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Testosterone for sarcopenia☆
Abstracts / Bone 47 (2010) S15–S28
IS13 Wnt signaling and anabolic bone strategies M. Kneissel⁎1 1 Novartis Institutes for Biomedical Research, Basel, Switzerland Wnt/β-catenin signaling - also termed canonical Wnt signaling - has emerged as a key regulatory pathway for adult bone homeostasis. Initial interest was sparked by the discovery of human low and high bone mass phenotypes associated with loss and gain of function mutations in the Wnt co-receptor LRP5. Interestingly, recent findings in mice suggest that Lrp5 might not act so much as a local Wnt signaling mediator in bone, but rather controls pre-osteoblast proliferation by inhibiting duodenal serotonin synthesis. Nevertheless an ever expanding number of genetically modified mouse models targeting various pathway components has established that Wnt/β-catenin signaling impacts osteoblasts at all stages of their life cycle and thus indirectly also osteoclast differentiation and activity. To date several lines of evidence implicate Wnt/β-catenin signaling in bone anabolism elicited by mechanotransduction and by PTH treatment. Osteocyte and osteoblast secreted sclerostin and Dkk1 are thought to antagonize Wnt signaling locally by binding to LRP5 and LRP6 co-receptors. Inhibition of their activity by neutralizing antibodies has proven to be bone anabolic in pre-clinical and in part also in clinical studies. Likewise low molecular weight inhibitors of Secreted frizzled-related protein (Sfrp) 1 have been demonstrated to increase bone formation in pre-clinical animal models. In contrast to sclerostin and Dkk1, Sfrps and Wnt inhibitory factors (Wifs) antagonize Wnt signaling by sequestering Wnt ligands directly. Depending on ligand specificity they can also inhibit non-canonical Wnt signaling, which has been implicated in regulation of osteoblastogenesis. Given the role of the pathway in multiple tissues, safety of bone anabolic osteoporosis therapies based on Wnt signaling stimulation will need to be established. Inhibition of secreted bone specific Wnt antagonists, such as sclerostin, represents hence a more promising approach compared to modulation of common intracellular pathway components like the serine/theorine kinase GSK3β, despite the ability of small molecule GSK3α/β inhibitors to increase bone mass in preclinical animal models. Risk of oncogenesis upon de-repression of the Wnt pathway will need to be explored as highlighted by recent findings linking loss of Wif1 to increased osteosarcoma susceptibility. Finally, the therapeutic window for such treatments will require optimization to avoid adverse effects from inappropriate excessive bone formation. Disclosure of Interest: M. Kneissel Employee of Novartis Institutes for Biomedical Research Keywords: bone anabolism, osteoporosis treatment, wnt signaling
S19
Testosterone administration to young and older men is associated with hypertrophy of both type I and II muscle fibers. The latter hypertrophy is attended by increased numbers of muscle satellite cells. The mechanisms by which testosterone induces skeletal muscle hypertrophy are poorly understood. Emerging data suggest that testosterone promotes the commitment and differentiation of mesenchymal, multipotent cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage by activation of Wnt signaling through a noncanonical pathway that involves association of androgen receptor with betacatenin and TCF-4. Concern about the potential adverse effects of testosterone on prostate, cardiovascular health, and erythropoiesis have encouraged enormous investment in the development of selective androgen receptor modulators that can improve physical function and health outcomes while sparing the prostate. Disclosure of Interest: S. Bhasin Grant / Research support from Solvay, Ligand, Merck, Consultant for GSK Keywords: None doi:10.1016/j.bone.2010.04.015
IS15 Frailty: Molecular and therapeutic approaches☆ L.P. Freedman⁎1 1 Jefferson Medical College, Philadelphia, United States As of next year, 78 million baby boomers will be age 65 or older in the United States. As this population ages but attempts to maintain an active lifestyle, musculoskeletal disorders will grow in prominence. Even now, they are the second most common reason to visit a doctor after the common cold. While osteoporosis remains a major women's health issue, other frailty-associated disorders, such as sarcopenia, are also significant contributing factors to fractures, mobility loss, and independence in both women and men, and thus represent important unmet medical needs. While much is known about the biology and pathophysiology of bone loss, and numerous established osteoporosis drug therapies are well established, with more on the way, very few targets have been elucidated for other aspects of frailty. This presentation will focus on members of two gene superfamilies that play critical roles in the musculoskeletal system: nuclear receptors and BMPs, and how they represent both exciting and challenging targets for drug development. Disclosure of Interest: None declared Keywords: BMPs, musculoskeletal, nuclear receptors
doi:10.1016/j.bone.2010.04.014 doi:10.1016/j.bone.2010.04.016 IS14 Testosterone for sarcopenia☆ S. Bhasin⁎1 1 Boston University School of Medicine, Boston, United States The loss of muscle mass with aging is associated with limitations of physical function and increased risk of falls, fractures, mobility limitation, and mortality. A number of pharmacologic function promoting anabolic therapies are in development for the prevention and treatment of functional limitations associated with aging; of these androgens are the farthest along. Testosterone supplementation increases muscle mass, strength, and leg power in men. These anabolic effects are related to the administered dose and to prevailing testosterone concentrations. Compared to younger men, older men are equally responsive to the anabolic effects of graded doses of testosterone, but experience a higher frequency of adverse effects.
