Osteodystrophy in the millennium

Osteodystrophy in the millennium. Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn of the millennium: poor control of hyperphosphatemia, relative inefficacy of active vitamin D to prevent progressive parathyroid hyperplasia, and persistence of bone disease despite lowering of parathyroid hormone (PTH) and administration of active vitamin D. Although predictions are problematic, it is not unreasonable to hope that, barring unforeseen side effects, calcimimetics will prove to be valuable for suppressing or even preventing hyperparathyroidism, thus potentially replacing, at least in part, active vitamin D. There is also reason to hope that more effective phosphate binders with fewer side effects will become available and that controlled studies will provide a rationale for the administration of estrogens to dialyzed women. As regards understanding the pathological mechanisms, one can anticipate that the disturbances leading to autonomous growth of parathyroid cells will be elucidated and the signals involved in osteoclast/osteoblast differentiation pathways and osteoclast/osteoblast coupling will be clarified, with obvious impact on patient management

Kyphoplasty Restores the Global Sagittal Balance of the Spine Independently from Pain Reduction

Kyphoplasty is the standard surgical treatment of vertebral compression fractures. We aimed to clarify the influence of kyphoplasty on the sagittal profile as well as the relation between posture improvement and pain relief. For this purpose, we evaluated various radiological parameters of the sagittal profile on whole spine standing radiographs of 73 Patients with a single vertebral fracture treated by kyphoplasty. The key outcome was the postoperative change of the sagittal vertical axis (SVA). Additionally, clinical parameters including pain scores on visual analogue scale (VAS) and use of analgesics were obtained from medical records. Pre- and postoperative radiological as well as clinical parameters were compared. Additionally, the correlation between changes of SVA and changes of local kyphotic angle (LKA) or VAS was examined. The clinical parameters as well as various radiographic parameters (SVA, LKA, Gardner, Cobb) improved significantly postoperatively. The improvement of SVA correlated significantly with the correction of the LKA but not with postoperative pain relief. We conclude that kyphoplasty helps to restore the global sagittal balance of the spine after vertebral fractures. The correction of the sagittal profile seems to depend on the correction of the local kyphotic angle but does not correlate with postoperative pain relief

ROXADUSTAT FOR THE TREATMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE PATIENTS NOT ON DIALYSIS: A PHASE 3 RANDOMIZED OPEN-LABEL ACTIVE-CONTROLLED STUDY (DOLOMITES)

Cilj rada: Ocjena oralnog inhibitora prolil-hidroksilaze hipoksijom induciranog faktora roksadustata za liječenje anemije povezane s kroničnom bubrežnom bolešću (KBB). Metode: U ovom su se randomiziranom, otvorenom, aktivnim lijekom kontroliranom ispitivanju faze 3 uspoređivali roksadustat i darbepoetin alfa (DA) u bolesnika s anemijom i KBB-om neovisnih o dijalizi tijekom razdoblja od ≤ 104 tjedna. Doze lijeka titrirale su se da bi se razina hemoglobina (Hb) korigirala i održala u rasponu od 10,0 do 12,0 g/dl. Primarna mjera ishoda bio je odgovor Hb-a u cjelovitom skupu podataka za analizu, koji se defi nirao kao Hb ≥ 11,0 g/dl i promjena početne vrijednosti Hb-a za ≥ 1,0 g/dl u bolesnika kojima je početni Hb iznosio > 8,0 g/dl odnosno promjena početne vrijednosti Hb-a za ≥ 2,0 g/dl u bolesnika kojima je početni Hb bio ≤ 8,0 g/dl tijekom prva 24 tjedna liječenja bez primjene dodatne terapije za postizanje zadovoljavajuće razine hemoglobina (rescue) (granica neinferiornosti: 15 %). Ključne sekundarne mjere ishoda uključivale su promjenu vrijednosti lipoproteina male gustoće (LDL), vrijeme do prve intravenske (i.v.) primjene željeza, promjenu srednjeg arterijskog tlaka i vrijeme do pojave hipertenzije. U ispitivanju su se ocjenjivale i nuspojave. Rezultati: Od 616 randomiziranih bolesnika (roksadustat: 323; DA: 293) 424 dovršilo je liječenje (roksadustat: 215; DA: 209). Odgovor Hb-a zabilježen uz roksadustat bio je neinferioran onome opaženome uz DA [roksadustat: 256/286 (89,5 %) u odnosu na DA: 213/273 (78,0 %); razlika: 11,51 %; interval pouzdanosti od 95 %: 5,66 - 17,36 %]. Roksadustat je održao vrijednosti Hb-a tijekom razdoblja do 2 godine. Roksadustat je bio neinferioran u odnosu na DA s obzirom na promjenu srednjeg arterijskog tlaka i vrijeme do nastupa hipertenzije, a superioran s obzirom na promjenu vrijednosti LDL-a i vrijeme do prve i.v. primjene željeza. Obje su skupine imale usporedive sigurnosne profi le. Rezultati pokazuju da nije bilo razlike između skupina s obzirom na kompozitne mjere ishoda, koje su uključivale velike kardiovaskularne štetne događaje (MACE) i MACE+ [MACE: 0,81 (0,52 - 1,25), P=0,339; MACE+: 0,90 (0,61 - 1,32), P=0,583]. Zaključak: Roksadustat je prihvatljiva opcija za liječenje anemije u bolesnika s KBB om neovisnih o dijalizi, koja omogućuje održane razine Hb-a tijekom razdoblja do 104 tjedna.Background: Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for the treatment of anemia of chronic kidney disease (CKD). Methods: This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anemia for ≤104 weeks. Doses were titrated to correct and maintain hemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defi ned as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the fi rst 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). The key secondary endpoints included change in low-density lipoprotein (LDL), time to fi rst intravenous (IV) iron use, change in mean arterial pressure (MAP), and time to hypertension occurrence. Adverse events were assessed. Results: Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confi dence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension, and superior for change in LDL and time to fi rst IV iron use. Safety profi les were comparable between the groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+[MACE: 0.81 (0.52-1.25), p=0.339; MACE+: 0.90 (0.61-1.32), p=0.583]. Conclusions: Roxadustat is a viable option to treat anemia in NDD CKD patients maintaining Hb levels for up to 104 weeks

