Comparable outcomes in fracture reduction and bone properties with RANKL inhibition and alendronate treatment in a mouse model of osteogenesis imperfecta

Abstract

We report a direct comparison of RANKL inhibition (RANK-Fc) with bisphosphonate treatment (ALN) from infancy through early adulthood in a mouse model of Osteogenesis Imperfecta. Both ALN and RANK-Fc decreased fracture incidence to the same degree with increases in metaphyseal bone volume via increased number of thinner trabeculae. The potential therapeutic benefit of RANKL inhibitors in OI is under investigation. We report a direct comparison of RANKL inhibition (RANK-Fc) with bisphosphonate treatment (alendronate; ALN) from infancy through early adulthood in a model of OI, the oim/oim mouse. Two week old oim/oim, oim/+ and wildtype (+/+) mice were treated with RANK-Fc 1.5 mg/kg twice per week, ALN 0.21 mg/kg/week or saline (n = 12-20 per group) for 12 weeks. ALN and RANK-Fc both decreased fracture incidence (9.0 ± 3.0 saline 4.4 ± 2.7 ALN, 4.3 ± 3.0 RANK-Fc fractures per mouse). Serum TRACP-5b activity decreased to 65% after 1 month in all treated mice, but increased to 130-200% at sacrifice with RANK-Fc. Metaphyseal density was significantly increased with ALN in +/+ and oim/oim mice (p < 0.05) and tended to increase with RANK-Fc in +/+ mice. No changes in oim/oim femur biomechanical parameters occurred with treatment. Both ALN and RANK-Fc significantly increased trabecular number (ie 3.73±0.77 1/mm for oim/oim saline vs 7.93±0.67ALN and 7.34±1.38 RANK-Fc) and decreased trabecular thickness (ie 0.045 mm ±0.003 for oim/oim saline vs 0.034±0.003 ALN and 0.032±0.002RANK-Fc) and separation in all genotypes (ie 0.28±0.08 mm for oim/oim saline vs 0.12±0.010 ALN and 13±0.03 RANK-Fc)., with significant increase in bone volume fraction (BVF) with ALN, and a trend towards increased BVF in RANK-Fc. Treatment of oim/oim mice with either a bisphosphonate or a RANK-Fc causes similar decreases in fracture incidence with increases in metaphyseal bone volume via increased number of thinner trabeculae.

Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

“…Treatment ended 12 weeks after the transition time point. Doses of RANK-Fc and ALN were based on results of previous studies that showed increased bone mineral density without side effects using the same dose [1][2][3]. Weaning was carried out between 3 and 4 weeks.…”

“…Our group has used the oim/oim mouse model as an analog for evaluating pharmaceutical therapies for moderate-to-severe OI [1-3, 9, 13, 27-29]. The oim/oim mice, as a result of an inappropriate stop codon in the collagen I alpha 2 chain's gene, have a aI(I) 3 triple helix instead of the expected aI(1) 2 aI(2) helix [11] and provide a reproducible model with a moderate-to-severe (Type III) form of OI [34], including the presence of spontaneous fractures. Both alendronate (a bisphosphonate) and RANKFc, an inhibitory antibody to RANKL (receptor activator of nuclear factor-jB ligand), tested in short-term (8-week) studies showed a comparable reduction in the number of fractures relative to saline-treated oim/oim mice [2].…”

“…The bone composition assessed by Fourier transform infrared (FTIR) imaging after short-term alendronate treatment of the oim/oim mouse, however, was unchanged relative to saline-treated mice [8]. RANK-Fc blocks the formation, activation, and survival of osteoclasts [2,3,13]. Because RANKL inhibitors have a shorter half-life in bone than do bisphosphonates, they are being investigated as an alternative therapy.…”

The C-Terminal Domain of Chondroadherin: A New Regulator of Osteoclast Motility Counteracting Bone Loss

“…Among the bone structural parameters, cyclicCHAD was especially effective in preserving the trabecular number. This effect could be explained by the preferential remove of the thinnest trabeculae (PRETT) mechanism, (37,38) that relies on the fact that the thinnest metaphyseal trabeculae, which play a prominent metabolic role, are more prone to be resorbed by osteoclasts and have a shorter lifetime. Therefore, blocking osteoclast bone resorption prevents their disappearance and, as a consequence, their number is higher than in vehicle-treated animals.…”

Response to Comment on Strontium Ranelate Reduces the Fracture Incidence in a Growing Mouse Model of Osteogenesis Imperfecta

“…In preclinical study, Raggio and colleagues found that BPs and RANK-FC could decrease fractures in the mouse model of OI. (2,3) In OI patients, however, the effects of BPs on the fracture reduction in several randomized control trials are still inconsistent. (4,5) The second issue raised by Raggio and colleagues was that we compared the treatment effect of strontium ranelate on fracture reduction to the brtl/þ mice but not to the results that they reported.…”