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Osteoporosis: HELP
Articles by Steven R. Cummings
Based on 78 articles published since 2008
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Between 2008 and 2019, S. Cummings wrote the following 78 articles about Osteoporosis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
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 / Anonymous5370732. ·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 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'.

4 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.

5 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 / Anonymous8770861. ·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.

6 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.

7 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.

8 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.

9 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.

10 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.

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 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 / Anonymous770857. ·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.

13 Article Abdominal aortic calcification and risk of fracture among older women - The SOF study. 2015

Szulc, Pawel / Blackwell, Terri / Kiel, Douglas P / Schousboe, John T / Cauley, Jane / Hillier, Teresa / Hochberg, Marc / Rodondi, Nicolas / Taylor, Brent C / Black, Dennis / Cummings, Steven / Ensrud, Kristine E / Anonymous4580834. ·INSERM UMR 1033, University of Lyon, Lyon, France. Electronic address: pawel.szulc@inserm.fr. · California Pacific Medical Center Research Institute, San Francisco, CA, USA. · Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. · Park Nicollet Institute, Minneapolis, MN, USA; Division of Health Policy and Management, University of Minnesota, Minneapolis, MN, USA. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · Center for Health Research, Kaiser Permanente Hawaii, Honolulu, HI, USA; Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA. · Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Department Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA. · Department of General Internal Medicine, University Hospital of Bern, Bern, Switzerland. · Department of Medicine and Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA; Center for Chronic Disease Outcomes Research, VA Health Care System, Minneapolis, MN, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA. ·Bone · Pubmed #26115911.

ABSTRACT: Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increase in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15 years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related.

14 Article Arterialized venous bicarbonate is associated with lower bone mineral density and an increased rate of bone loss in older men and women. 2015

Tabatabai, L S / Cummings, S R / Tylavsky, F A / Bauer, D C / Cauley, J A / Kritchevsky, S B / Newman, A / Simonsick, E M / Harris, T B / Sebastian, A / Sellmeyer, D E / Anonymous4630819. ·Division of Endocrinology (L.S.T., D.E.S.), Johns Hopkins Hospital, Johns Hopkins School of Medicine, Baltimore, Maryland 21224 · California Pacific Medical Center Research Institute (S.R.C.), San Francisco, California 94118 · Department of Preventive Medicine (F.A.T.), University of Tennessee Health Science Center, Memphis, Tennessee 38163 · Department of Medicine (D.C.B., A.S.), School of Medicine, University of California, San Francisco, San Francisco, California 94143 · Department of Epidemiology (J.A.C., A.N.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 · Department of Internal Medicine (S.B.K.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157 · Translational Gerontology Branch (E.M.S.), National Institute on Aging, Baltimore, Maryland 21224 · and Laboratory of Epidemiology and Population Science (T.B.H.), National Institute on Aging, Bethesda, Maryland 20892. ·J Clin Endocrinol Metab · Pubmed #25642590.

ABSTRACT: CONTEXT: Higher dietary net acid loads have been associated with increased bone resorption, reduced bone mineral density (BMD), and increased fracture risk. OBJECTIVE: The objective was to compare bicarbonate (HCO3) measured in arterialized venous blood samples to skeletal outcomes. DESIGN: Arterialized venous samples collected from participants in the Health, Aging and Body Composition (Health ABC) Study were compared to BMD and rate of bone loss. SETTING: The setting was a community-based observational cohort. PARTICIPANTS: A total of 2287 men and women age 74 ± 3 years participated. INTERVENTION: Arterialized venous blood was obtained at the year 3 study visit and analyzed for pH and pCO2. HCO3 was determined using the Henderson-Hasselbalch equation. MAIN OUTCOME MEASURE: BMD was measured at the hip by dual-energy x-ray absorptiometry at the year 1 (baseline) and year 3 study visits. RESULTS: Plasma HCO3 was positively associated with BMD at both year 1 (P = .001) and year 3 (P = .001) in models adjusted for age, race, sex, clinic site, smoking, weight, and estimated glomerular filtration rate. Plasma HCO3 was inversely associated with rate of bone loss at the total hip over the 2.1 ± 0.3 (mean ± SD) years between the two bone density measurements (P < .001). Across quartiles of plasma HCO3, the rate of change in BMD over the 2.1 years ranged from a loss of 0.72%/y in the lowest quartile to a gain of 0.15%/y in the highest quartile of HCO3. CONCLUSIONS: Arterialized plasma HCO3 was associated positively with cross-sectional BMD and inversely with the rate of bone loss, implying that systemic acid-base status is an important determinant of skeletal health during aging. Ongoing bone loss was linearly related to arterialized HCO3, even after adjustment for age and renal function. Further research in this area may have major public health implications because reducing dietary net acid load is possible through dietary intervention or through supplementation with alkaline potassium compounds.

