6. Data from: Comparison of denosumab and bisphosphonates in patients with osteoporosis: a meta-analysis of randomized controlled trials. The ePub format is best viewed in the iBooks reader. 2016 Mar 10;3:CD010429. Two studies had a relatively small sample size (n = 64 and n = 94) (9, 30). The PubMed, Embase, and the Cochrane Library databases were searched through November 2018 for head-to-head, randomized, controlled trials comparing denosumab and bisphosphonates among adult patients with low BMD or osteoporosis. Our study provides moderately strong evidence (41) that denosumab is more effective in increasing BMD at lumbar spine, total hip, and femoral neck than are bisphosphonates at 12 and 24 months. Copyright 2010 Elsevier Inc. All rights reserved. The ePub format is best viewed in the iBooks reader. You may notice problems with Harris ST, Watts NB, Genant HK, et al. BP, bisphosphonate; DMAb, denosumab; RR, risk ratio. -.
What is the mechanism of action of romosozumab? In contrast to the bisphosphonates, denosumab (like the other first-line therapeutics) does not become embedded within bone tissue. Sites of action for first-line osteoporosis treatments. The incidences of adverse events were similar between treatment groups.
Denosumab Campared Zoledronic | PDF | Multiple Myeloma | Bone Denosumab treatment results in increased BMD progressively, as long as the treatment is continued (44). Here, denosumab lowered uNTX by 80% compared with a 56% reduction in patients who remained on bisphosphonates. Pedersen AB, Heide-Jrgensen U, Srensen HT, Prieto-Alhambra D, Ehrenstein V. Risk of osteoporotic fractures in new users of denosumab compared with new users of alendronate: a Danish population-based cohort study, http://getdata-graph-digitizer.com/index.php. Reprinted from Denosumab: Mechanism of action and clinical outcomes, 43, 2, Paul D. Miller, Michael A. Bolognese, E. Michael Lewiecki, Michael R. McClung, Beiying Ding, Matthew Austin, Yu Liu, Javier San Martin, for the AMG 162 Bone Loss Study Group, 222229., 2008, with permission from Elsevier. Almost all pharmacological agents for osteoporosis specifically target the bone resorption component of bone remodelling pathways; they are therefore classified as anticatabolic or antiresorptive agents (e.g. Longitudinal studies with longer follow-up and large sample size are needed to confirm the efficacy difference. Given the wide range of effective osteoporosis treatments, failure to identify and treat individuals at risk of fracture represents a significant missed opportunity to reduce morbidity and mortality. First, results from indirect comparison and direct comparison are inconsistent (16, 17), which deserves further clarification. In addition, relevant studies were obtained by searching references of articles identified in the initial searches, relevant meta-analyses, and systematic reviews.
Bisphosphonates: Mechanism of Action and Role in Clinical Practice This article aims to review the mechanisms of action of pharmacological therapies for osteoporosis and to clarify the differences between the bisphosphonates and denosumab, a newly approved antiresorptive agent with a novel mechanism of action (7,11). There was no difference in the incidence rate of ONJ between bisphosphonate- and denosumab-treated cancer patients with skeletal metastases in the randomized double-blind controlled trial. 2022 Sep 22;6(10):e10681. Modified from Baron et al., 2011 (31). The New England journal of medicine, 2003, 348(7): 618-29. Subgroup analyses were performed on the basis of specific bisphosphonate and pretreatment status. Bisphosphonates work by slowing down the cells which break down bone (osteoclasts). Since 2014, five more pivotal head-to-head trials have been published. International 30 Rodan GA, Fleisch HA. Omori K, Otsuru M, Morishita K, Hayashida S, Suyama K, Naruse T, Soutome S, Umeda M. Int J Environ Res Public Health. The mean and SD, SE, and CI of percentage changes of BMD were extracted for calculation. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate. J Clin Endocrinol Metab. Medicine (Baltimore). Denosumab: a review of its use in the treatment of postmenopausal osteoporosis. The BMD increase difference was 1.91% (95% CI, 1.36% to 2.47%; P < 0.001) at lumbar spine for alendronate trials and 1.11% (95% CI, 0.63% to 1.58%; P < 0.001) for non-alendronate bisphosphonate use at 12 months (subgroup difference P = 0.031).
