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.

Multiple brown tumors: a bone complication due to long-term untreated pseudohypoparathyroidism.

Bone lytic lesions are a possible complication of pseudohypoparathyroidism type 1B, in undertreated adult patients. Whole body [18F] F-fluorocholine PET/CT is a useful imaging tool to assess brown tumor progression in this context. We describe the case of a 33-year-old woman, referred for the diagnostic evaluation of lytic bone lesions of the lower limbs, in the context of asymptomatic pseudohypoparathyroidism. She had been treated with alfacalcidol and calcium during her childhood. Treatment was discontinued at the age of 18 years old because of the lack of symptoms. A femur biopsy revealed a lesion rich in giant cells, without malignancy, consistent with a brown tumor. Laboratory tests showed a parathyroid level at 1387 pg/ml (14-50). Whole-body Fluorocholine PET/CT revealed hypermetabolism of bone lesions. The final diagnosis was brown tumors related to hyperparathyroidism complicating an untreated pseudohypoparathyroidism. Genetic testing confirmed PHP type 1B. Pseudohypoparathyroidism with radiographic evidence of hyperparathyroid bone disease, is a very rare condition due to parathyroid hormone resistance in target organs, i.e., kidney resistance, but with conserved bone cell sensitivity. It has been reported in only a few cases of pseudohypoparathyroidism type Ib. Long-term vitamin D treatment was required to correct bone hyperparathyroidism. With this rationale, the patient was treated with calcium, alfacalcidol, and cholecalciferol. One-year follow-up showed complete resolution of pain, improvement in serum calcium, and regression of bone lesions on [18F]F-fluorocholine PET/CT. This case illustrates the usefulness of [18F]F-fluorocholine PET/CT for the imaging of brown tumors in pseudohypoparathyroidism type 1B, and emphasizes the importance of calcium and vitamin D treatment in adult patients, to avoid the deleterious effects of high parathyroid hormone on skeletal integrity.

Refracture following vertebral fragility fracture when bone fragility is not recognized: summarizing findings from comparator arms of randomized clinical trials.

PURPOSE: Since vertebral fragility fractures (VFFs) might increase the risk of subsequent fractures, we evaluated the incidence rate and the refracture risk of subsequent vertebral and non-vertebral fragility fractures (nVFFs) in untreated patients with a previous VFF. METHODS: We systematically searched PubMed, Embase, and Cochrane Library up to February 2022 for randomized clinical trials (RCTs) that analyzed the occurrence of subsequent fractures in untreated patients with prior VFFs. Two authors independently extracted data and appraised the risk of bias in the selected studies. Primary outcomes were subsequent VFFs, while secondary outcomes were further nVFFs. The outcome of refracture within ≥ 2 years after the index fracture was measured as (i) rate, expressed per 100 person-years (PYs), and (ii) risk, expressed in percentage. RESULTS: Forty RCTs met our inclusion criteria, ranging from medium to high quality. Among untreated patients with prior VFFs, the rate of subsequent VFFs and nVFFs was 12 [95% confidence interval (CI) 9-16] and 6 (95% CI 5-8%) per 100 PYs, respectively. The higher the number of previous VFFs, the higher the incidence. Moreover, the risk of VFFs and nVFFs increased within 2 (16.6% and 8%) and 4 years (35.1% and 17.4%) based on the index VFF. CONCLUSION: The highest risk of subsequent VFFs or nVFFs was already detected within 2 years following the initial VFF. Thus, prompt interventions should be designed to improve the detection and treatment of VFFs, aiming to reduce the risk of future FFs and properly implement secondary preventive measures.

The integrated structure of care: evidence for the efficacy of models of clinical governance in the prevention of fragility fractures after recent sentinel fracture after the age of 50 years.