15 Article The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). 2015

Black, Dennis M / Reid, Ian R / Cauley, Jane A / Cosman, Felicia / Leung, Ping Chung / Lakatos, Peter / Lippuner, Kurt / Cummings, Steven R / Hue, Trisha F / Mukhopadhyay, Amitava / Tan, Monique / Aftring, R Paul / Eastell, Richard. ·University of California, San Francisco, CA, USA. ·J Bone Miner Res · Pubmed #25545380.

ABSTRACT: While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits.

16 Article Relationship between pretreatment rate of bone loss and bone density response to once-yearly ZOL: HORIZON-PFT extension study. 2015

Eastell, Richard / Boonen, Steven / Cosman, Felicia / Reid, Ian R / Palermo, Lisa / Cummings, Steven R / Black, Dennis M. ·Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK. ·J Bone Miner Res · Pubmed #25214069.

ABSTRACT: Several studies have shown that high bone turnover is associated with greater rates of bone loss and greater bone mineral density (BMD) response to antiresorptive therapy in postmenopausal osteoporosis. However, it is not known whether greater rates of bone loss before therapy are associated with greater BMD response to antiresorptive therapy. In the HORIZON-PFT study and its extension, one group of women who were randomized to receive placebo for 3 years (years 1, 2, and 3) were then switched to zoledronic acid (ZOL) 5 mg annually for up to three injections (years 4, 5, and 6, P3Z3 arm) (n = 1223). We measured total hip BMD at baseline, 1, 2, and 3 years on placebo and at 4.5 and 6 years on ZOL. The procollagen type I N-terminal propeptide (PINP) was measured at 3, 4.5, and 6 years. By design, not all subjects were followed for as long as 6 years, so this analysis focused on the results at 4.5 years. Those with the largest loss in total hip BMD on placebo in years 0 to 3 had the largest gain during ZOL (years 3 to 4.5): (r = -0.39, p < 0.0001). The change in total hip BMD in years 0 to 3 on placebo was related to the serum PINP at the end of the 3-year period (r = -0.24, p < 0.0001). The change in total hip BMD on ZOL from year 3 to 4.5 was related to the serum PINP at the end of the 3-year period (r = 0.26, p < 0.0001). We conclude that BMD response to ZOL is greater in postmenopausal women who had larger loss before treatment. This association may result from higher bone turnover being associated with both greater bone loss on placebo and greater BMD response to ZOL.

17 Article Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment? 2014

Cosman, Felicia / Cauley, Jane A / Eastell, Richard / Boonen, Steven / Palermo, Lisa / Reid, Ian R / Cummings, Steven R / Black, Dennis M. ·Helen Hayes Hospital (F.C.), West Haverstraw, New York 10993 · Department of Medicine (F.C.), Columbia University College of Physicians and Surgeons, New York, New York 10032 · Department of Epidemiology (J.A.C.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 · Academic Unit of Bone Metabolism (R.E.), University of Sheffield, Sheffield, United Kingdon, S5 7AU · Department of Experimental Medicine (S.B.) · Leuven University Hospital, Leuven, B-3000 Belgium · Department of Epidemiology and Department of Biostatistics (L.P., S.R.C., D.M.B.), University of California San Francisco, San Francisco, California 94107 · and Faculty of Medical and Health Sciences (I.R.R.), University of Auckland, Auckland, New Zealand, 1023. ·J Clin Endocrinol Metab · Pubmed #25215556.

