Synthetic analogues of the peptide hormone calcitonin have been used in medicine as biologic
drug therapies for decades, to treat pathological conditions of excessive bone turnover, such as osteoporosis,
where more bone is removed than replaced during bone remodeling. Osteoporosis and other chronic skeletal
diseases, including inflammatory arthritis, exact a substantial and growing toll on aging populations worldwide
however they respond poor to synthetic biologic drug therapy, due in part to the rapid half-life of
elimination, which for calcitonin is 43 minutes. To address those shortcomings, we have developed and synthesized
bone-targeting variants of calcitonin as a targeted drug delivery strategy, by conjugation to bisphosphonate
drug bone-seeking functional groups in highly specific reaction conditions. To evaluate their in vivo efficacy,
bisphosphonate-mediated bone targeting with PEGylated (polyethylene glycol conjugated) and non-PEGylated salmon
calcitonin analogues were synthesized and dose escalation was performed in female rats developing Osteoporosis. The
bone-targeting calcitonin analogues were also tested in a separate cohort of male rats developing adjuvant-induced arthritis.
Ovariectomized female rats developing Osteoporosis were administered daily sub-cutaneous injection of analogues
equivalent to 5, 10 and 20 IU/kg of calcitonin for 3 months. Adjuvant arthritis was developed in male rats by administering
Mycobacterium butyricum through tail base injection. Daily sub-cutaneous injection of analogues equivalent to 20
IU/kg of calcitonin was administered and the rats were measured for visible signs of inflammation to a 21 day endpoint. In
both studies, the effect of drug intervention upon bone volume and bone mineral density (BMD) was assessed by measuring
the trabecular bone volume percentage and BMD at the proximal tibial metaphysis using in vivo micro-computed tomography.
With dose escalation studies, only bone targeting analogue dosed groups showed a trend towards increased
BMD and bone volume at 4, 8 and 12 weeks. Significant preservation of bone volume and BMD as evidenced by nonsignificant
(P>0.05) loss of bone volume and BMD at the end of 3 month study endpoint was seen in animals dosed with
20 IU/kg of calcitonin compounds. Similarly, in case of adjuvant-induced arthritis rats, there was a significant increase
(P<0.05) in bone volume and BMD in calcitonin-bisphosphonate and calcitonin-PEG-bisphosphonate treated groups at 21
days compared to the baseline values. Improved efficacy in terms of preserving bone volume and BMD in Osteoporosis,
and in rats developing adjuvant-induced arthritis, by these analogues suggests their potential as new drug candidates for
further evaluation to determine their usefulness in bone diseases characterized by excessive bone resorption.
Keywords: Bisphosphonate, bone mineral density (BMD), bone targeting, bone volume, adjuvant arthritis, calcitonin, polyethylene
glycol (PEG), micro-CT, osteoporosis.
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