Randomized clinical trials and observational studies on the implementation of clinical governance models, in patients who had experienced a fragility fracture, were examined. Literature was systematically reviewed and summarized by a panel of experts who formulated recommendations for the Italian guideline. PURPOSE: After experiencing a fracture, several strategies may be adopted to reduce the risk of recurrent fragility fractures and associated morbidity and mortality. Clinical governance models, such as the fracture liaison service (FLS), have been introduced for the identification, treatment, and monitoring of patients with secondary fragility fractures. A systematic review was conducted to evaluate the association between multidisciplinary care systems and several outcomes in patients with a fragility fracture in the context of the development of the Italian Guidelines. METHODS: PubMed, Embase, and the Cochrane Library were investigated up to December 2020 to update the search of the Scottish Intercollegiate Guidelines Network. Randomized clinical trials (RCTs) and observational studies that analyzed clinical governance models in patients who had experienced a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using random-effects models. Primary outcomes were bone mineral density values, antiosteoporotic therapy initiation, adherence to antiosteoporotic medications, subsequent fracture, and mortality risk, while secondary outcomes were quality of life and physical performance. RESULTS: Fifteen RCTs and 62 observational studies, ranging from very low to low quality for bone mineral density values, antiosteoporotic initiation, adherence to antiosteoporotic medications, subsequent fracture, mortality, met our inclusion criteria. The implementation of clinical governance models compared to their pre-implementation or standard care/non-attenders significantly improved BMD testing rate, and increased the number of patients who initiated antiosteoporotic therapy and enhanced their adherence to the medications. Moreover, the treatment by clinical governance model respect to standard care/non-attenders significantly reduced the risk of subsequent fracture and mortality. The integrated structure of care enhanced the quality of life and physical function among patients with fragility fractures. CONCLUSIONS: Based on our findings, clinicians should promote the management of patients experiencing a fragility fracture through structured and integrated models of care. The task force has formulated appropriate recommendations on the implementation of multidisciplinary care systems in patients with, or at risk of, fragility fractures.

A systematic review on the performance of fracture risk assessment tools: FRAX, DeFRA, FRA-HS.

PURPOSE: Preventing fragility fractures by treating osteoporosis may reduce disability and mortality worldwide. Algorithms combining clinical risk factors with bone mineral density have been developed to better estimate fracture risk and possible treatment thresholds. This systematic review supported panel members of the Italian Fragility Fracture Guidelines in recommending the use of best-performant tool. The clinical performance of the three most used fracture risk assessment tools (DeFRA, FRAX, and FRA-HS) was assessed in at-risk patients. METHODS: PubMed, Embase, and Cochrane Library were searched till December 2020 for studies investigating risk assessment tools for predicting major osteoporotic or hip fractures in patients with osteoporosis or fragility fractures. Sensitivity (Sn), specificity (Sp), and areas under the curve (AUCs) were evaluated for all tools at different thresholds. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies-2; certainty of evidence (CoE) was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Forty-three articles were considered (40, 1, and 2 for FRAX, FRA-HS, and DeFRA, respectively), with the CoE ranging from very low to high quality. A reduction of Sn and increase of Sp for major osteoporotic fractures were observed among women and the entire population with cut-off augmentation. No significant differences were found on comparing FRAX to DeFRA in women (AUC 59-88% vs. 74%) and diabetics (AUC 73% vs. 89%). FRAX demonstrated non-significantly better discriminatory power than FRA-HS among men. CONCLUSION: The task force formulated appropriate recommendations on the use of any fracture risk assessment tools in patients with or at risk of fragility fractures, since no statistically significant differences emerged across different prediction tools.

Bone damage after chemotherapy for lymphoma: a real-world experience.

BACKGROUND: Despite recent improvements in survival due to advances in treatment, the quality of life of patients with lymphoma may be compromised by the long-term complications of chemotherapy and steroid therapy. Among these, a potentially relevant problem is bone loss and the development of fragility fractures. AIM: To provide further evidence of clinical or subclinical skeletal complications in correlation with biological variables and markers of bone disease in patients with complete response to therapy. METHOD: A cross-sectional observational study was conducted on subjects diagnosed with lymphoma with subsequent antineoplastic treatment, disease status after therapy defined as complete response disease for at least a year now. We performed: blood chemistry tests, imaging techniques and screening tools for the assessment of functional status and quality of life (SARC-F and mini-Osteoporosis Quality of Life). RESULTS: Approximately 50% of patients had osteoporosis, with a prevalence of vertebral fractures of 65.5%. In most patients, we found hypovitaminosis D and high levels of parathyroid hormone (PTH). Furthermore, a statistically significant association was observed between high PTH levels and previous lymphoma treatment. Finally, the Mini-Osteoporosis Quality of life (mini-OQLQ) questionnaire demonstrated a loss of quality of life as a consequence of the change in bone status. CONCLUSIONS: Patient treatment design for personalized chemotherapy would be desirable to reduce late effects on bone. Also, early prevention programs need to be applied before starting treatment. The most benefited subpopulations could be not only elderly but also young patients.

