When the bone drug Prolia (denosumab) first appeared in 2010, I looked closely at it because it used a completely different mechanism than the widely used bisphosphonates, targeting the RANK/RANK-L/OPG system to prevent osteoclasts from being “ activated” instead of decreasing their number like bisphosphonates. In 2010 I was not convinced that this drug was safer or more effective than bisphosphonates, and it is sad to say that my skepticism has been confirmed by recent research.
Dr. Brown’s 2024 Update:
Is Prolia a blockbuster bone drug or a flop?
The FREEDOM trial, which studied Prolia use in postmenopausal women for 3 years, found very little reduction in fracture risk. Vertebral and hip fractures were reduced by 4.8% and 0.3%, meaning that out of 100 women they treated, only 5 suffered fewer vertebral fractures than would be expected with a placebo, and Not even one woman was saved from a hip fracture due to the drug.. Since hip fractures are considerably more damaging than vertebral fractures, these are minimal benefits.
Although increases in bone density were observed, those gains were lost within 1 year of stopping medication (Cummings et al., 2017).
Furthermore, once they stopped using Prolia, patients’ risk of vertebral fracture quickly (<1 to 2 years) returned to the same risk seen in those who had never taken the drug in the first place (Cummings et al., 2017). . They also lost a significant amount of the bone they had gained using Prolia: 35.5% of the total gain at the spine, 44.6% of the total gain at the femoral neck, and 103.3% at the total hip (Zanchetta et al., 2017). In other words, the drug offered no lasting benefit.
Much more worrying: the finding that Patients were more susceptible to multiple vertebral fractures after stopping Prolia than patients who had never taken the drug. – and was especially high in those who had had such fractures before taking the drug (Cummings et al., 2017; Anastasilakis et al., 2017). This finding confirmed a number of previous case reports of “rebound fractures” in patients who had stopped treatment with Prolia in the previous 12 months. The researchers speculated that such fractures were a consequence of a sudden renewal of bone resorption after stopping the drug, in combination with the absence of repair mechanisms during its use (Anastasilakis et al., 2017; Lamy et al., 2017; Polyzos & Terpos, 2016). .
I’ve said repeatedly that working against nature comes with unintended consequences, so these results don’t surprise me. What is disappointing is the continued emphasis on the “magic bullet” approach to osteoporosis, when for so many years it has been clear that Prolia it just doesn’t work.
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Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical characteristics of 24 patients with rebound-associated vertebral fractures after discontinuation of denosumab: systematic review and additional cases. J Bone Miner Res. June 2017; 32(6):1291-1296. doi: 10.1002/jbmr.3110. Electronic publication of March 13, 2017.
Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP. Vertebral fractures after denosumab discontinuation: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. November 4, 2017. doi: 10.1002/jbmr.3337. [Epub ahead of print]
Lamy O, González-Rodríguez E, Stoll D, Hans D, Aubry-Rozier B1. Severe vertebral fractures associated with rebound after discontinuation of denosumab: report of 9 clinical cases. J Clin Endocrinol Metab. February 1, 2017; 102 (2): 354-358. doi:10.1210/jc.2016-3170
Polyzos SA, Terpos E. Clinical vertebral fractures after discontinuation of denosumab. Endocrine. October 2016; 54(1):271-272. Epub dated July 8, 2016.
Popp AW, Zysset PK, Lippuner K. Vertebral fractures associated with rebound after discontinuation of denosumab treatment from clinical and biomechanical perspectives. Osteoporosis international. May 2016; 27(5):1917-21. doi:10.1007/s00198-015-3458-6. Epub dated December 22, 2015.
Zanchetta MB, Boailchuk J, Massari F, Silveira F, Bogado C, Zanchetta JR. Significant bone loss after discontinuation of long-term denosumab treatment: a post-FREEDOM study. Osteoporosis international. January 29, 2018. doi: 10.1007/s00198-017-4242-6. [Epub ahead of print]
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