Denosumab no better than bisphosphonates at preventing fracture, and the cost is much higher

We have had enough difficulty educating physicians about the importance of fracture prevention, and this will make it more difficult.

Super frustrating especially as you mention the meta-analysis is not the best quality in terms of assessing fx outcomes as most of the included trials were not designed to assess fracture as primary endpoint.

This commentary on meta-analysis is based on poor quality data as opposed to an RCT. These trials were actually not generally designed to look at fractures (as primary outcome) , but more so at BMD (Not ideal end point)
Also only looking at 12 month fracture data. It actually appears that this POEM is biased towards BPs.

We have many trials showing superiority of DMAB over BPs so not sure where this comes from.
In addition the 10 year FREEDOM trial has demonstrated ongoing efficacy and safety while all the BP trials show a trailing off of efficacy at year 3-5. In addition data has consistently shown that DMAB is superior to BPs for Non-Vert fractures (including hip)
Surpised such a low quality POEM was published

POEM: Denosumab no better than bisphosphonates at preventing fracture, and the cost is much higher
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Joule - a CMA Company
7:00 AM (11 hours ago)
View the Web version POEMs Research Summaries Your daily update for the latest Patient Oriented Evidence that Matters Denosumab no better than bisphosphonates a

Ray Bouchard
12:08 PM (6 hours ago)
ouch. What do you think?

Paul Kostenuik
Attachments
2:14 PM (4 hours ago)
to me, Paul

Hi Ray,

As always, the devil is in the details. The paper that POEM unartfully tried to summarize is the first attachment. With one notable exception, every head-to-head trial of denosumab vs BP therapy that the original authors used in their meta-analysis was designed and powered to evaluate BMD and bone turnover markers, not fragility fractures. This is important because most of the enrolled subjects had a relatively low risk of fragility fractures (by design), and even the best anti-fracture drug of all, Amgen’s new anti-sclerostin antibody romosozumab, does not reduce fracture risk in patients with osteoporosis that have a relatively low baseline risk of fracture; this probably means that the fractures that occurred were not necessarily even “fragility” fractures. Whereas in patients who are truly at a high risk of fragility fractures, romo was shown to reduce the risk of hip, vertebral, and non-vertebral fractures compared with placebo and compared with alendronate. That was the first and only evidence that an osteoporosis drug had superior hip fracture efficacy compared with a different osteoporosis drug, which is no small feat.

By analogy, it would be unlikely to show significantly fewer CV events in a 12-to-24-month Phase 2 trial of high-vs-low-dose statin therapy in hyperlipidemic subjects who have few other risk factors for CV events. But high-dose statin therapy would likely show superiority in larger and longer-term trials of hyperlipidemic subjects with a high risk of CV events. If you personally believe that LDL lowering is a meaningful surrogate of efficacy for statins, the same reasoning should most definitely apply to reductions in bone resorption markers and increases in BMD with osteoporosis therapies, because the relationship of those surrogates with fragility fractures is even stronger than the relationships between LDL and CV events.

And in many of the trials summarized by Lyu, fractures were only evaluated as a safety measure, rather than for efficacy, because there was no expectation of seeing any difference in fracture rates, particularly when most of those trials involved only 1 or 2 years of therapy (the FDA insists in 3 years to show anti-fracture efficacy with antiresorptives). This is a relevant point because there are meaningful differences in the quality of evidence when incident fractures are captured as safety events rather than as an efficacy variable.

And about the “notable exception” I mentioned above: the second attachment shows the results of the only H-2-H trial of DMAb vs BPs where fractures were assessed as an efficacy variable in patients who had an increased risk of fragility fractures at baseline. And denosumab showed superior anti-fracture efficacy versus alendronate. That impressive result is not highlighted in the article because the Japanese company that ran the trial (Daiichi Sankyo) had a corporate agreement with Merck to obtain the alendronate, and that agreement precluded them from reporting direct statistical comparisons of the anti-fracture data. Those findings were presented several years ago to a packed house at a big conference, and hilarity ensued when the academic presenter had to dance around audience comments pointing to the “apparent superiority” of DMAb vs ALN on fracture risk, which he could not overtly acknowledge. Let’s just say he did his best to honor the corporate agreement while nodding to the truth.

This CMA-affiliated group correctly points out that branded denosumab is more expensive than generic BPs, which probably underlies their interest in the meta-analysis. I say openly and often that generic bisphosphonates are the best drugs for society at large (because they work well and they’re very cheap), but if it was my loved one, it would be denosumab all the way, every time, because it works better. Denosumab will be off-patent in a few years, at which point I will say openly and often that generic denosumab is the best drug for societies at large, while steering my loved ones to romosozumab 😊.

Cheers,

Paul

2 Attachments
https://mail.google.com/mail/u/0?ui=2&ik=3e6dafaac7&attid=0.1&permmsgid…

https://mail.google.com/mail/u/0?ui=2&ik=3e6dafaac7&attid=0.2&permmsgid…

We need to do better when making sweeping statement, see above

I appreciate the thoughtful comments above. The CMA should post a retraction of this POEM as it is in fact harmful should physicians decide to switch patients back to BPs from denosumab based on a poor data interpretation. Please have your POEMs reviewed by experts in the field before publishing. The CMA continues to shed credibility on an ongoing basis and truthfully has little reason for existence other than the billions in its pockets.