Radiofrequency echographic multispectrometry compared with dual X-ray absorptiometry for osteoporosis diagnosis on lumbar spine and femoral neck.

An innovative, non-ionizing technique to diagnose osteoporosis on lumbar spine and femoral neck was evaluated through a multicenter study involving 1914 women. The proposed method showed significant agreement with reference gold standard method and, therefore, a potential for early osteoporosis diagnoses and possibly improved patient management. INTRODUCTION: To assess precision (i.e., short term intra-operator precision) and diagnostic accuracy of an innovative non-ionizing technique, REMS (Radiofrequency Echographic Multi Spectrometry), in comparison with the clinical gold standard reference DXA (dual X-ray absorptiometry), through an observational multicenter clinical study. METHODS: In a multicenter cross-sectional observational study, a total of 1914 postmenopausal women (51-70 years) underwent spinal (n = 1553) and/or femoral (n = 1637) DXA, according to their medical prescription, and echographic scan of the same anatomical sites performed with the REMS approach. All the medical reports (DXA and REMS) were carefully checked to identify possible errors that could have caused inaccurate measurements: erroneous REMS reports were excluded, whereas erroneous DXA reports were re-analyzed where possible and otherwise excluded before assessing REMS accuracy. REMS precision was independently assessed. RESULTS: In the spinal group, quality assessment on medical reports produced the exclusion of 280 patients because of REMS errors and 78 patients because of DXA errors, whereas 296 DXA reports were re-analyzed and corrected. Analogously, in the femoral group there were 205 exclusions for REMS errors, 59 exclusions for DXA errors, and 217 re-analyzed DXA reports. In the resulting dataset (n = 1195 for spine, n = 1373 for femur) REMS outcome showed a good agreement with DXA: the average difference in bone mineral density (BMD, bias ± 2SD) was -0.004 ± 0.088 g/cm2 for spine and - 0.006 ± 0.076 g/cm2 for femur. Linear regression showed also that the two methods were well correlated: standard error of the estimate (SEE) was 5.3% for spine and 5.8% for femur. REMS precision, expressed as RMS-CV, was 0.38% for spine and 0.32% for femur. CONCLUSIONS: The REMS approach can be used for non-ionizing osteoporosis diagnosis directly on lumbar spine and femoral neck with a good level of accuracy and precision. However, a more rigorous operator training is needed to limit the erroneous acquisitions and to ensure the full clinical practicability.

From microvasculature to fibroblasts: Contribution of anti-endothelial cell antibodies in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and internal organ fibrosis, caused by microvascular dysfunction. In recent years, the hypothesis that anti-endothelial cell antibodies (AECA) play a key role in microvascular damage seems to be increasingly convincing. In fact, AECA can induce antibody-dependent cellular apoptosis and stimulate the microvasculature to release pro-inflammatory and pro-fibrotic cytokines. Human-microvascular-endothelial-cells (MVECs) were stimulated with SSc sera (with and without AECA) and with sera from healthy donors. The conditioned MVEC culture media were then added to fibroblast cultures obtained from control skin (CTR), non-affected skin of SSc patients (NA), and affected skin of the same sclerodermic (SSc) patients, respectively. AECA contributed to the MVEC increased release of endothelin-1 (ET-1) in the culture medium and to MVEC apoptosis. Fibroblast (CTR, NA, and SSc) proliferation was increased after treatment with AECA-positive conditioned media, compared to AECA-negative and control conditioned media. Furthermore, both AECA-positive (in major contribution) and AECA-negative conditioned media were responsible for alpha-smooth-muscle-actin (αSMA) over-expression in all fibroblast cultures, compared to control conditioned media. Fibroblast type I collagen synthesis was upregulated by both SSc conditioned media (with and without AECA). Finally, the synthesis of fibroblast transforming-growth-factor-beta (TGF-ß) was statistically higher in AECA-positive conditioned media, compared to AECA-negative and control conditioned media. These findings support the concept that AECA may mediate the crosstalk between endothelial damage and dermal-fibroblast activation in SSc.

