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      Verschiedene Perspektiven von Therapiepausen und Kombinations-therapien bei Osteoporose Translated title: Different Perspectives of Drug Holiday and Combination Therapies When Treating Osteoporosis

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          Abstract

          Zusammenfassung. Die sequenzielle und kombinierte Therapie der Osteoporose ist herausfordernd aufgrund der vielen Möglichkeiten und schwierig, weil insbesondere für Kombinationstherapien keine belastbaren Frakturdaten verfügbar sind, meistens aufgrund zu kleiner Studien. Grundsatz der sequenziellen und kombinierten Therapie der Osteoporose ist, dass die osteoanabole Therapie (Teriparatid, TPTD), ob sequenziell oder kombiniert, zu einer Zunahme der Knochendichte (BMD) vor allem im Bereich der LWS führt. Einzige Ausnahme bildet die Sequenz von TPTD nach Denosumab (Dmab), welche zu einem Verlust (transient) der BMD sowohl der LWS wie der Hüfte führt; aus diesem Grund ist diese Sequenz unbedingt zu vermeiden. Ein zweiter Grundsatz ist, dass die Wirkung der osteoanabolen Therapie (TPTD) umso mehr verzögert und verringert wird, je intensiver und länger die antiresorptive Vorbehandlung war. Ein dritter Grundsatz ist die Notwendigkeit einer antiresorptiven Nachbehandlung nach Therapien mit TPTD und Dmab oder deren Kombination, um vertebrale Frakturen zu verhindern (Dmab) und die Knochendichte zu erhalten (TPTD). Eine Wirkung der osteoanabolen Therapie mit TPTD auf die BMD der Hüfte ist nur in Kombination mit einer antiresorptiven Therapie (Bisphosphonate, Dmab) zu erwarten. Wird die antiresorptive Therapie nicht weitergeführt, kommt es zu einem transienten Verlust in den ersten Monaten der osteoanabolen Monotherapie, und zwar umso stärker, wenn die antiresorptive Vorbehandlung sehr intensiv war.

          Different Perspectives of Drug Holiday and Combination Therapies When Treating Osteoporosis

          Abstract. Sequential and combined therapy for osteoporosis is challenging because of the many options, and difficult because robust fracture data are not available, especially for combination therapies, mostly because the studies are too small. The principle of sequential and combined therapy for osteoporosis is that osteoanabolic therapy (teriparatide [TPTD]), whether sequential or combined, leads to an increase in bone mineral density (BMD), especially in the lumbar spine. The only exception is the sequence of TPTD after denosumab (Dmab), which leads to a loss (transient) of BMD in both the lumbar spine and the hip; for this reason, this sequence should be avoided at all costs. A second principle is that the stronger and longer the antiresorptive pretreatment was, the more delayed and reduced the effect of osteoanabolic therapy (TPTD). A third principle is the need for antiresorptive retreatment after therapies with TPTD and Dmab or their combination to prevent vertebral fractures (Dmab) and maintain bone density (TPTD). An effect of osteoanabolic therapy with TPTD on BMD of the hip is expected only in combination with antiresorptive therapy (bisphosphonates, Dmab). If the antiresorptive therapy is not continued, there is a transient loss in the first months of osteoanabolic monotherapy, the more so the stronger the antiresorptive pretreatment was.

          Translated abstract

          Résumé. Le traitement séquentiel et combiné de l’ostéoporose est un défi en raison des nombreuses options et il est difficile parce que des données robustes sur les fractures ne sont pas disponibles, en particulier pour les traitements combinés, principalement en raison d’études trop petites. Le principe de base du traitement séquentiel et combiné de l’ostéoporose est que le traitement ostéoanabolique (teriparatide [TPTD]), qu’il soit séquentiel ou combiné, entraîne une augmentation de la densité osseuse (DMO), notamment au niveau de la colonne lombaire. La seule exception est la séquence de TPTD après le dénosumab (Dmab), qui entraîne une perte (transitoire) de DMO à la fois au niveau de la colonne lombaire et de la hanche; pour cette raison, cette séquence doit être évitée à tout prix. Un deuxième principe est que plus le prétraitement antirésorptif est fort et long, plus l’effet du traitement ostéoanabolique est retardé et réduit (TPTD). Un troisième principe est la nécessité d’un suivi antirésorptif après les traitements par TPTD et Dmab ou leur combinaison pour prévenir les fractures vertébrales (Dmab) et maintenir la densité osseuse (TPTD). Un effet du traitement ostéoanabolique par TPTD sur la DMO de la hanche n’est attendu qu’en association avec un traitement antirésorptif (bisphosphonates, Dmab). Si le traitement antirésorptif n’est pas poursuivi, on observe une perte transitoire dans les premiers mois de la monothérapie ostéoanabolique, d’autant plus forte que le prétraitement antirésorptif était fort.

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          Most cited references49

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          Denosumab for prevention of fractures in postmenopausal women with osteoporosis.

          Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.) 2009 Massachusetts Medical Society
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            The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.

            Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy. Copyright 2003 Massachusetts Medical Society
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              Is Open Access

              The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)

              Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment. (ClinicalTrials.gov identifier: NCT00145327). © 2012 American Society for Bone and Mineral Research.
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                Author and article information

                Contributors
                Journal
                prx
                Praxis
                Hogrefe AG, Bern
                1661-8157
                1661-8165
                December 2021
                : 110
                : 16
                : 975-983
                Affiliations
                [ 1 ]Zentrum für Rheuma- und Knochenerkrankungen, Klinik Im Park, Zürich
                Author notes
                Dr. med. Sven Oser, Zentrum für Rheuma- und Knochenerkrankungen, Bellariastrasse 38, 8038 Zürich soser@ 123456rheumazentrum.ch
                Article
                prx_110_16_975
                10.1024/1661-8157/a003762
                c05e40c5-66b6-48f1-8cab-dca6970fc074
                Copyright @ 2021
                History
                : 21. Juni 2021
                : 16. August 2021
                Categories
                Mini-Review

                General medicine,Medicine,Cardiovascular Medicine,Radiology & Imaging,Respiratory medicine,Pharmacology & Pharmaceutical medicine
                Sequenz,ostéoanabolique,antirésorptif,combinaison,séquence,vacances médicamenteuses,Ostéoporose,osteoanabolic,antiresorptive,combination,sequence,drug holiday,Osteoporosis,osteoanabol,antiresorptiv,Kombination,Drug Holiday,Osteoporose

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