Therapeutic approaches to bone diseases.

The strength and integrity of our bones depends on maintaining a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. As we age or as a result of disease, this delicate balancing act becomes tipped in favor of osteoclasts so that bone resorption exceeds bone formation, rendering bones brittle and prone to fracture. A better understanding of the biology of osteoclasts and osteoblasts is providing opportunities for developing therapeutics to treat diseases of bone. Drugs that inhibit the formation or activity of osteoclasts are valuable for treating osteoporosis, Paget's disease, and inflammation of bone associated with rheumatoid arthritis or periodontal disease. Far less attention has been paid to promoting bone formation with, for example, growth factors or hormones, an approach that would be a valuable adjunct therapy for patients receiving inhibitors of bone resorption.

[1]  William M. O'Fallon,et al.  Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. , 1990 .

[2]  J. Bidwell,et al.  In vivo, human parathyroid hormone fragment (hPTH 1-34) transiently stimulates immediate early response gene expression, but not proliferation, in trabecular bone cells of young rats. , 1995, Bone.

[3]  A. Mithal,et al.  The calcium-sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. , 1996, Endocrine reviews.

[4]  W. Dougall,et al.  RANK is essential for osteoclast and lymph node development. , 1999, Genes & development.

[5]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[6]  C. Dunstan Osteoprotegerin and Osteoprotegerin Ligand Mediate the Local Regulation of Bone Resorption , 2000 .

[7]  S. Teitelbaum,et al.  Bone resorption by osteoclasts. , 2000, Science.

[8]  Michael J. Goodman,et al.  Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women , 2000, The Lancet.

[9]  N. Udagawa,et al.  Interleukin‐6 and soluble interleukin‐6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast‐like cell formation , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  S. Harris,et al.  Stimulation of bone formation in vitro and in rodents by statins. , 1999, Science.

[11]  C. Christiansen,et al.  Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. , 1997, The New England journal of medicine.

[12]  D E Griswold,et al.  Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. , 1996, The Journal of pharmacology and experimental therapeutics.

[13]  T. Martin,et al.  Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. , 2000, Arthritis and rheumatism.

[14]  D. Yamashita,et al.  Cathepsin K and the design of inhibitors of cathepsin K. , 2000, Current pharmaceutical design.

[15]  B. Hollis,et al.  Modulation of ovariectomy-related bone loss by parathyroid hormone in rats , 1990, Mechanisms of Ageing and Development.

[16]  H. Genant,et al.  Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. , 1998, The Journal of clinical investigation.

[17]  D. Copp,et al.  Changes in Response to Calcitonin Following Prolonged Administration to Intact Rats , 1974, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[18]  P. Kostenuik,et al.  Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy. , 2000, Cancer research.

[19]  B F Boyce,et al.  Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. , 1996, The Journal of clinical investigation.

[20]  L. Mosekilde,et al.  The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength--assessed in a sexually mature, ovariectomized rat model. , 1995, Bone.

[21]  R. Pitti,et al.  Effects of kistrin on bone resorption in vitro and serum calcium in vivo , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  H. Selye ON THE STIMULATION OF NEW BONE-FORMATION WITH PARATHYROID EXTRACT AND IRRADIATED ERGOSTEROL , 1932 .

[23]  Jeffrey Bonadio,et al.  Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration , 1999, Nature Medicine.

[24]  J. Blangero,et al.  Genetic Epidemiological Approaches to the Search for Osteoporosis Genes , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[25]  G. Rodan,et al.  Bisphosphonates Act Directly on the Osteoclast to Induce Caspase Cleavage of Mst1 Kinase during Apoptosis , 1999, The Journal of Biological Chemistry.

[26]  D. Holt,et al.  A Src SH2 selective binding compound inhibits osteoclast-mediated resorption. , 2000, Chemistry & biology.

[27]  R. Turner,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society The Effects of Programmed Administration of Human Parathyroid Hormone Fragment (1–34) on Bone Histomorphometry and Serum Chemistry in Rats* , 2022 .

[28]  G. Rodan,et al.  PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin, and phosphorylated by src kinase. , 1998, The Journal of clinical investigation.

[29]  R B Mazess,et al.  Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. , 1992, The New England journal of medicine.

[30]  T. Martin,et al.  Activated T lymphocytes support osteoclast formation in vitro. , 1999, Biochemical and biophysical research communications.

[31]  A. Parfitt,et al.  Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. , 1998, The Journal of clinical investigation.

[32]  M A Horton,et al.  A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. , 1997, The Journal of clinical investigation.

[33]  J. Hayman,et al.  Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. , 1991, Cancer research.

[34]  R. Pacifici Editorial: Cytokines, Estrogen, and Postmenopausal Osteoporosis-The Second Decade. , 1998, Endocrinology.

[35]  T. Yoneda Cellular and molecular mechanisms of breast and prostate cancer metastasis to bone. , 1998, European journal of cancer.

[36]  R. Wallace,et al.  Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis , 2000, Nature Genetics.

[37]  Sakae Tanaka,et al.  c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption , 1996, Nature.

[38]  J Dequeker,et al.  Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. , 1995, The New England journal of medicine.

