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Abstract
Summary Two alendronate-EP4 agonist (ALN-EP4a) conjugate
drugs, C1 and C2, which differ in structure by a short
linker molecule, were evaluated in ovariectomized (OVX) rats
for their anabolic effects.We showed that C1 led to significant
anabolic effects on cortical and trabecular bone while anabolic
effects associated with C2 were minimal.
Introduction EP4as were covalently linked to ALN to create
ALN-EP4a conjugate anabolic bone drugs, C1 and C2, which
differ in structure by a short linker molecule in C1. When
administered systemically, C1 and C2 are delivered to bone
through targeted binding of ALN, where local hydrolytic enzymes
liberate EP4a from ALN to exert anabolic effects.Here,
we compare effects of C1 to C2 in a curative in vivo study.
Methods Three-month-old female Sprague Dawley rats were
OVX or sham operated and allowed to lose bone for 3 months.
Animals were then treated via tail vein injections for 3 months
and sacrificed. Treatment groups were as follows: C1L
(5 mg/kg biweekly), C1H (5 mg/kg weekly), C2L (15 mg/kg
monthly), C2H (15 mg/kg biweekly), OVX and sham control
(phosphate-buffered saline (PBS) biweekly), and ALN/EP4aunconjugated
mixture (0.75 mg/kg each biweekly).
Results MicroCT analysis showed that C1H treatment significantly
increased vertebral bone mineral density (vBMD) and
trabecular bone volume versus OVX controls while C2 treatments
did not. Biomechanical testing showed that C1H treatment
but not C2 treatments led to significant improvement in
the load bearing abilities of the vertebrae compared to OVX
controls. C1 stimulated endocortical bone formation and increased
load bearing in femurs, while C2 did not.
Conclusions We showed that C1 led to significant anabolic
effects on cortical and trabecular bone while anabolic effects
associated with C2 were minimal. These results led us to hypothesize
a mode of action by which presence of a linker is
crucial in facilitating the anabolic effects of EP4a when dosed
as a prodrug with ALN.
Keywords Anabolic drug . Biomechanical testing .
Bisphosphonates .Bone histomorphometry .Conjugate drug .
Osteoporosis