Diagnosis and treatment of Paget's disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS).

INTRODUCTION: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. METHODS: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. RESULTS AND CONCLUSION: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Post-diagnosis serum 25-hydroxyvitamin D concentrations in women treated for breast cancer participating in a lifestyle trial in Italy.

OBJECTIVE: To report cross-sectionally serum levels of 25-hydroxyvitamin D [25(OH)D] in women living in Italy within 12 months from breast cancer (BC) diagnosis. METHODS: Baseline data were obtained from 394 women diagnosed with primary BC, enrolled from 2016 to 2019 in a lifestyle trial conducted in Italy. Subjects' characteristics were compared between two 25(OH)D concentrations (hypovitaminosis D<20 and ≥20 ng/mL) with the Chi-squared test or Fisher's exact test for small-expected counts. Using multiple logistic regression-adjusted models, we estimated odds ratios (ORs) of hypovitaminosis D with 95% confidence intervals (CIs) in the total sample and in the unsupplemented subgroup. RESULTS: Hypovitaminosis D was found in 39% of all subjects, 60% in unsupplemented subjects, and 10% in supplemented subjects. Increasing ORs of hypovitaminosis D were found with increasing body mass index, 25-30, >30, and ≥35 versus <25 kg/m2 (ORs: 2.50, 4.64, and 5.81, respectively, in the total cohort and ORs: 2.68, 5.38, and 7.08 in the unsupplemented); living in the most southern Italian region (OR 2.50, 95%CI 1.22-5.13); and with hypertriglyceridemia (OR 2.46; 95%CI 1.16-5.22), chemotherapy history (OR 1.86, 95%CI 1.03-3.38), and inversely with anti-estrogenic therapy (OR 0.43, 95%CI 0.24-0.75) in the total sample. CONCLUSIONS: Hypovitaminosis D in women recently diagnosed with BC and participating in a lifestyle trial in Italy was widespread and highest with obesity, hypertriglyceridemia, and chemotherapy use. Considering that hypovitaminosis D is a risk factor for lower efficacy of bone density treatments and possibly BC mortality, our results suggest the need to promptly address and treat vitamin D deficiency.

Vitamin D and disease severity in coronavirus disease 19 (COVID-19).

The role of 25-OH-vitamin D in the assessment of coronavirus disease 19 (COVID-19) has not been investigated. We sought to investigate the prevalence of 25-OH-vitamin D deficiency among COVID-19 patients, and to determine the associations between 25-OH-vitamin D status and the severity of the disease. We have conducted a retrospective observational study of COVID-19 patients admitted to the University of Verona Hospital Trust. Demographic, clinical and biochemical parameters were collected at hospital admission, and serum 25-OH-vitamin D levels were measured. The following outcomes were assessed: arterial partial oxygen pressure (PaO2); C-reactive protein (CRP); length of hospitalization; requirement of oxygen therapy; non-invasive ventilation (NIV); mechanical ventilation; and death. Among 61 patients enrolled, 72.1% was 25-OH-vitamin D deficient (<20 ng/mL) and 57.4% had 25-OHvitamin D <15 ng/mL. Patients with arterial PaO2 <60 mmHg had significantly lower mean 25-OH-vitamin D levels compared to patients with PaO2 ≥60 mmHg (13.3 ng/mL vs 20.4 ng/mL respectively, p=0.03). Vitamin D deficiency was associated with 3-fold higher risk of having arterial pO2 <60 mmHg. 25-OH-vitamin D deficiency was associated with increased CRP and dyspnea. 25-OH-vitamin D deficiency was associated with more severe systemic inflammatory response and respiratory failure in COVID-19 patients.

Risk of fragility fractures in obesity and diabetes: a retrospective analysis on a nation-wide cohort.