Improving adherence to and persistence with oral therapy of osteoporosis.

UNLABELLED: Osteoporosis treatment has low adherence and persistence. This study evaluated if greater patient involvement could improve them. At 12 months, only 114 out of 344 participants were "fully adherent and persistent" (all drug doses taken throughout the study). Only frequency of drug administration had a significant influence on adherence. INTRODUCTION: Osteoporosis affects millions of individuals worldwide. There are now several effective drugs, but adherence to and persistence with treatment are low. This 12-month multicenter, prospective, randomized study evaluated the efficacy of two different methods aimed at improving adherence and persistence through greater patient involvement, compared with standard clinical practice. METHODS: Three hundred thirty-four post-menopausal women, receiving an oral prescription for osteoporosis for the first time, were recruited and randomized into three groups: group 1 (controls, managed according to standard clinical practice) and groups 2 and 3 (managed with greater patient and caregiver involvement and special reinforcements: group 2, instructed to use several different "reminders"; group 3, same "reminders" as group 2, plus regular phone calls from and meetings at the referring Center). All enrolled women had two visits (baseline and 12 months). RESULTS: Of 334 enrolled women, 247 (74%) started the prescribed therapy. Of those who started, 219 (88.7%) persisted in therapy for at least 10 months. At final evaluation, only 114 women were considered as "fully adherent and persistent" (all doses taken throughout the 12 months). There were no significant differences regarding "full adherence" among the three randomized groups. The frequency of drug administration had a significant influence: weekly administration had a >5-fold higher adherence and monthly administration an 8-fold higher adherence (p < 0.0001) than daily administration. CONCLUSIONS: The special effort of devising and providing additional reminders did not prove effective. Additional interventions during the follow-up, including costly interventions such as phone calls and educational meetings, did not provide significant advantages.

Gender-specific associations of appendicular muscle mass with BMD in elderly Italian subjects.

Currently used diagnostic measures for sarcopenia are based on the evaluation of appendicular skeletal muscle mass (ASMM) divided by height-squared (ASMMI). This study aimed to investigate the associations between different operational definitions of appendicular muscle mass and BMD at different skeletal sites in aging Italian men and women. In 1199 consecutive healthy Italian subjects, aged 55 years or more (854 women, age 64.2 ± 6.4 years and 165 men, age 65.3 ± 6.1 years), we measured BMD at the lumbar spine (LS-BMD), at femoral neck (FN-BMD),at total hip (TH-BMD), at total body (WB-BMD) and at the right hand (H-BMD) and body composition parameters [ASMM, ASMMI, ASMM/Weight, total lean mass and total fat mass by DXA]. In all subjects, we also measured sex hormones, 25-hydroxyvitamin D and bone turnover markers. In men, both ASMM and ASMMI were positively correlated with BMD at all sites, whereas in women, ASMM and ASMMI did not show any significant correlation with BMD. In men, multiple regression analyses showed that ASMM was positively associated (p < 0.01) with FN-BMD, TH-BMD and H-BMD; however, these associations were no longer present when lean mass was included. In women, both fat mass and lean mass were found positively associated with BMD at all sites. In conclusion, among the different operational measures of the ASMM, only ASMM was significantly associated with BMD in elderly men, but not in elderly women.

A comparative study of dual-X-ray absorptiometry and quantitative ultrasonography for the evaluating bone status in subjects with Rett syndrome.