Denosumab for Treatment of Hypercalcemia of Malignancy - PMC Cummings SR, Black DM, Thompson DE, et al. Unable to load your collection due to an error, Unable to load your delegates due to an error. Endpoints were change from baseline in lumbar spine, total hip, femoral neck, and 1/3 radius BMD at month 12, change from baseline in serum CTX-1 and P1NP, and incidence of adverse events. Accessibility It is estimated that >9.9 million Americans have osteoporosis and an additional 43.1 million have low bone mineral density (BMD) (2). However, denosumab showed better performance in reducing risk of osteoporotic fracture than did alendronate (RR, 0.51; 95% CI, 0.27 to 0.97; Fig. Federal government websites often end in .gov or .mil. The opinions and analysis presented here are solely those of the authors. In our study, denosumab and bisphosphonate had different BMD increase profiles. This meta-analysis of head-to-head trials provided evidence of direct comparison between denosumab and bisphosphonates in treatment of low BMD or osteoporosis. Received 2018 Oct 15; Accepted 2018 Dec 5. However, several limitations should also be noted.
Bristol Myers Squibb to Participate in the Wolfe Research Healthcare What is the risk of developing osteonecrosis following dental Any disagreements were resolved by discussion or by seeking an independent third author (C.X.). There is strong evidence that this agent can be used to prevent vertebral and non-vertebral fractures, but insufficient evidence regarding hip fractures (Table 1) (14). Only one trial reported that denosumab was more effective than alendronate in preventing osteoporotic fractures at 24 months (RR, 0.51; 95% CI, 0.27 to 0.97) (28). Resorption of old bone matrix and deposition of mineral into new bone are linked. Medication-related osteonecrosis of the jaw after tooth extraction in patients receiving pharmaceutical treatment for osteoporosis: A retrospective cohort study. Methods: The larger efficacy difference in the latter subgroup may help us make clinical decisions regarding the sequential use of osteoporosis medication. Previous phase 3 clinical trials found both drugs increased BMD and reduced the risk of fracture compared with placebo (812). Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians, Bisphosphonates: mechanism of action and role in clinical practice. doi: 10.1002/jbm4.10681. D A Hanley, J D Adachi, [], and V Brown. You may switch to Article in classic view. doi: 10.1002/14651858.CD010429.pub2. Among the currently available osteoporosis therapeutics, bisphosphonates and denosumab are the most widely used (1, 4). Careers. Context: PMC In our current meta-analysis, the point estimates of BMD improvement difference in treatment-nave patients was 0.83% at spine, 0.93% at total hip, and 0.83% at femoral neck, which may reflect the true efficacy difference. Mechanism of Action Prolia (denosumab) is a fully human monoclonal antibody that binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Figshare 2018. There are two main pharmacological approaches to osteoporosis: anabolic therapy, which stimulates new bone formation (27); and anticatabolic or antiresorptive therapy, which decreases bone resorption and/or inhibits bone turnover (14). As with bisphosphonates, treatment with . Despite a range of dosing frequencies and administration routes, the Guidelines cite consistent evidence from randomized clinical trials, suggesting that currently available treatments reduce vertebral fracture risk in postmenopausal women with osteoporosis (14). Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Bolland MJ, Grey AB, Gamble GD, Reid IR. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.
Pharmacology: Mechanism of Action of Bisphosphonates Denosumab improved BMD significantly more than bisphosphonate treatment at the lumbar spine, total hip, and femoral neck at 12 and 24 months. Effect of osteoporosis treatment on mortality: a meta-analysis. The anti- osteolytic effect was seen - quite correctly - as a reduction in . Clearance of bisphosphonates from the circulation is via renal excretion or adsorption to bone mineral. Bone density and markers of bone turnover in predicting fracture risk and how changes in these measures predict fracture risk reduction, Therapy of endocrine disease: denosumab vs bisphosphonates for the treatment of postmenopausal osteoporosis. Ettinger B, Black DM, Mitlak BH, et al. Chan School of Public Health, Boston, Massachusetts, 6Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom, 7Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 8Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, 9Harvard Medical School, Boston, Massachusetts, 10Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Womens Hospital, Boston, Massachusetts. Current evidence on the difference in fracture risk reduction between denosumab and bisphosphonates is still limited. Bisphosphonates differ with respect to their affinity for the bone matrix: zoledronic acid binds more tightly than alendronate, which binds more tightly than risedronate. Two trials did not clearly report the random sequence generation (29, 31).
