10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension
University of Michigan1, Amgen2, University of Florence3, Laval University4, University of Lyon5, University of California, San Francisco6, University of Graz7, University of British Columbia8, University of Bern9, University of Liège10, Paris Descartes University11, Columbia University12, Leiden University Medical Center13
TL;DR: 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, and serious adverse event rates were generally stable over time.
About: This article is published in The Lancet Diabetes & Endocrinology.The article was published on 2017-07-01. It has received 590 citations till now. The article focuses on the topics: Denosumab & Femoral neck.
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Loyola University Chicago1, Cornell University2, University of Wisconsin-Madison3, University of Cincinnati Academic Health Center4, Harvard University5, Memorial Sloan Kettering Cancer Center6, University of California, San Francisco7, American Association of Clinical Endocrinologists8, University of Vermont Medical Center9, University of New Mexico10, Icahn School of Medicine at Mount Sinai11, Australian Catholic University12, Emory University13
TL;DR: A large number of the patients in this study had atypical femur fracture and the results confirmed the need for further investigation into the mechanisms leading to and effects of these fractures.
768 citations
TL;DR: The evolution of drug therapy for osteoporosis is traced, which began in the 1940s with the demonstration by Fuller Albright that treatment with oestrogen could reverse the negative calcium balance that developed in women after menopause or oophorectomy.
522 citations
McGill University1, University of Queensland2, University of Bristol3, Garvan Institute of Medical Research4, Imperial College London5, New York University6, McGill University Health Centre7, Erasmus University Rotterdam8, University of Rochester9, Anschutz Medical Campus10, University of Cambridge11, University of Oxford12, University of Southampton13, University Hospital Southampton NHS Foundation Trust14, Brown University15, University of Ioannina16, University of Gothenburg17, Children's Mercy Hospital18, Wellcome Trust Sanger Institute19
TL;DR: This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
Abstract: Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
466 citations
TL;DR: Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporeosis.
Abstract: Objective The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. Conclusions Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal women at risk with acceptable risk-benefit and safety profiles.
413 citations
TL;DR: There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking.
349 citations
References
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TL;DR: The semiquantitative approach can be applied reliably in vertebral fracture assessment when performed using well‐defined criteria, and this approach was compared with a quantitative morpho‐metric approach.
Abstract: The assessment of vertebral fracture by conventional radiography has been refined and improved using either semiquantitative or quantitative criteria. The inter- and intraobserver variability was determined for a semiquantitative visual approach that we routinely use in clinical studies for assessing prevalent and incident vertebral fractures. In addition, the semiquantitative approach was compared with a quantitative morphometric approach. The incidence and prevalence of vertebral fractures were determined in 57 postmenopausal women (age 65-75 years) by three independent observers. The radiographic basis for fracture definitions and the source of interobserver agreement for the semiquantitative technique. We conclude that the semiquantitative approach can be applied reliably in vertebral fracture assessment when performed using well-defined criteria.
3,019 citations
TL;DR: Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis.
Abstract: Methods We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. Results As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001) — a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P = 0.04) — a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) — a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. Conclusions Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)
2,687 citations
TL;DR: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo.
Abstract: Background A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period. Methods In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes. Results Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the ...
2,451 citations
Journal Article•
2,337 citations
TL;DR: The American Association of Oral and Maxillofacial Surgeons (AAOMS) developed guidelines for medication-related osteonecrosis of the jaw (MRONJ) in 2007 and 2009 as mentioned in this paper.
2,176 citations