Differential temporal effects of sclerostin antibody and parathyroid hormone on cancellous and cortical bone and quantitative differences in effects on the osteoblast lineage in young intact rats.
Sclerostin antibody (Scl-Ab) and parathyroid hormone (PTH) are bone-forming agents that have different modes of action on bone, although a study directly comparing their effects has not been conducted. The present study investigated the comparative quantitative effects of these two bone-forming agents over time on bone at the organ, tissue, and cellular level; specifically, at the level of the osteoblast (Ob) lineage in adolescent male and female rats. Briefly, eight-week old male and female Sprague-Dawley rats were administered either vehicle, Scl-Ab (3 or 50mg/kg/week subcutaneously), or human PTH (1-34) (75 μg/kg/day subcutaneously) for 4 or 26 weeks. The 50mg/kg Scl-Ab and the PTH dose were those used in the respective rat lifetime pharmacology studies. Using robust stereological methods, we compared the effects of these agents specifically at the level of the Ob lineage in vertebrae from female rats. Using RUNX2 or nestin immunostaining, location, and morphology, the total number of osteoprogenitor subpopulations, Ob, and lining cells were estimated using the fractionator or proportionator estimators. Density estimates were also calculated referent to total bone surface, total Ob surface, or total marrow volume. Scl-Ab generally effected greater increases in cancellous and cortical bone mass than PTH, correlating with higher bone formation rates (BFR) at 4 weeks in the spine and mid-femur without corresponding increases in bone resorption indices. The increases in vertebral BFR/BS at 4 weeks attenuated with continued treatment to a greater extent with Scl-Ab than with PTH. At 4 weeks, both Scl-Ab and PTH effected equivalent increases in total Ob number (Ob.N). Ob density on the formative surfaces (Ob.N/Ob.S) remained similar across groups while mineral apposition rate (MAR) was significantly higher with Scl-Ab at week 4, reflecting an increase in individual Ob vigor relative to vehicle and PTH. After 26 weeks, Scl-Ab maintained BFR/BS with fewer Ob and lower Ob.N/Ob.S by increasing the Ob footprint (bone surface area occupied by an Ob) and increasing MAR, compared with PTH. The lower Ob.N and Ob.N/Ob.S with Scl-Ab at 26 weeks were associated with decreased osteoprogenitor numbers compared with both vehicle and PTH, an effect not evident at week 4. Osteoprogenitor numbers were generally positively correlated with Ob.N across groups and timepoints, suggesting dynamic coordination between the progenitor and Ob populations. The time-dependent reductions in subpopulations of the Ob lineage with Scl-Ab may be integral to the greater attenuation or self-regulation of bone formation observed at the vertebra, as PTH required more Ob at the formative site with correlative increased numbers of progenitors compared with Scl-Ab indicating potentially greater stimulus for progenitor pool proliferation or differentiation.
Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
Michael S
MS
Ominsky
WIL Research Laboratories, Hillsborough, NC, USA.
Danielle L
DL
Brown
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Gwyneth
G
Van
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
David
D
Cordover
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Efrain
E
Pacheco
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Emily
E
Frazier
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Linda
L
Cherepow
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Marnie
M
Higgins-Garn
Department of Physiological Sciences, University of Florida, Gainesville, FL, USA.
J Ignacio
JI
Aguirre
Department of Physiological Sciences, University of Florida, Gainesville, FL, USA.
Thomas J
TJ
Wronski
Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
Marina
M
Stolina
Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, USA.
Lei
L
Zhou
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA.
Ian
I
Pyrah
Department of Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: rboyce@amgen.com.
Rogely Waite
RW
Boyce
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry; D015519:Bone Density / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D005260:Female; D005269:Femur / Q000187:drug effects; D005819:Genetic Markers / Q000276:immunology*; D006801:Humans; D008297:Male; D010006:Osteoblasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology; D013977:Tibia / Q000187:drug effects; D013997:Time Factors
D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C470125:PTH protein, human; D010281:Parathyroid Hormone; C486031:Sost protein, rat; C557282:romosozumab
Bone formation; Cancellous bone; Cortical bone; Osteoblast lineage; Parathyroid hormone; Sclerostin antibody