This study aims to investigate the role of obesity and diabetes on bone health in a nation-wide cohort of women with high risk of fracture. INTRODUCTION: The role of obesity and diabetes on fracture risk is yet poorly understood. Body mass index (BMI) and bone mineral density (BMD) are strongly correlated; however, patients with elevated BMI are not protected against fractures, configuring the obesity paradox. A similar controversial association has been also found in diabetic patients. Herein, we present a retrospective analysis on 59,950 women. METHODS: Using a new web-based fracture risk-assessment tool, we have collected demographic (including BMI), densitometric, and clinical data (including history of vertebral or hip and non-vertebral, non-hip fractures, presence of comorbidities). We performed a propensity score generation with 1:1 matching for patients in the obese (BMI ≥ 30) and non-obese (BMI < 30) groups, in the diabetics and non-diabetics. Propensity score estimates were estimated using a logistic regression model derived from the clinical variables: age, lumbar spine T-score, and femoral neck T-score. RESULTS: We found an association between diabetes and fractures of any kind (OR 1.3, 95% CI 1.1-1.4 and 1.3, 95% CI 1.2-1.5 for vertebral or hip fractures and non-vertebral, non-hip fractures, respectively). Obesity, on the other hand, was significantly associated only with non-vertebral, non-hip fractures (OR 1.3, 95% CI 1.1-1.6). To estimate the individual effect of obesity and diabetes on bone health, we ran sensitivity analyses which included obese non-diabetic patients and non-obese diabetic patients, respectively. CONCLUSIONS: Non-obese diabetics had the highest risk of vertebral or hip fracture, whereas obese non-diabetics predominantly had non-vertebral, non-hip fracture's risk. These results should raise awareness in clinical practice when evaluating diabetic and/or obese patients.

Vitamin D supplementation: much ado about nothing.

The scientific interest and the number of papers dealing with vitamin D supplementation has greatly grown in the last decades. Unfortunately, expert consensus on many clinical aspects of this topic is still lacking. In addition, data coming from recent clinical trials and meta-analyses seem to strongly put into doubt the real benefit of vitamin D supplementation, on both skeletal and extra-skeletal outcomes. This is further confusing since they seem to completely contradict the considerable body of evidence provided from previous epidemiological studies. This paper aims to analyze these new data in order to shed light onto the debated issues.

Correction to: Bone metabolism in patients with anorexia nervosa and amenorrhoea.

Unfortunately, the sixth author name was incorrectly spelled as "S. Fassio" instead of "A. Fassio" in the original publication.

The epidemiology of osteoporosis in Italian postmenopausal women according to the National Bone Health Alliance (NBHA) diagnostic criteria: a multicenter cohort study.

PURPOSE: The study was aimed at evaluating the prevalence of osteoporosis, defined by BMD and the National Bone Health Alliance (NBHA) criteria, and the prevalence of clinical risk factors for fractures in Italian postmenopausal women. METHODS: This is a cross-sectional, multicenter, cohort study evaluating 3247 postmenopausal women aged ≥ 50 and older in different areas of Italy in the period 2012-2014. All the participants were evaluated as far as anthropometrics; questionnaires for FRAX® and DeFRA calculation were administered and bone mineral density was measured at lumbar spine, femoral neck and total hip by DXA. RESULTS: The prevalence of osteoporosis, as assessed by BMD and NBHA criteria was 36.6 and 57%, respectively. Mean ± SD values of FRAX® and DeFRA were: 10.2 ± 7.3 and 11 ± 9.4 for major fractures, and 3.3 ± 4.9 and 3.9 ± 5.9 for hip fractures, respectively. Among clinical risk factors for fracture, the presence of previous fracture, particularly non-spine/non-hip fracture, parental history of hip fracture and current smoking were the most commonly observed. CONCLUSIONS: Our study showed that more that the half of postmenopausal women aged 50 and older in Italy has osteoporosis on the basis of the NBHA criteria. There is a relevant high risk of femur fracture, as assessed by the FRAX® and DeFRA and previous fracture, parental history of hip fracture and current smoking are the most common risk factors. The data should be considered particularly in relation to the need to increase prevention strategies on modifiable risk factors and therapeutic intervention.

Bone metabolism in patients with anorexia nervosa and amenorrhoea.

