Identification of Novel Biphenyl Carboxylic Acid Derivatives as Novel Antiresorptive Agents that Do Not Impair Parathyroid Hormone-Induced Bone Formation

Aymen I Idris, Iain R Greig, Euphemie Bassonga-Landao, Stuart H Ralston, Rob J van 't Hof

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Bisphosphonates are widely used in the treatment of osteoporosis, but they inhibit bone formation and blunt the anabolic effect of PTH. Here we describe a novel series of compounds that have potent antiresorptive effects in vitro and in vivo that do not adversely affect osteoblast function. The effects of the compounds on osteoclast formation and survival were studied on mouse osteoclasts generated from bone marrow macrophages and on osteoblast function using primary mouse calvarial osteoblast cultures and bone nodule cultures. Studies were performed in vivo using sham-operated or ovariectomized mice. The most potent compound tested was ABD350, a halogen-substituted derivative of the parent compound ABD56 in which the labile ester bond was replaced by a reduced ketone link, with IC50 osteoclast formation at a concentration of 1.3 μM. All compounds inhibited receptor activator of nuclear factor-κB ligand-induced inhibitor of nuclear factor κB phosphorylation and caused osteoclast apoptosis but no inhibitory effects on osteoblast function were observed at concentrations of up to 20μM. ABD350 prevented ovariectomy-induced bone loss when given ip (5 mg/kg · d), whereas ABD56 was only partially effective at this dose. In contrast to the bisphosphonate alendronate, ABD350 had no inhibitory effect on PTH-induced bone formation in ovariectomized mice. In conclusion, the biphenyl carboxylic acid derivatives like ABD350 represent a new class of antiresorptive drugs that inhibit osteoclast activity but have no significant inhibitory effects on osteoblast activity in vitro or PTH-induced bone formation in vivo.

Accelerated bone loss, mediated by the action of osteoclasts, plays a critical role in the pathogenesis of osteoporosis and other bone diseases. Whereas osteoclastic bone resorption is essential for the maintenance of a healthy skeleton, increased osteoclast activity or uncoupling of osteoclastic bone resorption from bone formation is deleterious to bone health, resulting in generalized bone loss such as occurs in osteoporosis (1), or focal bone loss such as occurs in conditions like Paget’s disease (2) and metastatic bone disease (3). Reflecting this fact, the vast majority of successful drug treatments for bone disease act by inhibiting osteoclastic bone resorption (4). Many osteoclast-inhibitory drugs that increase bone mass and reduce the risk of fragility fractures in patients with osteoporosis are now available for clinical use (5). However, recent studies indicate that bisphosphonates, the most widely used drugs for the treatment of osteoporosis, inhibit bone formation as well as inhibiting bone resorption and as a result of this fact blunt the therapeutic response to anabolic agents such as PTH (6, 7, 8). This indicates that there still remains a need for new drugs for the treatment of osteoporosis that can inhibit bone loss without negatively impacting on the osteoblast. We previously reported the identification of ABD56, the butanediol ester of biphenyl carboxylic acid as a small molecule inhibitor of osteoclastic bone resorption (9). ABD56 inhibits osteoclast formation and induces osteoclast apoptosis by inhibiting receptor activator of nuclear factor-κB ligand (RANKL) induced activation of the nuclear factor-κB (NFκB) and ERK MAPK pathways (10) Here we report on the development of a new class of compounds derived from ABD56 that inhibit osteoclast activity in vitro and can prevent ovariectomy-induced bone loss in vivo without impairing the anabolic response to parathyroid hormone.
Original languageEnglish
Pages (from-to)5-13
Number of pages9
JournalEndocrinology
Volume150
Issue number1
DOIs
Publication statusPublished - Jan 2009

Keywords / Materials (for Non-textual outputs)

  • Alendronate
  • Animals
  • Animals, Newborn
  • Benzoates
  • Biphenyl Compounds
  • Bone Marrow Cells
  • Bone Resorption
  • Female
  • Macrophage Colony-Stimulating Factor
  • Macrophages
  • Mice
  • Osteoblasts
  • Osteoclasts
  • Osteogenesis
  • Ovariectomy
  • Parathyroid Hormone
  • Skull

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