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Osteoporosis: HELP
Articles by Steven R. Cummings
Based on 64 articles published since 2010
(Why 64 articles?)
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Between 2010 and 2020, S. Cummings wrote the following 64 articles about Osteoporosis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Treat-to-target for osteoporosis: is now the time? 2013

Lewiecki, E Michael / Cummings, Steven R / Cosman, Felicia. ·New Mexico Clinical Research & Osteoporosis Center, 300 Oak Street NE, Albuquerque, New Mexico 87106, USA. mlewiecki@gmail.com ·J Clin Endocrinol Metab · Pubmed #23337726.

ABSTRACT: OBJECTIVES: Current clinical practice guidelines identify patients at high risk for fracture who are likely to benefit from pharmacological therapy and suggest ways to monitor for effectiveness of therapy. However, there is no clear guidance on when fracture risk has been reduced to an acceptably low level. As a consequence, some patients at low risk for fracture may be treated for longer than necessary, whereas others at high risk for fracture may have treatment stopped when they might benefit from continuation of the same treatment or a change to a more potent therapeutic agent. The objective of this statement is to describe the potential clinical utility of developing a "treat-to-target" strategy for the management of patients with osteoporosis. PARTICIPANTS: We recommend that a task force of clinicians, clinical investigators, and other stakeholders in the care of osteoporosis explore the options, review the evidence, and identify additional areas for investigation to establish osteoporosis treatment targets. EVIDENCE: Data from large, prospective, randomized, placebo-controlled registration trials for currently available osteoporosis therapies should be analyzed for commonalities of correlations between easily measured endpoints and fracture risk. CONSENSUS PROCESS: Osteoporosis experts, professional organizations, and patient care advocates should be involved in the process of developing consensus on easily measurable osteoporosis treatment targets that are supported by the best available evidence and likely to be accepted by clinicians and patients in the care of osteoporosis. CONCLUSIONS: A treat-to-target strategy for osteoporosis offers the potential of improving osteoporosis care by reducing the burden of osteoporotic fractures and limiting adverse effects of therapy.

2 Guideline Treatment failure in osteoporosis. 2012

Diez-Perez, A / Adachi, J D / Agnusdei, D / Bilezikian, J P / Compston, J E / Cummings, S R / Eastell, R / Eriksen, E F / Gonzalez-Macias, J / Liberman, U A / Wahl, D A / Seeman, E / Kanis, J A / Cooper, C / Anonymous5410732. ·Department of Internal Medicine and Infectious Diseases, Hospital del Mar-IMIM, Autonomous University of Barcelona, RETICEF, Instituto Carlos III, P. Maritim 25-29, 08003 Barcelona, Spain. adiez@parcdesalutmar.cat ·Osteoporos Int · Pubmed #22836278.

ABSTRACT: INTRODUCTION: This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture. METHODS: A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making. RESULTS: In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease. CONCLUSION: The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.

3 Editorial A History of Pivotal Advances in Clinical Research into Bone and Mineral Diseases. 2018

Cummings, Steven R / Eastell, Richard. ·San Francisco Coordinating Center, California Pacific Medical Center (CPMC) Research Institute and the University of California, San Francisco, CA, USA. · Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK. ·J Bone Miner Res · Pubmed #29329487.

ABSTRACT: -- No abstract --

4 Review Osteoporosis: the evolution of a diagnosis. 2015

Lorentzon, M / Cummings, S R. ·Geriatric Medicine, Institute of Medicine, Centre for Bone and Arthritis Research, Sahlgrenska Academy, Mölndal, Sweden. · University of California, the San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA. ·J Intern Med · Pubmed #25832448.

ABSTRACT: The global trend towards increased longevity has resulted in ageing populations and a rise in diseases or conditions that primarily affect older persons. One such condition is osteoporosis (fragile or porous bones), which causes an increased fracture risk. Vertebral and hip fractures lead to increased morbidity and mortality and result in enormous healthcare costs. Here, we review the evolution of the diagnosis of osteoporosis. In an attempt to separate patients with normal bones from those with osteoporosis and to define the osteoporosis diagnosis, multiple factors and characteristics have been considered. These include pathology and histology of the disease, the endocrine regulation of bone metabolism, bone mineral density (BMD), fracture type or trauma severity, risk models for fracture prediction, and thresholds for pharmacological intervention. The femoral neck BMD -2.5 SDs cut-off for the diagnosis of osteoporosis is arbitrarily chosen, and there is no evidence to support the notion that fracture location (except vertebral fractures) or severity is useful to discriminate osteoporotic from normal bones. Fracture risk models (including factors unrelated to bone) dissociate bone strength from the diagnosis, and treatment thresholds are often based on health-economic considerations rather than bone properties. Vertebral fractures are a primary feature of osteoporosis, characterized by decreased bone mass, strength and quality, and a high risk of another such fracture that can be considerably reduced by treatment. We believe that the 2001 definition of osteoporosis by the National Institutes of Health Consensus Development Panel on Osteoporosis is still valid and useful: 'Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture'.

5 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.

6 Clinical Trial Risk Factors for Hip Fracture in Older Men: The Osteoporotic Fractures in Men Study (MrOS). 2016

Cauley, Jane A / Cawthon, Peggy M / Peters, Katherine E / Cummings, Steven R / Ensrud, Kristine E / Bauer, Douglas C / Taylor, Brent C / Shikany, James M / Hoffman, Andrew R / Lane, Nancy E / Kado, Deborah M / Stefanick, Marcia L / Orwoll, Eric S / Anonymous8090861. ·University of Pittsburgh, Pittsburgh, PA, USA. jcauley@edc.pitt.edu. · California Pacific Medical Center Research Institute, San Francisco, CA, USA. · University of California, San Francisco, San Francisco, CA, USA. · Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. · Department of Medicine, University of Minnesota, Minneapolis, MN, USA. · Center for Chronic Disease Outcomes Research, VA Health Care System, Minneapolis, MN, USA. · University of Alabama at Birmingham, Birmingham, AL, USA. · Stanford University, Stanford, CA, USA. · University of California, Davis, Davis, CA, USA. · University of California, San Diego, San Diego, CA, USA. · Oregon Health & Science University, Portland, OR, USA. ·J Bone Miner Res · Pubmed #26988112.