ROXADUSTAT FOR THE TREATMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE PATIENTS NOT ON DIALYSIS: A PHASE 3 RANDOMIZED OPEN-LABEL ACTIVE-CONTROLLED STUDY (DOLOMITES)

Cilj rada: Ocjena oralnog inhibitora prolil-hidroksilaze hipoksijom induciranog faktora roksadustata za liječenje anemije povezane s kroničnom bubrežnom bolešću (KBB). Metode: U ovom su se randomiziranom, otvorenom, aktivnim lijekom kontroliranom ispitivanju faze 3 uspoređivali roksadustat i darbepoetin alfa (DA) u bolesnika s anemijom i KBB-om neovisnih o dijalizi tijekom razdoblja od ≤ 104 tjedna. Doze lijeka titrirale su se da bi se razina hemoglobina (Hb) korigirala i održala u rasponu od 10,0 do 12,0 g/dl. Primarna mjera ishoda bio je odgovor Hb-a u cjelovitom skupu podataka za analizu, koji se defi nirao kao Hb ≥ 11,0 g/dl i promjena početne vrijednosti Hb-a za ≥ 1,0 g/dl u bolesnika kojima je početni Hb iznosio > 8,0 g/dl odnosno promjena početne vrijednosti Hb-a za ≥ 2,0 g/dl u bolesnika kojima je početni Hb bio ≤ 8,0 g/dl tijekom prva 24 tjedna liječenja bez primjene dodatne terapije za postizanje zadovoljavajuće razine hemoglobina (rescue) (granica neinferiornosti: 15 %). Ključne sekundarne mjere ishoda uključivale su promjenu vrijednosti lipoproteina male gustoće (LDL), vrijeme do prve intravenske (i.v.) primjene željeza, promjenu srednjeg arterijskog tlaka i vrijeme do pojave hipertenzije. U ispitivanju su se ocjenjivale i nuspojave. Rezultati: Od 616 randomiziranih bolesnika (roksadustat: 323; DA: 293) 424 dovršilo je liječenje (roksadustat: 215; DA: 209). Odgovor Hb-a zabilježen uz roksadustat bio je neinferioran onome opaženome uz DA [roksadustat: 256/286 (89,5 %) u odnosu na DA: 213/273 (78,0 %); razlika: 11,51 %; interval pouzdanosti od 95 %: 5,66 - 17,36 %]. Roksadustat je održao vrijednosti Hb-a tijekom razdoblja do 2 godine. Roksadustat je bio neinferioran u odnosu na DA s obzirom na promjenu srednjeg arterijskog tlaka i vrijeme do nastupa hipertenzije, a superioran s obzirom na promjenu vrijednosti LDL-a i vrijeme do prve i.v. primjene željeza. Obje su skupine imale usporedive sigurnosne profi le. Rezultati pokazuju da nije bilo razlike između skupina s obzirom na kompozitne mjere ishoda, koje su uključivale velike kardiovaskularne štetne događaje (MACE) i MACE+ [MACE: 0,81 (0,52 - 1,25), P=0,339; MACE+: 0,90 (0,61 - 1,32), P=0,583]. Zaključak: Roksadustat je prihvatljiva opcija za liječenje anemije u bolesnika s KBB om neovisnih o dijalizi, koja omogućuje održane razine Hb-a tijekom razdoblja do 104 tjedna.Background: Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for the treatment of anemia of chronic kidney disease (CKD). Methods: This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anemia for ≤104 weeks. Doses were titrated to correct and maintain hemoglobin (Hb) within 10.0-12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defi ned as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the fi rst 24 weeks of treatment without rescue therapy (non-inferiority margin, -15%). The key secondary endpoints included change in low-density lipoprotein (LDL), time to fi rst intravenous (IV) iron use, change in mean arterial pressure (MAP), and time to hypertension occurrence. Adverse events were assessed. Results: Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confi dence interval 5.66-17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension, and superior for change in LDL and time to fi rst IV iron use. Safety profi les were comparable between the groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+[MACE: 0.81 (0.52-1.25), p=0.339; MACE+: 0.90 (0.61-1.32), p=0.583]. Conclusions: Roxadustat is a viable option to treat anemia in NDD CKD patients maintaining Hb levels for up to 104 weeks

Efficacy and Cardiovascular Safety of Roxadustat in Dialysis-Dependent Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies

Introduction: This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients. Methods: Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. Results: In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups. Conclusion: Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients