Risikoreduktion für vertebrale Frakturen unter Denosumab bei Patienten mit normaler und osteopenischer Knochendichte

Zusammenfassung

Einleitung: Die Ergebnisse der HALT-Prostatakarzinom-Studie (1) zeigten, dass Denosumab bei Prostatakarzinompatienten unter hormonablativer Therapie (HALT) die Knochenmineraldichte (BMD) gegenüber Placebo an allen Messorten signifikant erhöhte und die Inzidenz vertebraler Frakturen nach 36 Monaten signifikant um 62 % senkte. Keine Unterschiede wurden hinsichtlich der Zeit bis zur ersten klinischen Fraktur (jegliche nonvertebrale oder klinisch vertebrale Fraktur) beobachtet. In einer Post-hoc-Analyse wurde nun überprüft, ob Denosumab auch bei Patienten mit normaler bis osteopenischer Knochendichte das Risiko für neue vertebrale Frakturen reduziert.

Methoden: Hierzu wurde bei allen Teilnehmern der HALT-Studie (n = 1468) mit einem BMD-T-Score > –2,5 an Lendenwirbelsäule (LWS), Gesamthüfte und Schenkelhals sowie auswertbarem Frakturstatus die Inzidenz neuer vertebraler Frakturen nach 36 Mona-ten unter Behandlung mit Denosumab vs. Placebo ermittelt.

Ergebnisse: Zu Studienbeginn wiesen 1174 bzw. 80 % der Studienteilnehmer einen BMDT-Score > –2,5 an allen drei Messorten auf. 1087 bzw. 74 % der Studienteilnehmer erfüllten die Kriterien für die Frakturauswertung. In dieser Subgruppe reduzierte Denosumab das Risiko für vertebrale Frakturen nach 36 Mona-ten gegenüber Placebo signifikant um 61 % (Placebo: 2,8 %; Denosumab: 1,1 %; p = 0,0386). Weitere Frakturendpunkte wurden nicht untersucht.

Fazit: Denosumab reduzierte das Risiko für vertebrale Frakturen bei Patienten der HALT-Studie mit normaler und osteopenischer Knochendichte in ähnlichem Ausmaß wie im Gesamtkollektiv.

Summary

Introduction: Results from the HALT Prostate Cancer Trial (1) showed that denosumab increased bone mineral density (BMD) compared with placebo in men receiving androgen deprivation therapy (ADT; bilateral orchiectomy or GnRH-agonist therapy planned for ≥12 months) for nonmetastatic prostate cancer at all sites measured (lumbar spine [LS], total hip, femoral neck, 1/3 distal radius, and whole body). Of note, denosumab also decreased the cumulative incidence of new vertebral fractures by 62 % at 36 months (3.9 % in the placebo group and 1.5 % in the denosumab group, relative risk, 0.38; 95 % confidence interval [CI], 0.19 to 0.78; p = 0.006). We conducted a post-hoc subgroup analysis to determine if non-osteo -porotic patients also benefit from a reduction in fracture risk. Patients from the HALT Prostate Cancer Trial (n = 1,468) were included in this subgroup analysis, if their respective lowest baseline BMD T-Score at LS, total hip, or femoral neck was > –2.5. Incidence of new vertebral fractures between the denosumab and the placebo groups was compared after 36 months for all participants of the Vertebral Fracture Analysis Subset (VFAS: participants with baseline fracture status and more than one post baseline fracture evaluation) of this subgroup.

Results: A total of 1,174 patients (80 % of all enrolled patients) had a baseline BMD T-Score > –2.5 at all three sites and 1,087 (74 % of all enrolled patients) were included in the VFAS. Patients who received denosumab had a significantly decreased incidence of new vertebral fractures at 36 months (1.1 %, vs. 2.8 % with placebo; relative risk 0.39; 95 % CI 0.15 to 0.99; p = 0.0386), which was similar to the reduction in the total HALT Prostate Cancer Trial population (relative risk, 0.38, see above). In an additional analysis excluding patients with prevalent vertebral fractures at baseline (n = 845; VFAS n = 789), fracture incidence with denosumab (3/413 or 0.7 %) was still significant lower than with placebo (10/376 or 2.7 %) in the subgroup of non-osteo -porotic men (relative risk 0.27; 95 % CI 0.08 to 0.99; p = 0.0335). When analysing fracture risk subgroups according to the major DVO (Dachverband Osteologie) criteria (age, gender, T-score, and ADT) at baseline, the risk for new vertebral fractures in the low risk subgroup (10-year fracture risk for vertebral and hip fractures ≤30 %) was significantly reduced with denosumab compared with placebo (denosumab: 6/577 [1.0 %]; placebo: 16/560 [2.9 %]; relative risk 0.36; 95 % CI 0.14 to 0.92; p = 0.0248). There were no significant differences in the reduction of new vertebral fractures between subgroups based on minimal BMD T-Score (normal, osteopenic, or osteo -porotic), indicating BMD-independent efficacy of denosumab.

Conclusion: In summary, denosumab increased BMD at all sites in men receiving ADT for nonmetastatic prostate cancer. In addition, a reduction in the incidence of new vertebral fractures was shown with denosumab vs. placebo. Fracture risk reduction was similar in patients with BMD in the normal to osteopenic range as seen in the entire population, even after exclusion of men with prevalent vertebral fractures. A significant reduction in fracture risk was also observed in patients at low fracture risk according to DVO guidelines.

Schlüsselwörter

Denosumab - ADT - Prostatakarzinom - Osteoporose - Frakturrisiko

Keywords

Denosumab - ADT - prostate cancer - osteoporosis - fracture risk

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