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Polymyalgia rheumatica is an inflammatory rheumatic disease of the elderly characterised by pain and stiffness in the neck and pelvic girdle, and is the second most common inflammatory rheumatic condition in this age group, after rheumatoid arthritis. Polymyalgia rheumatica can occur independently or in association with giant cell arteritis, which is the most common form of primary vasculitis. The diagnosis of polymyalgia rheumatica is usually based on clinical presentation and increase of inflammatory markers. There are no pathognomonic findings that can confirm the diagnosis. However, different imaging techniques, especially ultrasonography, can assist in the identification of polymyalgia rheumatica. Glucocorticoids are the cornerstone of the treatment of polymyalgia rheumatica, but they might be associated with different adverse events. A subgroup of patients presents with a refractory disease course and, in these cases, adding methotrexate as a steroid-sparing agent could be useful. In this review, we summarise the latest findings regarding the pathogenesis, diagnosis and management of polymyalgia rheumatica and try to highlight the possible pitfalls, especially in elderly patients.

To investigate the effectiveness of the T-score values provided by Radiofrequency Echographic Multi Spectrometry (REMS) in the identification of patients at risk for incident osteoporotic fractures.A population of Caucasian women (30-90 years), enrolled from 2013 to 2016, underwent dual X-ray absorptiometry (DXA) and REMS scans at axial sites. The incidence of fragility fractures was assessed during a follow-up period up to 5 years. Afterwards, patients with and without incident fractures were stratified in two age-matched groups with a 1: 2 proportion (Group F' and Group NF', respectively). The performance of REMS T-score in discriminating between the two groups was quantitatively assessed and compared with DXA.1516 patients were enrolled and 1370 completed the follow-up (mean ± SD: 3.7 ± 0.8 years; range: 1.9-5.0 years). Fracture incidence was 14.0%. Age-matched groups included 175 fractured patients and 350 non-fractured ones, respectively (median age 70.2 [interquartile range: 61.0-73.3] and 67.3 [65.4-69.8] years, p-value ns). The groups resulted also balanced for height, weight and BMI (p-values ns). As expected, the differences in REMS T-score (for vertebral site, -2.9 [-3.6 to -1.9] in Group F', -2.2 [-2.9 to -1.2] in Group NF') and DXA T-score (-2.8 [-3.3 to -1.9] in Group F', -2.2 [-2.9 to -1.4] in Group NF') were statistically significant (p-value0.001). Analogous results were obtained for femoral neck. Considering the T-score cut-off of -2.5, REMS identified Group F' patients with a sensitivity of 65.1% and specificity of 57.7% of (OR = 2.6, 95%CI: 1.77-3.76, p 0.001), whereas DXA showed a sensitivity of 57.1% and a specificity of 56.3% (OR = 1.7, 95%CI: 1.20-2.51, p-value = 0.0032). For femoral neck, REMS sensitivity and specificity were 40.2% and 79.9%, respectively, with an OR of 2.81 (95%CI: 1.80-4.39, p 0.001). DXA, instead, showed a sensitivity and specificity of 42.3% and 79.3%, respectively, with an OR of 2.68 (95%CI: 1.71-4.21, p 0.001).REMS T-score resulted an effective predictor for the risk of incident fragility fractures in a population-based sample of female subjects, representing a promising parameter to enhance osteoporosis diagnosis in the clinical routine.

Background To date numerous quantitative methods to diagnose osteoporosis at peripheral sites have been developed. REMS (Radiofrequency Echographic Multi Spectrometry) is a non-ionizing instrument used to quantitatively evaluate bone mineral density at lumbar spine and femoral neck sites [1]. Objectives To assess the accuracy of REMS in osteoporosis diagnosis at axial sites (lumbar spine and hip) compared with the gold standard, Dual-energy X-ray absorptiometry (DXA). Methods We enrolled patients aged from 50 to 75 years and perfomed a total of 1,699 and 1,794 lumbar spine and proximal femur scans with REMS and DXA. A quality checks on DXA and REMS acquired data were performed through direct examination of scans by experienced operators. We investigated the agreement between the two techniques calculating: Pearson`s correlation coefficient (r), Standard Error of the Estimate (SEE) and efficiency (sensitivity and specificity) in identifying osteoporotic individuals (i.e. T-score ≤ -2.5). Results We found a good linear correlation between REMS and DXA BMD estimation, Pearson coefficient r=0.938 for lumbar spine and r=0.933 for proximal femur (p Conclusion REMS exhibited a high sensitivity and specificity in identifying osteoporotic patients at lumbar spine or proximal femur sites compared with gold-standard DXA. REMS accurately diagnosed osteoporotic patients in clinical routine, at both lumbar spine and proximal femur sites, without using ionizing radiation. References [1] Di Paola M, Gatti D, Viapiana O, et al. Osteoporos Int, 2018 Disclosure of Interests Giovanni Adami: None declared, Giovanni Arioli: None declared, Gerolamo Bianchi: None declared, Maria Luisa Brandi: None declared, Carla Caffarelli: None declared, Loredana Cavalli: None declared, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Luisella Cianferotti Speakers bureau: Abiogen Pharma, Bruno Farmaceutici, Shire, Francesco Conversano Shareholder of: Francesco Conversano own stocks of Echolight Spa, Marco Di Paola: None declared, Davide Gatti Speakers bureau: Abiogen, Amgen, Janssen-Cilag, Mundipharma, Pfeizer, Giuseppe Girasole: None declared, Andrea Giusti: None declared, Stefano Gonnelli: None declared, Monica Manfedini: None declared, Maurizio Muratore: None declared, Ranuccio Nuti: None declared, Paola Pisani: None declared, Laura Quarta: None declared, Ombretta Viapiana Speakers bureau: Novartis, Abbvie, Eli-Lilly, Sanofi Genzyme

Background Acute phase response (APR) is a transient, flu-like reaction to first exposure to intravenous nitrogen-containing bisphosphonate (NBP). APR is characterised by a strong inflammatory response, associated with increases in circulating levels of IL-6 and TNF-, that is thought to be due to activation and increased proliferation of γδ T cells related to the molecular mechanism of action of NBP. Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), in both its soluble (s) and membrane-bound forms, is involved in the downregulation of T cell proliferation, cell cycle progression and cytokine production. High levels of serum sCTLA-4 have been reported in several autoimmune diseases, and its role as both inhibitor and enhancer of the immune response has been proposed. Objectives To evaluate the potential relationship between sCTLA-4 and the development of APR in patients treated with zoledronic acid (ZOL). Methods Included in the study were patients treated with a single intravenous ZOL infusion 5 mg. Exclusion criteria were previous treatment with ZOL, treatments interfering with CTLA-4, and estimated glomerular filtration rate Results Ten female patients (mean age 73-10 years) were included (2 had vertebral fractures and the remaining had osteoporosis), 5 of whom experienced APR (APR+) associated with the expected increases in serum CRP and IL-6. Baseline levels of sCTLA-4 did not differ between APR+ and APR- patients and decreased significantly in all from 32-9 ng/ml to 24-9 ng/ml (p=0.007) at 24 hr, 16-8 ng/ml (p=0.004) at 48 hr and 7-6 ng/ml (p Conclusion Contrary to our hypothesis, sCTLA-4 was not related to the occurrence of APR after ZOL. The significance of the substantial decrease of circulating levels of sCTLA-4 after ZOL in all studied patients warrants further investigation. Disclosure of Interests Gerolamo Bianchi Consultant for: Alfa-Sigma, Amgen, BMS, Celgene, Medac, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Daniele Saverino: None declared, Dario Camellino Consultant for: Janssen-Cilag, Novartis, AbbVie, Sanofi, Paid instructor for: Mylan, Andrea Giusti Grant/research support from: Abiogen Pharma, Consultant for: EffRx, Speakers bureau: Abiogen Pharma, Eli Lilly, AMGEN, Erika Iervasi: None declared, Giuseppe Girasole: None declared, Socrates Papapoulos Grant/research support from: No in the last 3 years, Consultant for: Amgen, Axsome, Gador, Radius Health, UCB, Speakers bureau: Amgen, UCB

Background:Glucocorticoids (GC) are the cornerstone of the treatment of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), but they are associated with several adverse events (AEs). Moreover, a considerable proportion of patients relapse during GC tapering.Objectives:To describe the efficacy and safety of the JAK-inhibitor baricitinib (BARI) in a group of patients with PMR and/or GCA.Methods:Case series of patients with PMR and/or GCA with a refractory disease course, despite several lines of therapy, including methotrexate (MTX) and tocilizumab (TCZ), started treatment with BARI. All patients underwent periodic, standardised clinical and laboratory examinations, and also FDG-PET/CT. PMR-activity score (AS) was calculated at each visit except in patients with isolated large vessel vasculitis (LVV) or GCA.Results:A total of six patients (five females and one male, median age 64 years, range 50-83) were treated with BARI. Two of them had isolated PMR (patients #1 and #6), two had PMR with associated LVV (patients #2 and #5), and one (patient #3) had cranial-GCA. Demographic and clinical characteristics are provided in Table 1. At the time of starting BARI, patients were taking a median prednisone dose of 8.75 mg/day (range 0-25), and the 4 patients with PMR±LVV had a median PMR-activity score (PMR-AS) of 23.3 (indicating high disease activity), which decreased to 1.58 after 6 months of treatment with BARI. Two of them could stop GC and continued BARI monotherapy (in one case, BARI was tapered down to 2 mg/day after 12 months).After starting BARI, patient #3 (GCA) could gradually taper prednisone from 25 mg/day to 10 mg/day in six months, without reporting fever or headache. After one year of treatment, she feels well while taking prednisone 7.5 mg/day.Patient #4 (LVV) remained clinically stable during the treatment with BARI, but a follow-up FDG-PET/CT showed LVV, and we decided to stop BARI and restart TCZ. After 4 months of treatment with BARI, patient #5 suffered from pneumonia, while she was also taking prednisone 15 mg/day. BARI was therefore stopped. No other AEs attributable to BARI were detected.Conclusion:BARI appears as an appealing option for treating patients with PMR and/or GCA. Although these preliminary results should be confirmed by a RCT, BARI lowered rapidly disease activity and exerted a significant steroid-sparing effect, allowing GC withdrawal in 2 out of 6 patients.Table 1.Demographic and clinical characteristics of patients.Patient #SexAgeDiagnosisPrevious treatmentDisease duration (months)PMR-AS1F66PMRMTX, HCQ, SSZ25.540.52F78PMR+LVVTCZ, MTX41.828.83F61GCACYC, MMF, TCZ119.8N/A4F60LVVTCZ16.4N/A5F83PMR+LVVMTX, TCZ24.415.26M50PMRMTX24.617.8CYC: cyclophosphamide, GCA: giant cell arteritis, HCQ: hydroxychloroquine, LVV: large vessel vasculitis, MMF: mycophenolate mofetil, MTX: methotrexate, N/A: not applicable, PMR: polymyalgia rheumatica, PMR-AS: PMR-activity score, SSZ: sulfasalazine, TCZ: tocilizumab.Disclosure of Interests:Dario Camellino Speakers bureau: Medac, Eli Lilly, Paid instructor for: Mylan, Consultant of: Accord, Celgene, Novartis, Sanofi, Christian Dejaco Speakers bureau: Eli Lilly (