PURPOSE: Aim of this study is focusing on bone metabolism in AN patients with amenorrhoea and related estrogen deficiency effects. METHODS: AN patients were compared both with healthy females and with postmenopausal women (reference model for estrogen deficiency). The study sample included 81 females with AN. Laboratory tests [25-OH vitamin D, bone turnover markers, intact parathyroid hormone, sclerostin (SOST) and dickkopf-related protein (DKK1)] and dual energy X-ray absorptiometry (DXA) were taken into account. RESULTS: AN patients had higher levels of C-terminal telopeptide of type I collagen (CTX) than both control groups. AN adolescents had CTX higher than AN young adults. In postmenopausal women, intact N-propeptide of type I collagen was higher if compared with each other group. In AN groups, Dickkopf-related protein 1 was significantly lower than the two control groups. No differences were found in sclerostin except in adolescents. In AN adolescents, DXA values at femoral sites were higher than in AN young adults and a positive correlation was found with body weight (p < 0.01) and with fat mass evaluated using DXA (p < 0.01). CONCLUSIONS: AN women with amenorrhoea have an increased bone resorption like postmenopausal women but bone formation is depressed. The consequent remodeling uncoupling is considerably more severe than that occurring after menopause.

Long-term Effects of Neridronate in Adults with Osteogenesis Imperfecta: An Observational Three-Year Italian Study.

The aim of this study was to assess the long-term efficacy and safety of i.v. neridronate in the treatment of osteogenesis imperfecta (OI). One hundred and fourteen patients affected by OI were included in the study. Neridronate was administered by i.v. infusion at the dosage of 2 mg/kg, up to a maximum of 100 mg at three-month intervals for 3 years. Dual X-ray absorptiometry of the lumbar spine, hip, and ultradistal and proximal radius were evaluated every 6 months. Blood calcium, phosphate, albumin, fasting urinary calcium/creatinine ratio, total serum alkaline phosphatase, and bone alkaline phosphatase were obtained at baseline and every 3 months. The mean lumbar spine and total hip BMD significantly increased from baseline to any time point (p < 0.001). The mean ultradistal radius BMD significantly increased from baseline only at month 18 (p = 0.026), 30 (p = 0.046), and 36 (p = 0.013), respectively. The mean proximal radius BMD did not change during the whole observation. The levels of bone turnover markers significantly decreased from baseline to any post-baseline observation time. The study was not able to find any statistically significant effect on fracture risk (p = 0.185). The percentage of patients with fractures was unaltered during treatment as compared to the 3-year period before treatment. The most common AEs were fragility fractures, back pain, arthralgia, fever, and joint sprain. An acute phase reaction was reported in 26 (22.8%) patients. None of the reported SAEs were considered as treatment-related. Long-term treatment with i.v. neridronate has positive effects on BMD and bone turnover markers with a good safety profile, although no significant effect on the risk of fracture was observed.

Drug-induced osteonecrosis of the jaw: the state of the art.

Osteonecrosis of the jaw (ONJ) is a rare adverse event of antiresorptive drugs such as bisphosphonates (BP) and denosumab (DMAb). The diagnosis of ONJ is considered in cases where exposed bone in the maxillofacial region does not heal within 8 weeks in a patient previously treated with an antiresorptive agent. In patients with osteoporosis, ONJ is reported as a very rare adverse event while in oncologic patients with bone metastases or malignant hypercalcemia the incidence is significantly higher (up to the 1-10% of the patients). The pathophysiology of ONJ is still not completely understood but it is multi-factorial. ONJ is a condition associated with poor oral health, oral surgery, and use of antiresorptive agents. Prevention is of paramount importance especially in cancer patients, in whom the large majority of cases of ONJ (>90%) are reported, but it should also be considered in osteoporotic patients, especially during dental surgical procedure. Some simple prevention procedures are effective in reducing the risk of its appearance. When ONJ unfortunately occurs, the large majority of patients can be managed conservatively. In conclusion, ONJ is a rare condition associated with antiresorptive drugs. Both osteoporotic and oncologic patients should be well informed about its low absolute risk and regarding the fact that the benefits of antiresorptive therapy far outweigh this potential risk of ONJ.

Guidelines for the diagnosis, prevention and management of osteoporosis.

Osteoporosis poses a significant public health issue. National Societies have developed Guidelines for the diagnosis and treatment of this disorder with an effort of adapting specific tools for risk assessment on the peculiar characteristics of a given population. The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has recently revised the previously published Guidelines on the diagnosis, riskassessment, prevention and management of primary and secondary osteoporosis. The guidelines were first drafted by a working group and then approved by the board of SIOMMMS. Subsequently they received also the endorsement of other major Scientific Societies that deal with bone metabolic disease. These recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on leading experts' experience and opinion, and on good clinical practice. The osteoporosis prevention should be based on the elimination of specific risk factors. The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk, and this is the case only when the risk of fracture is rather high as measured with variables susceptible to pharmacological effect. DeFRA (FRAX® derived fracture risk assessment) is recognized as a useful tool for easily estimate the long-term fracture risk. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management.

