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Osteoporosis: HELP
Articles by Henry G. Bone
Based on 29 articles published since 2008
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Between 2008 and 2019, H. Bone wrote the following 29 articles about Osteoporosis.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Future directions in osteoporosis therapeutics. 2012

Bone, Henry. ·Section of Endocrinology and Metabolism, Michigan Bone and Mineral Clinic, St. John Hospital and Medical Center, 22201 Moross Road, Detroit, MI 48236, USA. hgbone.md@att.net ·Endocrinol Metab Clin North Am · Pubmed #22877435.

ABSTRACT: Future directions in osteoporosis treatment will include development of medications with increasingly precise mechanistic targets, including the RANK-ligand pathway, cathepsin K inhibition, and Wnt signaling manipulation. More gains are likely with anabolics and newer antiresorptives that cause little or no suppression of formation. Optimal treatment of osteoporosis may require coordination of anabolic and antiresorptive treatment, following stimulation of bone formation with consolidation and long-term maintenance. Some well-established drugs may be useful in such regimens. We can also anticipate emphasis on cost containment using currently available drugs, especially as they become generic. Effective implementation and treatment continuity will be important themes.

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

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

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

3 Clinical Trial Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension. 2017

Watts, Nelson B / Brown, Jacques P / Papapoulos, Socrates / Lewiecki, E Michael / Kendler, David L / Dakin, Paula / Wagman, Rachel B / Wang, Andrea / Daizadeh, Nadia S / Smith, Shawna / Bone, Henry G. ·Mercy Health, Cincinnati, OH, USA. · Laval University and CHU de Québec Research Centre, Quebec City, Canada. · Leiden University Medical Center, Leiden, The Netherlands. · New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA. · University of British Columbia, Vancouver, Canada. · Amgen Inc., Thousand Oaks, CA, USA. · Michigan Bone and Mineral Clinic, Detroit, MI, USA. ·J Bone Miner Res · Pubmed #28277603.

ABSTRACT: Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3-year fracture trial FREEDOM, denosumab 60 mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low-frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3-year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long-term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either low-frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.

4 Clinical Trial The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. 2015

Papapoulos, S / Lippuner, K / Roux, C / Lin, C J F / Kendler, D L / Lewiecki, E M / Brandi, M L / Czerwiński, E / Franek, E / Lakatos, P / Mautalen, C / Minisola, S / Reginster, J Y / Jensen, S / Daizadeh, N S / Wang, A / Gavin, M / Libanati, C / Wagman, R B / Bone, H G. ·Center for Bone Quality, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. M.V.Iken@lumc.nl. · Berne University Hospital and University, Berne, Switzerland. · Paris Descartes University, Paris, France. · Amgen Inc, Thousand Oaks, CA, USA. · University of British Columbia, Vancouver, BC, Canada. · New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA. · University of Florence, Florence, Italy. · Krakow Medical Center, Krakow, Poland. · Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. · Semmelweis University, Budapest, Hungary. · Centro de Osteopatias Medicas, Buenos Aires, Argentina. · Sapienza University, Rome, Italy. · University of Liège, Liège, Belgium. · Center for Clinical and Basic Research, Ballerup, Denmark. · Michigan Bone & Mineral Clinic, Detroit, MI, USA. ·Osteoporos Int · Pubmed #26202488.

ABSTRACT: INTRODUCTION: This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. METHODS: Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. RESULTS: Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. CONCLUSIONS: Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