Background:Secondary hyperparathyroidism (sHPTH) due to vitamin D deficiency impairs the bone mineral density (BMD) response to alendronate,1-2 but the optimal strategy for its correction in postmenopausal osteoporotic women (PMO) about to start zoledronic acid (ZOL) therapy is still unknown.Objectives:To evaluate the effects of cholecalciferol (D3) and calcifediol (25OHD) on serum 25-OH-vitamin D (s25OHD), parathyroid hormone (PTH) and BMD in PMO presenting with sHPTH due to vitamin D deficiency.Methods:PMO with s25OHD 65 pg/ml) and BMD T-score at the lumbar spine (LS), femoral neck (FN) or total hip (TH) < -2.5, or between -1 and -2.5 plus one vertebral/femoral fracture, were randomly assigned to receive a therapeutic dose of D3 (300.000 IU bolus) followed by 175 mcg/weekly of D3, or 175 mcg/weekly of 25OHD alone, 2 months before receiving a single intravenous infusion of ZOL (5 mg). BMD at the LS, FN and TH was assessed at baseline and after one year from ZOL. Serum calcium, PTH and s25OHD were measured at baseline, and 6- and 12-month after ZOL. Adverse and clinical events were ascertained by 3-and 9-month telephone interviews, and by 6- and 12-month clinical evaluation.Results:45 PMO (25OHD N=23, D3 N=22) were enrolled over one year and 32 subjects (mean age ±SD 75±10 years, range 51-91) completed the 1-year of treatment/follow-up (25OHD N=17, D3 N=15). Most PMO discontinued for protocol violation, while three deceased before study ending (25OHD N=1, D3 N=2) for reasons not related to the agents investigated. The baseline characteristics were comparable in both groups. At baseline mean s25OHD (±SE) was 8±1 ng/ml in the 25OHD group and 8±1 ng/ml in the D3 group. The corresponding figures for PTH were 111±6 pg/ml (25OHD) and 117±5 pg/ml (D3). Mean s25OHD (±SE) increased in both groups at 6- and 12-month, being significantly greater in the 25OHD group (12-month, 56±2 ng/ml) compared to the D3 group (12-month, 34±2 ng/ml, PConclusion:Calcifediol 175 mcg weekly appears more potent in improving s25OHD and decreasing PTH concentrations compared to cholecalciferol therapeutic dose (300’000 IU) plus 175 mcg weekly in PMO presenting with sHPTH due to severe vitamin D deficiency about to start ZOL therapy. Further studies are warranted to clarify implications on BMD improvements on the long-term of similar 25OHD and D3 regimens.References:[1]Barone A et al., J Am Geriatr Soc 2007.[2]Kincse G et al., BMC Musculoskelet Disord 2012.Disclosure of Interests:Giulia Botticella: None declared, Monica Pizzonia: None declared, Barbara Cossu: None declared, Roberta Bruno: None declared, Dario Camellino Speakers bureau: AbbVie, Celgene, Janssen-Cilag, Eli Lilly, Medac, Mylan, Novartis, and Sanofi, outside the submitted work, Giuseppe Girasole Speakers bureau: Abiogen Pharma and Novartis, outside the submitted work, Andrea Giusti Speakers bureau: UCB, Amgen, Kyowa Kirin, Abiogen Pharma, and Eli Lilly, outside the submitted work, Consultant of: EffRx and Abiogen Pharma, outside the submitted work, Mario Pedrazzoni: None declared, Simona Alexovits: None declared, Franco Pleitavino: None declared, Federico Santolini: None declared, Alessio Nencioni: None declared, Gerolamo Bianchi Speakers bureau: Abbvie, Abiogen Pharma, Amgen, BMS, Celgene, Eli Lilly, GSK, Janssen-Cilag, Medac, MSD, Novartis, Pfizer, Roche, Sanofi, Genzyme, and Servier, outside the submitted work.

The aim of this study was to determine the incidence of atypical femoral fractures (AFFs) seen in a large emergency department in Italy. It was a retrospective study of all men and women aged 40 years or older admitted to the Emergency Department of Parma University Hospital for a femoral fracture. Cases were identified in the hospital database with use of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 820 or 821 or text strings. All the radiographic images of fractures not clearly identified as proximal or condylar were retrieved and evaluated by three independent reviewers. Fractures were considered as atypical if all three reviewers agreed on at least four of five major features defined by the 2013 American Society for Bone and Mineral Research criteria. In the 7-year period (2007–2013), with a total follow-up of 1,383,154 patient-years, we found 22 AFFs in 21 patients, accounting for 7.1% of low-trauma subtrochanteric/femoral shaft fractures and 0.6% of all femoral fractures. The incidence was very low (1.6 in 100,000 patient-years in both sexes combined). In contrast, the incidence of classic fractures of the proximal end of the femur was at least two orders of magnitude higher (typical/atypical rate ratio 152). Bisphosphonate use was reported in 13 patients (62%; mean treatment duration 9 years; range 5–14 years). Among 286 patients with typical subtrochanteric/femoral shaft fractures, 20 were being treated with bisphosphonate (7%; odds ratio 22; 95% confidence interval 8–58; p

Background:bDMARDs are among the most effective therapies in the management of inflammatory arthritides, but they are associated with potentially severe adverse events (AEs), particularly infection. Tapering strategies of bDMARDs for patients in remission/low disease activity (R/LDA) have demonstrated comparable efficacy to standard-dose treatments, but their safety profile has not been studied yet.Objectives:To compare the number and the causes of hospital admissions in RA patients in R/LDA continuing or tapering bDMARDs.Methods:Consecutive patients with rheumatoid arthritis (RA) evaluated between 2011 and 2017, were assigned, based on treating physician’s discretion, to continue the standard dose (STD) of bDMARDs or to undergo a predetermined tapering strategy (TAP), after being in R/LDA for two consecutive visits at least 3 months apart. Down-titration of bDMARDs was obtained by a stepwise increase of the dosing interval to achieve a reduction of about 30% (e.g. administration of etanercept every 10 days instead of weekly). Demographic, clinical data and concomitant treatments were retrospectively retrieved from the electronic charts of the outpatient clinics. Information about hospital admissions, including main diagnosis, period and duration of hospitalization, and death were retrieved from the Regional Healthcare System Database.For the STD group, the observation period started with the occurrence of remission and finished with one of these events: loss of remission, switch to another bDMARD, withdrawal of the bDMARD, severe AE, death, end of the study period in (December 2017). For the TAP group, the observation period started with tapering onset and finished with one of these events: reduction of the dosing interval due to either a relapse (according to a DAS28 increase) or to a subjective, symptomatic relapse (according to the patient’s definition), switch to another bDMARD, withdrawal of the bDMARD, severe AE, death, end of the study period in (December 2017).Results:81 patients were included, of whom 40 underwent TAP. Demographic, clinical and treatment data are shown in table 1. Baseline characteristics were comparable between the two groups, except for the number of previous bDMARDs before observational period entry that was slightly higher in the STD group (STD 1.0±0.9 versus TAP 0.5±0.8, P=0.11).Table 1.Baseline demographic and clinical characteristics of the patients in remission or low disease activity.NO TAPERING(n=41)TAPERING(n=40)p valueMean age (yrs)57±1158±130.563Mean disease duration (yrs)12±912±70.897Starting bDMARD to tapering/monitoring (months)52±4567±410.128Mean monitoring period (months)22±2419±230.632Taking sDMARD at any time ((n (%))40 (98%)37 (92%)0.359Taking glucocorticoids29 (71%)28 (70%)0.999Mean prednisone dose (mg/day)2.5±2.92.1±2.70.527DAS28 at the time of tapering or first LDA/REM2.3±0.82.3±0.90.863Previous bDMARDs >1 (n (%))10 (24.4%)4 (10%)0.140In the STD group, 14 hospital admissions occurred, while in the TAP group there were 7 admissions (p=0.128). The corresponding figures for hospital admission due to infectious diseases were 6 in the STD group and 0 in the TAP group (p=0.026).Conclusion:Tapering bDMARDs in RA patients in R/LDA is associated with fewer hospital admissions, with a possible protective effect especially toward infections.Acknowledgments:The authors are indebted with Mrs Rosella Gramuglia and Mrs Cristina Olivieri for the management and analysis of the data on the flow of the drugs, and with Mrs Anna Consigliere, Mrs Anna Cosso, Mrs Romina Petralito and Mrs Laura Ravaschio for helping in retrieving clinical data.Disclosure of Interests:Dario Camellino Consultant of: I have received consultancy fees from Celgene, Sanofi, Novartis, Janssen-Cilag, Accord, Paid instructor for: I have served as a paid instructor for Mylan, Andrea Giusti Consultant of: UCB, Amgen, Janssen, Eli Lilly, Abiogen, EffRx, Speakers bureau: UCB, Amgen, Janssen, Eli Lilly, Abiogen, EffRx, Alfa-Sigma, Chiesi, Giuseppe Girasole: None declared, Chiara Craviotto: None declared, Paola Diana: None declared, Antonia Locaputo: None declared, Tiziana Caviglia: None declared, Lacramioara Luca: None declared, Gerolamo Bianchi Consultant of: Amgen, Janssen, Merck Sharp & Dohme, Novartis, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Chiesi, Eli Lilly, GSK, Janssen, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Genzyme, Servier, UCB

