Elsevier

Bone

Volume 101, August 2017, Pages 77-87
Bone

Full Length Article
Kinetic reconstruction reveals time-dependent effects of romosozumab on bone formation and osteoblast function in vertebral cancellous and cortical bone in cynomolgus monkeys

https://doi.org/10.1016/j.bone.2017.04.005Get rights and content
Under a Creative Commons license
open access

Highlights

  • Romosozumab causes an increase in bone formation.

  • Although bone formation attenuates, spine BMD progressively increases.

  • Reconstruction of cancellous formative sites revealed romosozumab increases W.Th.

  • Decreased ES/BS, Rs.P, and Rs.De accompany increased W.Th with a net positive BB.

  • These combined effects would contribute to progressive increase in spine BMD.

Abstract

Romosozumab, a humanized monoclonal sclerostin antibody under development for the treatment of osteoporosis, has a unique mechanism of action on bone—increasing bone formation and decreasing bone resorption. The effects on bone formation are transient, eliciting a rapid increase in bone formation that attenuates with continued treatment. Although bone formation attenuates, bone mineral density (BMD) continues to increase. To explore potential tissue-level mechanisms that could contribute to a progressive increase in spine BMD, we used kinetic reconstruction techniques to examine the effects of romosozumab on modeling and remodeling units in vertebral cancellous bone from adult cynomolgus monkeys administered romosozumab for 10 and 28 weeks.

The 10-week study duration captured a period of high modeling-based bone formation, and the 28-week study duration followed the self-regulation or attenuation of bone formation in cancellous bone that occurs with long-term treatment. Sequential fluorochrome labels applied for the kinetic reconstruction were also used to evaluate treatment effects on osteoblast function as early as 3 weeks, and on bone formation and bone accrual in the vertebral cortex over 28 weeks.

Kinetic reconstruction of remodeling and modeling formation sites in vertebral cancellous bone revealed that romosozumab effected significant transient increases in mineral apposition rate in remodeling sites at week 3 that was not sustained with continued treatment. However, romosozumab treatment caused sustained improvement in fractional labeling of osteoid, an index of osteoblast efficiency, at remodeling formative sites at both weeks 10 and 28 that was the major contributor to significant increases in final wall thickness (W.Th) of remodeling packets. Remodeling W.Th matched the final W.Th of modeling packets at week 10. At both weeks 10 and 28, romosozumab significantly decreased eroded surface (ES/BS). At week 28, romosozumab also significantly reduced resorption period (Rs.P) and final resorption depth (Rs.De). The reduced final Rs.De combined with the increased W.Th resulted in a significant increase in bone balance (BB) at the level of the remodeling unit. Assessment of bone formation on the vertebral periosteal and endocortical surfaces following 28 weeks of treatment revealed that romosozumab significantly increased bone formation on these surfaces, which had attenuated by week 28, resulting in significant increases in new periosteal and endocortical bone by week 28.

These data suggest that multiple factors potentially contribute to the increase in spine BMD with romosozumab treatment. In the early period of treatment, increased modeling-based bone formation, increased W.Th at remodeling sites, a decrease in remodeling space secondary to decreased ES/BS in vertebral cancellous bone, and increased periosteal and endocortical bone formation in the vertebral cortex contribute to the early increase in spine BMD. Following the self-regulation of bone formation when modeling-based bone formation has attenuated, a decrease in remodeling space secondary to reduced ES/BS and a positive BB secondary to decreased final Rs.De and increased W.Th contribute to the progressive increase in spine BMD with long-term treatment.

Abbreviations

2QM
twice per month
Ac.F
activation frequency
Aj.AR
adjusted apposition rate
BB
bone balance
Ct.B.Ar
cortical bone area
Ec.L.Pm
percent endocortical labeled perimeter
ES/BS
eroded surface
FP
formation period
ILD
interlabel distance
MAR
mineral apposition rate
MLT
mineralization lag time
MS/BS
modeling- and remodeling-based mineralizing surface
MS/OS
fractional labeling of osteoid
MS/OS
osteoid surface
New Ec.B.Ar
new endocortical bone area
New Ps.B.Ar
new periosteal bone area
O.Wi
osteoid width
Ps.L.Pm
percent periosteal labeled perimeter
Rs.De
resorption depth
Rs.P
resorption period
W.Th
wall thickness
W.Wi
mineralized wall width

Keywords

Osteoporosis
Therapeutics
Anabolics
Histomorphometry
Wnt signaling
Bone

Cited by (0)

Conflicts of interest: RWB is an employee of Amgen Inc. and holds Amgen Inc. stock and/or stock options. QN and MSO are former Amgen employees and hold Amgen stock.

1

Present address: 15137 Varsity St, Moorpark, CA 93021, USA.

2

Present address: Radius Health, Inc. 950 Winter St, Waltham, MA 02451, USA.