5 Clinical Trial A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial. 2015

Langdahl, Bente L / Teglbjærg, Christence Stubbe / Ho, Pei-Ran / Chapurlat, Roland / Czerwinski, Edward / Kendler, David L / Reginster, Jean-Yves / Kivitz, Alan / Lewiecki, E Michael / Miller, Paul D / Bolognese, Michael A / McClung, Michael R / Bone, Henry G / Ljunggren, Östen / Abrahamsen, Bo / Gruntmanis, Ugis / Yang, Yu-Ching / Wagman, Rachel B / Mirza, Faisal / Siddhanti, Suresh / Orwoll, Eric. ·Aarhus University Hospital (B.L.L.), DK-8000 Aarhus, Denmark · Center for Clinical and Basic Research (C.S.T.), 2750 Ballerup, Denmark · Amgen Inc. (P.-R.H., Y.-C.Y., R.B.W., F. M., S.S.), Thousand Oaks, California 91320 · INSERM UMR 1033 (R.C.), Université de Lyon, Hôpital Edouard Herriot, F-69437, Lyon, France · Krakow Medical Center (E.C.), Krakow, 31-501 Poland · University of British Columbia (D.L.K.), Vancouver, British Columbia V6T 1Z4, Canada · University of Liège (J.-Y.R.), 4000 Liège, Belgium · Altoona Center for Clinical Research (A.K.), Duncansville, Pennsylvania 16635 · New Mexico Clinical Research and Osteoporosis Center (E.M.L.), Albuquerque, New Mexico 87106 · Colorado Center for Bone Research (P.D.M.), Lakewood, Colorado 80227 · Bethesda Health Research Center (M.A.B.), Bethesda, Maryland 20817 · Oregon Osteoporosis Center (M.R.M.), Portland, Oregon 97213 · Michigan Bone and Mineral Clinic (H.G.B.), Detroit, Michigan 48236 · Uppsala University (Ö.L.), 751 05 Uppsala, Sweden · University of Southern Denmark and Glostrup Hospital (B.A.), DK-5000 Odense and Copenhagen, Denmark · Dallas Veterans Affairs Medical Center and University of Texas Southwestern (U.G.), Dallas, Texas 75390 · and Oregon Health and Science University (E.O.), Portland, Oregon 97239. ·J Clin Endocrinol Metab · Pubmed #25607608.

ABSTRACT: CONTEXT: One in 4 men in the United States aged >50 years will have an osteoporosis-related fracture. Fewer data are available on osteoporosis treatment in men than in women. OBJECTIVE: The purpose of this study was to evaluate denosumab therapy in men with low bone mineral density (BMD). DESIGN: This was a phase 3 study with 2 treatment periods: a previously reported 12-month double-blind, placebo-controlled phase and a 12-month open-label phase. SETTING: This was a multicenter study conducted in North America and Europe. PARTICIPANTS: A total of 228 men entered the open-label phase and 219 completed the study. INTERVENTION: Men from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of denosumab sc every 6 months. MAIN OUTCOME MEASURES: BMD, serum collagen type I C-telopeptide, and safety were measured. RESULTS: During the open-label phase, continued BMD increases occurred with long-term denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all P < .01). The crossover group showed BMD gains after 12 months of denosumab treatment similar to those of the long-term denosumab group during the first treatment year. Significant reductions in serum collagen type I C-teleopeptide were observed after denosumab administration. Adverse event rates were similar between groups, and no new safety signals were identified. CONCLUSIONS: In men with low BMD, denosumab treatment for a second year continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. BMD increased in men initiating denosumab during the second year. These effects were similar to those previously seen in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy.

6 Clinical Trial Efficacy and safety of oral recombinant calcitonin tablets in postmenopausal women with low bone mass and increased fracture risk: a randomized, placebo-controlled trial. 2014

Binkley, N / Bone, H / Gilligan, J P / Krause, D S. ·University of Wisconsin Osteoporosis Clinical Center and Research Program, Madison, WI, USA, nbinkley@wisc.edu. ·Osteoporos Int · Pubmed #25027109.

ABSTRACT: INTRODUCTION: An investigational oral salmon calcitonin preparation was previously shown to increase lumbar spine BMD in postmenopausal women with osteoporosis. Our objective was to evaluate the use of this agent in postmenopausal women with low bone mass and at increased fracture risk but not meeting BMD criteria for osteoporosis. METHODS: Treatment-naïve women were randomized to receive oral recombinant salmon calcitonin tablets or placebo once daily for 1 year. Dual-energy X-ray absorptiometry was performed at baseline and at study weeks 28 and 54. CTx-1, a bone resorption marker, was obtained at the same time points. Subjects returned periodically for tolerability assessment and adverse event (AE) recording. RESULTS: One hundred twenty-nine women in the USA were randomized, 86 to calcitonin and 43 to placebo. Calcitonin recipients experienced a significant increase from baseline in lumbar spine BMD; the difference compared with placebo was significant. Dosing at bedtime or with dinner was equally effective. CTx-1 was suppressed in calcitonin recipients but not in placebo subjects. Gastrointestinal AEs were common, but the overall safety profile was comparable between groups. CONCLUSIONS: Oral calcitonin may provide a useful therapeutic alternative for some women with low bone mass.