The commentary in Joule titled “Denosumab no better than bisphosphonates at preventing fracture, and the cost is much higher” offers an interpretation of a recent meta-analysis of osteoporosis therapies arriving at a conclusion not in accord with the paper's authors. We feel that this requires comment.

The article from which this commentary was derived is by Lyu et al. Comparisons of denosumab and bisphosphonates in patients with osteoporosis: a meta-analysis of randomized controlled trials. (J Clin Endocrinol Metab 2019;104:1753-1765). This meta-analysis included trials of subjects at low fracture risk. Indeed, 71% of subjects had prior osteoporosis therapy, reducing their incident fracture risk. The primary outcome was therefore change in BMD and not fracture.

Lyu et al found that greater increases in BMD were achieved with denosumab when compared to bisphosphonates. They further suggested that these differences would result in greater reductions in subsequent fractures. This was based on the work of the FNIH group(1) that examined 21 randomized placebo-controlled trials of over 83,395 subjects, including all available osteoporosis therapies showing that greater increases in BMD on treatment results in greater fracture reductions.

Looking specifically at osteoporotic fracture at 12 months, it is not surprising that this very low risk population in a head-to-head study would have insufficient events to demonstrate a difference in antifracture efficacy (27 v. 29 events for a 1-year rate of 2.7% for denosumab and 2.7% for bisphosphonates). However, in the single 24 month trial reporting fractures, Joule commentary conceded that there was a significant 49% fracture risk reduction on denosumab compared to alendronate. The Lyu paper discusses current evidence that the ongoing increases in BMD with denosumab offers greater anti-fracture efficacy over the longer term than the plateauing of BMD observed with bisphosphonates.

Finally, to state that the cost of denosumab is significantly greater than the bisphosphonates is a gratuitous comment suggesting that there are differences in cost-efficacy. This meta-analysis was not designed to evaluate cost-efficacy and Lyu made no statements in this regard. Factors such as adherence to generic therapy, therapy side-effects, infusion costs, monitoring costs, hospitalization costs, health utilities and quality of life, to name a few, are important considerations ignored by the Joule commentary.

The Lyu meta-analysis strongly supports BMD superiority of denosumab over bisphosphonate. As a secondary outcome in these head-to-head trials of low risk subjects, we can only conclude that perhaps greater antifracture efficacy (seen in a single study of denosumab v. alendronate) accumulates with increases in BMD on denosumab, as is indicated by other published reports.

Reference
1. J Bone Miner Res. 2019 Apr;34(4):632-642. doi: 10.1002/jbmr.3641. Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials. Bouxsein ML, Eastell R, Lui LY, Wu LA, de Papp AE, Grauer A, Marin F, Cauley JA, Bauer DC, Black DM; FNIH Bone Quality Project.)

Jonathan D. Adachi
Actavis Chair for Better Bone Health in Rheumatology
Professor Department of Medicine
St. Joseph’s Healthcare - McMaster University

COI:
Board of Directors International Osteoporosis Foundation
Board of Directors, Ontario Rheumatology Association
Past President Osteoporosis Canada
Member, Editorial Board, Osteoporosis International
Member, Editorial Board BMC Musculoskeletal Medicine

Grants/research funding from Amgen, Radius,
Consultant: Amgen

Jacques Brown
Senior Clinical Researcher
CHU de Quebec Research Centre
Clinical Professor of Medicine
Laval University, Quebec City, Quebec

COI:
Member, Scientific Advisory Council, Osteoporosis Canada
Member, Editorial Board, Osteoporosis International
Member, National Bone Health Advisory Board, Amgen Canada
Member, Ambassador Program, American Society for Bone and Mineral Research

Grants/research support from Mereo Biopharma, Radius Health and Servier;
consultant for Amgen and Servier; and speakers’ bureau for Amgen, Orimed and Janssen.

Vivien Brown,
Assistant Professor, Department of Family & Community Medicine, University of Toronto
VP Medical Affairs, Medisys Health Group
VP North America, Medical Women’s International Association
Member, Immunize Canada
Member, Women’s Brain Health Initiative

Consultant for Amgen, GSK, Merck, Pfizer, Sunovioum, Sprout

Larry Dian,
Clinical Professor, Department of Medicine U.B.C.
COI:
Grants/ research: Amgen
Speaker Board: Amgen, GSK, Pfizer

Robert Josse
Division of Endocrinology and Metabolism
St. Michael’s Hospital,
61 Queen Street East, 6th floor,
Toronto,Ontario M5C2T2
Professor of Medicine
University of Toronto

Algis Jovaisas
Funding from Amgen, Pfizer, Novartis, Sandoz, MSD, Orimed, Alexion, Eli Lilly

David Kendler
Professor, Department of Medicine (Endocrinology)
University of British Columbia, Vancouver, BC

COI:
Member, Committee of Scientific Advisors, International Osteoporosis Foundation
Treasurer, Specialists of BC
Member, Scientific Advisory Committee, Osteoporosis Canada
Member, Editorial Board, Osteoporosis International
Cochair, Western Osteoporosis Alliance

Grants/research funding: Radius, CIHR
Consultant: Amgen, Pfizer

Aliya Khan
Clinical Professor of Medicine
Director of Calcium Disorders Clinic
McMaster University
Chair Rapid Response Committee OC
Cochair. Knowledge Translation committee OC
Cochair International ONJ Task Force
Scientific Advisor International Osteoporosis Foundation

Current Research funding
Ascendis, Amgen, Alexion, Radius, Takeda, Ultragenyx

Advisory board
Amgen, Takeda