[39]  Arndt F Schilling,et al.  Leptin Inhibits Bone Formation through a Hypothalamic Relay A Central Control of Bone Mass , 2000, Cell.

[40]  R. Jilka,et al.  Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. , 1995, The New England journal of medicine.

[41]  J. Hayman,et al.  Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. , 1990, Cancer research.

[42]  HMG-CoA reductase inhibitors and the risk of fractures. , 2000 .

[43]  C. Leu,et al.  The integrin ligand echistatin prevents bone loss in ovariectomized mice and rats. , 1998, Endocrinology.

[44]  G. Rodan,et al.  Bone mass homeostasis and bisphosphonate action. , 1997, Bone.

[45]  G. Rodan,et al.  Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. , 2000, Archives of biochemistry and biophysics.

[46]  T. Martin,et al.  Short treatment of osteoclasts in bone marrow culture with calcitonin causes prolonged suppression of calcitonin receptor mRNA. , 1995, Bone.

[47]  G. Rodan,et al.  The role of prostaglandins in bone formation. , 1995, Connective tissue research.

[48]  T. Martin,et al.  IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. , 1999, The Journal of clinical investigation.

[49]  M. Rogers,et al.  Heterocycle‐Containing Bisphosphonates Cause Apoptosis and Inhibit Bone Resorption by Preventing Protein Prenylation: Evidence from Structure‐Activity Relationships in J774 Macrophages , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[50]  R. Lindsay,et al.  Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis , 1997, The Lancet.

[51]  X. Liang,et al.  A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. , 2000, The Journal of clinical investigation.

[52]  J. Milbrandt,et al.  Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1. , 1998, The Journal of clinical investigation.

[53]  B. R. Smith,et al.  Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. , 2000, The Journal of clinical investigation.

[54]  I. McInnes,et al.  A proinflammatory role for IL-18 in rheumatoid arthritis. , 1999, The Journal of clinical investigation.

[55]  R Wieser,et al.  TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. , 1999, The Journal of clinical investigation.

[56]  P. Mantyh,et al.  Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord , 2000, Nature Medicine.

[57]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[58]  S. Rodan,et al.  Sphingosine kinase mediates cyclic AMP suppression of apoptosis in rat periosteal cells. , 1998, Molecular pharmacology.

[59]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[60]  N. Athanasou,et al.  Human osteoclast ontogeny and pathological bone resorption. , 1999, Histology and histopathology.

[61]  J. Mönkkönen,et al.  Molecular mechanisms of action of bisphosphonates. , 1999, Bone.

[62]  H. Broxmeyer,et al.  Increased osteoclast development after estrogen loss: mediation by interleukin-6 , 1992 .

[63]  P. Roberson,et al.  Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. , 1999, The Journal of clinical investigation.

[64]  S Hulley,et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. , 1998, JAMA.

[65]  S. Cummings,et al.  Do statins prevent both cardiovascular disease and fracture? , 2000, JAMA.

[66]  M. Hatada,et al.  Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Yuqiong Liang,et al.  Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification , 1999, Nature Genetics.

[68]  C. Christiansen,et al.  Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. , 1998 .

[69]  Allan Bradley,et al.  Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice , 1991, Cell.

[70]  Farina,et al.  Selective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents. , 1999, Drug discovery today.

[71]  K Yano,et al.  Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[72]  S. Cummings,et al.  Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures , 1996, The Lancet.

[73]  W. Sly,et al.  Human carbonic anhydrases and carbonic anhydrase deficiencies. , 1995, Annual review of biochemistry.

[74]  T. Martin,et al.  Breast Cancer Cells Interact with Osteoblasts to Support Osteoclast Formation* , 2022 .

[75]  N. Takahashi,et al.  Glucocorticoid regulation of calcitonin receptor in mouse osteoclast‐like multinucleated cells , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[76]  R. Turner,et al.  Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. , 1995, Endocrinology.

[77]  Olof Johnell,et al.  Hormone replacement therapy and risk of hip fracture: population based case-control study , 1998, BMJ.

[78]  M. Ikegame,et al.  Morphology of bone metastasis. , 1998, European journal of cancer.

[79]  J. Pike,et al.  Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. , 1995, Molecular endocrinology.

[80]  F. Rousseau,et al.  The genetics of osteoporosis: ‘complexities and difficulties’ , 2000, Clinical genetics.

[81]  T. Martin,et al.  Physiological levels of calcitonin regulate the mouse osteoclast calcitonin receptor by a protein kinase Alpha-mediated mechanism. , 1996, Endocrinology.

[82]  S. Cummings,et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. , 1999, JAMA.

[83]  H. Okamura,et al.  Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor. , 1998, The Journal of clinical investigation.

[84]  C. Turner,et al.  Emerging therapies for the prevention or treatment of postmenopausal osteoporosis. , 1999, Journal of medicinal chemistry.

[85]  P. Fratzl,et al.  Abnormal bone mineralization after fluoride treatment in osteoporosis: A small‐angle x‐ray‐scattering study , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[86]  E. Nemeth,et al.  Calcimimetic Compounds: a Direct Approach to Controlling Plasma Levels of Parathyroid Hormone in Hyperparathyroidism , 1999, Trends in Endocrinology & Metabolism.