In vivo reference point indentation reveals positive effects of raloxifene on mechanical properties following 6months of treatment in skeletally mature beagle dogs

Abstract

Raloxifene treatment has been shown previously to positively affect bone mechanical properties following 1 year of treatment in skeletally mature dogs. Reference point indentation (RPI) can be used for in vivo assessment of mechanical properties and has been shown to produce values that are highly correlated with properties derived from traditional mechanical testing. The goal of this study was to use RPI to determine if raloxifene-induced alterations in mechanical properties occurred after 6 months of treatment. Twelve skeletally mature female beagle dogs were treated for 6 months with oral doses of saline vehicle (VEH, 1 ml/kg/day) or a clinically relevant dose of raloxifene (RAL, 0.5 mg/kg/day). At 6 months, all animals underwent in vivo RPI (10 N force, 10 cycles) of the anterior tibial midshaft. RPI data were analyzed using a custom MATLAB program, designed to provide cycle-by-cycle data from the RPI test and validated against the manufacturer-provided software. Indentation distance increase (IDI), a parameter that is inversely related to bone toughness, was significantly lower in RAL-treated animals compared to VEH (− 16.5%), suggesting increased bone toughness. Energy absorption within the first cycle was significantly lower with RAL compared to VEH (− 21%). These data build on previous work that has documented positive effects of raloxifene on material properties by showing that these changes exist after 6 months.

In vivo reference point indentation measurement variability in skeletally mature inbred mice

“…Our data also show an interesting pattern of variation among the RPI parameters. At both testing dates, the parameter with the least within-animal variation is US-1st, which is also observed in dogs 5 and rats. 15 The parameter with the most variation in the current study is IDI, which is also seen in rats.…”

“…3,4 In dogs, within-animal variation ranged from 5% in US-1st to 27% in ID-1st and ED-1st. 5 In rats, within-animal variation ranged from 13% in Tot ED and US-1st to 21% in IDI. 15 The data presented here for mice exceed the upper limit of these ranges at the first test date, as the variation in IDI within-animal exceeds 30%.…”

“…The recent development of RPI as a method for assessing material-level mechanical properties in vivo has the potential to revolutionize the field. [3][4][5] Whereas a number of studies have measureed RPI outcomes in rodents ex vivo, 6,12-14 only a single study has examined these measures in vivo. 15 The objective of this study was to assess the variability of RPI parameters measured in vivo within and among treatment naive, skeletally mature mice, because mice are among the most common first-line model in skeletal research.…”

“…4 A study in dogs demonstrated differences in RPI parameters measured in vivo between controls and animals treated for 6 months with raloxifene at clinically relevant doses. 5 These studies show the real potential for this tool in a clinical setting, even while we are only beginning to understand how RPI outcomes compare with properties measured using traditional mechanical testing modalities. [6][7][8][9] The present study is targeted at a more fundamental level than the clinical and preclinical assessments of RPI described above.…”

Exercise prevents β-aminopropionitrile-induced morphological changes to type I collagen in murine bone

“…Exercise prevents BAPN-induced changes to collagen MA Hammond and JM Wallace A custom Matlab (Mathworks, Natick, MA, USA) program was used to calculate the 1st cycle indentation distance (ID 1st), 1st cycle energy dissipation (ED 1st), US 1st, CID 1st, IDI, total indentation distance (TID), total energy dissipation (ED Tot), average creep indentation distance (Avg CID), average energy dissipation (Avg ED) and average unloading slope (Avg US). 41 All indentations used the same probe assembly and were performed on the same day.…”