ABSTRACT: Almost 30% of hip fractures occur in men; the mortality, morbidity, and loss of independence after hip fractures are greater in men than in women. To comprehensively evaluate risk factors for hip fracture in older men, we performed a prospective study of 5994 men, primarily white, age 65+ years recruited at six US clinical centers. During a mean of 8.6 years of 97% complete follow-up, 178 men experienced incident hip fractures. Information on risk factors including femoral neck bone mineral density (FNBMD) was obtained at the baseline visit. Cox proportional hazards models were used to calculate the hazard ratio (HR) with 95% confidence intervals; Fine and Gray models adjusted for competing mortality risk. Older age (≥75 years), low FNBMD, currently smoking, greater height and height loss since age 25 years, history of fracture, use of tricyclic antidepressants, history of myocardial infarction or angina, hyperthyroidism or Parkinson's disease, lower protein intake, and lower executive function were all associated with an increased hip fracture risk. Further adjustment for competing mortality attenuated HR for smoking, hyperthyroidism, and Parkinson's disease. The incidence rate of hip fracture per 1000 person-years (PY) was greatest in men with FNBMD T-scores <-2.5 (white women reference database) who also had 4+ risk factors, 33.4. Men age ≥80 years with 3+ major comorbidities experienced hip fracture at rates of 14.52 versus 0.88 per 1000 PY in men age <70 years with zero comorbidities. Older men with low FNBMD, multiple risk factors, and multimorbidity have a high risk of hip fracture. Many of these assessments can easily be incorporated into routine clinical practice and may lead to improved risk stratification. © 2016 American Society for Bone and Mineral Research.

7 Clinical Trial The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. 2013

Bone, Henry G / Chapurlat, Roland / Brandi, Maria-Luisa / Brown, Jacques P / Czerwinski, Edward / Krieg, Marc-Antoine / Mellström, Dan / Radominski, Sebastião C / Reginster, Jean-Yves / Resch, Heinrich / Ivorra, Jose A Román / Roux, Christian / Vittinghoff, Eric / Daizadeh, Nadia S / Wang, Andrea / Bradley, Michelle N / Franchimont, Nathalie / Geller, Michelle L / Wagman, Rachel B / Cummings, Steven R / Papapoulos, Socrates. ·MD, Michigan Bone and Mineral Clinic, 22201 Moross Road, Suite 260, Detroit, Michigan 48236. hgbone.md@att.net. ·J Clin Endocrinol Metab · Pubmed #23979955.

ABSTRACT: CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

8 Clinical Trial Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. 2012

Papapoulos, Socrates / Chapurlat, Roland / Libanati, Cesar / Brandi, Maria Luisa / Brown, Jacques P / Czerwiński, Edward / Krieg, Marc-Antoine / Man, Zulema / Mellström, Dan / Radominski, Sebastião C / Reginster, Jean-Yves / Resch, Heinrich / Román Ivorra, José A / Roux, Christian / Vittinghoff, Eric / Austin, Matthew / Daizadeh, Nadia / Bradley, Michelle N / Grauer, Andreas / Cummings, Steven R / Bone, Henry G. ·Department of Endocrinology & Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands. M.V.Iken@lumc.nl ·J Bone Miner Res · Pubmed #22113951.

ABSTRACT: The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a "virtual untreated twin" cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile.

9 Clinical Trial Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. 2011

Boonen, S / Adachi, J D / Man, Z / Cummings, S R / Lippuner, K / Törring, O / Gallagher, J C / Farrerons, J / Wang, A / Franchimont, N / San Martin, J / Grauer, A / McClung, M. ·Leuven University Division of Geriatric Medicine, B-3000 Leuven, Belgium. steven.boonen@uz.kuleuven.be ·J Clin Endocrinol Metab · Pubmed #21411557.

ABSTRACT: CONTEXT: The FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial showed denosumab significantly reduced the risk of fractures in postmenopausal women with osteoporosis. OBJECTIVE: We evaluated the effect of denosumab on the incidence of new vertebral and hip fractures in subgroups of women at higher risk for these fractures. DESIGN: FREEDOM was a 3-yr, randomized, double-blind, placebo-controlled, phase 3 trial. PARTICIPANTS AND SETTING: Postmenopausal women (N = 7808) with osteoporosis were enrolled at 213 study sites worldwide. INTERVENTIONS: Subjects received s.c. denosumab (60 mg) or placebo every 6 months and daily supplements of calcium (≥1000 mg) and vitamin D (≥400 IU). MAIN OUTCOME MEASURES: This post hoc analysis evaluated fracture incidence in women with known risk factors for fractures including multiple and/or moderate or severe prevalent vertebral fractures, aged 75 yr or older, and/or femoral neck bone mineral density T-score of -2.5 or less. RESULTS: Compared with placebo, denosumab significantly reduced the risk of new vertebral fractures in women with multiple and/or severe prevalent vertebral fractures (16.6% placebo vs. 7.5% denosumab; P < 0.001). Similarly, denosumab significantly reduced the risk of hip fractures in subjects aged 75 yr or older (2.3% placebo vs. 0.9% denosumab; P < 0.01) or with a baseline femoral neck bone mineral density T-score of -2.5 or less (2.8% placebo vs. 1.4% denosumab; P = 0.02). These risk reductions in higher-risk individuals were consistent with those seen in patients at lower risk of fracture. CONCLUSIONS: Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at higher risk for fracture. These results highlight the consistent antifracture efficacy of denosumab in patients with varying degrees of fracture risk.

