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Osteoporosis: HELP
Articles by Nicola Pannacciulli
Based on 12 articles published since 2010
(Why 12 articles?)
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Between 2010 and 2020, N. Pannacciulli wrote the following 12 articles about Osteoporosis.
 
+ Citations + Abstracts
1 Clinical Trial Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial. 2019

Saag, Kenneth G / Pannacciulli, Nicola / Geusens, Piet / Adachi, Jonathan D / Messina, Osvaldo D / Morales-Torres, Jorge / Emkey, Ronald / Butler, Peter W / Yin, Xiang / Lems, Willem F. ·University of Alabama at Birmingham. · Amgen Inc., Thousand Oaks, California. · Maastricht University, Maastricht, The Netherlands. · McMaster University, Hamilton, Ontario, Canada. · Cosme Argerich Hospital, Buenos Aires, Argentina. · Hospital Aranda de la Parra, León, Mexico. · Emkey Arthritis & Osteoporosis Clinic, Wyomissing, Pennsylvania. · VU University Medical Center, Amsterdam, The Netherlands. ·Arthritis Rheumatol · Pubmed #30816640.

ABSTRACT: OBJECTIVE: Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24. METHODS: This phase III study enrolled men and women ≥18 years old who had received ≥7.5 mg daily prednisone or equivalent for <3 months (glucocorticoid-initiating) or for ≥3 months (glucocorticoid-continuing) before screening. All patients <50 years old had a history of osteoporotic fracture. Glucocorticoid-continuing patients ≥50 years old had T scores of -2.0 or less (or -1.0 or less with fracture history). Patients were randomized (1:1) to receive denosumab 60 mg subcutaneously Q6M or risedronate 5 mg orally QD for 24 months, with daily calcium and vitamin D. RESULTS: Of 795 patients, 590 (74.2%) completed the study (in the glucocorticoid-initiating group, 109 of 145 patients treated with denosumab and 117 of 145 patients treated with risedronate; in the glucocorticoid-continuing group, 186 of 253 patients treated with denosumab and 178 of 252 patients treated with risedronate). Denosumab was superior to risedronate in increasing lumbar spine and total hip BMD at all time points assessed, among glucocorticoid-initiating patients (24-month lumbar spine: BMD increase of 6.2% versus 1.7%, respectively [P < 0.001]; 24-month total hip: BMD increase of 3.1% versus 0.0% [P < 0.001]) and among glucocorticoid-continuing patients (24-month lumbar spine: BMD increase of 6.4% versus 3.2% [P < 0.001]; 24-month total hip: BMD increase of 2.9% versus 0.5% [P < 0.001]). Adverse events, serious adverse events (including infections), and fractures were similar between treatment groups. CONCLUSION: Denosumab was superior to risedronate in terms of increases in spine and hip BMD through month 24, and the safety profile was similar between treatment groups. Denosumab may offer a new osteoporosis treatment option for glucocorticoid-treated patients.

2 Clinical Trial 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. 2017

Bone, Henry G / Wagman, Rachel B / Brandi, Maria L / Brown, Jacques P / Chapurlat, Roland / Cummings, Steven R / Czerwiński, Edward / Fahrleitner-Pammer, Astrid / Kendler, David L / Lippuner, Kurt / Reginster, Jean-Yves / Roux, Christian / Malouf, Jorge / Bradley, Michelle N / Daizadeh, Nadia S / Wang, Andrea / Dakin, Paula / Pannacciulli, Nicola / Dempster, David W / Papapoulos, Socrates. ·Michigan Bone and Mineral Clinic, Detroit, MI, USA; Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Harbor, MI, USA. Electronic address: hgbone.md@att.net. · Research and Development, Amgen, Thousand Oaks, CA, USA. · Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Department of Medicine, Laval University and CHU de Québec Research Centre, Quebec City, QC, Canada. · INSERM UMR 1033, Université de Lyon, Hôpital Edouard Herriot, Lyon, France. · San Francisco Coordinating Center, CPMC Research Institute, UCSF, San Francisco, CA, USA. · Krakow Medical Centre, Krakow, Poland. · Department of Endocrinology and Metabolism, Medical University Graz, Graz, Austria. · Department of Medicine, Division of Endocrinology, University of British Columbia, Vancouver, BC, Canada. · Department of Osteoporosis, Bern University Hospital, Bern, Switzerland. · Bone and Cartilage Metabolism Unit, University of Liège, Liège, Belgium. · Department of Rheumatology, Paris Descartes University, Paris, France. · Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, USA. · Center for Bone Quality, Leiden University Medical Center, Leiden, Netherlands. ·Lancet Diabetes Endocrinol · Pubmed #28546097.