Rett syndrome, an X-linked neurodevelopmental disorder primarily affecting girls, is frequently characterized by a reduced bone mineral density (BMD) with an increased risk of fragility fractures. The aim of the study was to assess bone status by DXA technique and by quantitative ultrasound (QUS) in subjects with Rett syndrome and to evaluate which DXA or QUS parameters better correlate with clinical features. In 156 Rett subjects (mean age 13.6 ± 8.2 years) and in 62 controls, we measured BMD at femoral neck (BMD-FN) and at total femur (BMD-TF). Apparent volumetric bone mineral density (vBMAD) was also calculated. In all subjects, QUS parameters at phalanges by Bone Profiler-IGEA (amplitude-dependent speed of sound: AD-SoS and bone transmission time: BTT) were evaluated. We found that both DXA parameters and QUS parameters were significantly lower in Rett subjects than in controls. All clinical characteristics were positively correlated to BMD-FN, BMD-TF, AD-SoS, and BTT (p < 0.001) but not with vBMAD-FN. All ultrasonographic parameters were significantly correlated to BMD-FN and BMD-TF, whereas vBMAD-FN showed only positive significant correlation with densitometric parameters (p < 001). In Rett subjects BMD-FN was predicted primarily by weight and movement capacity, whereas vBMAD-FN was predicted by weight, height, and calcium intake. Moreover, AD-SoS was predicted by weight, height, and age, while BTT was predicted only by height. In conclusion, in our study the performance of QUS at phalanges was similar to those of BMD at femur, therefore, both areal BMD at femur and QUS at phalanges (AD-SoS and BTT) may be equally useful in the evaluation of skeletal status in Rett patients.

Is osteopontin involved in cutaneous fibroblast activation? Its hypothetical role in scleroderma pathogenesis.

Osteopontin (OPN) is an extracellular matrix protein implicated in bone remodeling, but it presents also pro-inflammatory and pro-fibrotic properties. OPN expression also occurs upon exposure of cells to classical mediators of acute inflammation such as tumor necrosis growth factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), as well as fibrogenic cytokines such as transforming growth factor beta (TGF-beta), although a detailed understanding of these regulatory pathways is still unknown. Plasma OPN levels in both limited and diffuse systemic sclerosis patients (lSSc and dSSc) were statistically higher compared to those of control subjects. Immunohistology demonstrated that high TGF-beta levels, alpha smooth muscle actin (alphaSMA) levels and consequently high OPN levels were found in the affected skin of sclerodermic patients (lSSc and dSSc) compared to levels found in healthy skin. In order to better understand how OPN interferes with the fibrotic process, healthy skin fibroblasts were treated for 24 and 48 hours with bleomycin and with endothelin-1 (ET-1) plus TGF-beta in order to induce the fibrogenesis. After 48 hours of stimulation, healthy treated fibroblasts showed statistically increased alphaSMA levels (index of differentiation into myofibroblasts) and simultaneously statistically increased OPN levels compared to healthy untreated ones. This study demonstrates that OPN levels increase simultaneously with the increasing of alphaSMA levels, therefore it is reasonable to hypothesize that OPN interferes in the pathogenesis of Systemic Sclerosis in the early stage of fibroblast differentiation process.

Effects of intravenous zoledronate and ibandronate on carotid intima-media thickness, lipids and FGF-23 in postmenopausal osteoporotic women.

OBJECTIVE: Osteoporosis and atherosclerosis are interconnected entities and share also some pathophysiological mechanisms. Moreover, recent literature data have supported the hypothesis that bisphosphonates (BPs) may have some antiatherogenic actions. This study aimed to evaluate the effects of one year with zoledronate or ibandronate given intravenously on lipid profile and on carotid artery intima-media thickness (CA-IMT). METHODS: Sixty postmenopausal osteoporotic women (mean age: 66.6±7.8years) were randomly assigned to 1-year treatment with zoledronate 5mg i.v. annually or ibandronate 3mg i.v. every 3 months. In all patients at baseline and after 12months we measured CA-IMT, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), 25-hydroxyvitamin D (25OHD), bone alkaline phosphatase (B-ALP), type I collagen ß carboxy telopeptide (ßCTX), osteocalcin (OC), fibroblast growth factor 23 (FGF-23) and sclerostin. RESULTS: The osteoporotic women treated with zoledronate showed a greater reduction in CA-IMT than those treated with ibandronate. HDL-C and HDL-C/LDL-C ratio showed a significant (p<0.01) increase in the 2 groups, whereas, LDL-C showed a reduction in the two groups which, however, reached statistical significance (p<0.05) only in the zoledronate group. FGF-23 serum levels showed a similar and significant decrease in both the women treated with zoledronate and in those treated with ibandronate. At the end of the study period sclerostin serum levels showed a higher increase in the patients treated with zoledronate than in those treated with ibandronate. CONCLUSION: In osteoporotic women both zoledronate and ibandronate given intravenously resulted in an increase in HDL-C/LDL-C ratio and a reduction of CA-IMT which was significant only for zoledronate. Further prospective studies are needed to clarify whether the change in FGF-23 and sclerostin levels is a marker or a potential mechanism of the action of BPs at a vascular level.