10 Article Zoledronate. 2020

Reid, Ian R / Green, Jonathan R / Lyles, Kenneth W / Reid, David M / Trechsel, Ulrich / Hosking, David J / Black, Dennis M / Cummings, Steven R / Russell, R Graham G / Eriksen, Erik F. ·Department of Medicine, University of Auckland, Auckland, New Zealand. Electronic address: i.reid@auckland.ac.nz. · Novartis AG, Basel, Switzerland. · Duke University and VA Medical Centers, Durham, NC, USA. · School of Medicine, Dentistry and Nutrition, University of Aberdeen, UK. · Nottingham City Hospital, Nottingham, UK. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. · San Francisco Coordinating Center, Sutter Health Research, San Francisco, CA, USA; Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, CA, USA. · Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK; Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK. · Department of Clinical Medicine, University of Oslo, Oslo, Norway. ·Bone · Pubmed #32353565.

ABSTRACT: Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions.

11 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.

12 Article A Pooled Analysis of Fall Incidence From Placebo-Controlled Trials of Denosumab. 2020

Chotiyarnwong, Pojchong / McCloskey, Eugene / Eastell, Richard / McClung, Michael R / Gielen, Evelien / Gostage, John / McDermott, Michele / Chines, Arkadi / Huang, Shuang / Cummings, Steven R. ·Department of Orthopaedic Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. · Academic Unit of Bone Metabolism, Department of Oncology and Metabolism, The Mellanby Centre for Bone Research, The Centre for Integrated Research in Musculoskeletal Ageing, University of Sheffield, Sheffield, UK. · Oregon Osteoporosis Center, Portland, OR, USA. · Center for Metabolic Bone Diseases, University Hospitals Leuven, and Department of Chronic Diseases, Metabolism, and Aging, (CHROMETA), KU Leuven, Leuven, Belgium. · Amgen Inc., Thousand Oaks, CA, USA. · San Francisco Coordinating Center, California Pacific Medical Center (CPMC), Research Institute and the University of California, San Francisco, CA, USA. ·J Bone Miner Res · Pubmed #31999376.

ABSTRACT: Recent studies suggest that the RANK/RANKL system impacts muscle function and/or mass. In the pivotal placebo-controlled fracture trial of the RANKL inhibitor denosumab in women with postmenopausal osteoporosis, treatment was associated with a lower incidence of non-fracture-related falls (p = 0.02). This ad hoc exploratory analysis pooled data from five placebo-controlled trials of denosumab to determine consistency across trials, if any, of the reduction of fall incidence. The analysis included trials in women with postmenopausal osteoporosis and low bone mass, men with osteoporosis, women receiving adjuvant aromatase inhibitors for breast cancer, and men receiving androgen deprivation therapy for prostate cancer. The analysis was stratified by trial, and only included data from the placebo-controlled period of each trial. A time-to-event analysis of first fall and exposure-adjusted subject incidence rates of falls were analyzed. Falls were reported and captured as adverse events. The analysis comprised 10,036 individuals; 5030 received denosumab 60 mg subcutaneously once every 6 months for 12 to 36 months and 5006 received placebo. Kaplan-Meier estimates showed an occurrence of falls in 6.5% of subjects in the placebo group compared with 5.2% of subjects in the denosumab group (hazard ratio = 0.79; 95% confidence interval 0.66-0.93; p = 0.0061). Heterogeneity in study designs did not permit overall assessment of association with fracture outcomes. In conclusion, denosumab may reduce the risk of falls in addition to its established fracture risk reduction by reducing bone resorption and increasing bone mass. These observations require further exploration and confirmation in studies with muscle function or falls as the primary outcome. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

13 Article Red Cell Distribution Width Is a Risk Factor for Hip Fracture in Elderly Men Without Anemia. 2020

Kim, Kyoung Min / Lui, Li-Yung / Cauley, Jane A / Ensrud, Kristine E / Orwoll, Eric S / Schousboe, John T / Cummings, Steven R / Anonymous6261201. ·San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA. · Department of Endocrinology and Metabolism, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam, South Korea. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · Center for Chronic Disease Outcomes Research, Veterans Affairs Health Care System, Department of Medicine, University of Minnesota, Minneapolis, MN, USA. · Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA. · Oregon Health & Science University, Portland, OR, USA. · Park Nicollet Clinic and HealthPartners Institute, Bloomington, MN, USA. · University of Minnesota, Minneapolis, MN, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. ·J Bone Miner Res · Pubmed #31991005.

