Abstract
ABSTRACTPathological bone loss is a regular feature of postmenopausal osteoporosis, and the microstructural changes along with the bone loss make the individual prone to getting hip, spine, and wrist fractures. We have developed a new conjugate drug named C3, which has a synthetic, stable EP4 agonist (EP4a) covalently linked to an inactive alendronate (ALN) that binds to bone and allows physiological remodeling. After losing bone for 12 weeks, seven groups of rats were treated for 8 weeks via tail‐vein injection. The groups were: C3 conjugate at low and high doses, vehicle‐treated ovariectomy (OVX) and sham, C1 (a similar conjugate, but with active ALN at high dose), inactive ALN alone, and a mixture of unconjugated ALN and EP4a to evaluate the conjugation effects. Bone turnover was determined by dynamic and static histomorphometry; μCT was employed to determine bone microarchitecture; and bone mechanical properties were evaluated via biomechanical testing. Treatment with C3 significantly increased trabecular bone volume and vertebral BMD versus OVX controls. There was also significant improvement in the vertebral load‐bearing abilities and stimulation of bone formation in femurs after C3 treatment. This preclinical research revealed that C3 resulted in significant anabolic effects on trabecular bone, and EP4a and ALN conjugation components are vital to conjugate anabolic efficacy. A combined therapy using an EP4 selective agonist anabolic agent linked to an inactive ALN is presented here that produces significant anabolic effects, allows bone remodeling, and has the potential for treating postmenopausal osteoporosis or other diseases where bone strengthening would be beneficial. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Postmenopausal osteoporosis results in pathological bone loss owing to the negative bone balance caused by increased bone tissue turnover and resorptive activity, which is much greater than the natural bone formation.[1,2] Cancellous bone has a porous structure that exposes a greater surface area for osteoclast-based resorption and is affected more than cortical bone in osteoporosis.[3]. The microstructural changes along with the bone loss associated with the disease make the individual prone to getting hip, spine, and wrist fractures.[4,5] Current treatments for postmenopausal osteoporosis are commonly based around using bisphosphonate (BP) drugs and parathyroid hormone (PTH) therapy.[6,7,8,9]
Prostaglandin E2 (PGE2) is a natural hormone derived from arachidonic acid and is widely produced within the body that stimulates bone remodeling.[21]. Studies have shown that PGE2 can increase bone formation by stimulating osteoblast differentiation[22,23,24]; it stimulates osteoclastogenesis and bone-resorptive capacity in vitro.[25,26] In vivo, it can produce net anabolic effects with intermittent administration, such as increasing rat cortical bone mass,(27,28) enhancing rat trabecular bone volume,(29,30) inducing endosteal and periosteal bone formation,(31,32) preventing cancellous bone loss caused by ovariectomy,(33) and improving mechanical strength.[34]
PGE2 receptor knocked-out have revealed that the EP4 receptor is largely responsible for PGE2’s stimulatory effects on bone tissue formation and resorption.[36,42] EP4 agonists mimic PGE2 effects on bone, such as inducing woven bone formation in mice,(43) trabecular and cortical bone mass restoration and improving biomechanics in ovariectomized rats,(44) and stimulation of murine bone resorption.[42]. It has been demonstrated that PGE2 effects in vivo and in vitro are suppressed when a selective EP4 receptor antagonist is used.[45,46,47] the systemic administration of EP4 agonists results in a series of side-effects similar to those of native PGE2,(43) which limits their clinical usefulness in osteoporosis treatment despite the overall anabolic effects
Summary
Postmenopausal osteoporosis results in pathological bone loss owing to the negative bone balance caused by increased bone tissue turnover and resorptive activity, which is much greater than the natural bone formation.[1,2] Cancellous bone has a porous structure that exposes a greater surface area for osteoclast-based resorption and is affected more than cortical bone in osteoporosis.[3]. PGE2 receptor knocked-out have revealed that the EP4 receptor is largely responsible for PGE2’s stimulatory effects on bone tissue formation and resorption.[36,42] EP4 agonists (eg, EP4a) mimic PGE2 effects on bone, such as inducing woven bone formation in mice,(43) trabecular and cortical bone mass restoration and improving biomechanics in ovariectomized rats,(44) and stimulation of murine bone resorption.[42] It has been demonstrated that PGE2 effects in vivo and in vitro are suppressed when a selective EP4 receptor antagonist is used.[45,46,47] the systemic administration of EP4 agonists results in a series of side-effects similar to those of native PGE2,(43) which limits their clinical usefulness in osteoporosis treatment despite the overall anabolic effects. The effects of the novel conjugated drug C3 on microarchitecture, volumetric bone mineral density (vBMD), and mechanical properties are studied
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