Denosumab and bisphosphonates: different mechanisms of action - PubMed In contrast, bisphosphonates bind bone mineral, where they are absorbed by mature osteoclasts, inducing osteoclast apoptosis and suppressing resorption. 2016 Aug;101(8):3163-70. doi: 10.1210/jc.2016-1801. Denosumab therapy did not demonstrate a significant difference in reducing the risk of (a) any type of fracture, (b) osteoporotic fracture at 12 mo, or (c) the risk of any type of, The Journal of Clinical Endocrinology and Metabolism. Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: a systematic review and meta-analysis. In a head-to-head meta-analysis, Wu et al. In addition, bisphosphonates have been reported to depress accessory function of monocytes , inhibit the action of mitogens on mononuclear function and on the lymphoblastic response , influence the effect of antilymphocyte serum on T lymphocytes , and inhibit migratory activities of macrophages . Bone is continually remodelled by the interaction of osteoclasts (which resorb the existing bone) and osteoblasts (which form new bone matrix). Russell RG, Rogers MJ.
UpToDate 2016 Aug;101(8):3163-70 (45); reviewed in Ref. Prolia is a brand-name drug that contains the active drug denosumab. inhibits osteoclast farnesyl pyrophosphate synthase enzyme, required in mevalonate (cholesterol pathway) inhibits GTPase formation. Forest plot of the BMD changes at the following three anatomic sites at 12 mo (subgroup analysis stratified by previous treatment status): (a) lumbar spine, (b) total hip, and (c) femoral neck. The meta-analysis was analyzed using the statistical environment R, version 3.4.3 (https://cran.r-project.org) with the meta and metafor packages (24).
JCM | Free Full-Text | Periprosthetic Osteolysis: Mechanisms Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, Malouf J, Bone HG, Reginster JY, Singer A, Wang C, Wagman RB, Cummings SR. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. Perez-Lopez FR. Please enable it to take advantage of the complete set of features! Several knowledge gaps remain regarding the comparative effectiveness of denosumab and bisphosphonates. Previous meta-analyses either missed key studies [the study with fracture as end point for 2 years (28) and recently published trials (33)] or only focused on 12-month data. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. When comparing the effect of denosumab and bisphosphonates, prior treatment with bisphosphonates attenuates the efficacy of subsequent bisphosphonate treatment. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. Osteoblasts also produce OPG, which suppresses bone turnover. The primary outcomes were the mean percentage change in BMD at lumbar spine, total hip, and femoral neck at 12 months. 3). Denosumab has begun to play an important role in the primary care of postmenopausal osteoporosis, as clinical data confirm that it leads to significant increases in BMD, with decreased risk of vertebral, hip and non-vertebral fracture (22,44,4648). Oyajobi BO, Anderson DM, Traianedes K, Williams PJ, Yoneda T, Mundy GR. Anastasilakis AD, Polyzos SA, Gkiomisi A, Saridakis ZG, Digkas D, Bisbinas I, Sakellariou GT, Papatheodorou A, Kokkoris P, Makras P. Denosumab versus zoledronic acid in patients previously treated with zoledronic acid. Fortunately, Canadian physicians have a variety of effective therapeutics at their disposal. Denosumab is the first RANKL inhibitor to be approved by the FDA. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. There was a significant interaction between the subgroups of different bisphosphonate-pretreatment status in lumbar spine BMD improvement (previously treated with bisphosphonates: 1.75% vs not previously treated: 0.83%; P for interaction = 0.014). Like OPG (see Figure 1), denosumab prevents maturation of osteoclast precursors and promotes apoptosis of mature, multinucleated osteoclasts. *For menopausal women requiring treatment of osteoporosis in combination with treatment for vasomotor symptoms. Chan School of Public Health, Boston, Massachusetts, 5Department of Biostatistics, Harvard T.H.
The osteoclast cells, which . On 13 June 2013, the US FDA approved Denosumab for treatment of adults and skeletally mature adolescents with Giant cell tumor of bone that is unresectable or where resection would result in significant morbidity. 6). Supporting this conclusion is the observation that denosumab resulted in a 2.5-fold greater suppression of the osteoclast biomarker TRAP-5b than continuing IV BPs. Data from: Comparison of denosumab and bisphosphonates in patients with osteoporosis: a meta-analysis of randomized controlled trials. Roux C, Hofbauer LC, Ho PR, Wark JD, Zillikens MC, Fahrleitner-Pammer A, Hawkins F, Micaelo M, Minisola S, Papaioannou N, Stone M, Ferreira I, Siddhanti S, Wagman RB, Brown JP. For other sources of bias, we considered major imbalances in key baseline characteristics to represent a high risk of bias. McClung MR, Geusens P, Miller PD, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. BP, bisphosphonate; DMAb, denosumab; MD, mean difference. There is also significant recycling of bisphosphonates in bone, resulting in retention of measurable amounts for several years (35). Risk ratio of (a) any, MeSH Alendronate subjects discontinued treatment at Month 24 and were observed until Month 48.