Background:The monitoring of bone mineral density (BMD) is a key aspect for patients undergoing pharmacological treatments that might cause BMD changes at non-physiological rates. At present, the short-term follow-up of patients under treatment in terms of BMD change with time remains an unmet clinical need, since the current techniques, including the gold standard dual X-ray absorptiometry (DXA), require at least 1 year between two consecutive measurements [1]. Therefore, an effective strategy for the assessment of BMD should guarantee high accuracy, precision and repeatability of the measurements.Objectives:The aim is to assess the influence of the variation 1) in patient position, 2) operator (both intra- and inter-) and 3) device on the REMS performance at lumbar spine and femoral neck.Methods:210 women were enrolled, divided in 7 groups of 30-patient each for the assessment of the parameters of interest, i.e. inter-device, intra- and inter-operator repeatability for lumbar spine scans and inter-patient position, inter-device, intra- and inter-operator repeatability for femoral neck scans.All patients underwent 2 REMS scans at lumbar spine or femoral neck, performed by the same operator or by 2 different operators or by the same operator using 2 different devices or in different patient position (i.e. supine without constraints or with a constrained 25°-rotation of the leg). The percentage coefficient of variation (CV%) with 95% confidence interval and least significant change for a 95% confidence level (LSC) have been calculated.Results:For lumbar spine, intra-operator repeatability resulted in CV%=0.37% (95%CI: 0.26%-0.48%), with LSC=1.02%, inter-operator repeatability resulted in CV%=0.55% (95% CI: 0.42%-0.68%), with LSC=1.52%, inter-device repeatability resulted in CV%=0.53% (95% CI: 0.40%-0.66%), with LSC=1.47%.For femoral neck, intra-operator repeatability resulted in CV%=0.33% (95%CI: 0.23%-0.43%), with LSC=0.91%, inter-operator repeatability resulted in CV%=0.47% (95% CI: 0.35%-0.59%), with LSC=1.30%, inter-device repeatability resulted in CV%=0.42% (95% CI: 0.30%-0.51%), with LSC=1.16%, inter-patient position repeatability resulted in CV%=0.24% (95% CI: 0.18%-0.30%), with LSC=0.66%.Conclusion:REMS densitometry is highly precise for both anatomical sites, showing high performance in repeatability. These results suggest that REMS might be a suitable technology for short-term monitoring. Moreover, thanks to its ionizing radiation-free approach, it might be applied for population mass investigations and prevention programs also in paediatric patients and pregnant women.References:Note:Carla Caffarelli, Giovanni Adami§, Giovanni Arioli§, Gerolamo Bianchi§, Maria Luisa Brandi§, Sergio Casciaro§, Luisella Cianferotti§, Delia Ciardo§, Francesco Conversano§, Davide Gatti§, Giuseppe Girasole§, Monica Manfredini§, Maurizio Muratore§, Paola Pisani§, Eugenio Quarta§, Laura Quarta§, Stefano Gonnelli§Equal contributors listed in alphabetical orderDisclosure of Interests:Carla Caffarelli: None declared, Giovanni Adami: None declared, Giovanni Arioli *: None declared, Gerolamo Bianchi Grant/research support from: Celgene, Consultant of: Amgen, Janssen, Merck Sharp & Dohme, Novartis, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Chiesi, Eli Lilly, GSK, Janssen, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Genzyme, Servier, UCB, Maria Luisa Brandi: None declared, Sergio Casciaro: None declared, Luisella Cianferotti: None declared, Delia Ciardo: None declared, Francesco Conversano: None declared, Davide Gatti Speakers bureau: Davide Gatti reports personal fees from Abiogen, Amgen, Janssen-Cilag, Mundipharma, outside the submitted work., Giuseppe Girasole: None declared, Monica Manfedini: None declared, Maurizio Muratore: None declared, Paola Pisani: None declared, Eugenio Quarta: None declared, Laura Quarta: None declared, Stefano Gonnelli: None declared

Background:Radiofrequency Echographic Multi Spectrometry (REMS) is the first clinically available approach for direct non-ionizing measurement of bone mineral density (BMD) at lumbar spine (LS) and femoral neck (FN). Available scientific evidences describe BMD estimated by REMS as an accurate parameter for the diagnosis of osteoporosis [1].Objectives:To investigate the effectiveness of the T-score values provided by REMS scans at FN and LS in the identification of frail patients at risk for osteoporotic fractures and to compare the performance of REMS with the dual-energy X-ray absorptiometry (DXA) one.Methods:The patients underwent DXA and REMS scans at FN and at LS. Five clusters of fractures occurred during a median 3.5-year follow-up were identified whether involving the upper limb (forearm, elbow, humerus, wrist, hand), lower limb (tibia, ankle, metatarsus), thorax (shoulder blade, shoulder, rib), hip (femur or pelvis bones), or vertebrae. The ability of REMS and DXA T-score values to assess the incidence and site of fractures was evaluated through an analysis of covariance.Results:Seven hundred twenty-one Caucasian women were enrolled. Ninety-five fractures occurred, in particular 41 at upper limb, 16 at hip, 15 at thorax, 14 at lower limb, 9 at vertebrae. Patients characteristics are reported in table. Considering subcategories of fractured patients, there were not statistically significant differences for age, height, weight and BMI.In the analysis of covariance including age and BMI as covariates, the difference of T-score values between fractured and non-fractured patients is statistically significant for REMS and DXA at both sites.Lower FN T-score values were found for patients with fractures at hip or vertebra with respect to non-fractured patients both for REMS and DXA (pConclusion:REMS T-score measured at axial sites is an effective parameter for identification of patients at the risk of incident fragility fractures, in particular occurring at hip, vertebra or upper limb in a population-based sample of female subjects.References:[1]Diez-Perez, Aging Clin Exp Res 2019;31(10):1375–89Table 1.Baseline patient characteristics, expressed as median (25th– 75thpercentiles).Patients with incident fragility fracturePatients without incident fragility fracturep-value*Age [years]70 (60-73)59 (54-64)Height [cm]159 (155-164)160 (156-165)0.08Weight [kg]63 (58-70)62 (57-69)0.42BMI [kg/m2]24.97 (23.13-26.86)24.24 (22.22-26.59)0.04FN REMS T-score-2.3 (-2.8 – -1.7)-1.8 (-2.3 – -1.1)FN DXA T-score-2.2 (-2.8 – -1.6)-1.7 (-2.3 – -1.1)LS REMS T-score-3.0 (-3.5 – -2.0)-2.0 (-2.8 – -1.0)LS DXA T-score-2.8 (-3.4 – -1.8)-1.9 (-2.7 – -1.0)* Wilcoxon ranksum testFigure.Boxplot of the distribution of T-score values estimated REMS and DXA at FN and LS among patients without incident fragility fracture and patients with incident fragility fractures at different sites.Note:G. Adami, G. Arioli§, G. Bianchi§, M.L. Brandi§, C. Caffarelli§, L. Cianferotti§, G. Girasole§, S. Gonnelli§, M. Manfredini§, M. Muratore§, E. Quarta§, L. Quarta§, D. Gatti§ equal contributors listed in alphabetical order.Disclosure of Interests:Giovanni Adami: None declared, Giovanni Arioli *: None declared, Gerolamo Bianchi Grant/research support from: Celgene, Consultant of: Amgen, Janssen, Merck Sharp & Dohme, Novartis, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Chiesi, Eli Lilly, GSK, Janssen, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi Genzyme, Servier, UCB, Maria Luisa Brandi: None declared, Carla Caffarelli: None declared, Luisella Cianferotti: None declared, Giuseppe Girasole: None declared, Stefano Gonnelli: None declared, Monica Manfedini: None declared, Maurizio Muratore: None declared, Eugenio Quarta: None declared, Laura Quarta: None declared, Davide Gatti Speakers bureau: Davide Gatti reports personal fees from Abiogen, Amgen, Janssen-Cilag, Mundipharma, outside the submitted work.

