Info

for patients.

6.21.7.2 Alternative Antiresorptive Treatments

While bisphosphonates are highly effective antiresorptive treatments, they are not always well tolerated orally. This is particularly an issue for nonambulant patients or those with existing gastrointestinal disease, indicating the need for alternative approaches or formulations. Parenteral administration of bisphosphonates is a viable alternative, although the risk of osteonecrosis of the jaw has been identified with this approach. New therapies targeting RANKL signaling, cathepsin K, other osteoclast enzymes, and integrins are currently being investigated. RANKL is being targeted through the development of a neutralizing, fully human monoclonal antibody designated denosumab.54 Phase I results indicate that this antibody could be used in osteoporosis by subcutaneous injection at a dosing frequency of once every 6 months.

Cathepsin K is a proteolytic enzyme expressed with high specificity in osteoclasts and that is required for normal bone resorption. Extensive research activity by many research groups has identified potent inhibitors for this enzyme which show excellent in vivo activity in rat models of osteoporosis and are now in clinical trial. An example of these inhibitors is SB33 1 75 073 (Figure 8).

Osteoclasts also need to adhere to bone to activate bone resorption and the integrin avb3 is an important mediator of adhesion and the intracellular signaling related to adhesion to bone. Small-molecule antagonists of a^ (see Figure 8) with its ligand vitronectin are effective inhibitors of bone resorption in vivo and many of these are being investigated as therapeutic agents.74

In cancer metastasis patients, it is possible that even more potent antiresorptive action is required to improve skeletal protection, as clinical benefits from bisphosphonate treatment are only modest. Reductions in skeletal-related events of only 20-30% are seen and, while this is of significant benefit, in many patients skeletal complications of malignancy are not prevented. Studies with bisphosphonates have shown that incomplete control of bone resorption, as determined by the measurement of bone resorption surrogate markers, is associated with a higher risk of skeletal complications, providing support for this concept.

6.21.7.3 Anabolic Treatments

There is an enormous need for treatments that actually rebuild bone. Many patients with osteoporosis have reductions in BMD of more than 50%. Treatment with bisphosphonates results in only minor recovery (10% increase from current

Figure 8 Chemical structure of a cathepsin K inhibitor and an avb3 integrin inhibitor. Structures are shown for (a) the cathepsin K inhibitor SB331750,73 and (b) the avp3 integrin inhibitor (S)-3-oxo-8-[2-[6-(methylamino)-pyridin-2-yl]-1-ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid.74 These molecules reduce bone resorption by respectively inhibiting osteoclast-mediated bone matrix degradation by cathepsin K or by impairing osteoclast adhesion to bone matrix mediated by avp3 integrin.

Figure 8 Chemical structure of a cathepsin K inhibitor and an avb3 integrin inhibitor. Structures are shown for (a) the cathepsin K inhibitor SB331750,73 and (b) the avp3 integrin inhibitor (S)-3-oxo-8-[2-[6-(methylamino)-pyridin-2-yl]-1-ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid.74 These molecules reduce bone resorption by respectively inhibiting osteoclast-mediated bone matrix degradation by cathepsin K or by impairing osteoclast adhesion to bone matrix mediated by avp3 integrin.

BMD or less than 5% of original peak BMD). Teriparatide (PTH 1-34) treatment is the only currently approved anabolic treatment. While it is perhaps twice as effective67 as alendronate, teriparatide requires daily injections and does not return BMD to anywhere near original levels. New, more potent anabolic therapies are required and targets currently being investigated include Wnt pathway modulators, strontium (weak anabolic), IGF/IGFBP (IGF binding protein) combinations and other growth factors.75 The concern with anabolics is that treatment produces structurally competent bone, as loss of bone architecture can result in increased fragility despite increased bone density (as seen with fluoride). Thus, demonstration of fracture efficacy is particularly important for anabolic treatments.

An activating mutation in low density lipoprotein receptor-related protein 5 (LRP5), a component of the Wnt signaling pathway, produces strong, dense bones, and this observation has demonstrated the therapeutic potential of this pathway for anabolic treatment of bone diseases. One way the Wnt pathway is being targeted is by the antagonism of the SOST gene product, sclerostin, with a neutralizing monoclonal antibody. This protein normally acts as an inhibitor of Wnt signaling through its binding to LRP5 or LRP6. Its absence results in an upregulation of Wnt signaling and thus an increase in bone density in mice.76

Strontium ranelate has recently been approved for the treatment of osteoporosis. It appears to increase bone formation modestly and decrease bone resorption and this uncoupling of these processes produces an increase in BMD and a decrease in vertebral fracture incidence by 30-45%.75

IGF-1 and growth hormone have also been investigated and do increase bone formation and thus increase BMD. IGF-1, however, is able to act as a ligand to the insulin receptor and this has limited dosing. Use of concurrent IGF-binding proteins has been proposed as a way to minimize this effect. Growth hormone has the theoretical ability to cause diabetes. Both of these treatments require controlled fracture trials before they can be accepted.

