The Summary To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months... Show moreThe Summary To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab.Purpose In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years.Methods TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months +/- 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 +/- 2.3 years (range 1-10 years). Of these, 38 were treatment naive (group 1) and 21 had received other treatments prior Dmab (group 2).Results Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (r(s) = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites.Conclusion Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption. Show less
Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection.... Show moreDiscontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures. Trial Registration: NCT02499237; July 16, 2015 Show less
Introduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two... Show moreIntroduction: In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two years. The longer-term effects, however, of zoledronate treatment are unknown. We aimed to study the effect of a single zoledronate infusion during the third year following denosumab discontinuation, in initially treatment-naive postmenopausal women who became osteopenic after 2.4 +/- 0.2 years of denosumab therapy.Methods: We report the 1-year follow-up results of a single arm observational extension of a previously reported 2-year multicenter prospective randomized clinical trial. The primary endpoint of this extension was the change in lumbar spine bone mineral density (LS-BMD); secondary endpoints were changes in femoral neck (FN)-BMD and markers of bone turnover (BTM) during the 3rd year from the zoledronate infusion. Changes are presented as mean and SEM.Results: LS-BMD did not change significantly at year 3 compared to year 2 (-1.35 +/- 1.1%, p = 1.00) and compared to baseline ( -1.96 +/- 1.44%, p = 1.00). FN-BMD values did not change while serum P1NP values decreased and CTX values remained unchanged during the third-year of the follow-up. In 4 of the 23 studied women BMD values returned to the osteoporotic range at 3 years.Conclusions: A single i.v. infusion of zoledronate 5 mg, given 6 months after the last injection of denosumab therapy maintains for three years BMD gains in the majority of patients previously treated with denosumab for an approximate period of 2.5 years. Follow-up of patients is, however, recommended because about one-fifth of treated women will require additional antiosteoporotic treatment. Show less
Beekman, K.M.; Veldhuis-Vlug, A.G.; Heijer, M. den; Maas, M.; Oleksik, A.M.; Tanck, M.W.; ... ; Bravenboer, N. 2019
Het onderzoek in het proefschrift heeft betrekking op het opzetten van een theoretisch kader voor het modeleren van ziekteprogressie op een mechanistische grondslag. De nadruk ligt op de uitwerking... Show moreHet onderzoek in het proefschrift heeft betrekking op het opzetten van een theoretisch kader voor het modeleren van ziekteprogressie op een mechanistische grondslag. De nadruk ligt op de uitwerking van dit concept voor een chronisch progressieve ziekte; postmenopausale osteoporose. De onderliggende aanname is dat een betere, samenhangende, beschrijving van dit soort ziektes wordt verkregen door de combinatie van 1) een wiskundige structuur gebaseerd op het onderliggende biologische mechanisme met 2) fysiologische data die de ziekteprogressie en de behandelingseffecten weergeven. Het onderzoek heeft aangetoond dat het modeleren van postmenopausale osteoporose op basis van een ziektesysteem analyse (__disease system analysis__) leidt tot waardevolle inzichten in zowel symptomatische als beschermende (ziekte modificerende) effecten op verschillende biologische markers. Er kan gesteld worden dat deze mechanistische ziektesystemen een __kennisbank__ kunnen en moeten vormen om een beter ge_nformeerd besluitvormingsproces tijdens de ontwikkeling (farmaceutische industrie), de beoordeling (overheden) en uiteindelijk het klinische gebruik van geneesmiddelen. Ziekteprogressie modellen maken het steeds beter mogelijk om informatie vanuit meerdere bronnen samen te voegen op basis van de kennis over het geneesmiddel en de ziekte. Met toenemende kennis over het systeem en de behandelingseffecten van bestaande en nieuwe geneesmiddelen kunnen deze modellen continue worden verbeterd en ingezet in het onderzoek en gebruik van deze middelen. Uiteindelijk leidt dit tot een meer effici_nte en kosteneffectieve benadering van geneesmiddelontwikkeling en het klinisch gebruik van geneesmiddelen. Het is van groot belang dat de farmaceutische industrie, academische instellingen en de overheid verder samenwerken aan het onderzoeken en vergroten van de mogelijkheden van een dergelijke gestructureerde aanpak (www.tipharma.nl). Show less
