Effects of systemically administered abaloparatide, an osteoanabolic PTHrP analog, as an adjuvant therapy for spinal fusion in rats

Abstract

Background: Abaloparatide is a parathyroid hormone receptor agonist that increases bone formation and reduces vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis. Animal studies indicate abaloparatide stimulates vertebral bone formation and enhances bony bridging and biomechanical stability of fracture calluses.

Aims: The current study is evaluating the potential utility for abaloparatide as an adjunct therapy for spinal fusions.

Material and methods: The effects of 14 or 28 days of daily subcutaneous injections of abaloparatide (20 μg/kg/d) or vehicle were evaluated in 32 male Sprague-Dawley rats starting 1 day after noninstrumented posterolateral fusion (PLF) with bone autograft. Fusion mass microarchitecture was analyzed by micro-computed tomography (micro-CT) and serum markers of bone formation and bone resorption were evaluated. Motion segments were scored in a blinded manner as fused or unfused by postmortem radiography and manual palpation.

Results: Abaloparatide-treated rats showed higher bone formation (serum osteocalcin) at day 14 and 28 compared with vehicle controls, without increases in the bone resorption marker serum TRACP-5b. Micro-CT showed greater trabecular number in fusion masses from the abaloparatide group vs vehicle controls at day 14. Manual palpation and radiography indicated no fusions in either group at day 14, whereas 25% of vehicle-treated rats and 50% of abaloparatide-treated rats had bilateral fusion at day 28.

Discussion and conclusion: In summary, this rat PLF model showed that abaloparatide treatment was associated with higher levels of the bone formation marker osteocalcin, improved fusion mass architecture, and a non- significant 2-fold higher fusion rate compared with vehicle.

Keywords: arthrodesis; bone formation; bone‐forming agent; fusion mass; spine surgery.

FIGURE 1

2D micro‐computed tomography (micro‐CT) images of L4‐L5 transverse processes with interposed fusion masses comprising newly formed bone and bone autograft remnants. Images on the left and right are from animals that received daily injections of vehicle or abaloparatide 20 μg/kg/d, respectively, starting the day after surgery and continuing for 28 days. Asterisks indicate motion segments judged to be fused by radiographic and manual palpation assessments, which is corroborated visually in these micro‐CT images. White arrows highlight residual bone autograft fragments, many of which are not incorporated into the established fusion masses

FIGURE 2

3D micro‐computed tomography (micro‐CT) images of motion segments showing lack of fusion in representative animals from both treatment groups at day 14 and successful fusion in each treatment group at day 28. The day 14 examples were selected based on fusion mass bone volume that was closest to their group mean, whereas fusion mass bone volumes for the day 28 examples were closest to their group mean among the subset of animals deemed fused by radiographic and manual palpation asessments

FIGURE 3

Linear regressions of serum osteocalcin vs fusion mass bone microarchitecture. A, Day 14 serum osteocalcin vs day 14 trabecular number (Tb.N) by micro‐CT. B, Day 28 serum osteocalcin vs day 28 trabecular bone volume per tissue volume (BV/TV). R values represent both groups combined

FIGURE 4

Fusion status assessed by radiography, A and manual palpation, B indicated no fusions in either group at day 14, whereas both assessments indicated successful fusion in 2 of 8 vehicle control group animals and 4 of 8 abaloparatide group animals at day 28. Lumbar spine radiographs, C, show representative unfused examples at day 14, and fused examples at day 28. Day 14 examples were selected based on fusion mass bone volume closest to their group mean, whereas fusion mass bone volumes for the day 28 examples were closest to their group mean among the subset of animals deemed fused by radiography and manual palpation. White brackets identify motion segments and associated fusion masses