ABSTRACT: BACKGROUND: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. FINDINGS: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. INTERPRETATION: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. FUNDING: Amgen.

3 Article Estimation of Long-Term Efficacy of Denosumab Treatment in Postmenopausal Women With Osteoporosis: A FRAX- and Virtual Twin-Based Post Hoc Analysis From the FREEDOM and FREEDOM Extension Trials. 2020

Siris, Ethel / McDermott, Michele / Pannacciulli, Nicola / Miller, Paul D / Lewiecki, E Michael / Chapurlat, Roland / Jódar-Gimeno, Esteban / Huang, Shuang / Kanis, John A. ·Dept of Medicine Endocrinology, Columbia University Medical Center New York NY USA. · Amgen Inc. Thousand Oaks CA USA. · Colorado Center for Bone Research Lakewood CO USA. · New Mexico Clinical Research & Osteoporosis Center and University of New Mexico Health Sciences Center Albuquerque NM USA. · INSERM UMR 1033, Université de Lyon, Hôpital Edouard Herriot Lyon France. · Hospital Universitario Quirón Salud Madrid, Universidad Europea Madrid Spain. · Centre for Metabolic Diseases, University of Sheffield Sheffield UK. · Mary Mackillop Institute for Health Research, Australian Catholic University Melbourne Australia. ·JBMR Plus · Pubmed #32258966.

ABSTRACT: The 3-year placebo-controlled FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial established the antifracture efficacy of denosumab in postmenopausal women with osteoporosis. The 7-year open-label extension demonstrated that denosumab treatment for up to 10 years was associated with low rates of adverse events and low fracture incidence. The extension lacked a long-term control group, thus limiting the ability to fully evaluate long-term efficacy. This analysis provides a quantitative estimate of the long-term antifracture efficacy of denosumab based on two approaches: comparison with FRAX®- (Fracture Risk Assessment Tool-) and virtual twin-estimated 10-year fracture rates. Subjects who were randomized to denosumab in the FREEDOM trial, continued into the Extension study, completed the 10-year visit, and missed ≤1 dose in the FREEDOM trial and ≤1 dose in the Extension (

4 Article Modeling-Based Bone Formation in the Human Femoral Neck in Subjects Treated With Denosumab. 2020

Dempster, David W / Chines, Arkadi / Bostrom, Mathias P / Nieves, Jeri W / Zhou, Hua / Chen, Li / Pannacciulli, Nico / Wagman, Rachel B / Cosman, Felicia. ·Columbia University, New York, NY, USA. · Helen Hayes Hospital, West Haverstraw, NY, USA. · Amgen Inc, Thousand Oaks, CA, USA. · Hospital for Special Surgery, New York, NY, USA. ·J Bone Miner Res · Pubmed #32163613.

