In vivo local co-delivery of recombinant human bone morphogenetic protein-7 and pamidronate via poly-D, L-lactic acid

Eur Cell Mater. 2010 Dec 22:20:431-41; discussion 441-2. doi: 10.22203/ecm.v020a35.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density Conservation Agents / administration & dosage*
  • Bone Density Conservation Agents / pharmacology
  • Bone Morphogenetic Protein 7 / administration & dosage*
  • Bone Morphogenetic Protein 7 / pharmacology
  • Bone and Bones / drug effects*
  • Bone and Bones / physiology
  • Diphosphonates / administration & dosage*
  • Drug Carriers
  • Female
  • Humans
  • Lactic Acid*
  • Mice
  • Mice, Inbred C57BL
  • Osteogenesis
  • Pamidronate
  • Polyesters
  • Polymers*
  • Quadriceps Muscle
  • Recombinant Proteins / administration & dosage*
  • Recombinant Proteins / pharmacology
  • Tissue Engineering

Substances

  • BMP7 protein, human
  • Bone Density Conservation Agents
  • Bone Morphogenetic Protein 7
  • Diphosphonates
  • Drug Carriers
  • Polyesters
  • Polymers
  • Recombinant Proteins
  • Lactic Acid
  • poly(lactide)
  • Pamidronate