ABSTRACT: Red cell distribution width (RDW), routinely assessed as a component of a complete blood count (CBC), quantifies the variation in the size of red blood cells. It increases with age, and increased RDW predicts many aging-related diseases and mortality. However, whether it also predicts hip fracture is unknown. We prospectively evaluated the association between RDW and hip fracture using data from the Osteoporotic Fracture in Men (MrOS) study. RDW was measured in 3635 men (aged 71 to 99 years) along with bone mineral density (BMD) in MrOS. RDW ranged from 11.3% to 32.9% (median 14.0%; interquartile range 13.5% to 14.8%) and was categorized into four groups (≤13.0%, 13.1% to 14.0%, 14.1% to 15.0%, ≥15.1%). Study participants with a hemoglobin level <13.0 g/dL were classified as having anemia. During an average 8.1 years, 164 men suffered hip fractures. The risks of hip fractures increased with increase of RDW category. Furthermore, there was a significant interaction between anemia and RDW: An association between RDW and hip fractures was only observed in participants without anemia. In those without anemia, the relative hazard of hip fractures increased with increases in RDW category: Men in the highest RDW category had a 2.8 times higher risk of hip fractures than men in the lowest group (95% confidence interval 1.1 to 7.1). The risks of all-clinical fractures were also increased along with higher RDW values. Additionally, RDW was significantly associated with the risk of having a fall but not with femoral neck or total hip BMD. In conclusion, RDW and anemia defined by hemoglobin are widely available routine laboratory measurements that together could indicate increased risk of hip fracture, reflecting the neuromuscular effects of aging rather than lower hip BMD. © 2020 American Society for Bone and Mineral Research.

14 Article Dysmobility Syndrome Independently Increases Fracture Risk in the Osteoporotic Fractures in Men (MrOS) Prospective Cohort Study. 2018

Buehring, Bjoern / Hansen, Karen E / Lewis, Brian L / Cummings, Steven R / Lane, Nancy E / Binkley, Neil / Ensrud, Kristine E / Cawthon, Peggy M / Anonymous3971112. ·Osteoporosis Clinical Research Program, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA. · San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA. · Center for Musculoskeletal Health, University of California-Davis School of Medicine, Davis, CA, USA. · Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN, USA. ·J Bone Miner Res · Pubmed #29701911.

ABSTRACT: We proposed the term "dysmobility syndrome" (DS) to identify individuals with impaired musculoskeletal health, a risk factor for falls and fractures. Whether DS is associated with increased risk of incident fracture is unknown. The Osteoporotic Fractures in Men (MrOS) study enrolled 5994 men ages ≥65 years, between March 2000 and April 2002. We used baseline data to determine whether DS increased fracture risk, independent of the Fracture Risk Assessment Tool (FRAX). Men met DS criteria at baseline if they had three or more of the following: appendicular lean mass/height

15 Article Real-world effectiveness of osteoporosis therapies for fracture reduction in post-menopausal women. 2018

Yusuf, Akeem A / Cummings, Steven R / Watts, Nelson B / Feudjo, Maurille Tepie / Sprafka, J Michael / Zhou, Jincheng / Guo, Haifeng / Balasubramanian, Akhila / Cooper, Cyrus. ·Center for Observational Research (CfOR), 1 Amgen Center Drive, MS 24-2-A, Thousand Oaks, CA, 91320, USA. ayusuf01@amgen.com. · Department of Medicine, University of California, San Francisco, CA, USA. · , Mercy Health Osteoporosis and Bone Health Services, Cincinnati, OH, USA. · Amgen Inc., Uxbridge, UK. · Center for Observational Research (CfOR), 1 Amgen Center Drive, MS 24-2-A, Thousand Oaks, CA, 91320, USA. · Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA. · Chronic Disease Research Group, Minneapolis, MN, USA. · MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. ·Arch Osteoporos · Pubmed #29564735.

ABSTRACT: Studies examining real-world effectiveness of osteoporosis therapies are beset by limitations due to confounding by indication. By evaluating longitudinal changes in fracture incidence, we demonstrated that osteoporosis therapies are effective in reducing fracture risk in real-world practice settings. INTRODUCTION: Osteoporosis therapies have been shown to reduce incidence of vertebral and non-vertebral fractures in placebo-controlled randomized clinical trials. However, information on the real-world effectiveness of these therapies is limited. METHODS: We examined fracture risk reduction in older, post-menopausal women treated with osteoporosis therapies. Using Medicare claims, we identified 1,278,296 women age ≥ 65 years treated with zoledronic acid, oral bisphosphonates, denosumab, teriparatide, or raloxifene. Fracture incidence rates before and after treatment initiation were described to understand patients' fracture risk profile, and fracture reduction effectiveness of each therapy was evaluated as a longitudinal change in incidence rates. RESULTS: Fracture incidence rates increased during the period leading up to treatment initiation and were highest in the 3-month period most proximal to treatment initiation. Fracture incidence rates following treatment initiation were significantly lower than before treatment initiation. Compared with the 12-month pre-index period, there were reductions in clinical vertebral fractures for denosumab (45%; 95% confidence interval [CI] 39-51%), zoledronic acid (50%; 95% CI 47-52%), oral bisphosphonates (24%; 95% CI 22-26%), and teriparatide (72%; 95% CI 69-75%) during the subsequent 12 months. Relative to the first 3 months after initiation, clinical vertebral fractures were reduced for denosumab (51%; 95% CI 42-59%), zoledronic acid (25%; 95% CI 17-32%), oral bisphosphonates (23%; 95% CI 20-26%), and teriparatide (64%; 95% CI 58-69%) during the subsequent 12 months. CONCLUSION: In summary, reductions in fracture incidence over time were observed in cohorts of patients treated with osteoporosis therapies.

16 Article Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. 2018

Cummings, Steven R / Ferrari, Serge / Eastell, Richard / Gilchrist, Nigel / Jensen, Jens-Erik Beck / McClung, Michael / Roux, Christian / Törring, Ove / Valter, Ivo / Wang, Andrea T / Brown, Jacques P. ·San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA, USA. · Geneva University Hospital, Geneva, Switzerland. · The University of Sheffield, Sheffield, UK. · The Princess Margaret Hospital, Christchurch, New Zealand. · Hvidovre University Hospital, Hvidovre, Denmark. · Oregon Osteoporosis Center, Portland, OR, USA. · Paris Descartes University, Paris, France. · Karolinska Institutet, Södersjukhuset, Stockholm, Sweden. · Center for Clinical and Basic Research, Tallinn, Estonia. · Amgen Inc., Thousand Oaks, CA, USA. · Laval University and CHU de Québec-Université Laval (CHUL), Quebec City, Canada. ·J Bone Miner Res · Pubmed #29105841.