ABSTRACT: Denosumab is associated with continued gains in hip and spine BMD with up to 10 years of treatment in postmenopausal women with osteoporosis. Despite potent inhibition of bone remodeling, findings in nonhuman primates suggest modeling-based bone formation (MBBF) may persist during denosumab treatment. This study assessed whether MBBF in the femoral neck (FN) is preserved in the context of inhibited remodeling in subjects receiving denosumab. This open-label study enrolled postmenopausal women with osteoporosis who had received two or more doses of denosumab (60 mg subcutaneously every 6 months [Q6M]) per standard of care and were planning elective total hip replacement (THR) owing to osteoarthritis of the hip. Transverse sections of the FN were obtained after THR and analyzed histomorphometrically. MBBF, based on fluorochrome labeling and presence of smooth cement lines, was evaluated in cancellous, endocortical, and periosteal envelopes of the FN. Histomorphometric parameters were used to assess MBBF and remodeling-based bone formation (RBBF) in denosumab-treated subjects (n = 4; mean age = 73.5 years; range, 70 to 78 years) and historical female controls (n = 11; mean age = 67.8 years; range, 62 to 80 years) obtained from the placebo group of a prior study and not treated with denosumab. All analyses were descriptive. All subjects in both groups exhibited MBBF in the periosteal envelope; in cancellous and endocortical envelopes, all denosumab-treated subjects and 81.8% of controls showed evidence of MBBF. Compared with controls, denosumab-treated subjects showed 9.4-fold and 2.0-fold higher mean values of MBBF in cancellous and endocortical envelopes, respectively, whereas RBBF mean values were 5.0-fold and 5.3-fold lower. In the periosteal envelope, MBBF and RBBF rates were similar between subjects and controls. These results demonstrate the occurrence of MBBF in the human FN and suggest that denosumab preserves MBBF while inhibiting remodeling, which may contribute to the observed continued gains in BMD over time after remodeling is maximally inhibited. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

5 Article Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed. 2020

Ferrari, Serge / Lewiecki, E Michael / Butler, Peter W / Kendler, David L / Napoli, Nicola / Huang, Shuang / Crittenden, Daria B / Pannacciulli, Nicola / Siris, Ethel / Binkley, Neil. ·Geneva University Hospital, Geneva, Switzerland. Electronic address: Serge.Ferrari@unige.ch. · New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA. · Amgen Inc., Thousand Oaks, CA, USA. · University of British Columbia, Vancouver, BC, Canada. · Università Campus Bio-Medico di Roma, Roma, Italy; Division of Bone and Mineral Diseases, Washington University, St. Louis, MO, USA. · Columbia University Medical Center, New York, NY, USA. · University of Wisconsin-Madison, Madison, WI, USA. ·Bone · Pubmed #32092479.

ABSTRACT: Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791, NCT00523341.

6 Article Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension. 2020

Ferrari, Serge / Eastell, Richard / Napoli, Nicola / Schwartz, Ann / Hofbauer, Lorenz C / Chines, Arkadi / Wang, Andrea / Pannacciulli, Nico / Cummings, Steven R. ·Division of Bone Diseases, Geneva University Hospitals, Geneva, Switzerland. Electronic address: Serge.Ferrari@unige.ch. · Academic unit of Bone Metabolism, University of Sheffield, Sheffield, UK. · John T. Milliken Department of Medicine, Campus Bio-Medico, University of Rome, Rome, Italy; Ospedale Galeazzi IRCCS, Milan, Italy. · School of Medicine, University of California San Francisco, San Francisco, CA, USA. · Center for Healthy Aging and Division of Endocrinology, Diabetes, and Bone Diseases, Technische Universität Dresden, Dresden, Germany. · Global Development, Amgen Inc., Thousand Oaks, CA, USA. · Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA. ·Bone · Pubmed #32058020.

ABSTRACT: PURPOSE: Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated. METHODS: Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated. RESULTS: Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07-0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00-3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [1]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group. CONCLUSION: Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed.

7 Article Glucocorticoid Exposure and Fracture Risk in a Cohort of US Patients With Selected Conditions. 2018

Balasubramanian, Akhila / Wade, Sally W / Adler, Robert A / Saag, Kenneth / Pannacciulli, Nicola / Curtis, Jeffrey R. ·Amgen Inc., Thousand Oaks, CA, USA. · Wade Outcomes Research and Consulting, Salt Lake City, UT, USA. · McGuire Veterans Affairs Medical Center and Virginia Commonwealth University, Richmond, VA, USA. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA. ·J Bone Miner Res · Pubmed #29924418.

ABSTRACT: The purpose of this work was to evaluate systemic glucocorticoid exposure and fracture among patients with newly-diagnosed inflammatory and immune-modulated conditions. Using administrative data, inception cohorts of rheumatoid arthritis (RA), asthma/chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), multiple sclerosis (MS), lupus, and sarcoidosis patients age 18 to 64 years with benefits coverage ≥12 months before diagnosis (January 1, 2005 to December 31, 2012) were followed to clinical fracture, cancer diagnosis, or December 31, 2012. Glucocorticoid users were new to therapy. Fracture incidence rates (IRs) per 1000 person-years were stratified by prednisone equivalent doses. Cox's proportional hazards models assessed risk by daily and cumulative dose, and by time since discontinuation, adjusted for baseline characteristics. Most patients (72% of 403,337) had glucocorticoid exposure; 52% were under age 50. IR (95% confidence interval [CI]) of any osteoporotic fracture was elevated at doses <5 mg/day (IR 9.33; 95% CI, 7.29 to 11.77) versus 0 mg/day (IR 4.87 (95% CI, 4.72 to 5.02). Fracture rates were elevated at doses <5 mg/day in patients <50 years and those ≥50 years. In both age groups, fracture risk increased with increasing cumulative exposure, being approximately 2.5-fold higher at cumulative dose ≥5400 mg compared to <675 mg. At ≥5400 mg, IR values were 5.69 (95% CI, 4.32 to 7.35) in patients <50 years and 17.10 (95% CI, 14.97 to 19.46) in older patients. Fracture risk decreased significantly within months following glucocorticoid discontinuation. In patients with a variety of inflammatory conditions, fracture risk increased at doses as low as <5 mg/day. Risk increased with increasing cumulative exposure and decreased soon following glucocorticoid discontinuation. Trends were similar between patients older and younger than 50 years. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

8 Article Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study. 2018

Saag, Kenneth G / Wagman, Rachel B / Geusens, Piet / Adachi, Jonathan D / Messina, Osvaldo D / Emkey, Ronald / Chapurlat, Roland / Wang, Andrea / Pannacciulli, Nicola / Lems, Willem F. ·University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: ksaag@uabmc.edu. · Amgen, Thousand Oaks, CA, USA. · Maastricht University, Maastricht, Netherlands. · McMaster University, Hamilton, ON, Canada. · Cosme Argerich Hospital, Buenos Aires, Argentina. · Emkey Arthritis & Osteoporosis Clinic, Wyomissing, PA, USA. · Hôpital Edouard Herriot, Lyon, France. · Amsterdam Rheumatology & Immunology Center, Amsterdam, Netherlands. ·Lancet Diabetes Endocrinol · Pubmed #29631782.