Background Radiofrequency Echographic Multi Spectrometry (REMS) is an innovative densitometric technique able to automatically provide BMD values, which it has been shown to highly correlate with BMD obtained by DXA.1 Objectives To evaluate the accuracy of REMS measurements in postmenopausal women’s femoral neck health assessment versus DXA results in a multicenter clinical study. Methods In seven Italian referral centres for osteoporosis management, 1659 postmenopausal women (51–70 years old) were enrolled. Both DXA and REMS examinations were performed on each patient at femoral neck, in the strictest adherence to the corresponding guidelines. After excluding the scans affecting by errors, the REMS diagnostic accuracy was evaluated by assessing sensibility and specificity in the discrimination between “osteoporotic” and “healthy” patients; the degree of correlation between DXA-BMD and REMS-BMD was quantified through Pearson’s correlation coefficient (r) evaluation. In addition, the agreement between DXA-BMD and REMS-BMD was measured calculating the root mean square error (RMSE). Results A strong correlation (r=0.94, p Conclusions Thanks to its high capability to identify osteoporotic patients, and the strong correlation with DXA parameters, REMS has been shown to be an accurate non-ionising approach to detect osteoporosis at femoral neck. Reference [1] Casciaro S, et al. UMB2016;42:1337–56. Disclosure of Interest None declared

Background: Methotrexate (MTX) remains the cornerstone of the treatment of rheumatoid arthritis (RA). However, MTX is frequently underutilized in terms of suboptimal dosage, insufficient duration of treatment, and route of administration. Objectives: To evaluate the tolerability and the safety of higher-dose, subcutaneous methotrexate (MTX) in patients with rheumatoid arthritis (RA). Methods: The STEp-down MEthotrexate Therapy in Rheumatoid Arthritis (STEMETRA) was an open-label, monocentric, pilot study of 12-week duration. The protocol treatment schedule consisted of subcutaneous (SC) MTX 50 mg/week for 4 consecutive weeks, followed by 25 mg/week for 4 weeks and then 15 mg/week for 4 weeks. All patients received oral supplementation of folinic acid (leucovorin) 12 mg, administered twelve hours after the injection of SC-MTX. Results: Ten patients (7 females and 3 males), with a mean age of 58.1 (±12.1), were enrolled in this study; one of them withdrew consent before taking study drug. Therefore, nine patients were treated. MTX was well tolerated: a total of 5 adverse events (AEs) occurred in 4 patients, none of which was severe. AEs consisted in: transient elevation of alanine aminotransferase ( 1.2 from baseline. Conclusions: In this study, short-term higher dose MTX was well tolerated. Based on the tolerability observed in this preliminary study, a randomized controlled study of higher dose induction therapy versus traditional dosing will be conducted. Disclosure of Interest: None declared

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.

OBJECTIVES: To compare the effects on parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25(OH)D) of two dosing regimens of cholecalciferol in women with secondary hyperparathyroidism (sHPTH) and hypovitaminosis D and to investigate variables affecting 25(OH)D response to cholecalciferol. DESIGN: Randomized-controlled trial with 6-month follow-up. SETTING: Two osteoporosis centers in northern Italy. PARTICIPANTS: Sixty community-dwelling women aged 65 and older with sHPTH and hypovitaminosis D, creatinine clearance greater than 65 mL/min and without diseases or drugs known to influence bone and vitamin D metabolism. INTERVENTION: Cholecalciferol 300,000 IU every 3 months, once at baseline and once at 3 months (intermittent D3 group) or cholecalciferol 1,000 IU/day (daily D3 group). MEASUREMENTS: Serum PTH, 25(OH)D, calcium, bone-specific alkaline phosphatase, β-C-terminal telopeptide of type I collagen, phosphate, 24-hour urinary calcium excretion. RESULTS: The two groups had similar baseline characteristics. All participants had vitamin D deficiency [25(OH)D

With the aging of the population worldwide, osteoporotic fractures are becoming a serious problem in the Western world. Male osteoporosis is associated with a significant burden in terms of morbidity, mortality and economic cost. Although less frequent in men than women, osteoporosis is a relatively common problem. The increasing prevalence and awareness of osteoporosis and fractures in men, together with the development of easy-to-measure tools and risk indicators to optimize case-finding strategies, has increased the demand for a better understanding of the pathogenesis of this condition and, in turn, for appropriate and effective treatments. This article reports recent findings regarding the pathophysiology and treatment of male osteoporosis that have been discussed by some of the most outstanding scientists in this field at a meeting held in Santa Margherita, Italy, on 6–8 November 2008.

BACKGROUND The role of bisphosphonates (BPs) in the management of patients with hypercalciuria (HC) associated with osteoporosis is still uncertain. The aim of the study was to evaluate the effect of alendronate and indapamide alone or in combination on bone mineral density (BMD) and 24-h urinary calcium excretion (24-CaU) in post-menopausal women with HC and low BMD. METHODS A total of 77 post-menopausal women with HC (24-CaU > 4 mg/kg/day) and low BMD [T-score < -2.0 at lumbar spine (LS), femoral neck (FN) or total hip (TH)] from two centres of Northern Italy were randomized to receive indapamide 2.5 mg daily alone (24 patients, IND group), alendronate 70 mg weekly alone (27 patients, ALN group) or the combination therapy (26 patients, ALN + IND group). Throughout the study, all subjects received daily calcium supplements, depending on their dietary intake, to maintain a daily input of 1000 mg. Patients were instructed to increase water intake up to 2000 mL daily. The percentage and absolute changes of BMD at LS, FN and TH, and the variation of 24-CaU from baseline at 1 year were the primary outcomes. Serum calcium, phosphate, parathyroid hormone and bone alkaline phosphatase were also measured. RESULTS Overall 67 women completed the study and were included in the final analysis. Patients in the three groups were similar with regard to baseline characteristics. BMD did not significantly change from baseline after 1 year of treatment with indapamide (LS: +1 +/- 3.1%; FN: -0.3 +/- 3.5%; TH: -0.4 +/- 3.1%), while it showed a significant increase from baseline in the other two groups (ALN; LS: +5.8 +/- 4.2%, P < 0.001; FN: +3.9 +/- 7.9%, P = 0.018; TH: +2 +/- 3.6%, P = 0.006) (ALN + IND; LS: +8.2 +/- 5.3%, P < 0.001; FN: +4.9 +/- 6.7%, P = 0.007; TH: +2.9 +/- 4.2%, P = 0.004). Patients in the combination group showed a significantly higher increase of BMD at LS compared to ALN (P = 0.04). After 1 year, 24-CaU values significantly decreased from baseline in all groups (IND, 239 +/- 78 versus 364 +/- 44, P < 0.001) (ALN, 279 +/- 68 versus 379 +/- 79, P < 0.001) (ALN + IND, 191 +/- 68 versus 390 +/- 55, P < 0.001). The mean percentage decrease of 24-CaU in ALN + IND group (-50%) was significantly greater compared to ALN (-24%, P < 0.001) and IND (-35%, P = 0.012). CONCLUSIONS These results show a benefit, in terms of BMD improvement and 24-CaU reduction, associated with BPs' therapy in combination with indapamide in HC associated with osteoporosis. The combination therapy demonstrated a reduction of 24-CaU and an increase in LS BMD superior to that observed with alendronate alone. Our results support a new potential approach with BPs associated with thiazide diuretics or indapamide in the management of post-menopausal women with HC and associated bone loss. Studies on the larger sample size are needed to demonstrate the efficacy on the fracture outcome.

OBJECTIVES: To determine whether secondary hyperparathyroidism (HPTH) due to hypovitaminosis D affects bone mineral density (BMD) response to alendronate (ALN) in elderly women with osteoporosis. DESIGN: Randomized, controlled trial with 1-year follow-up. SETTING: Two osteoporosis centers in northern Italy. PARTICIPANTS: Community-dwelling women aged 60 and older with a BMD T-score below -2.5 and secondary HPTH with vitamin D insufficiency. INTERVENTION: One hundred twenty subjects were randomly assigned to receive ALN 70 mg once a week alone or ALN 70 mg once a week plus calcitriol (1,25D3) 0.5 microg daily. MEASUREMENTS: BMD measured using dual-energy x-ray absorptiometry at the lumbar spine (L1-L4), femoral neck, and total hip and serum levels of intact PTH at baseline and 12 months. RESULTS: After 1 year, BMD of the lumbar spine, femoral neck, and total hip significantly increased from baseline in both groups (P

Much work has been directed at establishing the impact of osteoporosis and related fragility fractures in rheumatic diseases. Several cross-sectional studies reported that disability and reduced motility that are due to functional impairment are among the most important determinants of bone loss in different rheumatic diseases. At the same time, longitudinal studies have confirmed the detrimental effect of uncontrolled disease activity on bone density. In this perspective, the suppression of inflammation probably remains the main concern when considering treatment options. Besides these variables, pharmacologic agents that are used commonly in the treatment of these conditions probably have an adjunctive effect on bone loss in rheumatic patients. Large epidemiologic studies have demonstrated clearly that patients who have RA, SLE, or AS are at an increased risk for fragility fractures. Further studies are required to investigate the effective impact of osteoporosis and fragility fractures in other rheumatic diseases, and to define the relationship between OA and osteoporosis. A better appreciation of the impact and mechanisms of osteoporosis in rheumatic diseases by rheumatologists represents a clinical challenge; however, a greater understanding of this frequent complication will improve the quality of health care and the lives of patients who have rheumatic diseases.

