Fracture Risk and Management of Discontinuation of Denosumab Therapy: A Systematic Review and Position Statement by ECTS

Abstract

Context Denosumab discontinuation is characterized by an increase in bone turnover overriding pre-treatment status, a rapid bone loss in the majority and multiple vertebral fractures (VFx) in some patients. Methods A working group of the European Calcified Tissue Society (ECTS) performed an updated systematic review of existing literature on changes of bone turnover, bone mineral density (BMD), and fracture risk after denosumab discontinuation and provided advice on management based on expert opinion. Results Important risk factors for multiple VFx following denosumab cessation are prevalent VFx, longer duration off therapy, greater gain in hip BMD during therapy, and greater loss of hip BMD after therapy according to a retrospective analysis of the FREEDOM Extension Study. Case series indicate that prior bisphosphonate therapy mitigates the biochemical rebound phenomenon after denosumab discontinuation, but it is uncertain whether this attenuation prevents BMD loss and fractures. Current evidence indicates partial efficacy of subsequent antiresorptive treatment with results seemingly dependent on duration of denosumab treatment. Conclusions A careful assessment of indications to start denosumab treatment is advised, especially for younger patients. A case for long-term treatment with denosumab can be made for patients at high fracture risk already on denosumab treatment given the favorable efficacy and safety profile. In case of denosumab discontinuation, alternative antiresorptive treatment should be initiated 6 months after the final denosumab injection. Assessment of bone turnover markers may help define the optimal regimen, pending results of ongoing RCTs. Patients having sustained VFx should be offered prompt treatment to reduce high bone turnover.

Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review

“…Of note, in such patients, Dmab treatment should not be discontinued in the first place, even if their BMD has been improved significantly, as the presence of fracture(s) is indicative of severe bone disease and outweighs the improvement of BMD [ 59 , 60 ]. The rate of BMD loss off-treatment per se could be a risk factor, as it was higher in patients who suffered multiple VFs compared to those with a single VF or without VFs, and higher in case of a single VF compared to no VF [ 61 ].…”

“…In case Dmab discontinuation is decided, it is the rebound phenomenon in bone remodeling that needs to be quickly counteracted in order to avoid bone loss and to minimize the risk of subsequent multiple VFs [ 61 ], although other mechanisms might also be involved [ 66 ]. In this context the administration of an anabolic agent such as teriparatide is expected to further increase bone remodeling and thus transiently enhance bone loss especially at cortical sites [ 67 ].…”

“…In this context the administration of an anabolic agent such as teriparatide is expected to further increase bone remodeling and thus transiently enhance bone loss especially at cortical sites [ 67 ]. Although data are currently lacking regarding the subsequent fracture risk if monotherapy with teriparatide is given following Dmab discontinuation, this option should rather be discouraged at present [ 61 ]. Cyclic 6-monthy alternation between teriparatide and Dmab for 3 years preserved BMD at highly cortical sites and total body bone mineral during the 6-month teriparatide administration intervals [ 68 ].…”

“…Given all the available information and recent recommendations, a rational approach would be the initiation of either oral BPs or zoledronate following Dmab discontinuation. As oral BPs might not adequately consolidate the BMD gains, the measurement of BTM is suggested after 3 months in order to monitor the efficacy and adherence through a level below the mean of healthy premenopausal women (CTX < 280 ng/L, P1NP < 35 μg/L) [ 61 ]. BTM measurement could also be useful 6 months after zoledronate infusion, and a second infusion might be considered if a level above the mean of the age and gender-matched controls is found [ 61 ].…”

Questions and facts regarding denosumab discontinuation among postmenopausal women

“…Finally, a rational and probably optimal approach has been recently suggested involving the administration of ZOL 6 months following the last Dmab injection and then close monitoring of the BTMs 3 and 6 months after ZOL infusion rather than waiting for the annual BMD changes; with this approach in case of increased BTMs (i.e. above the mean found in age and gender-matched cohorts) an early repeated infusion of ZOL could be considered [17]. Nevertheless, this approach, which is up to now based on an opinion of experts, might confront difficulties with the current country-specific guidelines regarding the use of ZOL in postmenopausal osteoporosis.…”