ABSTRACT: Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with ≥1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.

17 Article Effect of Combination Folic Acid, Vitamin B 2017

Stone, Katie L / Lui, Li-Yung / Christen, William G / Troen, Aron M / Bauer, Douglas C / Kado, Deborah / Schambach, Christopher / Cummings, Steven R / Manson, JoAnn E. ·Research Institute, California Pacific Medical Center, San Francisco, CA, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. · Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Vitamin Metabolism Laboratory, Jean Mayer United States Department of Agriculture (USDA) Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · Institute of Biochemistry, Food and Nutrition Science, The Robert H. Smith Faculty of Agriculture Food and Environment, The Hebrew University of Jerusalem, Jerusalem, Israel. · Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. · Department of Family Medicine & Public Health, University of California, San Diego, San Diego, CA, USA. · Department of Internal Medicine, University of California, San Diego, San Diego, CA, USA. ·J Bone Miner Res · Pubmed #29244251.

ABSTRACT: Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B

18 Article Comparison of fracture risk assessment tools in older men without prior hip or spine fracture: the MrOS study. 2017

Gourlay, Margaret L / Ritter, Victor S / Fine, Jason P / Overman, Robert A / Schousboe, John T / Cawthon, Peggy M / Orwoll, Eric S / Nguyen, Tuan V / Lane, Nancy E / Cummings, Steven R / Kado, Deborah M / Lapidus, Jodi A / Diem, Susan J / Ensrud, Kristine E / Anonymous1110924. ·Department of Family Medicine, University of North Carolina, Aycock Building, Manning Drive, CB #7595, UNC-Chapel Hill, Chapel Hill, NC, 27599-7595, USA. margaret_gourlay@med.unc.edu. · Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA. · NoviSci, LLC, Durham, NC, USA. · Department of Rheumatology, Park Nicollet Health Services, Minneapolis, MN, USA. · Division of Health Policy and Management, University of Minnesota, Minneapolis, MN, USA. · Research Institute, California Pacific Medical Center, San Francisco, CA, USA. · Bone and Mineral Unit, Oregon Health and Science University, Portland, OR, USA. · Garvan Institute of Medical Research, UNSW School of Public Health and Community Medicine, Kensington, NSW, Australia. · Centre for Health Technologies, University of Technology, Sydney, Australia. · Division of Rheumatology, Department of Medicine, Center for Musculoskeletal Health, UC Davis Health System, Sacramento, CA, USA. · Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA. · Department of Medicine, University of California, San Diego, La Jolla, CA, USA. · School of Public Health, Oregon Health and Science University, Portland, OR, USA. · Department of Medicine, University of Minnesota, Minneapolis, MN, USA. · Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA. · Center for Chronic Disease Outcomes Research, VA Health Care System, Minneapolis, MN, USA. ·Arch Osteoporos · Pubmed #29052793.

ABSTRACT: Femoral neck bone mineral density (BMD), age plus femoral neck BMD T score, and three externally generated fracture risk tools had similar accuracy to identify older men who developed osteoporotic fractures. Risk tools with femoral neck BMD performed better than those without BMD. The externally developed risk tools were poorly calibrated. INTRODUCTION: We compared the performance of fracture risk assessment tools in older men, accounting for competing risks including mortality. METHODS: A comparative ROC curve analysis assessed the ability of the QFracture, FRAX® and Garvan fracture risk tools, and femoral neck bone mineral density (BMD) T score with or without age to identify incident fracture in community-dwelling men aged 65 years or older (N = 4994) without hip or clinical vertebral fracture or antifracture treatment at baseline. RESULTS: Among risk tools calculated with BMD, the discriminative ability to identify men with incident hip fracture was similar for FRAX (AUC 0.77, 95% CI 0.73, 0.81), the Garvan tool (AUC 0.78, 95% CI 0.74, 0.82), age plus femoral neck BMD T score (AUC 0.79, 95% CI 0.75, 0.83), and femoral neck BMD T score alone (AUC 0.76, 95% CI 0.72, 0.81). Among risk tools calculated without BMD, the discriminative ability to identify hip fracture was similar for QFracture (AUC 0.69, 95% CI 0.66, 0.73), FRAX (AUC 0.70, 95% CI 0.66, 0.73), and the Garvan tool (AUC 0.71, 95% CI 0.67, 0.74). Correlated ROC curve analyses revealed better diagnostic accuracy for risk scores calculated with BMD compared with QFracture (P < 0.0001). Calibration was good for the internally generated BMD T score predictor with or without age and poor for the externally developed risk tools. CONCLUSION: In untreated older men without fragility fractures at baseline, an age plus femoral neck BMD T score classifier identified men with incident hip fracture as accurately as more complicated fracture risk scores.