7 Clinical Trial Romosozumab in postmenopausal women with low bone mineral density. 2014

McClung, Michael R / Grauer, Andreas / Boonen, Steven / Bolognese, Michael A / Brown, Jacques P / Diez-Perez, Adolfo / Langdahl, Bente L / Reginster, Jean-Yves / Zanchetta, Jose R / Wasserman, Scott M / Katz, Leonid / Maddox, Judy / Yang, Yu-Ching / Libanati, Cesar / Bone, Henry G. ·From the Oregon Osteoporosis Center, Portland (M.R.M.) · Amgen, Thousand Oaks, CA (A.G., S.M.W., L.K., J.M., Y.-C.Y., C.L.) · Leuven University, Leuven (S.B.), and University of Liege, Liege (J.-Y.R.) - both in Belgium · Bethesda Health Research Center, Bethesda, MD (M.A.B.) · Laval University and Centre Hospitalier Universitaire de Québec Research Centre, Quebec, QC, Canada (J.P.B.) · Hospital del Mar, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad, Autonomous University of Barcelona, Barcelona (A.D.-P.) · Aarhus University Hospital, Aarhus, Denmark (B.L.L.) · Instituto de Investigaciones Metabólicas, Buenos Aires (J.R.Z.) · and Michigan Bone and Mineral Clinic, Detroit (H.G.B.). ·N Engl J Med · Pubmed #24382002.

ABSTRACT: BACKGROUND: Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS: In a phase 2, multicenter, international, randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS: All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS: In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).

8 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.

9 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.

10 Clinical Trial Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. 2011

Bone, Henry G / Bolognese, Michael A / Yuen, Chui Kin / Kendler, David L / Miller, Paul D / Yang, Yu-Ching / Grazette, Luanda / San Martin, Javier / Gallagher, J Christopher. ·Michigan Bone and Mineral Clinic, Detroit, Michigan 48236, USA. hgbone.md@att.net ·J Clin Endocrinol Metab · Pubmed #21289258.

ABSTRACT: CONTEXT: Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. OBJECTIVE: The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. DESIGN: We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. PARTICIPANTS: A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. INTERVENTIONS: Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. MAIN OUTCOME MEASURES: We measured the percentage changes in BMD and BTM, and evaluated safety. RESULTS: Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. CONCLUSIONS: In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.

11 Clinical Trial Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. 2010

Bone, Henry G / McClung, Michael R / Roux, Christian / Recker, Robert R / Eisman, John A / Verbruggen, Nadia / Hustad, Carolyn M / DaSilva, Carolyn / Santora, Arthur C / Ince, B Avery. ·Michigan Bone and Mineral Clinic, Detroit, MI 48236, USA. hgbone.md@att.net ·J Bone Miner Res · Pubmed #19874198.

ABSTRACT: Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.

12 Clinical Trial Preference and satisfaction with a 6-month subcutaneous injection versus a weekly tablet for treatment of low bone mass. 2010

Kendler, D L / Bessette, L / Hill, C D / Gold, D T / Horne, R / Varon, S F / Borenstein, J / Wang, H / Man, H-S / Wagman, R B / Siddhanti, S / Macarios, D / Bone, H G. ·Prohealth Clinical Research, University of British Columbia, Vancouver, BC, Canada. kendler@ca.inter.net ·Osteoporos Int · Pubmed #19657689.

ABSTRACT: INTRODUCTION: The PSQ compares patient preference and satisfaction between a 6-month subcutaneous injection and a weekly oral tablet for treatment of bone loss. METHODS: Postmenopausal women with low bone mass who enrolled in two separate randomized phase 3 double-blind, double-dummy studies received a 6-month subcutaneous denosumab injection (60 mg) plus a weekly oral placebo or a weekly alendronate tablet (70 mg) plus a 6-month subcutaneous placebo injection. After 12 months, patients completed the PSQ to rate their preference, satisfaction, and degree of bother with each regimen. RESULTS: Most enrolled patients (1,583 out of 1,693; 93.5%) answered >or=1 item of the PSQ. Significantly more patients preferred and were more satisfied with the 6-month injection versus the weekly tablet (P < 0.001). More patients reported no bother with the 6-month injection (90%) than the weekly tablet (62%). CONCLUSION: Patients preferred, were more satisfied, and less bothered with a 6-month injection regimen for osteoporosis.

