T-Score as an Indicator of Fracture Risk During Treatment With Romosozumab or Alendronate in the ARCH Trial

Abstract

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p < .001). The proportion of patients with TH T-score > -2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Keywords: ALENDRONATE; BONE MINERAL DENSITY; POSTMENOPAUSAL OSTEOPOROSIS; ROMOSOZUMAB; T-SCORE.

© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Figures

Figure 1

Percentage of patients with achieved T‐scores > −2.5 and > −2.0 at the total hip (A), femoral neck (B), and lumbar spine (C) at month 12. The analysis included patients with BMD values at baseline and at least one open‐label alendronate dose. p values were based on a logistic regression model adjusting for treatment, age strata (<75 versus ≥75 years), presence of severe vertebral fracture at baseline, and baseline T‐score. Missing values were imputed by carrying forward the last nonmissing postbaseline value prior to the missing value and within the treatment period. n/N1 = number of patients with T‐score change above the threshold/number of patients with an evaluation at that time point.

Figure 2

Incidence of fracture during the post‐romosozumab open‐label alendronate period. aAnalysis set included all randomized patients who received at least one open‐label alendronate dose and had an evaluation of vertebral fracture at month 12 and at or before month 24; analysis was based on the Mantel‐Haenszel method adjusting for age strata, baseline total hip BMD T‐score, and presence of severe vertebral fracture at baseline, without multiplicity adjustment. bAnalysis set included all randomized patients who had received at least one open‐label alendronate dose; analysis was based on the Cox proportional hazards model adjusting for age strata, baseline total hip BMD T‐score, and presence of severe vertebral fracture at baseline, without multiplicity adjustment. n/N1 = number of patients with fractures/number of patients in the efficacy analysis set; RRR = relative risk reduction.

Figure 3

Month 12 total hip (A,B), femoral neck (C,D), and lumbar spine (E,F) T‐scores and subsequent nonvertebral and new or worsening vertebral fracture incidence. The analysis included patients who had a month 12 total hip or femoral neck BMD T‐score and had at least one open‐label alendronate dose (3342 patients [romosozumab, 1679; alendronate, 1663] for both total hip and femoral neck and 3232 patients [romosozumab, 1625; alendronate, 1607] for lumbar spine) and was based on the Cox proportional hazards model with time to fracture as the response and total hip T‐score at month 12 as a covariate. Dashed lines indicate upper and lower 95% CIs. P‐values were based on the likelihood ratio test.

Figure 4

Month 24 total hip (A,B), femoral neck (C,D), and lumbar spine (E,F) T‐scores and subsequent nonvertebral and new or worsening vertebral fracture incidence. The analysis included patients who had a month 24 total hip or femoral neck BMD T‐score and at least one open‐label alendronate dose (3243 patients [romosozumab, 1619; alendronate, 1624] for both total hip and femoral neck and 3142 patients [romosozumab, 1568; alendronate, 1574] for lumbar spine) and was based on the Cox proportional hazards model with time to fracture as the response and total hip T‐score at month 24 as a covariate. Dashed lines indicate upper and lower 95% CIs. P‐values were based on the likelihood ratio test.

Figure 5

Modeled month 6 total hip (A,B), femoral neck (C,D), and lumbar spine (E,F) T‐scores and subsequent nonvertebral and new or worsening vertebral fracture incidence. All observed postbaseline BMD T‐scores were used to predict month 6 BMD T‐scores using the mixed‐effect model adjusting for baseline BMD, age strata, and presence of severe vertebral fracture at baseline. Then the predicted month 6 BMD T‐scores were used to determine the relationship between month 6 total hip T‐score and subsequent nonvertebral and new or worsening vertebral fracture incidence after month 6. The analysis included patients who had an observed BMD T‐score at baseline and at least one observed postbaseline BMD T‐score (4092 patients [romosozumab, 2046; alendronate, 2046] for both total hip and femoral neck and 3896 patients [romosozumab, 1950; alendronate, 1946] for lumbar spine) and was based on the Cox proportional hazards model with time to fracture as the response and total hip T‐score at month 6 as a covariate. Dashed lines indicate upper and lower 95% CIs. P‐values were based on the likelihood ratio test.