Bone health and body composition in prostate cancer: Meet-URO and AIOM consensus about prevention and management strategies.

BACKGROUND: Prostate cancer (PCa) treatments are associated with a detrimental impact on bone health (BH) and body composition. However, the evidence on these issues is limited and contradictory. This consensus, based on the Delphi method, provides further guidance on BH management in PCa. MATERIALS AND METHODS: In May 2023, a survey made up of 37 questions and 74 statements was developed by a group of oncologists and endocrinologists with expertise in PCa and BH. In June 2023, 67 selected Italian experts, belonging to the Italian scientific societies Italian Association of Medical Oncology and Italian Network for Research in Urologic-Oncology (Meet-URO), were invited by e-mail to complete it, rating their strength of agreement with each statement on a 5-point scale. An agreement ≥75% defined the statement as accepted. RESULTS: In non-metastatic hormone-sensitive PCa, the panel agreed that androgen deprivation therapy (ADT) alone implies sufficient fracture risk to warrant antifracture therapy with bone-targeting agents (BTAs) for cancer treatment-induced bone loss (CTIBL) prevention (79%). Therefore, no consensus was reached (48%) for the treatment with BTAs of patients receiving short-term ADT (<6 months). All patients receiving active treatment for metastatic hormone-sensitive PCa (75%), non-metastatic castration-resistant PCa (89%) and metastatic castration-resistant PCa (mCRPC) without bone metastases (84%) should be treated with BTAs at the doses and schedule for CTIBL prevention. All mCRPC patients with bone metastasis should be treated with BTAs to reduce skeletal-related events (94%). In all settings, the panel analyzed the type and timing of treatments and examinations to carry out for BH monitoring. The panel agreed on the higher risk of sarcopenic obesity of these patients and its correlation with bone fragility. CONCLUSIONS: This consensus highlights areas lacking major agreement, like non-metastatic hormone-sensitive prostate cancer patients undergoing short-term ADT. Evaluation of these issues in prospective clinical trials and identification of early biomarkers of bone loss are particularly urgent.

Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature.

The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction.

[Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project]. / Evidenze di sicurezza e tollerabilità dell'acido zoledronico 5 mg una volta all'anno nell'osteoporosi postmenopausale: il progetto HORIZON.

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Despite evidence supporting the anti-fracture efficacy of aminobisphosphonates approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within the first year. Poor compliance is associated with negative outcomes, including increased fracture risk. Tolerability and safety are among the causes of poor compliance. Intravenous bisphosphonates avoids the gastrointestial intolerance and the complex dosing instruction of the oral route ensuring full compliance which may provide improved efficacy. However, there are some concerns regarding potent intravenous bisphosphonates as zoledronic acid with respect to tolerability, mainly the acute phase response and to safety, mainly a theoretical risk of over suppression of bone turnover, renal toxicity and osteonecrosis of the jaw. In the HORIZON study, 152 patients on active treatment (82) or placebo (70) underwent to a bone biopsy after double tetracycline labeling. Bone biopsies (iliac crest) were obtained at the final visit at month 36, 1 year after the last infusion. The biopsies were analyzed by histomorphometry on bone sections and by micro-CT (microCT) analysis. One hundred forthy-three biopsies (76 zoledronic acid, 67 placebo) had at least one microCT parameter measured and 111 were available for quantitative histomorphometry (59 zoledronic acid, 52 placebo). Micro-CT analysis of bone structure revealed higher trabecular bone volume (BV/TV), decreased trabecular separation (Tb.Sp), and a strong trend towards improvement in connectivity density in biopsies obtained from patients treated with zoledronic acid, indicating preservation of trabecular bone structure with respect to placebo. Histomorphometric analysis obtained from patients treated with zoledronic acid exhibited reduction of bone turnover, as suggested by decreased activation frequency (Ac.F) by 63%, mineralizing surface (MS/BS), bone formation rate (BFR/BV). In addition, mineral appositional rate (MAR), reflecting the bone-forming capacity of osteoblastic teams at the bone multicellular unit (BMU) level, was significantly higher in patients on active treatment. No sign of excessive suppression of bone turnover or mineralization impairment was detected, confirming the safety of the treatment with intravenous zoledronic acid once a year. These interesting findings are discussed in the article, particularly in terms of new histomorphometric results and clinical findings supporting the tolerability and safety of zoledronic acid.

