroidism as assuming chronic therapy with active vitamin D metabolites (AVDM). The number of people taking AVDM for a period equal to or longer than 6 months till the end of the study period, with ICD9 exemption code for hypoparathyroidism, and with a disease-related discharge code were identified. Within this restricted group, patients with chronic kidney disease and osteoporosis were excluded. The indirect estimate of chronic hypoparathyroidism in a European Mediterranean subpopulation by means of the analysis of chronic therapy with AVDM was 27/100,000 inhabitants (female:male ratio = 2.2:1), with a mean age of 63.5 ± 16.7 years. The risk of developing hypoparathyroidism after neck surgery was 1.5%. While the epidemiological approaches based on disease code and hospital discharge code greatly underestimates the prevalence of hypoparathyroidism, the indirect estimate of this disease through the analysis of prescriptions of AVDM in a European region is in line with the results of studies performed in other regions of the world.

Causes and pathophysiology of hypoparathyroidism.

Hypoparathyroidism, a disorder characterized by hypocalcemia ensuing from inadequate parathyroid hormone secretion, is a rather rare disorder caused by multiple etiologies. When not caused by inadvertent damage or removal of the parathyroids during neck surgery, it is usually genetically determined. Epidemiological figures of this disease are still scarce and mainly limited to countries where non-anonymous databases are available and to surgical case series. Both the surgical and non-surgical forms pose diagnostic challenges. For surgical hypoparathyroidism, transient forms have to be ruled out even in the long term, in order to avoid unnecessary chronic replacement therapy with calcium and calcitriol. Regarding non-surgical hypoparathyroidism, once referred to as idiopathic, a systematic clinically and genetically-driven approach to define the precise diagnosis have to be pursued. In the case of syndromic hypoparathyroidism, patients have to be screened for associated abnormalities. Autoimmune, non-genetic hypoparathyroidism is still a diagnosis of exclusion, since no specific autoantibodies are specific for this condition.

Clinical presentation and management of hypoparathyroidism.

The clinical manifestations of hypoparathyroidism are variable and can involve almost any organ system. The main clinical features of the hypoparathyroidism are typically signs or symptoms due to neuromuscular irritability owing to low serum calcium level. In addition to hypocalcemia, hyperphosphatemia can contribute to long-term complications, including extra-skeletal calcifications. Bone turnover markers are generally decreased, and bone mass density is usually normal-increased compared to age- and gender-matched controls. It is still unclear whether or not these bone features could have an impact on the risk of fracture. Impaired renal function is a common complication described in patients treated for hypoparathyroidism. Other complications include premature cataracts, seizures, basal ganglia calcifications, and cardiac arrhythmias. Lastly, some clinical studies have also reported a reduced quality of life of patients with hypoparathyroidism. Increased awareness of the clinical manifestations of this disease is important to improve its clinical management.

Oxidative stress in bone remodeling: role of antioxidants.

ROS are highly reactive molecules which consist of a number of diverse chemical species, including radical and non-radical oxygen species. Oxidative stress occurs as a result of an overproduction of ROS not balanced by an adequate level of antioxidants. The natural antioxidants are: thiol compounds among which GSH is the most representative, and non-thiol compounds such as polyphenols, vitamins and also various enzymes. Many diseases have been linked to oxidative stress including bone diseases among which one of the most important is the osteoporosis. The redox state changes are also related to the bone remodeling process which allows the continuous bone regeneration through the coordinated action of bone cells: osteoclasts, osteoblasts and osteocytes. Changes in ROS and/or antioxidant systems seem to be involved in the pathogenesis of bone loss. ROS induce the apoptosis of osteoblasts and osteocytes, and this favours osteoclastogenesis and inhibits the mineralization and osteogenesis. Excessive osteocyte apoptosis correlates with oxidative stress causing an imbalance in favor of osteoclastogenesis which leads to increased turnover of bone remodeling and bone loss. Antioxidants either directly or by counteracting the action of oxidants contribute to activate the differentiation of osteoblasts, mineralization process and the reduction of osteoclast activity. In fact, a marked decrease in plasma antioxidants was found in aged or osteoporotic women. Some evidence shows a link among nutrients, antioxidant intake and bone health. Recent data demonstrate the antioxidant properties of various nutrients and their influence on bone metabolism. Polyphenols and anthocyanins are the most abundant antioxidants in the diet, and nutritional approaches to antioxidant strategies, in animals or selected groups of patients with osteoporosis or inflammatory bone diseases, suggest the antioxidant use in anti-resorptive therapies for the treatment and prevention of bone loss.

Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology.

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.