ABSTRACT: CONTEXT: Data are needed to guide therapeutic decisions about stopping bisphosphonates after an initial treatment period. OBJECTIVE: To define significant predictors of fracture and quantify fracture incidence in risk factor-defined subgroups of women who discontinue zoledronic acid (ZOL) after 3 years of treatment. To determine if continuing ZOL reduces fracture risk in subgroups. DESIGN: This study is based on data from the 3 year extension of HORIZON. SETTING: Subjects were in the ZOL arm of the Multicenter HORIZON trial. PARTICIPANTS: One thousand two hundred thirty three women who previously received 3 ZOL treatments during the Core trial. INTERVENTION: Randomization to three additional annual ZOL (Z6, n = 616) or placebo infusions (Z3P3, n = 617). MAIN OUTCOMES: The risk of morphometric vertebral fractures (MorphVertFx) and clinical nonvertebral fractures (NVF). RESULTS: The incidence of MorphVertFx in Z3P3 was predicted by femoral neck (FN) t-score ≤-2.5 [OR 3.3 (1.4, 8.0), p = .008], total hip (TH) t-score ≤-2.5 [OR 4.0 (1.8, 9.0), p = .0007], and incident MorphVertFx during Core [OR 4.75 (1.4, 16.8), p < .015]. Incidence of NVF was predicted by TH t-score [for 1 decline, HR 1.7 (1.2, 2.6), p = .008], incident NVF during Core [HR 2.5 (1.2, 5.3), p = .014], and prevalent vertebral fracture [HR 3.0 (1.4, 6.3), p = .005]. For MorphVertFx, there were no significant treatment subgroup interactions; absolute fracture reductions with continued ZOL were greatest in high-risk subgroups. For NVF, there were no significant treatment reductions overall or in subgroups and no significant interactions. CONCLUSIONS: After 3 years of ZOL, in women who have a TH t-score above -2.5, no recent incident fracture and no more than one risk factor (almost 55% of the population), risk for subsequent fracture (over three additional years) is low if treatment is discontinued (for MorphVertFx, average risk 3.2% and for NVF, average risk 5.8%). In these patients, discontinuation for up to 3 years is reasonable.

18 Article Prediction models of prevalent radiographic vertebral fractures among older women. 2014

Schousboe, John T / Rosen, Harold R / Vokes, Tamara J / Cauley, Jane A / Cummings, Steven R / Nevitt, Michael / Black, Dennis M / Orwoll, Eric S / Kado, Deborah M / Ensrud, Kristine E / Anonymous4260786. ·Park Nicollet Osteoporosis Center and Institute for Research and Education, Minneapolis, MN, USA and Division of Health Policy and Management, University of Minnesota, Minneapolis, MN, USA. Electronic address: john.schousboe@parknicollet.com. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Department of Medicine, University of Chicago, Chicago, IL, USA. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · San Francisco Coordinating Center, California Pacific Medical Center, San Francisco, CA, USA. · Division of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA. · Bone and Mineral Unit, Oregon Health and Science University, Portland, OR, USA. · Departments of Family and Preventive Medicine and Internal Medicine, University of California at San Diego, San Diego, CA, USA. · Division of Epidemiology, University of Minnesota, Minneapolis, MN, USA and Minneapolis Veterans Administration Medical Center, Minneapolis, MN, USA. ·J Clin Densitom · Pubmed #24582085.

ABSTRACT: It is unknown how well prediction models incorporating multiple risk factors identify women with radiographic prevalent vertebral fracture (PVFx) compared with simpler models and what their value might be in clinical practice to select older women for lateral spine imaging. We compared 4 regression models for predicting PVFx in women aged 68 y and older enrolled in the Study of Osteoporotic Fractures with a femoral neck T-score ≤ -1.0, using area under receiving operator characteristic curves (AUROC) and a net reclassification index. The AUROC for a model with age, femoral neck bone mineral density, historical height loss (HHL), prior nonspine fracture, body mass index, back pain, and grip strength was only minimally better than that of a more parsimonious model with age, femoral neck bone mineral density, and historical height loss (AUROC 0.689 vs 0.679, p values for difference in 5 bootstrapped samples <0.001-0.35). The prevalence of PVFx among this older population of Caucasian women remained more than 20% even when women with low probability of PVFx, as estimated by the prediction models, were included in the screened population. These results suggest that lateral spine imaging is appropriate to consider for all Caucasian women aged 70 y and older with low bone mass to identify those with PVFx.

