title: In vivo local co-delivery of recombinant human bone morphogenetic protein-7 and pamidronate via poly-D, L-lactic acid.
abstract: The effects of bone anabolic agents such as bone morphogenetic proteins (BMPs) have the potential to be augmented by co-treatment with an anti-catabolic such as a bisphosphonate. We hypothesised that the effects of bisphosphonates on BMP-induced bone anabolism would be dose dependent, and we aimed to test this in a small animal model. Agents were delivered locally using a biodegradable poly-D, L-lactic-acid (PDLLA) polymer delivery system. Recombinant human BMP-7 (25 µg) was tested with a range of doses of the bisphosphonate pamidronate (0.02 mg, 0.2 mg and 2 mg local PAM; 0.3 mg/kg and 3 mg/kg thrice-weekly systemic PAM) versus BMP-7 alone. Polymer pellets were surgically implanted in the hind limbs of female C57BL6/J mice (8-10 week) and ectopic bone nodules were harvested at 3 and 8 weeks post-operatively. At 3 weeks, local low dose PAM (0.02 mg) induced a 102% increase in rhBMP-7 induced bone volume (p<0.01) as measured by miroCT, and this was comparable to systemic PAM (0.3 mg/kg thrice-weekly). In contrast, local high dose PAM (2 mg) resulted in a 97% decrease in bone volume (p<0.01). Radiography and histology indicated that the polymer vehicle was still largely present at 8 weeks indicating inefficient biodegradation. This is the first study to validate the utility of local co-delivery of BMP/bisphosphonate via biodegradable polymer and supports the continued refinement of more advanced bioresorbable delivery systems for clinical applications.
authors.affiliation: Department of Orthopaedic Research & Biotechnology, The Children's Hospital at Westmead, Westmead, Sydney, NSW, Australia. nicole.yu@sydney.edu.au
authors.forename: Nicole Y C
authors.initials: NY
authors.lastname: Yu
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
authors.forename: Lauren
authors.initials: L
authors.lastname: Peacock
authors.forename: Kathy
authors.initials: K
authors.lastname: Mikulec
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ruys
authors.forename: David G
authors.initials: DG
authors.lastname: Little
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7 / Q000008:administration & dosage* / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D004164:Diphosphonates / Q000008:administration & dosage*; D004337:Drug Carriers; D005260:Female; D006801:Humans; D019344:Lactic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis; D000077268:Pamidronate; D011091:Polyesters; D011108:Polymers; D052097:Quadriceps Muscle; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D023822:Tissue Engineering
chemical_list: C525819:BMP7 protein, human; D050071:Bone Density Conservation Agents; D055419:Bone Morphogenetic Protein 7; D004164:Diphosphonates; D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; D011994:Recombinant Proteins; D019344:Lactic Acid; C033616:poly(lactide); D000077268:Pamidronate