OBJECTIVE Interleukin-6 (IL-6) seems to be a key mediator of the increased bone loss that follows loss of ovarian function. Based on this and on evidence that oestrogen deficiency may also increase cell sensitivity to IL-6, we studied the effects of ovariectomy and of oestrogen replacement therapy on the serum levels of IL-6 and of soluble IL-6 receptor (sIL-6R) in vivo. DESIGN AND PATIENTS Thirty-seven fertile women undergoing surgery for benign uterine diseases were divided into 3 groups and monitored for 12 months: hysterectomized women (n = 9), ovariectomized untreated women (n = 12) and ovariectomized women starting treatment with transdermal estradiol (E2, 50 μg/d) 1 month after surgery (n = 16). RESULTS Hysterectomy alone caused no significant changes of sIL6R whereas serum levels of sIL-6R rose progressively after ovariectomy (mean ± SEM: 31 ± 9% and 38 ± 7% over baseline, at 6 and 12 months, respectively; P

Alcohol abuse is commonly associated with reduced bone mass and osteoporosis as a consequence of both systemic and direct cellular effects. To clarify some of the pathways by which alcohol exerts its actions directly on bone cells, we investigated the formation of early osteoblast progenitors (colony-forming units for fibroblasts; CFU-F) in long-term murine and human bone marrow cultures exposed to ethanol and to its main metabolite, acetaldehyde. In murine bone marrow cultures, obtained from Swiss female mice, ethanol inhibited CFU-F formation (maximal reduction +/- SEM: 50 +/- 2%; p0.01) at concentrations ranging from 0.04% to 0.6% that are similar to those reached in vivo in alcoholics. Acetaldehyde strongly reduced CFU-F formation at concentrations of 0.004% and 0.02%, and completely abolished it at the dose of 0.06%. Similarly, ethanol (at concentrationsor =0.02%) and acetaldehyde (from 0.004% to 0.06%) significantly decreased the number of CFU-F in human bone marrow cultures; the mean reduction observed with ethanol was 63 +/- 12% (p0.05), whereas acetaldehyde completely prevented CFU-F formation at the concentration of 0.06%. These in vitro observations were confirmed by the in vivo findings that the CFU-F formation in bone marrow cultures from nine young, chronic, noncirrhotic alcoholics was significantly reduced (70 +/- 15%), compared with seven age-matched normal subjects (p0.01). In addition, acetaldehyde inhibited cell proliferation in human osteoblastic cells (MG-63 and HOBIT cell lines), whereas ethanol reduced proliferation only in MG-63 cells. Our results indicate that ethanol and acetaldehyde may directly inhibit the osteoblastogenic potential of the bone marrow, and this effect may contribute to the decreased bone formation observed in alcoholics.

Both estrogen and androgen exert their antiosteoporotic effects, at least in part, by inhibiting IL-6 production, thereby suppressing osteoclastogenesis. Several observations, however, suggest that besides increased IL-6 production, sensitivity of the osteoclastogenic process to this cytokine is altered after ovariectomy. Based on this and evidence that the ligand-binding subunit of the IL-6 receptor (gp80) is a limiting factor for the actions of IL-6 on bone, we hypothesized that sex steroids regulate expression of the IL-6 receptor as well. We report that 17beta-estradiol or dihydrotestosterone in vitro decreased the abundance of the gp80 mRNA as well as the mRNA of the signal-transducing subunit of the IL-6 receptor (gp130) in cells of the bone marrow stromal/osteoblastic lineage, and also decreased gp130 protein levels. These effects did not require new protein synthesis. In contrast to sex steroids, parathyroid hormone stimulated gp130 expression; this effect was opposed by sex steroids. Consistent with these findings, ovariectomy in mice caused an increase in expression of gp80, gp130, and IL-6 mRNAs in ex vivo bone marrow cell cultures as determined by quantitative reverse transcription (RT)-PCR, and confirmed on an individual cell basis using in situ RT-PCR. The demonstration of increased expression of the IL-6 receptor after loss of sex steroids provides an explanation for why IL-6 is important for skeletal homeostasis in the sex steroid-deficient, but not replete, state.

Bisphosphonates are known to be potent inhibitors of osteoclast activity and their only clinically relevant effect in the short-term is the selective inhibition of bone resorption. The purpose of this study was to compare the response to the intravenous administration of two bisphosphonates, clodronate and alendronate, of several biochemical markers of bone resorption, including tartrate-resistant acid phosphatase (TRAP) and cross-linked carboxyterminal telopeptide of collagen I (ICTP) in serum and hydroxyproline (OHP), free pyridinium cross-links (Pyr), and crosslinked N-telopeptides of collagen I (NTx) in urine. The study was carried out on 11 osteoporotic and 12 Pagetic subjects of both sexes, treated with clodronate (600 mg/day for 2 days) or alendronate (5 mg/day for 2 days), and monitored for 28 days after bisphosphonate administration. All the urinary markers of bone resorption showed a prompt decline after bisphosphonates, with maximum reductions after 7–14 days: Pyr decreased by 43%±9% and 42%±22% (mean ± SD), respectively in osteoporotic and pagetic subjects, OHP by 51%±14% and 51%±20%, and NTx by 55%±15% and 65%±26%. In the osteoporotic group, the urinary markers began to increase again at 30 days, though still remaining well below the basal level, whereas in the pagetic group, the excretion of all markers remained depressed until the end of the observation period. The reduction of NTx was significantly greater than that of Pyr and OHP in pagetic patients (P

The aim of the study was to estimate the absolute risk of fracture in a sample of postmenopausal women with the Italian version of FRAX®, using femoral neck bone mineral density (BMD) and 3 internationally validated clinical risk factors (CRFs) (history of fragility fracture, family history of hip fracture, current smoking). We retrospectively studied 9586 women (mean age 64.1 yr) examined in three osteoporosis centers from Northern Italy over two years (2001-2002). The risk of major osteoporotic (clinical spine, hip, forearm and humerus) and hip fractures was estimated using the online version of the FRAX algorithm adapted for Italy. The median 10-year risk was 7.5% for osteoporotic fracture and 1.7% for hip fracture. 25% of subjects had a 10-year risk ≥ 12.1% for osteoporotic fracture and ≥ 4.1% for hip fracture. The median 10-year risk of fracture increased with the number of prevalent CRFs. For major osteoporotic fractures risk rose from 6.3% to 10.9%, 21.4% and 40.9% with 1, 2 and 3 prevalent CRFs, respectively. For hip fractures the corresponding figures were: 1.3%, 2.7%, 7.0% and 21.9%, respectively. However, it must be emphasized that in 2 out of 3 women, none of the CRFs examined was present and the assessment of risk was limited to age and BMD. Our data provide the first description of the effect of the combination of BMD, age and CRFs on fracture risk stratification in a large sample of Italian postmenopausal women using FRAX®. The results are a useful starting point to define criteria for the application of FRAX® in clinical practice in Italy.

To compare the effects on parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25(OH)D) of two dosing regimens of cholecalciferol in women with secondary hyperparathyroidism (sHPTH) and hypovitaminosis D and to investigate variables affecting 25(OH)D response to cholecalciferol.Randomized-controlled trial with 6-month follow-up.Two osteoporosis centers in northern Italy.Sixty community-dwelling women aged 65 and older with sHPTH and hypovitaminosis D, creatinine clearance greater than 65 mL/min and without diseases or drugs known to influence bone and vitamin D metabolism.Cholecalciferol 300,000 IU every 3 months, once at baseline and once at 3 months (intermittent D(3) group) or cholecalciferol 1,000 IU/day (daily D(3) group).Serum PTH, 25(OH)D, calcium, bone-specific alkaline phosphatase, β-C-terminal telopeptide of type I collagen, phosphate, 24-hour urinary calcium excretion.The two groups had similar baseline characteristics. All participants had vitamin D deficiency [25(OH)D20 ng/mL)], and 36 subjects (60%) had severe deficiency (10 ng/mL), with no difference between the groups (severe deficiency: intermittent D(3) group, n=18; daily D(3) group, n=18). After 3 and 6 months, both groups had a significant increase in 25(OH)D and a reduction in PTH. Mean absolute increase ± standard deviation of 25(OH)D at 6 months was higher in the intermittent D(3) group (22.7±11.8 ng/mL) than in the daily D(3) group (13.7±6.7 ng/mL, P.001), with a higher proportion of participants in the intermittent D(3) group reaching desirable serum concentration of 25(OH)D≥30 ng/mL (55% in the intermittent D(3) group vs 20% in the daily D(3) group, P.001). Mean percentage decrease of PTH in the two groups was comparable, and at 6 months, a similar proportion of participants reached normal PTH values. 25(OH)D response to cholecalciferol showed a wide variability. In a logistic regression analysis, body mass index and type of treatment appeared to be significantly associated with normalization of 25(OH)D values.Cholecalciferol 300,000 IU every 3 months was more effective than 1,000 IU daily in correcting vitamin D deficiency, although the two groups achieved similar effects on PTH at 6 months. Only 55% of the higher-dose intermittent group reached desirable concentrations of 25(OH)D, suggesting that yet-higher doses will be required for adequate vitamin D repletion.

Idiopathic hypercalciuria (IHC) is defined as a 24-hour urinary calcium excretion that exceeds 4 mg/kg/day, regardless of gender and in absence of systemic diseases or pharmacological treatments that may cause normocalcemic hypercalciuria (eg sarcoidosis, normocalcemic primary hyperparathyroidism, vitamin D intoxication, hyperthyroidism). Patients with IHC and nephrolithiasis often present increased bone turnover, decreased bone mineral density (BMD) and increased susceptibility to fragility fractures. Although the pathogenesis of IHC seems complex and multifactorial, recent evidences suggest that cells involved in bone resorption may play a critical role in the chain of events leading to the excessive urinary calcium excretion. Therefore, it has been proposed that bisphosphonates, potent inhibitors of bone resorption, may have beneficial effects in hypercalciuric patients with low BMD. This manuscript reports recent findings regarding the role of bone tissue in the pathogenesis of IHC, and supports the use of bisphosphonates in such conditions. It also reviews the literature on the effects of bisphosphonates in subjects with osteoporosis-associated IHC.