Antidiabetic therapy effects on bone metabolism and fracture risk.

Patients with diabetes are at greater risk of fractures mostly due to not only to extraskeletal factors, such as propensity to fall, but also to bone quality alteration, which reduces bone strength. In people with diabetes, insulin deficiency and hyperglycaemia seem to play a role in determining bone formation alteration by advanced glycation end product (AGE) accumulation or AGE/RAGE (receptors for AGE) axis imbalance, which directly influence osteoblast activity. Moreover, hyperglycaemia and oxidative stress are able to negatively influence osteocalcin production and the Wnt signalling pathways with an imbalance of osteoblast/osteoclast activity leading to bone quality reduction as global effect. In addition, other factors such as insulin growth factors and peroxisome proliferator-activated receptor-γ pathways seem to have an important role in the pathophysiology of osteoporosis in diabetes. Although there are conflicting data in literature, adequate glycaemic control with hypoglycaemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 diabetes. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycaemic control. Finally, preliminary data on animals and in humans suggest the hypothesis that incretins and dipeptidyl peptidase-4 inhibitors could have a positive effect on bone metabolism by a direct effect on bone cells; however, such issue needs further investigations.

The assessment of vertebral fractures in elderly women with recent hip fractures: the BREAK Study.

UNLABELLED: This study aimed to evaluate the prevalence of vertebral fractures in elderly women with a recent hip fracture. The burden of vertebral fractures expressed by the Spinal Deformity Index (SDI) is more strictly associated with the trochanteric than the cervical localization of hip fracture and may influence short-term functional outcomes. INTRODUCTION: This study aimed to determine the prevalence and severity of vertebral fractures in elderly women with recent hip fracture and to assess whether the burden of vertebral fractures may be differently associated with trochanteric hip fractures with respect to cervical hip fractures. METHODS: We studied 689 Italian women aged 60 years or over with a recent low trauma hip fracture and for whom an adequate X-ray evaluation of spine was available. All radiographs were examined centrally for the presence of any vertebral deformities and radiological morphometry was performed. The SDI, which integrates both the number and the severity of fractures, was also calculated. RESULTS: Prevalent vertebral fractures were present in 55.7% of subjects and 95 women (13.7%) had at least one severe fracture. The women with trochanteric hip fracture showed higher SDI and higher prevalence of diabetes with respect to those with cervical hip fracture, p=0.017 and p=0.001, respectively. SDI, surgical menopause, family history of fragility fracture, and type2 diabetes mellitus were independently associated with the risk of trochanteric hip fracture. Moreover, a higher SDI was associated with a higher percentage of post-surgery complications (p=0.05) and slower recovery (p<0.05). CONCLUSIONS: Our study suggests that the burden of prevalent vertebral fractures is more strictly associated with the trochanteric than the cervical localisation of hip fracture and that elevated values of SDI negatively influence short term functional outcomes in women with hip fracture.

The relationship between serum ghrelin and body composition with bone mineral density and QUS parameters in subjects with Rett syndrome.

Several studies have reported that females with Rett's syndrome frequently have marked decreases in bone mineral density (BMD). However, the pathogenesis of impaired bone status in RTT girls remains controversial. This study aimed to investigate whether ghrelin, an orexigenic peptide secreted by the stomach, was associated with body composition parameters, bone mineral density and quantitative ultrasound (QUS) in girls with Rett's syndrome. In 123 Rett girls (13.6±8.2 years) and in 55 similar age range controls we evaluated ghrelin serum levels, 25OHD, quantitative ultrasound parameters at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT), total body bone mineral density (BMD-WB) by Hologic QDR 4500. Whole body mineral content (BMC-WB), BMC-WB/height, fat mass (FM), fat percentage and lean mass (LM) were determined by using the same DXA device. We found that serum ghrelin levels were significantly higher in the Rett patients with respect to the control group (p<0.05). In Rett girls ghrelin serum levels were inversely correlated with both age (R(2)=0.17, p<0.001) and BMI (R(2)=0.14, p<0.001). Moreover, in Rett subjects the values of BMD-WB, BMC-WB, BMC-WB/height and QUS parameters were significantly lower than in control subjects. Fat mass and lean mass were lower in Rett subjects than in controls, but the difference reached the statistical significance only for lean mass. In Rett girls ghrelin serum levels were not predictors of bone status. Instead, we found that in Rett subjects, lean mass, age and 25OHD were significant independent predictors of BMC-WB/h, whereas both age and height were independent predictors of BMD-WB. Moreover, AD-SoS was predicted by age, fat percentage and height; while BTT was predicted only by height. In conclusion, our findings indicate that ghrelin levels were higher in Rett girls with respect to healthy controls, and negatively associated with both DXA and QUS parameters. However, in our study ghrelin was not found to be an independent predictor of bone mass, so supporting the hypothesis that ghrelin is elevated in Rett subjects in a compensatory manner.