19 Article Vertebral fracture in postmenopausal Chinese women: a population-based study. 2017

Cui, L / Chen, L / Xia, W / Jiang, Y / Cui, L / Huang, W / Wang, W / Wang, X / Pei, Y / Zheng, X / Wang, Q / Ning, Z / Li, M / Wang, O / Xing, X / Lin, Q / Yu, W / Weng, X / Xu, L / Cummings, S R. ·Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China. · Department of Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China. · Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China. xiaweibo@medmail.com.cn. · Department of Endocrinology, BeiJing HaiDian Hospital, Beijing, 100080, China. · Department of Endocrinology, Peking University Shougang Hospital, Beijing, 100144, China. · Department of Cadre Unit, General Hospital of the Second Artillery Force, Beijing, 100088, China. · Department of Geriatric Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China. · Department of Endocrinology, China Rehabilitation Research Center, Beijing, 100068, China. · Department of Endocrinology, Beijing Liangxiang Hospital, Beijing, 102401, China. · Department of Endocrinology, Beijing Chaoyang Hospital, Beijing, 100020, China. · Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China. · Department of Orthopedics, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China. · Department of Gynaecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China. · San Francisco Coordinating Center, CPMC Research Institute and Department of Epidemiology and Biostatistics, University of California, San Francisco, USA. ·Osteoporos Int · Pubmed #28560474.

ABSTRACT: In a random sample of postmenopausal Chinese women, the prevalence of radiographic vertebral fractures increased from 13% between ages 50 and 59 to over 50% after age 80 years. A model with seven clinical risk factors predicted the probability of vertebral fractures as well with as without BMD and better than a model with only three risk factors. More than half an hour of outdoor activity per day might correlate with lower risk of vertebral fracture in this population. INTRODUCTION: We aimed to describe the prevalence and develop a model for prediction of radiographic vertebral fractures in a large random sample of postmenopausal Chinese women. METHODS: We enrolled 1760 women from an age-stratified random sample of postmenopausal women in Beijing, China. The presence of vertebral fracture was assessed by semi-quantitative grading of lateral thoracolumbar radiographs, risk factors by interview, bone mineral density (BMD) of the proximal femur and lumbar spine by dual x-ray absorptiometry (DXA), and markers of bone turnover from a fasting blood sample. Associations of these factors were analyzed in logistic models and discrimination by areas of receiver operating characteristics curves (AUC). RESULTS: The prevalence of vertebral fracture, ranged from 13.4% ages 50 to 59 years old to 58.1% at age 80 years or older. Older age, a history of non-vertebral fracture, lower femoral neck BMD T-score, body mass index (BMI), height loss, housework, and less than half an hour of outdoor activity were significantly associated with increased probability of having a vertebral fracture. A model with those seven factors had a similar AUC with or without BMD and performed better than a simple model with three factors. CONCLUSION: This study is from a true random sample of postmenopausal women in urban China with high response rate. The prevalence of vertebral fractures in postmenopausal women in Beijing increases from 13% under age 60 to over 50% by age 80 years. A model with seven clinical risk factors with or without BMD is better than simple models and may guide the use of spine x-rays to identify women with vertebral fractures. More than half an hour of outdoor activity might correlate with lower risk of vertebral fracture in this population.

20 Article Goal-Directed Treatment for Osteoporosis: A Progress Report From the ASBMR-NOF Working Group on Goal-Directed Treatment for Osteoporosis. 2017

Cummings, Steven R / Cosman, Felicia / Lewiecki, E Michael / Schousboe, John T / Bauer, Douglas C / Black, Dennis M / Brown, Thomas D / Cheung, Angela M / Cody, Kathleen / Cooper, Cyrus / Diez-Perez, Adolfo / Eastell, Richard / Hadji, Peyman / Hosoi, Takayuki / Jan De Beur, Suzanne / Kagan, Risa / Kiel, Douglas P / Reid, Ian R / Solomon, Daniel H / Randall, Susan. ·California Pacific Medical Center, Research Institute, San Francisco, CA, USA. · Helen Hayes Hospital and Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA. · New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA. · Park Nicollet Institute for Research and Education, Division of Rheumatology, Minneapolis, MN, USA. · Departments of Medicine and Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA. · University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, CA, USA. · University of Iowa, Department of Orthopedics and Rehabilitation, Iowa City, IA, USA. · University of Toronto, Faculty of Medicine, Ontario, Canada. · Foundation for Osteoporosis Research and Education, Oakland, CA, USA. · University of Southampton, MRC Lifecourse Epidemiology Unit, Southhampton, United Kingdom. · Hospital del Mar-IMIM-Universitat Autònoma de Barcelona and RETICEF, Instituto Carlos III, Spain, Internal Medicine - Infectious Diseases, Barcelona, Spain. · University of Sheffield, Human Metabolism, England, United Kingdom. · Philipps-University of Marburg, Department of Endocrinology, Osteoporosis, and Reproductive Medicine, Marburg, Germany. · National Center for Geriatrics and Gerontology, Obu City, Aichi Prefecture, Japan. · Johns Hopkins University, Baltimore, MD, USA. · University of California, San Francisco, San Francisco, CA, USA. · Hebrew SeniorLife, Institute for Aging Research, Boston, MA, USA. · University of Auckland, Department of Medicine, Auckland, New Zealand. · Brigham and Women's Hospital, Division of Rheumatology, Boston, MA, USA. · National Osteoporosis Foundation, Arlington, VA, USA. ·J Bone Miner Res · Pubmed #27864889.

ABSTRACT: The American Society for Bone and Mineral Research and the United States National Osteoporosis Foundation (NOF) formed a working group to develop principles of goal-directed treatment and identify gaps that need to be filled to implement this approach. With goal-directed treatment, a treatment goal would first be established and choice of treatment determined by the probability of achieving that goal. Goals of treatment would be freedom from fracture, a T-score > -2.5, which is above the NOF threshold for initiating treatment, or achievement of an estimated risk level below the threshold for initiating treatment. Progress toward reaching the patient's goal would be periodically and systematically assessed by estimating the patient's compliance with treatment, reviewing fracture history, repeating vertebral imaging when indicated, and repeating measurement of bone mineral density (BMD). Using these data, a decision would be made to stop, continue, or change therapy. Some of these approaches can now be applied to clinical practice. However, the application of goal-directed treatment cannot be fully achieved until medications are available that provide greater increases in BMD and greater reduction in fracture risk than those that are currently approved; only then can patients with very high fracture risk and very low BMD achieve such goals. Furthermore, assessing future fracture risk in patients on treatment requires a new assessment tool that accurately captures the change in fracture risk associated with treatment and should also be sensitive to the importance of recent fractures as predictors of imminent fracture risk. Lastly, evidence is needed to confirm that selecting and switching treatments to achieve goals reduces fracture risk more effectively than current standard care. © 2016 American Society for Bone and Mineral Research.