19 Article Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. 2014

Moayyeri, Alireza / Hsu, Yi-Hsiang / Karasik, David / Estrada, Karol / Xiao, Su-Mei / Nielson, Carrie / Srikanth, Priya / Giroux, Sylvie / Wilson, Scott G / Zheng, Hou-Feng / Smith, Albert V / Pye, Stephen R / Leo, Paul J / Teumer, Alexander / Hwang, Joo-Yeon / Ohlsson, Claes / McGuigan, Fiona / Minster, Ryan L / Hayward, Caroline / Olmos, José M / Lyytikäinen, Leo-Pekka / Lewis, Joshua R / Swart, Karin M A / Masi, Laura / Oldmeadow, Chris / Holliday, Elizabeth G / Cheng, Sulin / van Schoor, Natasja M / Harvey, Nicholas C / Kruk, Marcin / del Greco M, Fabiola / Igl, Wilmar / Trummer, Olivia / Grigoriou, Efi / Luben, Robert / Liu, Ching-Ti / Zhou, Yanhua / Oei, Ling / Medina-Gomez, Carolina / Zmuda, Joseph / Tranah, Greg / Brown, Suzanne J / Williams, Frances M / Soranzo, Nicole / Jakobsdottir, Johanna / Siggeirsdottir, Kristin / Holliday, Kate L / Hannemann, Anke / Go, Min Jin / Garcia, Melissa / Polasek, Ozren / Laaksonen, Marika / Zhu, Kun / Enneman, Anke W / McEvoy, Mark / Peel, Roseanne / Sham, Pak Chung / Jaworski, Maciej / Johansson, Åsa / Hicks, Andrew A / Pludowski, Pawel / Scott, Rodney / Dhonukshe-Rutten, Rosalie A M / van der Velde, Nathalie / Kähönen, Mika / Viikari, Jorma S / Sievänen, Harri / Raitakari, Olli T / González-Macías, Jesús / Hernández, Jose L / Mellström, Dan / Ljunggren, Osten / Cho, Yoon Shin / Völker, Uwe / Nauck, Matthias / Homuth, Georg / Völzke, Henry / Haring, Robin / Brown, Matthew A / McCloskey, Eugene / Nicholson, Geoffrey C / Eastell, Richard / Eisman, John A / Jones, Graeme / Reid, Ian R / Dennison, Elaine M / Wark, John / Boonen, Steven / Vanderschueren, Dirk / Wu, Frederick C W / Aspelund, Thor / Richards, J Brent / Bauer, Doug / Hofman, Albert / Khaw, Kay-Tee / Dedoussis, George / Obermayer-Pietsch, Barbara / Gyllensten, Ulf / Pramstaller, Peter P / Lorenc, Roman S / Cooper, Cyrus / Kung, Annie Wai Chee / Lips, Paul / Alen, Markku / Attia, John / Brandi, Maria Luisa / de Groot, Lisette C P G M / Lehtimäki, Terho / Riancho, José A / Campbell, Harry / Liu, Yongmei / Harris, Tamara B / Akesson, Kristina / Karlsson, Magnus / Lee, Jong-Young / Wallaschofski, Henri / Duncan, Emma L / O'Neill, Terence W / Gudnason, Vilmundur / Spector, Timothy D / Rousseau, François / Orwoll, Eric / Cummings, Steven R / Wareham, Nick J / Rivadeneira, Fernando / Uitterlinden, Andre G / Prince, Richard L / Kiel, Douglas P / Reeve, Jonathan / Kaptoge, Stephen K. ·Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ·Hum Mol Genet · Pubmed #24430505.

ABSTRACT: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

20 Article Standardising the descriptive epidemiology of osteoporosis: recommendations from the Epidemiology and Quality of Life Working Group of IOF. 2013

Kanis, J A / Adachi, J D / Cooper, C / Clark, P / Cummings, S R / Diaz-Curiel, M / Harvey, N / Hiligsmann, M / Papaioannou, A / Pierroz, D D / Silverman, S L / Szulc, P / Anonymous1101055. ·WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK, w.j.pontefract@sheffield.ac.uk. ·Osteoporos Int · Pubmed #23884436.

ABSTRACT: INTRODUCTION: The prevalence of osteoporosis as defined by the T-score is inconsistently reported in the literature which makes comparisons between studies problematic. METHODS: The Epidemiology and Quality of Life Working Group of IOF convened to make its recommendations and endorsement sought thereafter from the Committee of Scientific Advisors of IOF. RESULTS: The Committee of Scientific Advisors of IOF recommends that papers describing the descriptive epidemiology of osteoporosis using BMD at the femoral neck include T-scores derived from the National Health and Nutrition Examination Survey III reference database for femoral neck measurements in Caucasian women aged 20-29 years. CONCLUSIONS: It is expected that the use of the reference standard will help resolve difficulties in the comparison of results between studies and the comparative assessment of new technologies.

