Efficacy and safety of romosozumab among Japanese postmenopausal women with osteoporosis and mild-to-moderate chronic kidney disease.

INTRODUCTION: This post hoc analysis of the placebo-controlled phase 3 FRAME study assessed the efficacy and safety of romosozumab in a subpopulation of Japanese postmenopausal women with osteoporosis and chronic kidney disease (CKD). MATERIALS AND METHODS: Data were analyzed by baseline estimated glomerular filtration rate (eGFR), where < 90 mL/min/1.73 m2 denoted CKD and ≥ 90 mL/min/1.73 m2 indicated normal renal function. Efficacy outcomes included percent change in lumbar spine, total hip, and femoral neck bone mineral density (BMD) at 12 months from baseline (primary) and incidence of new vertebral and non-vertebral fractures. Tolerability was also assessed. RESULTS: Of 489 Japanese patients with available eGFR data, 339 had mild-to-moderate CKD (romosozumab, n = 170; placebo, n = 169) and 150 had normal renal function (romosozumab, n = 75; placebo, n = 75). Compared with placebo, romosozumab increased lumbar spine BMD by 14.8% (95% confidence interval [CI] 13.7-15.9) and 15.2% (95% CI 13.4-16.9) in the eGFR < 90 and ≥ 90 mL/min/1.73 m2 subgroups, total hip BMD by 4.6% (95% CI 3.8-5.4) and 5.5% (95% CI 4.4-6.7), and femoral neck BMD by 4.0% (95% CI 2.9-5.2) and 5.5% (95% CI 3.8-7.1) at 12 months, respectively (all p < 0.001 vs. placebo). New vertebral fracture incidence was numerically lower with romosozumab than placebo at 12 months in both eGFR subgroups, while the incidence of adverse events was similar between subgroups. CONCLUSION: Romosozumab for 12 months is an effective and well-tolerated treatment option for Japanese patients with osteoporosis and mild-to-moderate CKD.

Romosozumab followed by denosumab in Japanese women with high fracture risk in the FRAME trial.

INTRODUCTION: This post-hoc analysis of the FRAME study investigated the long-term efficacy and safety of romosozumab followed by denosumab in postmenopausal Japanese women with osteoporosis at high fracture risk. MATERIALS AND METHODS: Data from Japanese women with a high fracture risk participating in the international, randomised, double-blind, placebo-controlled, phase 3 FRAME study were analysed. High risk of fracture was defined as ≥ 1 fragility fracture with bone mineral density (BMD) ≤ - 2.5 standard deviations [SD], > 2 prevalent vertebral fractures, prevalent semiquantitative grade 3 vertebral fracture, or lumbar spine BMD < - 3.3 SD. Endpoints included incidence of new vertebral fracture at 12, 24 and 36 months and percentage change from baseline in BMD at the lumbar spine, total hip and femoral neck. RESULTS: 187 Japanese subjects at high risk of fracture were enrolled in FRAME. Incidence of new vertebral fractures was lower with romosozumab/denosumab vs. placebo/denosumab at 12, 24 and 36 months (relative risk reduction at all timepoints: 84%; p = 0.056). BMD increases at 12, 24 and 36 months were greater in subjects receiving romosozumab/denosumab than placebo/denosumab (lumbar spine: 16.3%, 21.5% and 23.2% vs 0.4%, 8.1% and 10.4%; total hip: 4.9%, 7.9% and 8.9% vs 0.4%, 2.8% and 4.1%; femoral neck: 4.8%, 7.6% and 8.1% vs 0.3%, 3.3% and 3.7%, respectively; all p < 0.001 vs placebo/denosumab). Adverse events were generally balanced between groups. CONCLUSION: Romosozumab/denosumab in Japanese subjects at high risk of fracture resulted in significant BMD gains and numerically lower vertebral fracture rate vs. placebo/denosumab at all timepoints measured.

Functional data analysis applied to a randomized controlled clinical trial in hemodialysis patients describes the variability of patient responses in the control of renal anemia.

The achievement of desirable hemoglobin levels in renal anemia that is treated with epoetins is often incomplete and subject to much variation of outcome values and applied dosage. The further development of clinical decision support for renal anemia requires the characterization of patient responses and an analysis of the dynamics of the dosage and response variables. In this methodologic article, the extended data of a randomized, controlled clinical trial comparing two epoetins were examined by the techniques of functional data analysis to establish how precisely the patterns of treatment response might be described and analyzed. The description of the trajectory of hemoglobin values in each patient as a mathematical function allowed the characterization of individual responses, with a wide variety of patterns being revealed. An analysis of the degree of system control in the management of the anemia was then possible through phase plotting. The analysis also allowed an expression of the dynamic characteristics of the entire experimental system, analyzed in summary group waveforms with standard statistical properties. In addition, a quantification of the notional instability of patient responses enabled the determination of a subset of patients for whom control might be improved in a modified management system. It is concluded that functional data analysis does provide the basis for further characterization and experimental study of the control of renal anemia.

Development and exploitation of a clinical decision support system for the management of renal anaemia.

The management of renal disease and its comorbidities lends itself to the use of computer-assisted decision support systems (CDSS); however, several issues with regard to computer-based treatment algorithms remain unresolved. This review examines the development and application of a clinical decision support system for the management of renal anaemia. Studies illustrate the dependence of outcome on prespecified haemoglobin (Hb) intervention values (thresholds) and the use of a computer program containing treatment algorithms to manage Epoetin doses and iron supplements. Early experimental studies and randomized, controlled studies are discussed that examine the use of clinical measures of haemodialysis (HD) and peritoneal dialysis (PD), including Hb, serum ferritin and red cell hypochromia or transferrin saturation. Broad flexibility of erythropoietic agent, dosing, route of administration and frequency has been built into computer programs written for clinical and experimental application. While further studies with the system are anticipated, predictability and sustainability of Hb outcomes and a capacity to manage large patient groups have been demonstrated and wider application appears promising.

Structured conversion from thrice weekly to weekly erythropoietic regimens using a computerized decision-support system: a randomized clinical study.

In view of the recent interest in weekly erythropoietic regimens and the lack of studies directly comparing the available agents, the clinical effectiveness of darbepoetin-alpha (DA) and epoetin-beta (EB), when administered via the subcutaneous route on a weekly basis, after conversion from thrice-weekly subcutaneous EB, was studied. In this 9-mo, single-center, randomized study of an unselected hemodialysis population, anemia was managed with a computerized decision-support system. Per-protocol analysis of the 81 patients in each arm who completed the study showed similar hemoglobin outcomes between treatment arms, both at randomization and at the end of the study. After conversion from thrice-weekly EB to DA (at a ratio of 200 IU:1 microg, at which products are cost-neutral in the European Union), a significant fall in dose from a mean of 0.59 microg/kg per wk after randomization to 0.46 microg/kg per wk in the last month (P = 0.002) was observed; in the comparator arm, the reduction in frequency of administration of EB was associated with a significant dose increase from a mean of 107.5 to 133.2 IU/kg per wk (P = 0.002) during the same period. At hemoglobin stability, mean EB dose was found to be 44% higher than DA dose (when multiplied by 200). Similar significant dose differences were apparent in a modified intention-to-treat analysis. The study demonstrated that, under a decision-support system, both products were capable of adequately maintaining hemoglobin outcome when administered on a weekly basis but with significant dose differences at 9 mo.