ABSTRACT: BACKGROUND: Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and is associated with an estimated annual fracture rate of 5%. We aimed to assess the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis. METHODS: We did a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study at 79 centres in Europe, Latin America, Asia, and North America. Eligible patients were aged 18 years or older and were receiving glucocorticoids (≥7·5 mg prednisone daily, or equivalent) for at least 3 months (glucocorticoid continuing) or less than 3 months (glucocorticoid initiating) before screening. Patients younger than 50 years needed to have a history of osteoporosis-related fracture; glucocorticoid-continuing patients aged 50 years or older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of -2·0 or less, or -1·0 or less if they had a history of osteoporosis-related fracture. Participants were randomly assigned (1:1) to either 60 mg subcutaneous denosumab every 6 months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every 6 months for 24 months. Randomisation was stratified by sex within each subpopulation, and was done with an interactive voice-response system. Active drugs and corresponding placebos had identical packaging, labels, and appearance. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins (-0·7 and -1·1 percentage points for the glucocorticoid-continuing and glucocorticoid-initiating subpopulations, respectively). Superiority was also assessed as a secondary outcome. The primary efficacy set included all randomly assigned participants who had a baseline and postbaseline lumbar spine bone mineral density measurement, and was analysed according to randomised treatment assignment. The safety analysis set included all randomly assigned participants who received at least one dose of investigational product, and was analysed by actual treatment received. This study is registered with ClinicalTrials.gov (NCT01575873) and is completed. FINDINGS: Between March 28, 2012, and June 30, 2015, 795 patients, 505 of whom were glucocorticoid continuing and 290 of whom were glucocorticoid initiating, were enrolled and randomly assigned (398 to denosumab, 397 to risedronate). Denosumab was both non-inferior and superior to risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid-continuing (4·4% [95% CI 3·8-5·0] vs 2·3% [1·7-2·9]; p<0·0001) and glucocorticoid-initiating (3·8% [3·1-4·5] vs 0·8% [0·2-1·5]; p<0·0001) subpopulations. Incidence of adverse events, serious adverse events (including infections), and fractures was similar between treatment groups. The most common adverse events were back pain (17 [4%] patients in the risedronate group and 18 [5%] in the denosumab group) and arthralgia (21 [5%] patients in the risedronate group and 17 [4%] in the denosumab group). Serious infection occurred in 15 (4%) patients in the risedronate group and 17 (4%) patients in the denosumab group. INTERPRETATION: Denosumab could be a useful treatment option for patients newly initiating or continuing glucocorticoids who are at risk of fractures. FUNDING: Amgen.

9 Article Effect of denosumab on fasting glucose in women with diabetes or prediabetes from the FREEDOM trial. 2018

Napoli, Nicola / Pannacciulli, Nicola / Vittinghoff, Eric / Crittenden, Daria / Yun, Jang / Wang, Andrea / Wagman, Rachel / Schwartz, Ann V. ·Division of Endocrinology and Diabetes, University Campus Bio-Medico di Roma, Rome, Italy. · Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, MO, USA. · Amgen, Inc, Thousand Oaks, CA, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. ·Diabetes Metab Res Rev · Pubmed #29430796.

ABSTRACT: BACKGROUND: RANKL is a key regulator of bone resorption that may also modulate glucose metabolism. Denosumab (DMAb) is a fully human monoclonal antibody that binds RANKL and was associated with fracture risk reduction in the FREEDOM trial. We hypothesized that DMAb treatment decreased fasting serum glucose (FSG) relative to placebo in women with diabetes or prediabetes enrolled in FREEDOM trial. METHODS: Post hoc analysis of FREEDOM, in which 7808 postmenopausal osteoporotic women were randomized to receive DMAb or placebo every 6 months for 36 months. All diabetes group included subjects with a self-report of diabetes, use of antidiabetic medication (ADM), or an FSG ≥ 126 mg/dL at baseline. The diabetes group without prior ADM use included subjects with a self-reported history of diabetes or FSG level ≥ 126 mg/dL at baseline. Prediabetes was defined as an FSG of 100 to 125 mg/dL on no ADM. Average postbaseline FSG across visits was estimated and compared between DMAb and placebo. Main outcome measures are the difference in average postbaseline FSG across follow-up visits between DMAb and placebo. RESULTS: Estimated average postbaseline FSG across visits was not different between DMAb and placebo in either all diabetes group (P = .20) or those with prediabetes (P = .42); in diabetic women not on ADM, estimated average postbaseline FSG across visits was lower with DMAb than placebo (-6.8 mg/dL; 95% CI, -12.6 to -1.0; P = .02). CONCLUSIONS: DMAb did not affect FSG in postmenopausal osteoporotic women with prediabetes or diabetes. There was evidence of modest FSG lowering with DMAb in those with diabetes who were not on ADM. It remains to be determined whether blockade of RANKL has a clinically important effect on glucose metabolism.