21 Article Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. 2013

Schwartz, Ann V / Schafer, Anne L / Grey, Andrew / Vittinghoff, Eric / Palermo, Lisa / Lui, Li-Yung L / Wallace, Robert B / Cummings, Steven R / Black, Dennis M / Bauer, Douglas C / Reid, Ian R. ·University of California San Francisco, San Francisco, CA, USA. aschwartz@psg.ucsf.edu ·J Bone Miner Res · Pubmed #23322676.

ABSTRACT: In rodent models, undercarboxylated osteocalcin (ucOC) acts as a hormone that promotes insulin sensitivity and secretion. If ucOC plays a similar role in humans, then antiresorptive therapies, which reduce ucOC levels, may increase the risk of insulin resistance and diabetes. We tested whether antiresorptive therapies result in higher fasting glucose, increased weight, or greater diabetes incidence in post hoc analyses of three randomized, placebo-controlled trials in postmenopausal women: Fracture Intervention Trial (FIT) (N = 6151) of alendronate (4 years), Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N = 7113) of zoledronic acid (3 years), and Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (N = 7076) of denosumab (3 years). Fasting glucose was measured annually in FIT and HORIZON in a subset of women, and every 6 months in FREEDOM in all participants. Weight was measured annually in all trials. Incident diabetes was identified from adverse event reports, initiation of diabetes medication, or elevated fasting glucose. Differences in fasting glucose changes from randomization to trial conclusion between treatment and placebo groups were not statistically significant: -0.47 mg/dL in FIT, 0.20 mg/dL in HORIZON-PFT, and 0.09 mg/dL in FREEDOM, all p > 0.6. Weight change differed between treatment and placebo groups in FIT (0.32 kg, p = 0.003) and FREEDOM (0.31 kg, p = 0.023) but not in HORIZON-PFT (0.15 kg, p = 0.132). In the three trials combined, diabetes occurred in 203 and 225 women assigned to treatment or placebo, respectively. Diabetes incidence was not increased in any of the treatment groups or in the pooled estimate (pooled relative risk [RR] = 0.90; 95% confidence interval [CI] 0.74-1.10). Antiresorptive therapy does not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women. Contrary to predictions from mouse models, reduced bone turnover does not appear to play a significant role in glucose metabolism in humans.

22 Article Cystatin C and risk of hip fractures in older women. 2013

Ensrud, Kristine E / Parimi, Neeta / Cauley, Jane A / Ishani, Areef / Slinin, Yelena / Hillier, Teresa A / Taylor, Brent C / Steffes, Michael / Cummings, Steven R / Anonymous4670746. ·Department of Medicine, University of Minnesota, Minneapolis, MN, USA. ensru001@umn.edu ·J Bone Miner Res · Pubmed #23300153.

ABSTRACT: To test the hypothesis that older women with higher cystatin C are at increased risk of hip fracture independent of traditional risk factors including hip bone mineral density (BMD), we performed a case-cohort analysis nested in a cohort of 4709 white women attending a Year 10 (1997-1998) examination of the Study of Osteoporotic Fractures that included a random sample of 1170 women and the first 300 women with incident hip fracture occurring after Year 10 examination. Serum cystatin C and creatinine were measured in Year 10 sera. In a model adjusted for age, clinical site, body mass index, and total hip BMD, higher cystatin C was associated with an increased risk of hip fracture (p for linear trend 0.008) with women in quartile 4 having a 1.9-fold higher risk (hazard ratio [HR] 1.91; 95% confidence interval [CI], 1.24-2.95) compared with those in quartile 1 (referent group). Further adjustment for additional risk factors only slightly attenuated the association; the risk for hip fracture was 1.7-fold higher (HR 1.74; 95% CI, 1.11-2.72) in women in quartile 4 compared with those in quartile 1. In contrast, neither serum creatinine nor creatinine-based estimated glomerular filtration rate (eGFRCr ) were associated with risk of hip fracture. Older women with higher cystatin C, but not higher serum creatinine or lower eGFRCr , have an increased risk of hip fracture independent of traditional risk factors. These findings suggest that cystatin C may be a promising biomarker for identification of older adults at high risk of hip fracture.