[Guidelines for the diagnosis, prevention and treatment of osteoporosis]. / Linee guida per la diagnosi, prevenzione e terapia dell'osteoporosi Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro - SIOMMMS.

UNLABELLED: The guidelines for the osteoporosis management were first drafted by a working group and then critically evaluated by the board of SIOMMMS. The most relevant points are: DEFINITION: Osteoporosis is defined as a quantitative and qualitative deterioration of bone tissue leading to increased risk of fracture. Postmenopausal and senile osteoporosis are defined as primitive. DIAGNOSIS: The cornerstone for the diagnosis of osteoporosis is the measurement of bone mineral density (BMD) by DXA (dual-energy X-ray absortiometry) at the femoral neck with T-score values <-2.5, following the WHO definition. Other DXA sites or technologies for measuring bone mass are also acceptable when the former is not accessible. A BMD evaluation is recommended to all women above 65 years of age. At younger age or in man the bone assessment is recommended only in subjects with specific risk factors. A control of bone mass measurement is seldom required before 2 years. DIFFERENTIAL DIAGNOSIS: A few biochemical tests such as serum and urinary calcium, protein electrophoresis, serum creatinine and ESR are usually sufficient to exclude most secondary types of osteoporosis. The value of the so called bone turnover markers for the diagnosis and follow-up of osteoporosis remains uncertain. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management. PREVENTION: The osteoporosis prevention should be based on the elimination of specific risk factors such as inadequate calcium and vitamin D intake, smoking and sedentary life. The use of pharmacological agents in subjects with BMD values >-2.5 is usually not justified. Pharmacological intervention: The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk. This is the case only when the risk of fracture is rather high. FRAX is recognized as a useful tool for easily estimate the long-term fracture risk. SIOMMMS with these guidelines is committed to validate and further develop this diagnostic tool.

Trabecular bone microarchitecture in mild primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disease. High levels of PTH cause demineralization of bone and increased risk of fracture. On the other hand, the effect of PHPT on bone structure is more ambiguous. The aim of this study was to evaluate the effect of PHPT on cancellous bone volume, structure, and microarchitecture. Thirteen transiliac biopsy specimens taken in untreated post-menopausal women aged 65+/-5 yr with primary hyperparathyroidism were compared with 13 biopsies taken in normal women aged 66+/-6 yr. None of the patients presented any other disorder affecting bone metabolism. In these samples we evaluated the direct and indirect histomorphometric parameters of bone microarchitecture using an image analysis system consisting of an epifluorescent microscope (Leica DMR) connected to an analogic 3 CCD camera (Sony DXC 390P) and a computer equipped with specific software for histomorphometric analyses. No significant differences between PHPT patients and controls in cancellous bone volume, trabecular thickness, and number were found. Two-dimensional parameters showed a preserved microarchitecture in PHPT patients. On the other hand, indirect parameters of microarchitecture [Marrow Star Volume (MSV) and Trabecular Bone Pattern Factor (TBPf)] showed a significant compromising of microarchitecture in these patients. PHPT patients have similar structural parameters to normal subjects. Concerning microarchitecture, indirect approach by MSV and TBPf shows a significant compromising of connectivity. These results can explain trabecular fragility observed in clinical studies on PHPT.

Risedronate prevents the loss of microarchitecture in glucocorticoid-induced osteoporosis in rats.