The association of body composition and sex hormones with quantitative ultrasound parameters at the calcaneus and phalanxes in elderly women.

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

Rare localizations of bone sarcoidosis: two case reports and review of the literature.

Sarcoidosis is a multisystem disease of unknown origin. Granulomatous bone involvement has an overall incidence of 1-13%. This incidence is probably underestimated in certain patient series because bone involvement is often asymptomatic. The small bones of hands and feet are the most common localizations, while skull, knee, rib, pelvic and sternal localizations are rarely reported. Here we describe some interesting cases of chronic sarcoidosis with unusual bone localizations observed at our regional referral centre for sarcoidosis. We also review the literature to underline the complexity of the disease, the problem of differential diagnosis with respect to malignancies and the need for appropriate and effective therapy of this rare localization.

Effect of inhaled glucocorticoids and beta(2) agonists on vertebral fracture risk in COPD patients: the EOLO study.

Although inhaled glucocorticoids (GCs) and beta(2) agonists are being more frequently prescribed in the management of chronic obstructive pulmonary disease (COPD), their role in the impairment of bone status and in fracture risk remains controversial. This study aimed to evaluate whether the dose of inhaled GCs and beta(2) agonists may independently influence bone status and vertebral fracture risk in COPD patients aged 50 years or over. COPD severity, presence of vertebral fractures on lateral chest X-ray, and bone status by quantitative ultrasound (QUS) at the calcaneus were evaluated. The risk of vertebral fractures was significantly increased in patients taking the highest daily dose (>1,500 microg) of inhaled GCs (OR = 1.4, CI 1.04-1.89). The highest dose of inhaled GCs was significantly associated with low values of stiffness index (OR = 1.74, CI 1.03-2.94). Inhaled beta(2) agonists were not associated either with increased risk of vertebral fracture or with reduced values of stiffness. Moreover, the risk of fractures was markedly increased in patients with very severe or severe COPD (OR = 2.05, CI 1.28-3.28, and OR = 1.40, CI 1.06-1.82, respectively). In conclusion, in COPD patients high doses of inhaled GCs, but not beta(2) agonists, are associated with an increased risk of vertebral fractures and a reduction of QUS at the calcaneus.

Osteoporosis risk in patients with chronic obstructive pulmonary disease: the EOLO study.

Chronic obstructive pulmonary disease (COPD) appears to be associated with osteoporosis. The aim of the study was to evaluate the prevalence of osteoporosis risk (OP risk) in a sample of patients with COPD. In 3030 patients (1768 men and 1262 women) aged >50 yr, we evaluated COPD severity with spirometry and OP risk by using a quantitative ultrasound device. We analyzed several risk factors for osteoporosis, such as age, gender, body mass index (BMI), fracture history, smoking status, glucocorticoid (GC) treatment in univariate and in multinomial logistic regressions. The risk of osteoporosis was higher in women and in older participants, among those with more severe COPD, treated with GC. In multivariate analysis, we found interactions between fracture history and smoking and between age and gender. Significant associations were found with BMI and GC treatment, whereas only a tendency, not statistically significant, was found for very severe COPD being associated to high risk of osteoporosis. In COPD patients the risk of osteoporosis is high, in particular at severe stages of the disease, but seems to be due to traditional risk factors, such as older age, female gender, low BMI, history of smoking and fractures, GC treatment.