23 Article Goal-directed treatment of osteoporosis. 2013

Cummings, Steven R / Cosman, Felicia / Eastell, Richard / Reid, Ian R / Mehta, Mona / Lewiecki, E Michael. ·San Francisco Coordinating Center, California Pacific Medical Center Research Institute and the Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. scummings@sfcc-cpmc.net ·J Bone Miner Res · Pubmed #23300146.

ABSTRACT: Drug treatment for osteoporosis typically begins with an oral bisphosphonate, regardless of initial bone mineral density (BMD) or fracture risk, and decisions to continue or change treatment are often based on evidence of response to treatment based on changes in BMD, bone turnover markers, and occurrence of fractures. This pattern differs from preventive therapy for other conditions, such as hypertension, where treatment is based on achieving a goal. We propose that a goal be established to guide treatments to reduce fracture risk. The goal could be a certain risk of fracture or level of BMD. Goal-directed treatment would individualize the initial choice of treatment based on the probability that alternatives would achieve the patient's goal. In contrast to changing treatments based on years of use or failure to respond, the patient's BMD and risk would be reassessed periodically and decisions to stop or change treatment would be based on achieving or maximizing the chance of reaching an acceptable level of fracture risk or BMD. The acceptance of goal-directed treatment and application to practice will require a consensus on a number of issues about goals along with models of fracture risk while on treatment and probabilities of achieving goals. The result could be more rational and effective use of the expanding array of treatments for osteoporosis.

24 Article Cost-effectiveness of bone densitometry among Caucasian women and men without a prior fracture according to age and body weight. 2013

Schousboe, J T / Gourlay, M / Fink, H A / Taylor, B C / Orwoll, E S / Barrett-Connor, E / Melton, L J / Cummings, S R / Ensrud, K E / Anonymous4910718. ·Park Nicollet Institute, Minneapolis, MN, USA. john.schousboe@parknicollet.com ·Osteoporos Int · Pubmed #22349916.

ABSTRACT: INTRODUCTION: Bone densitometry may be more cost-effective for those with lower body weight since the prevalence of osteoporosis is higher for those with low body weight. Our purpose was to estimate weight thresholds below which bone densitometry is cost-effective for women and men without a prior clinical fracture at ages 55, 60, 65, 75, and 80 years. METHODS: We used a microsimulation model to estimate the costs and health benefits of bone densitometry and 5 years of fracture prevention therapy for those without prior fracture but with femoral neck osteoporosis (T-score ≤ -2.5) and a 10-year hip fracture risk of ≥3%. Threshold pre-test probabilities of low BMD warranting drug therapy at which bone densitometry is cost-effective were calculated. Corresponding body weight thresholds were estimated using data from the Study of Osteoporotic Fractures (SOF), the Osteoporotic Fractures in Men (MrOS) study, and the National Health and Nutrition Examination Survey (NHANES) for 2005-2006. RESULTS: Assuming a willingness to pay of $75,000 per quality adjusted life year (QALY) and drug cost of $500/year, body weight thresholds below which bone densitometry is cost-effective for those without a prior fracture were 74, 90, and 100 kg, respectively, for women aged 55, 65, and 80 years; and were 67, 101, and 108 kg, respectively, for men aged 55, 75, and 80 years. CONCLUSIONS: For women aged 55-65 years and men aged 55-75 years without a prior fracture, body weight can be used to select those for whom bone densitometry is cost-effective.

25 Article Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. 2012

Adami, Silvano / Libanati, Cesar / Boonen, Steven / Cummings, Steven R / Ho, Pei-Ran / Wang, Andrea / Siris, Ethel / Lane, Joseph / Anonymous3440740 / Adachi, Jonathan D / Bhandari, Mohit / de Gregorio, Luiz / Gilchrist, Nigel / Lyritis, George / Möller, Gerd / Palacios, Santiago / Pavelka, Karel / Heinrich, Resch / Roux, Christian / Uebelhart, Daniel. ·Faculty of Medicine & Surgery, University of Verona, P. le Scuro 10, 37134, Verona, Italy. ·J Bone Joint Surg Am · Pubmed #23097066.

ABSTRACT: BACKGROUND: Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture. METHODS: Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture. RESULTS: Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009). CONCLUSIONS: Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.

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