13 Clinical Trial Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. 2009

Ellis, Georgiana K / Bone, Henry G / Chlebowski, Rowan / Paul, Devchand / Spadafora, Silvana / Fan, Michelle / Kim, Dennis. ·Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Mail Stop G3-200, Seattle, WA, 98109-1023, USA. gellis@u.washington.edu ·Breast Cancer Res Treat · Pubmed #19308727.

ABSTRACT: Denosumab increased lumbar spine bone mineral density (BMD) versus placebo in a 2-year, randomized, placebo-controlled, phase 3 study of patients with hormone-receptor-positive, non-metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy. In subgroup analyses at 12 and 24 months, we evaluated factors (duration and type of aromatase inhibitor, tamoxifen use, age, time since menopause, body mass index, T-score) that might influence BMD at the lumbar spine, total hip, femoral neck, and 1/3 radius. Patients were randomized to receive placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months. In all subgroups, 12 or 24 months' treatment with denosumab was associated with larger BMD gains than placebo across multiple skeletal sites. Most increases were statistically significant (P < 0.05). Twice-yearly administration of denosumab, regardless of patient subgroup or skeletal site, resulted in consistent increases in BMD versus placebo at 12 and 24 months.

14 Clinical Trial Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. 2008

Ellis, Georgiana K / Bone, Henry G / Chlebowski, Rowan / Paul, Devchand / Spadafora, Silvana / Smith, Judy / Fan, Michelle / Jun, Susie. ·Seattle Cancer Care Alliance, Seattle, WA 98109-1023, USA. gellis@u.washington.edu ·J Clin Oncol · Pubmed #18725648.

ABSTRACT: PURPOSE: Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, to protect against aromatase inhibitor-induced bone loss. PATIENTS AND METHODS: Eligible women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (< or = 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). RESULTS: At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. CONCLUSION: In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.

15 Clinical Trial Adherence to and gastrointestinal tolerability of monthly oral or quarterly intravenous ibandronate therapy in women with previous intolerance to oral bisphosphonates: a 12-month, open-label, prospective evaluation. 2008

Lewiecki, E Michael / Babbitt, Ann M / Piziak, Veronica K / Ozturk, Zafer E / Bone, Henry G. ·New Mexico Clinical Research & Osteoporosis Center, Albuquerque, New Mexico 87106, USA. lewiecki@aol.com ·Clin Ther · Pubmed #18498910.

ABSTRACT: BACKGROUND: Gastrointestinal (GI) symptoms and high dosing frequency have been cited as reasons for inadequate adherence to daily or weekly oral bisphosphonate therapy. Inadequate adherence may lead to poor therapeutic outcomes. OBJECTIVE: The PRIOR study evaluated adherence to and GI tolerability of monthly therapy with oral and quarterly intravenous ibandronate in postmenopausal women with osteoporosis or osteopenia. METHODS: This 12-month, multicenter, prospective, nonrandomized, open-label, noninferiority study included postmenopausal women with osteoporosis or osteopenia who had discontinued previous daily or weekly oral bisphosphonate therapy because of GI intolerance. Participants chose to receive either monthly oral ibandronate 150 mg or quarterly intravenous ibandronate 3 mg and were permitted to switch formulations once during the study. For oral treatment, adherence was assessed based on doses taken, as recorded on the case-report form; for intravenous treatment, adherence was assessed based on doses administered, as recorded by study site personnel. Participants who took >or=75% of protocol-specified doses were considered adherent. The rate of adherence to oral ibandronate was protocol defined as noninferior to that of intravenous ibandronate if the upper limit of the 2-sided 90% CI for the adjusted difference in adherence rates was >20%. At screening, participants assessed the tolerability of their previous bisphosphonate therapy using the GI Experience Survey; using the same instrument, they assessed the tolerability of ibandronate 1 month from baseline and at months 4, 7, and 10. RESULTS: Of 543 participants in the intent-to-treat population, 147 (27.1%) chose to receive oral treatment and 396 (72.9%) chose to receive intravenous treatment. The mean age of participants was approximately 66 years in both groups, and >90% of participants were white. A significantly greater proportion of participants who selected intravenous versus oral treatment had a primary diagnosis of osteoporosis (72.2% vs 57.1%, respectively; P<0.001) and a history of fracture as an adult (35.6% vs 22.4%; P >or= 0.004); significantly fewer recipients of intravenous versus oral ibandronate were currently working (29.0% vs 39.5%; P >or= 0.021). Overall, 82.9% of participants had previously received alendronate and 44.9% had previously received risedronate. Eleven participants switched from oral to intravenous therapy and 16 switched from intravenous to oral therapy during the study. In the perprotocol population, 69.7% of participants in the oral group (101/145) and 82.9% of participants in the intravenous group (325/392) were adherent to their originally selected therapy. Adherence to oral therapy fell within the prespecified boundary for noninferiority to intravenous therapy (adjusted difference: 12.4%; 90% CI, 5.1-19.7). Mean GI tolerance scores were significantly improved from screening at all subsequent assessment times in both treatment groups (P < 0.001); >75% of participants had a >or=10% increase in GI tolerability scores from screening. Both dosing regimens were generally well tolerated. CONCLUSION: Self-selected monthly oral or quarterly intravenous ibandronate therapy was associated with high adherence rates among these postmenopausal women with osteoporosis or osteopenia who had previously discontinued oral bisphosphonate treatment because of GI intolerance.

