Combination Therapy With Zoledronic Acid and FES-Row Training Mitigates Bone Loss in Paralyzed Legs: Results of a Randomized Comparative Clinical Trial

Abstract

Spinal cord injury (SCI) results in rapid, severe osteoporosis and an increased risk of lower extremity fractures. Despite the medical complications associated with these fractures, there is no standard of care to prevent osteoporotic fractures following SCI. Functional electrical stimulation- (FES-) assisted rowing is a promising intervention to improve bone health in SCI because of its ability to generate a muscular contraction in conjunction with mechanical loading of the lower extremity long bones. Combination therapy consisting of FES-rowing plus zoledronic acid (ZA) may be a superior treatment via inhibition of bone resorption and stimulation of new bone formation. We studied participants enrolled in a randomized clinical trial comparing FES-rowing alone with FES-rowing plus ZA to improve bone health in SCI. Volumetric CT scans at the distal femur and proximal tibial metaphyses were performed. Bone geometric properties (cortical thickness index [CTI], cortical compressive strength index [CSI], buckling ratio [BR], bending strength index) and mineral (cortical bone volume [CBV], cortical bone mineral density, cortical bone mineral content) indices were determined. In models adjusting for baseline values, we found that the CBV (p = 0.05 to 0.006), the CTI (p = 0.009), and the BR (p = 0.001) at both the distal femoral and proximal tibial metaphyses were greater in the ZA plus rowing group compared with the rowing-only group. Similarly, there was a significant positive association between the total rowing work completed and the BR at the proximal tibia (p = 0.05). A subgroup analysis of the rowing-only arm showed that gains in the CSI at the tibial metaphysis varied in a dose-dependent fashion based on the total amount of exercise performed (p = 0.009). These findings demonstrate that the osteogenic response to FES-rowing is dose-dependent. Combination therapy with ZA and FES-row training has therapeutic potential to improve bone quality, and perhaps reduce fracture risk at the most common fracture site following SCI. © 2019 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Keywords: ANTIRESORPTIVES; BONE QCT; CLINICAL TRIALS; OSTEOPOROSIS; THERAPEUTICS.

Figure 1

Study flow.

Figure 2

Factors associated with end‐of‐study cortical bone volume. Confidence intervals presented for models cortical bone volume (adjusted for baseline values, rowing‐only group is the reference) at the distal femur or proximal tibia. ZA = zoledronic acid.

Figure 3

Percent change in cortical bone volume or bone geometry based on treatment group (rowing‐only or rowing + zoledronic acid). Change in cortical bone volume (CBV), cortical thickness index (CTI), and buckling ratio (BR) are presented for distal femur and proximal tibia.

Figure 4

Factors associated with end‐of‐study bone geometry. Confidence intervals presented for cortical thickness index (CTI) and buckling ratio (BR) adjusted for baseline values (rowing‐only group is the reference) at the distal femur or proximal tibia.

Figure 5

The geometry and density distribution of two tibial metaphysis with high (left; CTI = 0.058, BR = 0.198) and low (right; CTI = 0.021, BR = 0.058) cortical thickness index (CTI) and buckling ratio (BR). CTI and BR are calculated based on the assumption that the region of interest (tibial metaphysis) is a right circular hollow cylinder with outer diameter of D, inner diameter of d, and height of h.