Lanthanide Compounds for Bone Resorption Disorders

Bone density disorders, including osteoporosis, affect 1 in 4 women and 1 in 8 men over age 50 in North America; as the population ages, these diseases are incurring substantial annual health care costs escalating into billions of dollars.  Osteoporosis is characterized by low bone mineral density that leads to enhanced bone fragility and a consequent risk of low-impact bone fractures.  The low bone mineral density is a result of an imbalance between bone resorption and bone formation.  Normally, building and absorption of bone is a tightly regulated cycle wherein the bone matrix is manufactured by osteoblast cells and removed by osteoclast cells.  Either increased activity of osteoclasts or decreased bone formation by osteoblasts leads to microarchitectural deterioration of bone tissue.  Many contributing factors are known to influence the pathogenesis of the disease with the most prominent being inadequate calcium uptake.

Few therapeutic agents exist currently, either for prevention or for amelioration of these serious diseases, and patient compliance with the existing treatments is low due to adverse gastrointestinal side effects and/or high costs.  A new class of osteoporosis drugs, including oral strontium ranelate, stimulate osteoblast proliferation and inhibit osteoclast activity; however, uncertainty regarding the potential toxicity of chronic strontium accumulation in bone may limit the utility of this product.  Lanthanides Ln(III) are known for their therapeutic and diagnostic applications as agents for magnetic resonance imaging, cancer and radiotherapy.  Low doses of Ln have been shown to act similarly to strontium ranelate.  In vivo, Ln(III), a functional mimic of Ca(II), has been found to exchange with Ca(II) in bone to modify the bone remodeling cycle by stimulating osteoblast proliferation and impeding bone resorption by inhibiting osteoclast differentiation.  Based on this evidence, lanthanum carbonate (La₂(CO₃)₃) has been proposed as a potential preventative measure for post-menopausal osteoporosis; however, gastrointestinal upset is a known negative side effect of this treatment.  La₂(CO₃)₃ is currently being used to treat hyperphosphatemia under the trade name of Fosrenol™.  Unfortunately, due to its extremely low bioavailability (<0.0007%), high doses of elemental La(III) are administered for this application, leading to adverse gastrointestinal (GI) tract side effects.

Adjustments to the ligand structure around the Ln(III) ions have the potential to increase the oral bioavailability of Ln(III) for the treatment of bone density disorders while decreasing unwanted side effects.  In collaboration with Prof. K. Wasan of UBC’s Faculty of Pharmaceutical Sciences and Prof. Rizhi Wang of UBC’s Biomaterials Group, we are investigating neutral Ln(III) tris(bidentate ligand) complexes as bone agents.  La(III)_, Gd(III), and Yb(III) ions were investigated, with selection of specific lanthanides based on their known medicinal applications and for size comparison and the potential of these compounds as therapeutic agents for the treatment of bone resorption disorders is being assessed in cytotoxicity studies, in comparative bifunctional transport in human colon carcinoma cells with intestinal cell like properties (Caco-2 cells), in hydroxyapatite binding and in a variety of other in vitro tests preparing for the 2012 in vivo studies of our two lead candidates.