16 Clinical Trial Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. 2008

Bone, Henry G / Bolognese, Michael A / Yuen, Chui Kin / Kendler, David L / Wang, Huei / Liu, Yu / San Martin, Javier. ·Michigan Bone and Mineral Clinic, 22201 Moross Road, Detroit, MI 48236, USA. hgbone.md@att.net ·J Clin Endocrinol Metab · Pubmed #18381571.

ABSTRACT: CONTEXT: Denosumab is an investigational fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, a mediator of osteoclastogenesis and osteoclast survival. OBJECTIVE: This study evaluated the ability of denosumab to increase bone mineral density (BMD) and decrease bone turnover markers (BTMs) in early and later postmenopausal women with low BMD. DESIGN AND SETTING: This 2-yr randomized, double-blind, placebo-controlled study was conducted in North America. PARTICIPANTS: Subjects included 332 postmenopausal women with lumbar spine BMD T-scores between -1.0 and -2.5. INTERVENTIONS: SUBJECTS were randomly assigned to receive denosumab sc, 60 mg every 6 months, or placebo. Randomization was stratified by time since onset of menopause (< or =5 yr or > 5 yr). MAIN OUTCOME MEASURES: The primary end point was the percent change in lumbar spine BMD by dual-energy x-ray absorptiometry at 24 months. Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography; percent change in BMD by dual-energy x-ray absorptiometry for the total hip, one-third radius, and total body; hip structural analysis; percent change in BTMs; and safety. RESULTS: Denosumab significantly increased lumbar spine BMD, compared with placebo at 24 months (6.5 vs. -0.6%; P<0.0001) with similar results for both strata. Denosumab also produced significant increases in BMD at the total hip, one-third radius, and total body (P < 0.0001 vs. placebo); increased distal radius volumetric BMD (P < 0.01); improved hip structural analysis parameters; and significantly suppressed serum C-telopeptide, tartrate-resistant acid phosphatase-5b, and intact N-terminal propeptide of type 1 procollagen. The overall incidence of adverse events was similar between both study groups. CONCLUSIONS: Twice-yearly denosumab increased BMD and decreased BTMs in early and later postmenopausal women.

17 Article The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. 2019

Kendler, D L / Chines, A / Brandi, M L / Papapoulos, S / Lewiecki, E M / Reginster, J-Y / Muñoz Torres, M / Wang, A / Bone, H G. ·University of British Columbia, Vancouver, BC, Canada. davidkendler@gmail.com. · Amgen Inc., Thousand Oaks, CA, USA. · University of Florence, Florence, Italy. · Leiden University Medical Center, Leiden, The Netherlands. · New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA. · University of Liège, Liège, Belgium. · Hospital Universitario San Cecilio, Granada, Spain. · Michigan Bone and Mineral Clinic, Detroit, MI, USA. ·Osteoporos Int · Pubmed #30244369.

ABSTRACT: This post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response. INTRODUCTION: This analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment. METHODS: In FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Here we compare subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM. RESULTS: During FREEDOM, 438 placebo- and 272 denosumab-treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43-0.81]; P = 0.0012). CONCLUSIONS: These data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.