21 Article Bone Density Loss Is Associated With Blood Cell Counts. 2017

Valderrábano, Rodrigo J / Lui, Li-Yung / Lee, Jennifer / Cummings, Steven R / Orwoll, Eric S / Hoffman, Andrew R / Wu, Joy Y / Anonymous9830881. ·Division of Endocrinology, Stanford University School of Medicine, Stanford, CA, USA. · San Francisco Coordinating Center, California Pacific Medical Center, San Francisco, CA, USA. · Palo Alto Veteran Affairs Health Care System, Palo Alto, CA, USA. · Department of Medicine, Bone and Mineral Unit, Oregon Health and Science University, Portland, OR, USA. ·J Bone Miner Res · Pubmed #27653240.

ABSTRACT: Hematopoiesis depends on a supportive microenvironment. Preclinical studies in mice have demonstrated that osteoblasts influence the development of blood cells, particularly erythrocytes, B lymphocytes, and neutrophils. However, it is unknown whether osteoblast numbers or function impact blood cell counts in humans. We tested the hypothesis that men with low BMD or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells. We performed a cross-sectional analysis and prospective analysis in the Osteoporotic Fractures in Men (MrOS) study, a multisite longitudinal cohort study. A total of 2571 community-dwelling men (≥65 years) who were able to walk without assistance, did not have a hip replacement or fracture, and had complete blood counts (CBCs) at the third study visit were analyzed. Multivariable (MV)-adjusted logistic regression estimated odds of white blood cell (WBC) subtypes (highest and lowest quintile versus middle), and anemia (clinically defined) associated with BMD by DXA scan (at visit 3), annualized percent BMD change (baseline to visit 3), and high BMD loss (>0.5%/year, from baseline to visit 3) at the femoral neck (FN) and total hip (TH). MV-adjusted models included age, BMI, cancer history, smoking status, alcohol intake, corticosteroid use, self-reported health, thiazide use, and physical activity. At visit 3 greater TH BMD loss (per 1 SD) was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Annualized BMD loss of >0.5% was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Similar results were observed for FN BMD regarding anemia and lymphocytes. We conclude that community-dwelling older men with declining hip BMD over about 7 years had increased risks of anemia, lower lymphocyte count, and higher neutrophil count, consistent with preclinical studies. Bone health and hematopoiesis may have greater interdependency than previously recognized. © 2016 American Society for Bone and Mineral Research.

22 Article Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2. 2016

Nielson, Carrie M / Liu, Ching-Ti / Smith, Albert V / Ackert-Bicknell, Cheryl L / Reppe, Sjur / Jakobsdottir, Johanna / Wassel, Christina / Register, Thomas C / Oei, Ling / Alonso, Nerea / Oei, Edwin H / Parimi, Neeta / Samelson, Elizabeth J / Nalls, Mike A / Zmuda, Joseph / Lang, Thomas / Bouxsein, Mary / Latourelle, Jeanne / Claussnitzer, Melina / Siggeirsdottir, Kristin / Srikanth, Priya / Lorentzen, Erik / Vandenput, Liesbeth / Langefeld, Carl / Raffield, Laura / Terry, Greg / Cox, Amanda J / Allison, Matthew A / Criqui, Michael H / Bowden, Don / Ikram, M Arfan / Mellström, Dan / Karlsson, Magnus K / Carr, John / Budoff, Matthew / Phillips, Caroline / Cupples, L Adrienne / Chou, Wen-Chi / Myers, Richard H / Ralston, Stuart H / Gautvik, Kaare M / Cawthon, Peggy M / Cummings, Steven / Karasik, David / Rivadeneira, Fernando / Gudnason, Vilmundur / Orwoll, Eric S / Harris, Tamara B / Ohlsson, Claes / Kiel, Douglas P / Hsu, Yi-Hsiang. ·School of Public Health, Oregon Health & Science University, Portland, OR, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. · Icelandic Heart Association, Kópavogur, Iceland. · Faculty of Medicine, University of Iceland, Reykjavík, Iceland. · Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, NY, USA. · Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway. · Lovisenberg Diakonale Hospital, Oslo, Norway. · Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. · Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA. · Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands. · Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK. · Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. · California Pacific Medical Center Research Institute, San Francisco, CA, USA. · Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA. · National Institute on Aging (NIA), National Institutes of Health, Bethesda, MD, USA. · Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. · Department of Radiology, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA. · Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA. · Department of Neurology, Boston University, Boston, MA, USA. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA. · Broad Institute of MIT and Harvard, Cambridge, MA, USA. · Technical University Munich, Munich, Germany. · Imaging, Icelandic Heart Association, Kópavogur, Iceland. · Department of Bioinformatics, Gothenburg University, Gothenburg, Sweden. · Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA. · Center for Diabetes Research, Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Department of Family Medicine and Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA. · Internal Medicine/Endocrinology, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. · Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Department of Orthopaedics and Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden. · Los Angeles Biomedical Research Institute, Torrance, CA, USA. · Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. · Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel. · Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · Division of Endocrinology, Oregon Health & Science University, Portland, OR, USA. · Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA. ·J Bone Miner Res · Pubmed #27476799.