Background and aims: In advanced age, the influence of vertebral fractures on quality of life extends well beyond the usual sequelae of osteoporosis. In order to intercept older subjects’ distress associated with the clinical, functional, social and psychological consequences of the disease, we developed and validated a multidimensional instrument (the triple-Q questionnaire) tailored to older women with osteoporotic fractures. We also examined specific aspects of the questionnaire correlated with bone mineral density. Methods: 100 osteoporotic women with vertebral fractures and 100 controls aged >65 years, underwent a thorough examination, which also included X-ray of the thoraco-lumbar spine, hip densitometry, the triple-Q questionnaire, and five referral instruments evaluating function, cognition, perception of general health, mood and pain. Results: The questionnaire was repeatable and able to discriminate between older women with and without vertebral fractures. There was a strong association between referral instrument scores and the corresponding single domain score of the questionnaire. Femoral BMD was also associated with scores indicating fear of falling, fear of fracture, and pain. Conclusions: The questionnaire intercepted the influence of osteoporosis on the quality of life of elderly women with vertebral fractures. Subjects who suffered from severe pain and were more fearful of falling were most likely to be severely osteoporotic.

The effect of 17 beta-estradiol on interleukin-6 (IL-6) synthesis was examined in murine bone marrow-derived stromal cell lines, normal human bone-derived cells, and nontransformed osteoblast cell lines from mice and rats. In all these cell types IL-6 production was stimulated as much as 10,000-fold in response to the combination of recombinant interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha). Addition of 17 beta-estradiol in the cultures exerted a dose-dependent inhibition of IL-1-, TNF-, and IL-1 + TNF-induced production of bioassayable IL-6. Testosterone and progesterone (but not 17 alpha-estradiol) also inhibited IL-6, but their effective concentrations were two orders of magnitude higher than 17 beta-estradiol. 17 beta-estradiol also decreased the levels of the IL-6 mRNA. In addition, estradiol inhibited both TNF-induced IL-6 production and osteoclast development in primary bone cell cultures derived from neonatal murine calvaria. The TNF-stimulated osteoclast development was also suppressed by a neutralizing monoclonal anti-IL-6 antibody. This in vitro evidence suggests, for the first time, a mechanistic paradigm by which estrogens might exert at least part of their antiresorptive influence on the skeleton.

L’osteoporosi e definita, per entrambi i sessi, come una malattia sistemica dello scheletro caratterizzata da una riduzione della massa ossea e dalla compromissione della microarchitettura scheletrica tali da predisporre a un aumentato rischio di frattura [1]. La frattura da fragilita rappresenta quindi la principale conseguenza clinica dell’osteoporosi.

The aim of the study was to investigate the metabolic clearance rate (MCR) and the secretion rate (SR) of calcitonin (CT) in elderly men and women (mean age +/- SE: 75 +/- 3 and 78 +/- 3 yr, respectively). The basal levels of CT were higher in men than in women (9.6 +/- 3.2 vs 6.0 +/- 1.5 pg/ml; p less than 0.05). The MCR was not significantly different between sexes (905 +/- 54.2 vs 810 +/- 165.1 l/day). In contrast, CT SR was significantly higher in male subjects compared to women (8.7 +/- 3.1 vs 4.8 +/- 1.5 micrograms/day; p less than 0.05). These findings suggest that only a few units of CT are secreted daily by elderly subjects and that the lower basal values of the hormone in women are probably the result of a lower production rate.

The aim of this study was to evaluate beta-endorphin, ACTH, and cortisol plasma levels during metyrapone administration in man after chronic opioid receptor stimulation. Metyrapone (750 mg every 4 hr for 6 doses) was administered to ten male heroin addicts, who had been on a maintenance therapy with methadone for at least 6 months and to ten healthy sex- and age-matched volunteers. Before metyrapone administration the basal levels of cortisol and ACTH were significantly decreased in addicts as compared to normal controls, while plasma beta-endorphin was not different. The response of beta-endorphin and ACTH to metyrapone administration was significantly blunted in addicts (p less than 0.01). These results suggest that the chronic stimulation of opiate receptors can impair the function of the anterior pituitary gland.

Osteoporosis is currently defined on the basis of the T-score by dual-energy X-ray absorptiometry (DXA). Despite its limitations, this definition is applied worldwide. However, the normal values provided by manufacturers may not be fully representative of specific local populations. So far, there are no normative data in the Italian population using Hologic densitometers. The Densitometric Italian Normative Study (DINS) is an ongoing multi-center study that aims to establish reference values for bone densitometry with dual-energy X-ray absorptiometry (DXA) in the male and female Italian population. In this paper we report the results of the lumbar vertebrae (L2-L4) and proximal femur in 1,622 women aged 20-79 years. Bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry (DXA) on Hologic bone densitometers (Hologic, Waltham, Mass.). Most of the subjects were examined with a QDR 4500. The BMD of the lumbar vertebrae was virtually constant between 20 and 49 years (test for trend: P=0.66); the BMD values between 20-45 in premenopausal women (mean 1.036; SD 0.109 g/cm(2)) were thus defined as the peak bone mass values, significantly lower compared to the Hologic reference curve (mean 1.079, SD 0.11 g/cm(2)). The mean BMD values of the femoral neck were virtually identical to those of the NHANES study in the first 3 decades; after the age of 50 the BMD values were slightly greater than those of the NHANES subject. The subject classification according to the WHO criteria was similar using the DINS and NHANES reference values for the femur; for the spine, the Hologic reference values classified a larger proportion of women as osteoporotic (21 vs. 16%) or osteopenic (42 vs. 38%) compared to DINS.

Growing evidence suggests that interleukin-6 (IL-6) may play a pathogenetic role in postmenopausal bone loss and in other age-related pathological conditions. In this study, we have examined the age-related changes in the serum levels of IL-6 and the soluble receptors that modulate its biological activity--soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130)--in 220 women (from 25 to 104yr old), including 22 centenarians. Serum IL-6 rose exponentially with age (r=0.74, p

Interleukin-6 (IL-6) seems to be a key mediator of the increased bone loss that follows loss of ovarian function. Based on this and on evidence that oestrogen deficiency may also increase cell sensitivity to IL-6, we studied the effects of ovariectomy and of oestrogen replacement therapy on the serum levels of IL-6 and of soluble IL-6 receptor (sIL-6R) in vivo.Thirty-seven fertile women undergoing surgery for benign uterine diseases were divided into 3 groups and monitored for 12 months: hysterectomized women (n = 9), ovariectomized untreated women (n = 12) and ovariectomized women starting treatment with transdermal estradiol (E2, 50 microg/d) 1 month after surgery (n = 16).Hysterectomy alone caused no significant changes of sIL6R whereas serum levels of sIL-6R rose progressively after ovariectomy (mean +/- SEM: 31 +/- 9% and 38 +/- 7% over baseline, at 6 and 12 months, respectively; P0.01). Oestrogen replacement therapy prevented the increase of sIL6R over a 1-year period. A similar pattern was also found for serum IL-6 but the changes did not reach statistical significance. In ovariectomized (OVX) women there were significant correlations between serum sIL-6R levels and FSH (r = 0.59; P0. 01), oestradiol (r = - 0.43; P0.01), testosterone (r = - 0.41; P0.05), osteocalcin (r = 0.42; P0.05) and bone alkaline phosphatase (r = 0.44; P0.05). To examine whether oestrogen directly regulates sIL-6R secretion by bone cells, we studied in vitro the basal and phorbol ester (PMA) stimulated release of sIL-6R in a human osteoblastic cell-line (MG-63) and in a tumour-derived osteoclastic cell line (GCT-51). Osteoblastic (but not osteoclastic) cells spontaneously produced considerable amounts of sIL-6R and the protein kinase-C activator PMA (10-8 M) increased the release of sIL-6R by osteoblasts more than 3-fold. More strikingly, 17beta E2 (but not 17alpha) significantly inhibited both the spontaneous- and PMA-induced release of sIL-6R by osteoblastic cells (P0.05).These results indicate that oestrogen loss causes alterations of the IL-6 system, and that sIL-6R is under the direct inhibitory control of oestrogens both in vivo and in vitro.

It has been recently shown that bisphosphonates may affect bone resorption either directly on osteoclast activity or through the mediation of osteoblasts activity. In this experimental study the potential effects of etidronate and alendronate on osteoblastic bone formation are investigated.The number of fibroblastic colony forming units (CFU-F) and mineralized nodules (CFU-OB) in murine and human bone marrow cultures, assessed. In addition, the basic-FGF production by human osteoblastic cells MG-63 measured.In murine bone marrow cultures etidronate and alendronate stimulate CFU-F formation with a mean increases vs control of 106 +/- 17% at 10(-5) M and 78 +/- 5% at 10(-7) M respectively (p0.001). The formation of bone nodules is inhibited by bisphosphonates at high concentrations (10(-6) M) and stimulated at lower concentrations (from 10(-7) M to 10(-9) M for etidronate and from 10(-7) M to 10(-10) M for alendronate; p0.001). Similarly, in human bone marrow cultures alendronate increases CFU-F formation with a maximal effect at 10(-10) M (+161 +/- 12% vs control; p0.01) and the formation of CFU-OB with a maximal effect at 10(-10) M (+133 +/- 34%; p0.001). Finally, etidronate (from 10(-9) to 10(-11) M) and alendronate (from 10(-9) to 10(-12) M) stimulate the b-FGF production by human osteoblastic cells (p0.01).In line with previous histomorphometric and clinical observations, the results obtained indicate that bisphosphonates directly affect osteoblastic cells with a positive effect on bone formation, probably via the stimulation of growth factors.