10 Article Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting. 2018

Lau, Arthur N / Wong-Pack, Matthew / Rodjanapiches, Rod / Ioannidis, George / Wade, Sally / Spangler, Leslie / Balasubramanian, Akhila / Pannacciulli, Nicola / Lin, Celia J F / Roy-Gayos, Patrick / Bensen, William G / Bensen, Robert / Adachi, Jonathan D. ·From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA. arthur.lau@medportal.ca. · A.N. Lau, MD, Assistant Professor, Division of Rheumatology, McMaster University; M. Wong-Pack, BHSc, Faculty of Health Sciences, McMaster University; R. Rodjanapiches, BHSc, Faculty of Health Sciences, McMaster University; G. Ioannidis, MSc, PhD, GERAS Scientist, Geriatric Education and Research in Aging Sciences Centre and Assistant Professor (part-time), divisions of Rheumatology and Geriatrics, McMaster University and Hamilton Health Sciences, St. Peter's Hospital; S. Wade, MPH, Consultant, Wade Outcomes Research and Consulting; L. Spangler, VMD, PhD, Senior Manager, Global Health Economics, Amgen Inc.; A. Balasubramanian, MPH, PhD, Observational Research Senior Manager, Center for Observational Research, Amgen Inc.; N. Pannacciulli, MD, PhD, Clinical Research Medical Director, Clinical Development, Amgen Inc.; C.J. Lin, MD, currently Genentech, South San Francisco, California, USA; P. Roy-Gayos, BSc, Faculty of Science, McMaster University; W.G. Bensen, MD, Clinical Professor, Department of Medicine, McMaster University and St. Joseph's Healthcare Hamilton; R. Bensen, MSc, Charlton Healthcare Hamilton and St. Joseph's Healthcare Hamilton; J.D. Adachi, MD, Professor, Department of Medicine, McMaster University and St. Joseph's Healthcare Hamilton. arthur.lau@medportal.ca. · From the Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Faculty of Science, and Geriatric Education and Research in Aging Sciences Centre, McMaster University; Charlton Healthcare and St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Wade Outcomes Research and Consulting, Salt Lake City, Utah; Global Health Economics, Clinical Development, Amgen Inc., Thousand Oaks, California, USA. · A.N. Lau, MD, Assistant Professor, Division of Rheumatology, McMaster University; M. Wong-Pack, BHSc, Faculty of Health Sciences, McMaster University; R. Rodjanapiches, BHSc, Faculty of Health Sciences, McMaster University; G. Ioannidis, MSc, PhD, GERAS Scientist, Geriatric Education and Research in Aging Sciences Centre and Assistant Professor (part-time), divisions of Rheumatology and Geriatrics, McMaster University and Hamilton Health Sciences, St. Peter's Hospital; S. Wade, MPH, Consultant, Wade Outcomes Research and Consulting; L. Spangler, VMD, PhD, Senior Manager, Global Health Economics, Amgen Inc.; A. Balasubramanian, MPH, PhD, Observational Research Senior Manager, Center for Observational Research, Amgen Inc.; N. Pannacciulli, MD, PhD, Clinical Research Medical Director, Clinical Development, Amgen Inc.; C.J. Lin, MD, currently Genentech, South San Francisco, California, USA; P. Roy-Gayos, BSc, Faculty of Science, McMaster University; W.G. Bensen, MD, Clinical Professor, Department of Medicine, McMaster University and St. Joseph's Healthcare Hamilton; R. Bensen, MSc, Charlton Healthcare Hamilton and St. Joseph's Healthcare Hamilton; J.D. Adachi, MD, Professor, Department of Medicine, McMaster University and St. Joseph's Healthcare Hamilton. ·J Rheumatol · Pubmed #29142041.

ABSTRACT: OBJECTIVE: Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone. METHODS: A chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded. RESULTS: A total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period. CONCLUSION: This study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use.