UNLABELLED: Osteoporosis is a severe complication of glucocorticoid treatment. Bisphosphonates are a powerful therapeutic option to prevent osteoporotic fractures. The aims of this study were: a) to determine bone alterations induced by therapy with glucocorticoids (GC); b) to establish the efficacy of risedronate (Ris) in the prevention of these effects. We studied 40 female Sprague-Dawley rats randomly divided into 4 groups of treatment, administered 3 times a week sc: 1. CONTROL: vehicle of methylprednisolone (GC) + vehicle of Ris; 2. Ris: Ris 5 mug/kg body weight vehicle of GC; 3. GC: GC 7 mg/kg + vehicle of Ris; 4. GC+Ris: GC 7 mg/kg, Ris 5 microg/kg. Animals were treated for 30 days and then were sacrificed. Densitometry was performed at baseline and at the end of the treatment. Right tibiae were removed for histomorphometric analyses. The GC group showed a 7% decrease in bone density vs controls (p<0.05), while the GC+Ris group was associated with a 3.5% increase in bone density vs controls (p<0.05). In the GC group, histomorphometric evaluations showed reduced bone volume (BV/TV) and thinning of trabeculae (Tb.Th) vs controls (BV/TV: 31+/-1 vs 35+/-1%, p<0.05; Tb.Th: 43+/-2 vs 50+/-3 microm, p<0.01; Ac.f: 1.8+/-0.2 vs 1.6+/-0.3 N/yr). The GC+Ris group had increased BV/TV and Tb.Th, and reduced Ac.f vs the GC group. Ris also maintained trabecular microarchitecture. At the histological level, glucocorticoid-induced osteoporosis was characterized by decreased bone volume, reduced osteoblastic activity, and deterioration of microarchitecture. Ris counteracted these effects both by prolonging osteoblast activity, and by maintaining bone microarchitecture.

Treatment with neridronate in children and adolescents with osteogenesis imperfecta: Data from open-label, not controlled, three-year Italian study.

INTRODUCTION: The present study assessed the long-term efficacy and safety of intravenous (i.v.) neridronate in children and adolescents affected by osteogenesis imperfecta (OI). METHODS: 55 young patients (mean age 12.6±3.9years) affected by OI were included in the study. Neridronate was administered by i.v. infusion at a dose of 2mg/kg (maximum dose of 100mg) at intervals of three-months for three years. Dual X-ray absorptiometry of the lumbar spine, hip and ultradistal and proximal radius were evaluated every 6months. Blood calcium, phosphate, albumin, fasting urinary calcium/creatinine ratio were obtained at baseline and every 3months. Serum bone turnover markers total and bone alkaline phosphatase were performed every 12months in a proportion of patients. RESULTS: Mean lumbar spine and total hip bone mineral density (BMD) and bone mineral content significantly increased from baseline compared to all subsequent time points (p<0.001). Mean ultradistal radius BMD significantly increased from month 18 (p=0.026). Levels of bone turnover markers significantly decreased from baseline to all post-baseline observation time points. There was no statistically significant effect on fracture risk (p=0.185), although a significant reduction was observed in the mean number of fractures occurring during treatment compared to pre-treatment values. The most frequent adverse events were arthralgia, fever, joint sprain. An acute phase reaction was reported in 26 (22.8%) patients. None of the reported serious adverse events was considered as treatment-related. CONCLUSION: Long-term i.v. neridronate treatment has positive effects on BMD, bone turnover markers and fracture risk with a good safety profile.

Histomorphometric analysis of glucocorticoid-induced osteoporosis.

Bone histomorphometry or quantitative histology consists of counting or measuring tissue components: cells, extracellular constituents and microarchitecture. Bone histomorphometry is the only method that allows the measurement of mineralization rate and the study of bone formation at three levels: cell, remodeling unit and tissue levels. It is a useful tool to explain the pathogenesis and cellular mechanisms of different metabolic bone diseases such as glucocorticoid-induced osteoporosis (GIO). Glucocorticoids (GC) affect calcium and bone metabolism at every level, but the main effect is the osteoblastic dysfunction. Concerning the bone formation, some histomorphometric studies have shown a depressed osteoblastic activity at a cell, bone remodeling unit, and tissue levels. In addition, there is evidence of a shortening of the period in which the osteoblasts work actively forming the bone matrix. This latter effect seems to occur after high cumulative doses of GC. With regard to the resorption, the results are still debated, but histomorphometric parameters seem to be increased in the majority of studies, at least in the first period of the GC treatment. From a structural point of view, GC seem to induce a thinning of the trabeculae without their perforation, which occurs only after high cumulative doses. Anti-resorptive treatments, such as bisphosphonates, are able to counteract the negative effects of GC on bone. In particular, along with their active working period, they prolong the lifespan of osteoblasts and osteocytes. In addition, the anti-resorptive treatments seem to extend the time for secondary mineralization through a reduction of the Activation Frequency. The latter is an intriguing mechanism of bisphosphonates in GIO that needs further ad hoc investigations.