Recent in vitro findings suggest that bisphosphonates, potent inhibitors of osteoclastic bone resorption, may also have a direct action on osteoblasts. The purpose of this study was to search for potential effects of etidronate and alendronate on the formation of early and late osteoblastic cell precursors by measuring the number of colony-forming units for fibroblasts (CFU-F) and colony-forming units for osteoblasts (CFU-OB) in murine and human bone marrow cultures. In murine marrow cultures, etidronate (10(-5) to 10(-9) mol/L) significantly stimulated the formation of CFU-F with a maximal effect at 10(-5) mol/L (mean increase over control values+/-SD: 106+/-17%;p0.001), whereas alendronate had a biphasic effect, being stimulatory at concentrations below 10(-7) mol/L (78+/-5%; p0.001), and inhibitory at higher doses. The formation of CFU-OB was also inhibited by both bisphosphonates at the highest concentrations (10(-5) mol/L and 10(-6) mol/L), but it was significantly stimulated at lower concentrations (from 10(-7) to 10(-9) mol/L for etidronate and 10(-7) to 10(-10) mol/I, for alendronate; p0.001). In human bone marrow cultures, alendronate (10(-8) to 10-(12) mol/L) increased CFU-F formation with a maximal effect at 10(-10) mol/L (161+/-12 %; p0.01). CFU-OB formation, observed only in the presence of dexamethasone (10(-8) mol/L), was markedly stimulated by alendronate at the above concentrations with a maximal increase at 10(-10) mol/L (133+/-34%; p0.001). The in vivo short-term effects of bisphosphonates on the formation of early osteoblast precursors were also studied in bone marrow cultures from young female mice treated with weekly subcutaneous injections of etidronate (0.3, 3, and 30 mg/kg) or alendronate (0.3, 3, and 30 microg/kg) and from aging female mice treated with the two lowest doses of both drugs. After 1 month of treatment, etidronate (0.3 and 3 mg/kg) and alendronate (0.3 and 3 microg/kg) significantly increased the number of CFU-F colonies in the bone marrow from young and old animals, whereas the highest dose of both drugs had no effect in young mice. Our results, together with previously reported observations of bone-forming effects in osteoporosis, suggest that bisphosphonates may have, in vivo, a potentially relevant influence on cells of the osteoblastic lineage, distinct from their inhibitory action on osteoclasts.

Since bisphosphonates prevent bone loss in osteoporosis and rheumatoid arthritis, diseases in which the osteoclastogenic and inflammatory cytokine interleukin-6 plays a pathophysiologic role, we studied whether these drugs regulate the production of this cytokine by osteoblasts. Spontaneous and IL-1 + TNF-alpha stimulated IL-6 release was measured in supernatants of cultures of human osteoblastic osteosarcoma cells MG-63, pretreated for 4 hours with different doses of etidronate, clodronate or alendronate using a specific bioassay. Etidronate [from 10(-4) to 10(-8) M] or alendronate [from 10(-6) to 10(-11) M] inhibited in a dose-dependent manner the cytokine-induced IL-6 secretion [60+/-9.5% at 10(-5) M and 65+/-12% at 10(-7) M, respectively; p < 0.01]. Though significant, the inhibitory effect of clodronate was less [35+/-7% at 10(-5) M, p < 0.05]. These in vitro observations might have in vivo relevance in explaining at least in part the mechanisms by which bisphosphonates inhibit systemic and periarticular bone resorption.

The purpose of this study was to examine the serum levels of bone alkaline phosphatase (BALP) measured with a new assay in normal and in osteoporotic women, and to evaluate prospectively its responsiveness to changes of bone metabolism. The following groups of subjects were studied: (1) 95 healthy women (44–75 years) (22 pre- and 73 postmenopausal) and 35 osteoporotic women [vertebral bone mineral density (BMD) more than 2.5 SD below the normal adult mean]; (2) 10 women (44–50 years) ovariectomized (OVX) for benign uterine diseases, examined before and 12 months after surgery; (3) 16 OVX women (36–54 years), examined before and after 12 months of transdermal estrogen replacement therapy (50 μg/day); (4) 12 previously untreated pagetic patients (4 women and 8 men, 50–80 years), examined before and 3 months after the I.V. administration of clodronate (600 mg) or alendronate (5 mg) for 2 consecutive days. The median BALP value was 11.6 U/liter (25–75th percentiles: 10.5–12.7; range 7.7–19.3) in healthy premenopausal (PreMP) women and significantly higher (median: 16.8 U/liter; 25–75th percentile: 13.8–21.8; P < 0.01) in postmenopausal (PostMP) women. There was a clear age-related increase in normal subjects (r = 0.43; P < 0.001). In the osteoporotic group, BALP levels, as well as other biochemical parameters of bone turnover, were not significantly different from those of normal women when adjusted for age. In OVX women, BALP levels showed a marked increase 12 months after surgery (median: 113%; 25–75th percentile: 87–139%), significantly higher than the increase of total ALP (median: 43%; 25–75th percentile: 25–66%; P < 0.001), and similar to the increases of serum osteocalcin and urinary hydroxyproline. Transdermal estrogen treatment prevented the BALP increase, even if no reduction was observed; total ALP showed a similar behavior. The basal levels of BALP were significantly elevated in pagetic patients (median: 91 U/liter; range 18–610 U/liter) and correlated to the scintigraphic extent of the disease (r = 0.76; P < 0.01). Three months after the I.V. administration of bisphosphonates, the decrease of BALP was more marked than that of total ALP (median: −54% versus −41%; P < 0.05). In conclusion, these results suggest that BALP measurement with this immunoassay may be clinically useful, and more sensitive than total ALP, in the assessment of bone turnover during changes of the estrogen status as well as in monitoring the effects of treatments that modify the metabolic activity of the skeleton.

Increased serum interleukin-6 (IL-6) concentrations have been reported in patients with thyroid destructive processes. In the present study we measured IL-6 and soluble IL-6 receptor (sIL-6R) concentrations in the serum of normal subjects and patients with Graves' disease using a high sensitivity sandwich enzyme-linked immunoassay. We found increased serum IL-6 and sIL-6R concentrations (69.3 fmol/L, and 964 pmol/L, respectively) in 49 hyperthyroid patients with Graves' disease (GD) compared to those in controls [55.8 fmol/L (P = 0.019) and 772 pmol/L (P = 0.007), respectively]. In 31 newly diagnosed GD patients, serum concentrations of IL-6 and sIL-6R during the hyperthyroid phase were elevated, and after therapy with methimazole only, serum sIL-6R concentrations returned to normal (940 vs. 726 pmol/L; P < 0.001) but serum IL-6 did not. Serum sIL-6R concentrations (mean +/- 2 SD) were higher in GD patients with active inflammatory thyroid-associated ophthalmopathy than those in patients with inactive or absent thyroid-associated ophthalmopathy (P < 0.05). In conclusion, we have demonstrated activation of the IL-6 system in GD and, for the first time, have measured and found increased serum sIL-6R concentrations in hyperthyroid GD patients.

Bone remodelling continues throughout life and depends on two processes that are tightly coupled: resorption of old bone by osteoclasts and subsequent new bone formation by osteoblasts. Evidence accumulated during the last few years has clearly indicated that bone marrow microenvironment plays an essential role in regulating bone remodelling. Indeed major advances in our understanding of the ontogeny of osteoclasts and osteoblasts indicate that both cell types derive from progenitors present in the marrow, and that systemic and local factors regulate their development and the coupling of their function. In particular, a network of cytokines and growth factors is essential for the regulation of both osteoclastogenesis and osteoblast formation: these factors play a pivotal role in the paracrine regulatory control of bone turnover under physiological conditions. Among this array of local factors, IL-6, IL-1, TNF, GM-CSF, cytokines with osteoclastogenic and bone resorptive properties, have been implicated in the pathophysiology of osteoporosis since their production is increased in vivo in humans and animals with estrogen deficiency. These findings provide emerging insights into the pathophysiology of osteoporosis and deserve further investigation.

We have previously demonstrated that ovariectomy causes an increase in the number of colony-forming unit granulocyte/macrophage (CFU-GM) and an upregulation of osteoclastogenesis in mice, both of which are mediated by interleukin-6 (IL-6). IL-6 is involved in the development of several hematopoietic progenitors, including the burst-forming unit-erythroid (BFU-E) and multipotent CFUs (CFU-GEMM). Therefore, we performed studies to examine if other hematopoietic progenitors, besides CFU-GM and their progeny, are affected by estrogen loss. We found that ovariectomy caused an increase in the number of CFU-GEMM and BFU-E, as well as an increase of CFU-GM in marrow cells of the femur. Administration of 17 beta-estradiol or a neutralizing antibody against IL-6 prevented the ovariectomy-induced increase in the number of these progenitors in the marrow. Ovariectomy also caused an increase in the number of circulating lymphocytes, neutrophils, and monocytes, which were suppressed by administration of 17 beta-estradiol or the neutralizing antibody against IL-6; however, the number of circulating platelets was unaffected by loss of ovarian function. These data establish that, in addition to upregulation of osteoclastogenesis, loss of estrogens in the mouse causes widespread effects on hematopoiesis, which are apparently mediated by IL-6.

Interleukin-6 is an essential mediator of the bone loss caused by loss of estrogens. Because loss of androgens also causes bone loss, we have examined whether the IL-6 gene is regulated by androgens, and whether IL-6 plays a role in the bone loss caused by androgen deficiency. Both testosterone and dihydrotestosterone inhibited IL-6 production by murine bone marrow-derived stromal cells. In addition, testosterone, dihydrotestosterone, and adrenal androgens inhibited the expression of a chloramphenicol acetyl transferase reporter plasmid driven by the human IL-6 promoter in HeLa cells cotransfected with an androgen receptor expression plasmid; however, these steroids were ineffective when the cells were cotransfected with an estrogen receptor expression plasmid. In accordance with the in vitro findings, orchidectomy in mice caused an increase in the replication of osteoclast progenitors in the bone marrow which could be prevented by androgen replacement or administration of an IL-6 neutralizing antibody. Moreover, bone histomorphometric analysis of trabecular bone revealed that, in contrast to IL-6 sufficient mice which exhibited increased osteoclast numbers and bone loss following orchidectomy, IL-6 deficient mice (generated by targeted gene disruption) did not. This evidence demonstrates that male sex steroids, acting through the androgen-specific receptor, inhibit the expression of the IL-6 gene; and that IL-6 mediates the upregulation of osteoclastogenesis and therefore the bone loss caused by androgen deficiency, as it does in estrogen deficiency.