FGF-1 and -2 are profoundly anabolic to bone in rodents and have the unique ability to increase trabecular number.77 However, FGF-1 and FGF-2 systemic treatment is associated with acute suppression of blood pressure and these growth factors have potential pleiotropic proliferative effects on many cell types. Thus the use of these agents is probably limited to local defect repair and systemic therapeutic use would likely require specific targeting to bone.

For local bone defects and nonunion fractures, considerable progress has been made with various combinations of natural and synthetic matrices and growth factors. Use of BMPs has been a significant advance. Two BMPs are currently approved for local bone repair: BMP-7 (also known as osteogenic protein-1) and BMP-2. These are both delivered in collagen-based matrices to provide a scaffold for new bone formation, which is enhanced by the presence of the BMP.78'79 However, in this area, products with improved efficacy and/or ease of delivery would be of clinical value.

6.21.7.4 Gene Therapies and Stem Cell Therapies

Gene and stem cell therapies provide the long-term promise of sustained clinical improvement, particularly in patients with congenital disorders of bone metabolism. Treatments for children with osteogenesis imperfecta and osteopetrosis are particularly needed, given the continuing poor outcomes with current treatments. The use of a patient's own stem cells to fill defects or produce systemic improvements in bone formation in aged or severely osteoporotic patients is also an attractive concept. Significant challenges lie in producing sufficient genetically modified osteoprogenitors or early stem cells, delivering these cells to the whole skeleton, and producing consistent and sustained function.80,81

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Biographies

Colin R Dunstan was born in Sydney, Australia, and studied at the University of Sydney, where he obtained a BSc (Hons) in 1977 and a PhD in 1991 under the supervision of Dr RA Evans. After completing his PhD he worked for 3 years in the laboratory of Dr GR Mundy in San Antonio, Texas. Dr Dunstan then worked for 6 years in the Pathology Department of Amgen Inc. in Thousand Oaks, California, as a Senior Research Scientist. Subsequently, in 2002 he was awarded a New South Wales Government BioFirst Award and returned to Sydney to take up his present position as Principal Research Fellow in the Bone Research Program at the ANZAC Research Institute. His scientific interests include all aspects of bone metabolism, with particular interest in osteoclast regulation and processes promoting cancer metastasis to bone.

Julie M Blair was born in Londonderry, Northern Ireland and studied at the University of Sheffield, UK, where she obtained a BSc (Hons) in 1991 and an MPhil in 1994. She also studied at the University of Bath, where she obtained a

PhD in 1998 under the direction of Dr J N Beresford. After a 3-year senior postdoctoral fellowship in the laboratories of Prof R L Vessella at the University of Washington, US, she moved to Prince of Wales Hospital, Sydney, Australia, as a senior hospital scientist. Subsequently, she took up the position of senior hospital scientist in the Molecular Bone Biology Laboratory at the ANZAC Research Institute in 2005. Her scientific interests include all aspects of bone metastasis, with a particular focus on prostate and breast cancer bone tumors.

Hong Zhou was born in Shanghai, China, and studied at Ningxia Medical Collage, where she obtained an MD in 1983. She obtained her PhD in 1992 under the supervision of Associate Professor KW Ng at the University of Melbourne, Australia. She then worked for 11 years in the laboratory of Prof T J Martin in St Vincent's Institute of Medical Research, Melbourne. In 2004, she took up the position as Senior Research Fellow at ANZAC Research Institute, the University of Sydney. Her scientific interests include bone cell biology and molecular biology, in particular, effects of steroid hormones on osteoblast differentiation, osteoblast-osteoclast interactions, and the biology of bone cancers.

Markus J Seibel holds the position of Professor and Chair of Endocrinology at the University of Sydney, Australia. He is also the Head of the Department of Endocrinology & Metabolism at Concord General Hospital, Sydney, and the Director of the Bone Research Program at ANZAC Research Institute. The focus of his clinical and research activities is the pathophysiology of bone metabolism, especially in osteoporosis and metastatic bone disease.

He completed his medical training in Germany (University of Heidelberg), Switzerland (University of Basel), and in the US (Columbia University New York), and until 2001 was the Vice-Director at the Department of Endocrinology at the University of Heidelberg, Germany. In November 2001, he moved to Sydney, Australia.

Markus was the Past-President of the German Academy of Bone and Joint Sciences. He is a member of the Professional Practice Committee of the American Society of Bone and Mineral Research (ASBMR) and a member of the

International Osteoporosis Foundation's (IOF) Scientific Advisory Board. He is on the Editorial Boards of the Journal of Clinical Endocrinology and Metabolism, Calcified Tissue International, Journal of Clinical Densitometry, Clinical Endocrinology, Clinical Laboratory, and others. He has written over 200 scientific articles, reviews, editorials, and book chapters, and is the editor of five books.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 6) 0-08-044519-5; pp. 495-520

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