18 Article ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis. 2018

Bone, Henry G / Cosman, Felicia / Miller, Paul D / Williams, Gregory C / Hattersley, Gary / Hu, Ming-Yi / Fitzpatrick, Lorraine A / Mitlak, Bruce / Papapoulos, Socrates / Rizzoli, René / Dore, Robin K / Bilezikian, John P / Saag, Kenneth G. ·Michigan Bone and Mineral Clinic, P.C., Detroit, Michigan. · Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan. · Department of Clinical Medicine, Columbia University, New York, New York. · Clinical Research Center, Helen Hayes Hospital, West Haverstraw, New York. · Colorado Center for Bone Research, Lakewood, Colorado. · Radius Health, Inc., Waltham, Massachusetts. · Center for Bone Quality, Leiden University Medical Center, ZA Leiden, Netherlands. · Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland. · David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California. · Division of Endocrinology, Columbia University College of Physicians and Surgeons, New York, New York. · Division of Clinical Immunology and Rheumatology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. ·J Clin Endocrinol Metab · Pubmed #29800372.

ABSTRACT: Purpose: In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods: Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results: Five hundred fifty-eight women from ACTIVE's ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan-Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Conclusions: Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures.

19 Article Effect of denosumab on trabecular bone score in postmenopausal women with osteoporosis. 2017

McClung, M R / Lippuner, K / Brandi, M L / Zanchetta, J R / Bone, H G / Chapurlat, R / Hans, D / Wang, A / Zapalowski, C / Libanati, C. ·Oregon Osteoporosis Center, Portland, OR, USA. mmcclung.ooc@gmail.com. · Institute for Health and Ageing, Australian Catholic University, Melbourne, Australia. mmcclung.ooc@gmail.com. · University of Berne, Berne, Switzerland. · University of Florence, Florence, Italy. · Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina. · Michigan Bone and Mineral Clinic, Detroit, MI, USA. · INSERM UMR 1033, Université de Lyon, Hôpital Edouard Herriot, Lyon, France. · Lausanne University Hospital, Center of Bone Diseases, Lausanne, Switzerland. · Amgen Inc., Thousand Oaks, CA, USA. · Radius Health, Waltham, MA, USA. · UCB Pharma, Brussels, Belgium. ·Osteoporos Int · Pubmed #28748386.

ABSTRACT: Trabecular bone score (TBS) assesses bone quality in the lumbar spine using dual-energy X-ray absorptiometry (DXA) scans. In postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of bone mineral density (BMD). This practical technique may have a role in managing patients with osteoporosis. INTRODUCTION: TBS, a gray-level texture index determined from lumbar spine DXA scans, correlates with bone microarchitecture and enhances assessment of vertebral fracture risk independently of BMD. In the FREEDOM study, denosumab increased BMD and reduced new vertebral fractures in postmenopausal women with osteoporosis. This retrospective analysis explored the effect of denosumab on TBS and the association between TBS and BMD in FREEDOM. METHODS: Postmenopausal women with lumbar spine or total hip BMD T-score <-2.5 and -4.0 or higher at both sites received placebo or denosumab 60 mg subcutaneously every 6 months. TBS indices were determined from DXA scans at baseline and months 12, 24, and 36 in a subset of 285 women (128 placebo, 157 denosumab) who had TBS values at baseline and ≥1 postbaseline visit. RESULTS: Baseline characteristics were comparable between treatment groups; mean (SD) lumbar spine BMD T-score was -2.79 (0.64), and mean (standard deviation [SD]) TBS was 1.200 (0.101) overall. In the placebo group, BMD and TBS increased by ≤0.2% or decreased from baseline at each visit. In the denosumab group, progressive increases from baseline at 12, 24, and 36 months were observed for BMD (5.7, 7.8, and 9.8%) and TBS (1.4, 1.9, and 2.4%). Percentage changes in TBS were statistically significant compared with baseline (p < 0.001) and placebo (p ≤ 0.014). TBS was largely unrelated to BMD, regardless of treatment, either at baseline or for annual changes from baseline (all r CONCLUSIONS: In postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of BMD.

20 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.

21 Article Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. 2015

Bone, H G / Dempster, D W / Eisman, J A / Greenspan, S L / McClung, M R / Nakamura, T / Papapoulos, S / Shih, W J / Rybak-Feiglin, A / Santora, A C / Verbruggen, N / Leung, A T / Lombardi, A. ·Michigan Bone & Mineral Clinic, Detroit, MI, USA, hgbone.md@att.net. ·Osteoporos Int · Pubmed #25432773.