[PDF] Denosumab and bisphosphonates: different mechanisms of action and Hussar DA, Stevenson T. New drugs: denosumab, dienogest/estradiol valerate, and polidocanol. Data from: Comparison of denosumab and bisphosphonates in patients with osteoporosis: a meta-analysis of randomized controlled trials. Pharmacologic Mechanisms of Therapeutics: Parathyroid Hormone. Patients received 60 mg denosumab once every 6 months or a bisphosphonate (oral alendronate, risedronate, ibandronate, or intravenous zoledronic acid). It was documented that bisphosphonates and denosumab are effective in fracture prevention among patients with osteoporosis and/or prevalent vertebral fracture, decreasing the incidence of vertebral fractures by more than 50%, non-vertebral fracture by 20-25% and hip fractures by 40-50%. Denosumab improved BMD significantly more than bisphosphonate treatment at the lumbar spine, total hip, and femoral neck at 12 and 24 months. However, if the trial did not clearly report the methods, it was regarded as an unclear risk of bias; if the trial inadequately reported methods, it was regarded as a high risk of bias. Denosumab is characterised by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. There were some methodological limitations in some of the included trials, such as the inadequate concealment of treatment allocation. Front Pharmacol. Key differences between and bisphosphonates and denosumab. At 12 months, denosumab increased mean BMD significantly more than bisphosphonates at the lumbar spine (mean difference, 1.42%; 95% CI, 0.95%-1.89%; P <.001), total hip (mean difference, 1.11%; 95% CI, 0.91%-1.30%; P <.001), and femoral neck (mean difference, 1.00%; 95% CI, 0.78%-1.22%; P <.001). Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. Hanley DA, Watson PM, Hodsman AB, Dempster DM. In addition to the bisphosphonates, raloxifene is also effective in preventing vertebral fractures (14,36,37). The ability of denosumab to further suppress bone resorption in patients who were already receiving IV BPs indicates a mode of action different from bisphosphonates. In Ontario, more than half a million individuals were estimated to have osteoporosis in 2005, leading to approximately 57,000 osteoporosis-related fractures per year, along with $500 million in hospitalisation and long-term care costs (16). In clinical practice, the most commonly used antiosteoporosis medication is bisphosphonates. study (17): 1.31% at lumbar spine, 1.11% at total hip, and 1.01% at femoral neck. A high affinity for hydroxyapatite enables . We are experimenting with display styles that make it easier to read articles in PMC. 2022 Oct 28;14:1759720X221133429. According to a recent meta-analysis using individual patient data from 21 randomized, placebo-controlled osteoporosis trials of >83,395 subjects, changes in total hip and femoral neck BMD over 2 years explained 60% to 65% of the treatment-related reduction in fracture risk (42). Cranney Ae G, Willan A, Griffith L, et al. Bethesda, MD 20894, Web Policies
Denosumab and bisphosphonates: rivals or potential "partners"? A Denosumab: mechanism of action and clinical outcomes. Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. government site. Given these limitations, results of this meta-analysis should be interpreted cautiously. Another subgroup analysis was performed on data on use of alendronate or non-alendronate bisphosphonates. Five trials used an open-label design (27, 29, 30, 32, 33). Belavic JM. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Summary 1070. Denosumab subjects were transitioned to placebo at Month 24, with their last active treatment at Month 21; they reinitiated active treatment at Month 36 with the 60 mg Q6M dose.
Preventing metastases to bone: Denosumab or bisphosphonates? BMUs like the one depicted here occur by the millions throughout the skeleton.
Osteoporosis - Knowledge @ AMBOSS Methods Published literatures, only including randomized controlled trials (RCTs), were searched in the following electronic databases: PubMed . Cumulative meta-analysis (35) showed that more BMD improvement with denosumab became evident in 2010, when 1769 patients had been randomly assigned in trials. This topic review provides an overview of the pharmacology of the bisphosphonates and of the differences between the preparations that are either currently available or undergoing clinical testing. -, Curr Med Res Opin. Results: We identified 10 eligible trials including 5361 participants. Rizzoli R, Yasothan U, Kirkpatrick P. Denosumab. 8600 Rockville Pike However, the incidence of hypocalcemia was significantly higher in cancer patients receiving denosumab than bisphosphonates. HHS Vulnerability Disclosure, Help Results of this study suggest that, in patients treated with a prior bisphosphonate, switching to denosumab would result in greater BMD increase than would switching to another bisphosphonate. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG. 2022 May;29(2):83-92. doi: 10.11005/jbm.2022.29.2.83. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ. People who take a bisphosphonate are less likely to break (fracture) a bone. Bisphosphonates: from the laboratory to the clinic and back again. Brown JP, Roux C, Ho PR, Bolognese MA, Hall J, Bone HG, Bonnick S, van den Bergh JP, Ferreira I, Dakin P, Wagman RB, Recknor C. Osteoporos Int.
