Antagonism of the Osteoclast Vitronectin Receptor with an Orally Active Nonpeptide Inhibitor Prevents Cancellous Bone Loss in the Ovariectomized Rat

Lark, Michael W.; Stroup, George B.; Dodds, Robert A.; Kapadia, Rasesh; Hoffman, Sandra J.; Hwang, Shing Mei; James, Ian E.; Lechowska, Beata; Liang, Xiaoguang; Rieman, David J.; Salyers, Kevin L.; Ward, Keith W.; Smith, Brian R.; Miller, William H.; Huffman, William F.; Gowen, Maxine

doi:10.1359/jbmr.2001.16.2.319

Cited by 52 publications

(27 citation statements)

References 26 publications

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“…Peptide and non-peptide integrin antagonists can prevent bone resorption [Engleman et al, 1997;Lark et al, 1999;Lark et al, 2001;Hutchinson et al, 2003;Wu et al, 2006]. Integrin attachment is a pro-survival event, and activates survival pathways [Cordes, 2006].…”

Section: Newer Antiresorptive Agents Andmentioning

confidence: 99%

Antiresorptive agents and osteoclast apoptosis

Stern

2007

J of Cellular Biochemistry

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Antiresorptive agents have proven to be effective therapies for the treatment of bone diseases associated with excessive osteoclast activity. Decreased osteoclast formation, inhibition of osteoclast actions, and reduced osteoclast survival represent mechanisms by which antiresorptive agents could act. The goals of this article are to present the evidence that antiresorptive agents can decrease osteoclast survival through apoptosis, to review the mechanisms by which they are thought to activate the apoptotic process, and to consider whether the actions on apoptosis fully account for the antiresorptive effects. As background, the apoptotic process will be briefly summarized together with the evidence that factors that promote osteoclast survival affect steps in the process. Following this, therapeutic agents that are both antiresorptive and can stimulate osteoclast apoptosis will be discussed. Other bone therapeutic agents that are either antiresorptive or apoptotic, but not both, will be described. Finally, newer antiresorptive compounds that elicit apoptosis and could represent potential therapeutic agents will be noted.

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Section: Newer Antiresorptive Agents Andmentioning

confidence: 99%

Antiresorptive agents and osteoclast apoptosis

Stern

2007

J of Cellular Biochemistry

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“…SB-273005 reduced resorption by inhibiting the parathyroid hormonestimulated calcemic response of hypocalcemic thyroparathyroidectomized rats, and in the OVX rat SB-273005 reduced the bone resorption marker, Dpd, and prevented bone loss in the lumbar vertebrae (Lark et al, 2001). In a study by Engleman et al (1997), a peptide mimetic of the vitronectin receptor was administered intravenously in the rat, and inhibited the OVX-induced increase in urinary pyridinyl cross-links and prevented trabecular bone loss.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike ␣ v ␤ 3 , which is expressed on mature osteoclasts, ␣ v ␤ 5 is expressed on osteoclast precursors and has been proposed to play a role in osteoclast differentiation (Sago et al, 1999). SB-273005, a potent antagonist of both of these integrins, inhibits bone resorption in cultures of human osteoclasts with an IC 50 of 11 nM (Lark et al, 2001). This compound also inhibits bone resorption after oral administration in the thyroparathyroidectomized rat and prevents bone loss in ovariectomized (OVX) rats (Lark et al, 2001).…”

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confidence: 99%

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Rapid Inhibition of Thyroxine-Induced Bone Resorption in the Rat by an Orally Active Vitronectin Receptor Antagonist

Hoffman

Vasko-Moser²,

Miller³

et al. 2002

J Pharmacol Exp Ther

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An excess of thyroid hormone results in increased bone turnover and loss of bone mass in humans. Exogenous administration of thyroid hormone to rats has served as a model of human hyperthyroidism in which antiresorptive therapies have been tested. We have further refined this model of thyroxine (T4)-induced turnover in the rat. Daily administration of T4 to aged rats for as short as 1 week resulted in elevated bone resorption determined by significantly higher urinary deoxypyridinoline (Dpd) compared with vehicle controls or animals receiving T4 plus estradiol. Three weeks of daily administration of T4 led to significantly lower bone mineral density compared with untreated controls or animals receiving T4 plus estradiol. In a follow-up study, a depot formulation of T4 caused an increase in Dpd identical to that achieved with a bolus dose. SB-273005 [(4S)-2,3,4,5-tetrahydro-8-[2-[6-(methylamino)-2-pyridinyl] ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-acetic acid] a potent antagonist of the integrins ␣ v ␤ 3 and ␣ v ␤ 5 , has been shown previously to inhibit bone resorption in cultures of human osteoclasts and to protect bone in ovariectomized rats. The effect of SB-273005 by oral administration was evaluated in this thyroxine-induced turnover model. Dose-dependent inhibition of resorption was seen with SB-273005 after 7 days of dosing using Dpd as a measure of bone resorption. In summary, it has been demonstrated that the antiresorptive activity of a vitronectin receptor antagonist can be measured after only 7 days of treatment in this refined rat model of thyroxine-induced bone turnover. These data suggest that SB-273005 may be useful for the treatment of metabolic bone diseases, including those resulting from hyperthyroidism.