ABSTRACT: SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

22 Article Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate. 2014

Brown, J P / Roux, C / Ho, P R / Bolognese, M A / Hall, J / Bone, H G / Bonnick, S / van den Bergh, J P / Ferreira, I / Dakin, P / Wagman, R B / Recknor, C. ·CHU de Québec Research Centre and Laval University, Room S-763, 2705 Laurier Boulevard, Quebec City, QC, G1V 4G2, Canada, jacques.brown@crchul.ulaval.ca. ·Osteoporos Int · Pubmed #24676847.

ABSTRACT: INTRODUCTION: A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate). METHODS: In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months (N = 852) or oral BP 150 mg monthly (N = 851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed. RESULTS: In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine (p < 0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) (p < 0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 (p < 0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups. CONCLUSIONS: Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment.

23 Article Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. 2013

Recknor, Chris / Czerwinski, Edward / Bone, Henry G / Bonnick, Sydney L / Binkley, Neil / Palacios, Santiago / Moffett, Alfred / Siddhanti, Suresh / Ferreira, Irene / Ghelani, Prayashi / Wagman, Rachel B / Hall, Jesse W / Bolognese, Michael A / Benhamou, Claude-Laurent. ·United Osteoporosis Centers, Gainesville, Georgia 30501, USA. crecknor@uochs.org ·Obstet Gynecol · Pubmed #23812464.

ABSTRACT: OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was -81.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified.

24 Article Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis. 2013

Black, D M / Bilezikian, J P / Greenspan, S L / Wüster, C / Muñoz-Torres, M / Bone, H G / Rosen, C J / Andersen, H S / Hanley, D A. ·Department of Epidemiology and Biostatistics, University of California, San Fransisco, Suite 5700, 185 Berry Street, San Francisco, CA 94107, USA. dblack@psg.ucsf.edu ·Osteoporos Int · Pubmed #22930240.

ABSTRACT: INTRODUCTION: There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. METHODS: Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. RESULTS: PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p<0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with ≥80% adherence to daily injections of PTH(1-84) (8.3% in adherent vs 4.9% in poorly adherent patients). Total hip BMD gains were 1.7% in adherent vs 0.6% in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. CONCLUSIONS: PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy.

25 Article Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. 2012

McClung, Michael R / Boonen, Steven / Törring, Ove / Roux, Christian / Rizzoli, René / Bone, Henry G / Benhamou, Claude-Laurent / Lems, Willem F / Minisola, Salvatore / Halse, Johan / Hoeck, Hans C / Eastell, Richard / Wang, Andrea / Siddhanti, Suresh / Cummings, Steven R. ·Oregon Osteoporosis Center, Portland, OR 97213, USA. mmcclung@orost.com ·J Bone Miner Res · Pubmed #21976367.

ABSTRACT: Denosumab reduces the risk of new vertebral and nonvertebral fractures. Previous trials suggest that the efficacy of antiresorptives on fractures might differ by patients' characteristics, such as age, bone mineral density (BMD), and fracture history. In the FREEDOM study, 7808 women aged 60 to 90 years with osteoporosis were randomly assigned to receive subcutaneous injections of denosumab (60 mg) or placebo every 6 months for 3 years. New vertebral and nonvertebral fractures were radiologically confirmed. Subgroup analyses described in this article were prospectively planned before study unblinding to evaluate the effect of denosumab on new vertebral and nonvertebral fractures across various subgroups. Compared with placebo, denosumab decreased the risk of new vertebral fractures in the overall study population over 3 years. This effect did not significantly differ for any of the nine subgroups analyzed (p > 0.09 for all potential interactions). Denosumab also reduced all nonvertebral fractures by 20% in the full study cohort over 3 years. This risk reduction was statistically significant in women with a baseline femoral neck BMD T-score ≤ -2.5 but not in those with a T-score > -2.5; in those with a body mass index (BMI) < 25 kg/m(2) but not ≥ 25 kg/m(2); and in those without but not with a prevalent vertebral fracture. These differential treatment effects were not explained by differences in BMD responses to denosumab. Denosumab 60 mg administered every 6 months for 3 years in women with osteoporosis reduced the risk of new vertebral fractures to a similar degree in all subgroups. The effect of denosumab on nonvertebral fracture risk differed by femoral neck BMD, BMI, and prevalent vertebral fracture at baseline.

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