Bisphosphonates - Basic Science - Orthobullets 5). After excluding the duplicated and irrelevant articles, the full text of the remaining studies was reviewed to ascertain whether they should be included according to the eligibility criteria. [Erratum appears in N Engl J Med. 2019 May 1;104(5):1753-1765 According to the 2010 OC Clinical Practice Guidelines, currently available pharmacotherapy reduces the relative risk of vertebral fractures by 3070%, depending on the agent and the level of adherence (14). The only anabolic agent currently available is teriparatide (7). MeSH This may explain differences in the degree and rapidity of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and the reversibility of their actions. Papaioannou A, Morin S, Cheung AM, et al. There was no difference in fracture end point at 12 months, but denosumab had a lower osteoporotic fracture incidence than alendronate at 24 months (risk ratio, 0.51; 95% CI, 0.27 to 0.97). You may notice problems with Moen MD, Keam SJ. Results: As the OC Clinical Practice Guidelines emphasise, effective risk assessment, with prompt introduction of pharmacotherapy to patients at high risk, are key steps in fracture prevention (14). Osteocytes, osteoblasts and osteoclasts are the main cells of the BMU of remodelling bone. Resorption of old bone matrix and deposition of mineral into new bone are linked. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. Five trials (25, 26, 29, 31, 33) (n = 3540 patients) reported fracture data at 12 months, and one trial (28) (n = 714 patients) reported fracture data at 24 months. Subjects were randomised to denosumab 30 mg Q3M or placebo twice yearly or, on an open-label basis, to alendronate once weekly. Placebo-treated patients showed a consistent loss of BMD throughout the study period, affecting both sites. One key to understanding the difference between these antiresorptive agents is their disposition within the body. It is usually injected by a healthcare provider in a doctor's office, hospital, or clinic. Clinical studies, as well as in vitro and in vivo experiments have demonstrated that byproducts from joint replacements induce an inflammatory reaction that can result in periprosthetic osteolysis (PPOL) and aseptic loosening (AL). Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE; Fracture Intervention Trial Research Group . Denosumab increased BMD more than bisphosphonate at 12 months (mean difference, 1.42%; 95% CI, 0.95% to 1.89%; P < 0.001) at lumbar spine, 1.11% (95% CI, 0.91% to 1.30%; P < 0.001) at total hip, and 1.00% (95% CI, 0.78% to 1.22%; P < 0.001) at femoral neck. The bisphosphonates included alendronate, ibandronate, risedronate, and zoledronic acid. Denosumab, a recently approved therapy, is a fully human monoclonal antibody that .
The role of bisphosphonates or denosumab in light of the availability Discussion Effective pharmacotherapy is necessary for patients at high risk of fracture. They act by binding the mineral component of bone and interfere with the action of osteoclasts. Bone turnover markers return to pretreatment levels within 9 months of treatment cessation (11). Forest plot for the mean difference of BMD changes (%) at lumbar spine, total hip, and femoral neck at 24 mo.
Bisphosphonates | Side-effects, uses, time to work - Versus Arthritis Forest plot of adverse events at 12 mo. 2014 Jul;25(7):1953-61. doi: 10.1007/s00198-014-2692-7. A newer type is called 'denosumab'. Epub 2014 Mar 28. You may switch to Article in classic view. The Writing Group for the PEPI. 39 Berenson JR, Lichtenstein A, Porter L, Mateos MV et al. Epub 2011 Apr 8. PMC Bisphosphonates inhibit osteoclasts which are responsible for breaking down and reabsorbing minerals such as calcium from bone (the process is known as bone resorption). The primary analysis involved 10 trials with a total of 5254 patients. Osteoporotic fractures account for approximately 80% of all fractures occurring in postmenopausal women (14). Denosumab circulates in blood and extracellular fluid. Bisphosphonates all induce osteoclast apoptosis; bone-associated osteoclasts that do survive may remain in the bone, but with reduced resorptive activity (31,34). Third, whether there would be a response difference to treatment with denosumab between patients previously treated with bisphosphonates and treatment-nave patients also remains unclear.