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“…Interactions between the osteoclast vitronectin receptor and the Arg-Gly-Asp tripeptide sequence found in several bone matrix proteins lead to osteoclast attachment, activation, and the release of cathepsins into the resorption lacuna. Several small-molecule inhibitors of the vitronectin receptor inhibit bone resorption in vitro and in vivo and may soon enter clinical testing (21,22).…”

Section: Inhibitors Of Cell-matrix Interaction and The Cytoskeletonmentioning

confidence: 99%

Future Treatment of Bone Metastases

Lipton

2006

Clinical Cancer Research

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All bone surfaces are periodically remodeled by the coupled and balanced action of osteoclasts and osteoblasts, of which the activities are regulated by a variety of cytokines and growth factors. Patients with cancer metastatic to the skeleton often develop osteolytic bone lesions, in which the actions of osteoclasts and osteoblasts remain coupled, but become imbalanced in sites adjacent to the tumor. The result is net bone loss. Many cancers secrete osteoclast-stimulating cytokines, which increase bone resorption by osteoclasts. In turn, factors released from the bone matrix during osteolysis can stimulate tumor growth. In this so-called ''vicious cycle,'' there are multiple sites that are targets for new bone-directed therapies. A variety of new agents for the treatment and prevention of osteolytic bone metastasis are currently being developed. These include new agents that inhibit osteoclast differentiation, bone adhesion, and osteoclast function. These new strategies have evolved from a better understanding of the interaction between tumor cells and cells in the bone marrow microenvironment. There is great promise that these new bone-targeted therapies can decrease the frequent skeletal-related events that greatly diminish quality of life of patients with bone metastases.The skeleton is the most common site of tumor metastasis, and malignant bone pain is the most common cause of severe cancer-associated pain (1). Patients with bone metastases are at risk of skeletal-related events (e.g., fracture, need for radiation therapy, and surgery) that can result in decreased quality of life (2, 3). Among patients with bone metastases from solid tumors or multiple myeloma, the annual incidence of skeletal complications is in the range of 1.5 to 4.0 events per year.Patients with cancer metastatic to the skeleton often develop osteolytic bone lesions, in which osteoclast and osteoblast functions typically become uncoupled as well as imbalanced. Although a degree of coupling persists, the tight relationship between bone cell functions is typically lost. These cancers secrete osteoclast-stimulating cytokines, which increase bone resorption by osteoclasts. In turn, factors released from the bone matrix during osteolysis can stimulate tumor growth. In this so-called ''vicious cycle,'' there are multiple sites that are targets for new bone-directed therapies (Fig. 1).Some tumors, such as prostate cancer, may secrete cytokines that stimulate adjacent osteoblasts to increase their boneforming activity, resulting in osteoblastic lesions (Fig. 2). Disruption or imbalance of the bone remodeling activities of osteoclasts and osteoblasts leads to the progressive deterioration of skeletal integrity that underlies skeletal complications. Nitrogen-Containing BisphosphonatesNitrogen-containing bisphosphonates have been introduced into clinical practice during the last decade, and successive generations of more potent agents with higher therapeutic indices have been developed (2, 3). Bisphosphonates preferentially bind to bone ...

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Antagonism of the Osteoclast Vitronectin Receptor with an Orally Active Nonpeptide Inhibitor Prevents Cancellous Bone Loss in the Ovariectomized Rat

Abstract: ABSTRACT

Cited by 52 publications

References 26 publications

Antiresorptive agents and osteoclast apoptosis

Antiresorptive agents and osteoclast apoptosis

Rapid Inhibition of Thyroxine-Induced Bone Resorption in the Rat by an Orally Active Vitronectin Receptor Antagonist

Future Treatment of Bone Metastases

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