11 Article Denosumab or Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates. 2016

Miller, P D / Pannacciulli, N / Brown, J P / Czerwinski, E / Nedergaard, B S / Bolognese, M A / Malouf, J / Bone, H G / Reginster, J-Y / Singer, A / Wang, C / Wagman, R B / Cummings, S R. ·Colorado Center for Bone Research (P.D.M.), Lakewood, Colorado 80277 · Amgen Inc (N.P., C.W., R.B.W.), Thousand Oaks, California 91320 · Laval University and Centre Hospitalier Universitaire de Québec Research Centre (J.P.B.), Québec City, Québec G1V 4G2, Canada · Krakow Medical Center (E.C.), 31-501 Krakow, Poland · Center for Clinical and Basic Research (B.S.N.), Aalborg, DK-9000 Aalborg, Denmark · Bethesda Health Research Center (M.A.B.), Bethesda, Maryland 20817 · Hospital de la Santa Creu i Sant Pau (J.M.), 08025 Barcelona, Spain · Michigan Bone and Mineral Clinic (H.G.B.), Detroit, Michigan 48236 · University of Liège (J.-Y.R.), 4000 Liège, Belgium · Georgetown University Medical Center (A.S.), Washington, DC 20007 · and San Francisco Coordinating Center (S.R.C.), California Pacific Medical Center Research Institute, San Francisco, California 94143. ·J Clin Endocrinol Metab · Pubmed #27270237.

ABSTRACT: CONTEXT: Denosumab and zoledronic acid (ZOL) are parenteral treatments for patients with osteoporosis. OBJECTIVE: The objective of the study was to compare the effect of transitioning from oral bisphosphonates to denosumab or ZOL on bone mineral density (BMD) and bone turnover. DESIGN AND SETTING: This was an international, multicenter, randomized, double-blind trial. PARTICIPANTS: A total of 643 postmenopausal women with osteoporosis previously treated with oral bisphosphonates participated in the study. INTERVENTIONS: Subjects were randomized 1:1 to sc denosumab 60 mg every 6 months plus iv placebo once or ZOL 5 mg iv once plus sc placebo every 6 months for 12 months. MAIN OUTCOME MEASURES: Changes in BMD and bone turnover markers were measured. RESULTS: BMD change from baseline at month 12 was significantly greater with denosumab compared with ZOL at the lumbar spine (primary end point; 3.2% vs 1.1%; P < .0001), total hip (1.9% vs 0.6%; P < .0001), femoral neck (1.2% vs -0.1%; P < .0001), and one-third radius (0.6% vs 0.0%; P < .05). The median decrease from baseline was greater with denosumab than ZOL for serum C-telopeptide of type 1 collagen at all time points after day 10 and for serum procollagen type 1 N-terminal propeptide at month 1 and at all time points after month 3 (all P < .05). Median percentage changes from baseline in serum intact PTH were significantly greater at months 3 and 9 with denosumab compared with ZOL (all P < .05). Adverse events were similar between groups. Three events consistent with the definition of atypical femoral fracture were observed (two denosumab and one ZOL). CONCLUSIONS: In postmenopausal women with osteoporosis previously treated with oral bisphosphonates, denosumab was associated with greater BMD increases at all measured skeletal sites and greater inhibition of bone remodeling compared with ZOL.

12 Minor Denosumab treatment in postmenopausal women with osteoporosis - Authors' reply. 2017

Bone, Henry G / Wagman, Rachel B / Pannacciulli, Nicola / Papapoulos, Socrates. ·Michigan Bone and Mineral Clinic, Detroit, MI 48236, USA; Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA. Electronic address: hgbone.md@att.net. · Research and Development, Amgen, Thousand Oaks, CA, USA. · Center for Bone Quality, Leiden, Netherlands; University Medical Center, Leiden, Netherlands. ·Lancet Diabetes Endocrinol · Pubmed #28938993.

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