ABSTRACT: Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10

23 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.

24 Article Digital X-ray radiogrammetry in the study of osteoporotic fractures: Comparison to dual energy X-ray absorptiometry and FRAX. 2016

Kälvesten, Johan / Lui, Li-Yung / Brismar, Torkel / Cummings, Steven. ·Radiology, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Östergötland County Council, University hospital, Linköping, Sweden; Center for Medical Image Science and Visualization zCMIV), Linköping University, Sweden; Sectra AB, Linköping, Sweden. Electronic address: johan.kalvesten@gmail.com. · San Francisco Coordinating Center, California Pacific Medical Center, San Francisco, CA, USA. · Karolinska Institutet, Department for Clinical Science, Intervention and Technology, Division of Radiology, Karolinska University Hospital, Sweden. ·Bone · Pubmed #26921822.

ABSTRACT: Osteoporosis is often underdiagnosed and undertreated. Screening of post-menopausal women for clinical risk factors and/or low bone mineral density (BMD) has been proposed to overcome this. Digital X-ray radiogrammetry (DXR) estimates hand BMD from standard hand X-ray images and have shown to predict fractures and osteoporosis. Recently, digital radiology and the internet have opened up the possibility of conducting automated opportunistic screening with DXR in post-fracture care or in combination with mammography. This study compared the performance of DXR with FRAX® and DXA in discriminating major osteoporotic fracture (MOF) (hip, clinical spine, forearm or shoulder), hip fracture and femoral neck osteoporosis. This prospective cohort study was conducted on 5278 women 65years and older in the Study of Osteoporotic Fractures (SOF) cohort. Baseline hand X-ray images were analyzed and fractures were ascertained during 10years of follow up. Age-adjusted area under receiver operating characteristic curve (AUC) for MOF and hip fracture and for femoral neck osteoporosis (DXA FN BMD T-score ≤-2.5) was used to compare the methods. Sensitivity to femoral neck osteoporosis at equal selection rates was tabulated for FRAX and DXR. DXR-BMD, FRAX (no BMD) and lumbar spine DXA BMD were all similar in fracture discriminative performance with an AUC around 0.65 for MOF and 0.70 for hip fractures for all three methods. As expected femoral neck DXA provided fracture discrimination superior both to other BMD measurements and to FRAX. AUC for selection of patients with femoral neck osteoporosis was higher with DXR-BMD, 0.76 (0.74-0.77), than with FRAX, 0.69 (0.67-0.71), (p<0.0001). In conclusion, DXR-BMD discriminates incident fractures to a similar degree as FRAX and predicts femoral neck osteoporosis to a larger degree than FRAX. DXR shows promise as a method to automatically flag individuals who might benefit from an osteoporosis assessment.

25 Article Relationship of Bisphosphonate Therapy and Atrial Fibrillation/Flutter: Outcomes of Sleep Disorders in Older Men (MrOS Sleep) Study. 2016

Thadani, Samir R / Ristow, Bryan / Blackwell, Terri / Mehra, Reena / Stone, Katie L / Marcus, Gregory M / Varosy, Paul D / Cummings, Steven R / Cawthon, Peggy M / Anonymous371077. ·Division of Cardiology, Department of Medicine, Kaiser Permanente, South San Francisco, CA; Division of Cardiology, Department of Medicine, University of California, San Francisco, CA. Electronic address: samir.r.thadani@kp.org. · Division of Cardiology, Department of Medicine, California Pacific Medical Center, San Francisco, CA. · California Pacific Medical Center Research Institute, San Francisco, CA. · Sleep Disorders Center, Neurologic Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, OH. · Division of Cardiology, Electrophysiology Section, Department of Medicine, University of California, San Francisco, CA. · VA Eastern Colorado Health Care System; University of Colorado, Denver; and the Colorado Outcomes Research Group, Denver, CO. ·Chest · Pubmed #26836889.

ABSTRACT: BACKGROUND: Prior studies suggested an association between bisphosphonates and atrial fibrillation/flutter (AF) in women. This relationship in men, including those with sleep-disordered breathing (SDB), remains unclear. This study evaluated the relationship between bisphosphonate use and prevalent (nocturnal) and incident (clinically relevant) AF in a population of community-dwelling older men. METHODS: A total of 2,911 male participants (mean age, 76 years) of the prospective observational Osteoporotic Fractures in Men Study sleep cohort with overnight in-home polysomnography (PSG) constituted the analytic cohort. Nocturnal AF from ECGs during PSG and incident AF events were centrally adjudicated. The association of bisphosphonate use and AF was examined using multivariable-adjusted logistic regression for prevalent AF and Cox proportional hazards regression for incident AF. RESULTS: A total of 123 (4.2%) men were current bisphosphonate users. Prevalent nocturnal AF was present in 138 participants (4.6%). After multivariable adjustment, there was a significant association between current bisphosphonate use and prevalent AF (OR, 2.33; 95% CI, 1.13-4.79). In the subset of men with moderate to severe SDB, this association was even more pronounced (OR, 3.22; 95% CI, 1.29-8.03). However, the multivariable-adjusted relationship between bisphosphonate use and incident AF did not reach statistical significance (adjusted hazard ratio, 1.53; 95% CI, 0.96-2.45). CONCLUSIONS: These results support an association between bisphosphonate use and prevalent nocturnal AF in community-dwelling older men. The data further suggest that those with moderate to severe SDB may be a particularly vulnerable group susceptible to bisphosphonate-related AF. Similar associations were not seen for bisphosphonate use and clinically relevant incident AF.

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