Findings from a new study in the United Kingdom, which was presented in a recent issue of the Journal of Bone and Mineral Research, have identified a series of biphenylcarboxylic acid (biphenyl) derivatives that have potent inhibitory effects on osteoclast formation and osteoclastic bone resorption in vitro, and on ovariectomy-induced bone loss in vivo.¹

The results of the study "identify compounds that represent a new class of antiresorptive drug" that may be of therapeutic value in the prevention and treatment of diseases characterized by osteoclast activation, such as osteoporosis, Paget's disease, and cancer-associated bone disorders, according to lead investigator Rob J. van't Hof, PhD, Research Fellow at the Bone Research Group in the Department of Medicine and Therapeutics, University of Aberdeen's Institute of Medical Sciences in Scotland, UK.

The research also demonstrated that the biphenyl derivatives work to inhibit tumor necrosis factor-α (TNF-α)-induced NF-κB, a pathway that is crucial in inflammation. "This may eventually provide an alternative to anti-TNF drugs at much lower cost," Dr. van't Hof told CIAOMed.

The most effective osteoclast inhibitors among the biphenyl derivatives identified in the current study, 1,4-butanediol biphenylcarboxylic acid ester (ABD056) and 6-hydroxy-1-(4-biphenyl) hexan-1-one (ABD068), were found to exert their inhibitory effects on osteoclast formation and activity.

Most of the current investigation's studies were performed with ABD056, which was found to be effective at inhibiting osteoclast formation and osteoclastic bone resorption in experimental systems, including rabbit osteoclast cultures and human osteoclast cultures generated from peripheral blood mononuclear cells, as well as in mouse osteoblast-bone marrow co-cultures and macrophage colony stimulating factor-stimulated and receptor activator of NF-κB ligand-stimulated mouse bone marrow cultures.

The mechanism of osteoclast inhibition by ABD056 was attributable, in part, to stimulation of osteoclast apoptosis. The pro-apoptotic effects observed in the current investigation were relatively specific for osteoclasts and related cells. Accordingly, the in vivo studies showed that ABD056 inhibited ovariectomy-induced bone loss in mice primarily by inhibiting bone resorption, but had no significant inhibitory effect on bone formation.

Prevention and treatment of many common bone diseases that result from accelerated osteoclastic bone resorption are based on osteoclastic inhibition. Bisphosphonates, the most widely used osteoclast inhibitors among currently available therapies, have been shown to effectively inhibit osteoclast-mediated bone resorption and are considered integral in the treatment of benign and malignant bone diseases.² Over the past 30 years, the evolution of this therapy has led to the development of nitrogen-containing bisphosphonates, which exert their effects on osteoclasts by inhibiting farnesyl disphosphate (FPP) synthase, a key enzyme in the mevalonate pathway.

Currently available agents for osteoporosis, Paget's disease, and cancer-associated bone disease fall into relatively few mechanistic classes, according to Dr. van't Hof. "A problem with the current therapies is that bisphosphonates, for unknown reasons, do not work well with bone-building drugs," he noted.

As with bisphosphonates, ABD056 and ABD068 were found to have similar structure activity for inhibition of murine macrophages as well as authentic osteoclasts. However, the researchers showed that these compounds in vitro clearly have a different mechanism of action than the bisphosphonates in that they do not inhibit FPP synthase activity or prenylation of Rap1A.

Potentially, this shows a distinct advantage of ABD056 as compared to the bisphosphonates. "What is significant about the biphenyl derivatives is that they do not inhibit bone formation and could be very useful if used in combination with bone anabolics to help regain new bone while helping repress bone destruction," Dr. van't Hof stated.

The aim of the current study was "to synthesize and characterize novel biphenyl derivatives in which inhibitory effects on osteoclastic activity could be dissociated from the inhibitory effects on cyclooxygenase activity," Dr. van't Hof stated. Known to be potent agonists, prostaglandins such as cyclooxygenase (COX) can inhibit osteoclastic bone resorption in organ cultures and in vitro studies have shown that COX inhibitors (eg, indomethacin) inhibit osteoclastic bone resorption induced by certain cytokines and growth factors.³

Clinicians who treat patients with diseases characterized by excessive bone loss would welcome an addition to their armamentarium, said Michael Holick, MD, PhD, professor of medicine at the Boston University Medical Center, Boston, Massachusetts. Many patients have difficulty tolerating bisphosphonates, and "it would be an improvement to have an additional class of agents that are potent inhibitors of bone marrow resorption and that are not also inhibitors of bone formation," he said.

Evidence also suggested that ABD056 and ABD068 act on precursor cells to inhibit osteoclast differentiation; the inhibitory effects of both compounds on osteoclast formation were enhanced when they were added at the beginning of osteoblast-bone marrow cultures, before mature osteoclasts had formed.

However, Dr. van't Hof observed that further studies will need to be performed to define the precise molecular target or targets for the action of ABD056 and to determine whether these compounds affect other signaling pathways that are involved in osteoclast survival. "These compounds are pro-drugs," he emphasized, "and they are not ready for clinical use at this time."

The study was supported by grants from the Arthritis Research Campaign (UK), Medical Research Council, and Scottish Enterprise.

References:

1. van't Hof RJ, Idris AI, Ridge SA, Dunford J, Grieg IR, Ralston SH. Identification of biphenylcarboxylic acid derivatives as a novel class of bone resorption inhibitors. J Bone Miner Res. 2004;19:1651-1660.
2. Green JR. Bisphosphonates: preclinical review. Oncologist. 2004;9(suppl 4):3-13.
3. Kawaguchi H, Pilbeam CC, Harrison JR, Raisz LG. The role of prostaglandins in the regulation of bone metabolism. Clin Orthop. 1995;313:36-46.