Monocytes/macrophages and activated (but not resting) lymphocytes as well as certain subsets of thymocytes express the VDR. This protein is indistinguishable from the classical 50-kDa VDR and is encoded by an mRNA with identical nucleotide sequence to that of the human intestinal VDR. Acting via the VDR, 1,25(OH)2D3 modulates the production of a plethora of monocyte, lymphocyte, and bone marrow stromal cell products, including several interleukins and other cytokines, as well as various oncogenes and transcription factors. However, these hormonal effects vary depending on the signals used to activate blood mononuclear cells; moreover, each of the effects of the hormone can be either attenuated, abolished, or even reversed from negative to positive in the presence of phorbol esters. Lymphocytes also express a previously unrecognized 80-kDa cytosolic protein that shares immunologic cross-reactivity with the VDR. This protein is induced on activation and is downregulated by 1,25(OH)2D3, whereas the VDR is upregulated by 1,25(OH)2D3. In contrast to the signal-dependent effects of the hormone on cytokine production and lymphocyte proliferation, the effects of 1,25(OH)2D3 on the 80-kDa protein and VDR are independent of the activation signals. This apparent mechanistic distinction raises the possibility that the signal-independent effects of 1,25(OH)2D3 on the 80-kDa protein and the VDR might be due to direct interactions of the 1,25(OH)2D3-VDR complex with specific response elements (negative and positive VDREs, respectively) on these two genes; as opposed to the signal-dependent effects that might be due to influences of the 1,25(OH)2D3-VDR complex on other transcription factors that are generated in response to the different activation stimuli. Consistent with the second part of this contention, we have recently found that 1,25(OH)2D3 regulates the 50-kDa DNA binding subunit of the pleiotropic transcription factor NF-kappa B and the 105-kDa precursor of this subunit; as well as other members of the rel-related family of proteins, including v-rel and its normal cellular homolog c-rel, in activated normal human lymphocytes. Besides its influence on immune cell products, 1,25(OH)2D3 is a potent agent for the differentiation of cells of the myeloid lineage. In addition, 1,25(OH)2D3 stimulates the fusion and differentiation of hematopoietic progenitors into osteoclasts, an effect which accounts for the potent role of the hormone in bone resorption.(ABSTRACT TRUNCATED AT 400 WORDS)

A well-known in vivo mouse model for postmenopausal osteoporosis is the ovariectomized (OVX)mousemodel, commonly used to study the effect of treatments. Although many studies have investigated the treatment of osteoporosis with parathyroid hormone (PTH), some information is lacking about several histomorphometric parameters, non-collagen protein expression, Ca/P ratio, and mechanical properties in this particular model. The aim of this study was to investigate the effect of PTH through histological, biochemical, histomorphometric and mechanical analyses in OVX mice. To simulate postmenopausal osteoporosis, forty C57BL/6 female mice (15 w old) were ovariectomized. A subcutaneous injection of PTH (hPTH 1–34, Bachem AG, Switzerland) or just vehicle was administered daily. To explore structural changes and bone loss with time in vivo, microtomographic scans of the sixth caudal vertebra (C6) were performed from the day of surgery till the end of the experiment. Histomorphometric, histological, western blotting (wb), immunohistochemical and energy dispersive X-ray (EDX) analyses were performed on one femur to investigate trabecular and cortical thickness, the mineral apposition rate (MAR), osteoid and osteoclast surface, osteocytes apoptosis, osteopontin (OP) and osteocalcin (OC) expression and Ca/P ratio. On the contralateral bone one 4-point bending tests were performed to determine the mechanical stiffness in four directions and the failure strength of the diaphysis. Furthermore, a fracture test of the femoral neck was performed. Comparing the PTHgroup to thevehicle: themicroCTanalysis demonstratedaweak increase over time only in trabecular thickness in the C6, up to ~10% at the time of sacrifice; histology and histomorphometry revealed significant increase in trabecular and cortical thickness (~45% and ~15%, respectively), the MAR increased (~20%), the osteoid surface strongly increased (~60%) together with the osteoclast surface and the number of apoptotic osteocytes greatly decreased (~60%); wb showed no significant difference in OP content, while immunohistochemistry revealed a strong increase of OC (~80%); EDX showedno significant variation in Ca/P content. All mechanical properties significantly increased (10–20%). These findings demonstrate that PTH treatment positively affects biochemical, histomorphometric and mechanical properties of this mouse model. This work was funded by the European Community (project no.: FP7-223865, acronym VPHOP). This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. doi:10.1016/j.bone.2011.03.489 PP359-M Sustained increase in bone mineral density with alendronate in combination with indapamide in postmenopausal women with idiopathic hypercalciuria associated to osteoporosis: A 1-year randomized trial followed by a 2-year extension A. Giusti ⁎, A. Barone , G. Girasole , M. Razzano , M. Plzzonia , E. Palummeri , M. Pedrazzoni , G. Bianchi , G. Pioli d a Gerontology, Galliera Hospital, Genoa, Italy b Rheumatology, La Colletta Hospital, Arenzano, Italy c Internal Medicine, Parma University, Parma, Italy d Geriatrics, ASMN Hospital, Reggio nell'Emilia, Italy Abstract: Introduction: A recent 1-year randomized trial (Giusti A et al., NDT 2009) demonstrated the beneficial effect of alendronate (ALN)+indapamide (IND) in the treatment of women with idiopathic hypercalciuria (IHC) and associated bone loss. Methods: To evaluate the effect of ALN alone or in combination with IND on bone mineral density (BMD) and 24-hour urinary calciumexcretion (CaU), 77 postmenopausalwomenwith CaU>4mg/ kg/die and low BMD were randomized to receive for 1-year: indapamide 2.5 mg/daily alone (24 patients, IND group), alendronate 70mg/weekly alone (27 patients, ALN group) or the combination therapy (26 patients, ALN+IND group). 50 women (IND: 14, ALN: 17, ALN+IND: 19) who completed the first yearandconsented toparticipatewereenrolled ina2-yearextension.All subjects received daily calcium supplements to maintain a daily input of 1000mg, and were instructed to increase water intake up to 2000ml daily. The percentage change of BMD at lumbar spine (LS), femoral neck (FN) and total hip (TH) after 3-year, and the variation of 24-hour CaU from baseline at 2-year were the primary outcomes. Serum calcium, PTH and bone alkaline phosphatase were also measured. Results: After 2-year CaU values significantly decreased from baseline in all groups (IND, 210±89vs382±54,p

Preincubation for 20 h with 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) markedly augmented the chemotactic responsiveness of human blood monocytes to the classical chemoattractant, FMLP. A modest enhancement of monocyte spontaneous locomotion in the absence of chemoattractants was also observed. Maximal increase of monocyte migration was observed after pretreatment with 10(-9) M 1,25(OH)2D3 and was detectable at FMLP concentrations ranging from 10(-10) to 10(-7) M. Pretreatment with 1,25(OH)2D3 augmented the number of monocyte high affinity FMLP receptors (1500 +/- 220 and 3800 +/- 300 sites per cell for untreated and 1,25(OH)2D3-pretreated cells, respectively) with no significant changes in Kd values (2 +/- 0.5 nM and 4 +/- 1 nM, for untreated and 1,25(OH)2D3-pretreated monocytes). Enhanced chemotaxis was not restricted to FMLP, because 1,25(OH)2D3-treated monocytes showed enhanced migration also in response to activated C components and chemotactic cytokines. In agreement with previous observations, monocytes from AIDS patients showed defective migration capacity. In vitro exposure to 1,25(OH)2D3 stimulated monocyte migration in all 10 patients examined with considerable quantitative differences among individuals. Regulating the responsiveness of mature monocytes to chemo-attractants, 1,25(OH)2D3, produced systemically or in situ by immunocompetent cells, could play a role in the regulation of the recruitment of monocytes at sites of inflammation, cell-mediated immunity, or bone resorption. The potential of 1,25(OH)2D3 as a restorative agent under conditions of defective phagocyte recruitment deserves further exploration.

The clinical, morphological, immunological, and molecular features of a case of expansion of large granular lymphocytes (LGL) are reported. Surface marker analysis of peripheral blood and spleen mononuclear cells showed that the majority of these cells were CD3 − , CD2 + , CD16 + , and Leu 7 − . Ultrastructural characteristics of CD16 + cells revealed a low nuclear/cytoplasmatic ratio, irregularly shaped nucleus, and numerous cytoplasmatic granules. Functional studies showed reduced proliferative responses to mitogens (PHA, Con A, PWM) and high levels of natural killer (NK) activity as well as antibody-dependent cell cytotoxicity (ADCC) and lymphokine-activated killer (LAK) activities. Molecular analysis of the T cell receptor genes revealed a germline configuration of the β, γ, and δ genes; however, as for normal NK cells, δ-related mRNA transcripts were found. Three months from diagnosis, the patient developed profound thrombocytopenia and splenectomy was carried out with complete normalization of the platelet counts and of hematological values while LGL lymphocytosis persisted. Although no tools are available for studying the monoclonality of CD3 − lymphoproliferative disease, the clinical course, the absence of chromosomal abnormalities, and a liver histology indicative of chronic active hepatitis suggest that LGL expansion in this patient could be part of a benign, possibly reactive, process.