IS16 VEGF in bone development and homeostasis B.R. Olsen⁎1 1 Harvard School of Dental Medicine, Boston, United States Vascular endothelial growth factor-A (VEGF) serves to couple endochondral bone formation and vascularization. In addition, it plays an important role in chondrocyte differentiation and survival, osteoblast and osteoclast differentiation, and osteoclast recruitment. During skeletal development blood vessel invasion into primary ossification centers within the cartilage models of future bones is preceded by VEGF-dependent sprouting angiogenesis into the perichondrium. Subsequent unregulated expression of VEGF in hypertrophic chondrocytes provides the chemotactic stimulus for migration of vascular endothelial cells, osteoclasts/chondroclasts and
IS13 Wnt signaling and anabolic bone strategies M. Kneissel⁎1 1 Novartis Institutes for Biomedical Research, Basel, Switzerland Wnt/β-catenin signaling - also termed canonical Wnt signaling - has emerged as a key regulatory pathway for adult bone homeostasis. Initial interest was sparked by the discovery of human low and high bone mass phenotypes associated with loss and gain of function mutations in the Wnt co-receptor LRP5. Interestingly, recent findings in mice suggest that Lrp5 might not act so much as a local Wnt signaling mediator in bone, but rather controls pre-osteoblast proliferation by inhibiting duodenal serotonin synthesis. Nevertheless an ever expanding number of genetically modified mouse models targeting various pathway components has established that Wnt/β-catenin signaling impacts osteoblasts at all stages of their life cycle and thus indirectly also osteoclast differentiation and activity. To date several lines of evidence implicate Wnt/β-catenin signaling in bone anabolism elicited by mechanotransduction and by PTH treatment. Osteocyte and osteoblast secreted sclerostin and Dkk1 are thought to antagonize Wnt signaling locally by binding to LRP5 and LRP6 co-receptors. Inhibition of their activity by neutralizing antibodies has proven to be bone anabolic in pre-clinical and in part also in clinical studies. Likewise low molecular weight inhibitors of Secreted frizzled-related protein (Sfrp) 1 have been demonstrated to increase bone formation in pre-clinical animal models. In contrast to sclerostin and Dkk1, Sfrps and Wnt inhibitory factors (Wifs) antagonize Wnt signaling by sequestering Wnt ligands directly. Depending on ligand specificity they can also inhibit non-canonical Wnt signaling, which has been implicated in regulation of osteoblastogenesis. Given the role of the pathway in multiple tissues, safety of bone anabolic osteoporosis therapies based on Wnt signaling stimulation will need to be established. Inhibition of secreted bone specific Wnt antagonists, such as sclerostin, represents hence a more promising approach compared to modulation of common intracellular pathway components like the serine/theorine kinase GSK3β, despite the ability of small molecule GSK3α/β inhibitors to increase bone mass in preclinical animal models. Risk of oncogenesis upon de-repression of the Wnt pathway will need to be explored as highlighted by recent findings linking loss of Wif1 to increased osteosarcoma susceptibility. Finally, the therapeutic window for such treatments will require optimization to avoid adverse effects from inappropriate excessive bone formation. Disclosure of Interest: M. Kneissel Employee of Novartis Institutes for Biomedical Research Keywords: bone anabolism, osteoporosis treatment, wnt signaling
S19
Testosterone administration to young and older men is associated with hypertrophy of both type I and II muscle fibers. The latter hypertrophy is attended by increased numbers of muscle satellite cells. The mechanisms by which testosterone induces skeletal muscle hypertrophy are poorly understood. Emerging data suggest that testosterone promotes the commitment and differentiation of mesenchymal, multipotent cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage by activation of Wnt signaling through a noncanonical pathway that involves association of androgen receptor with betacatenin and TCF-4. Concern about the potential adverse effects of testosterone on prostate, cardiovascular health, and erythropoiesis have encouraged enormous investment in the development of selective androgen receptor modulators that can improve physical function and health outcomes while sparing the prostate. Disclosure of Interest: S. Bhasin Grant / Research support from Solvay, Ligand, Merck, Consultant for GSK Keywords: None doi:10.1016/j.bone.2010.04.015
IS15 Frailty: Molecular and therapeutic approaches☆ L.P. Freedman⁎1 1 Jefferson Medical College, Philadelphia, United States As of next year, 78 million baby boomers will be age 65 or older in the United States. As this population ages but attempts to maintain an active lifestyle, musculoskeletal disorders will grow in prominence. Even now, they are the second most common reason to visit a doctor after the common cold. While osteoporosis remains a major women's health issue, other frailty-associated disorders, such as sarcopenia, are also significant contributing factors to fractures, mobility loss, and independence in both women and men, and thus represent important unmet medical needs. While much is known about the biology and pathophysiology of bone loss, and numerous established osteoporosis drug therapies are well established, with more on the way, very few targets have been elucidated for other aspects of frailty. This presentation will focus on members of two gene superfamilies that play critical roles in the musculoskeletal system: nuclear receptors and BMPs, and how they represent both exciting and challenging targets for drug development. Disclosure of Interest: None declared Keywords: BMPs, musculoskeletal, nuclear receptors
doi:10.1016/j.bone.2010.04.014 doi:10.1016/j.bone.2010.04.016 IS14 Testosterone for sarcopenia☆ S. Bhasin⁎1 1 Boston University School of Medicine, Boston, United States The loss of muscle mass with aging is associated with limitations of physical function and increased risk of falls, fractures, mobility limitation, and mortality. A number of pharmacologic function promoting anabolic therapies are in development for the prevention and treatment of functional limitations associated with aging; of these androgens are the farthest along. Testosterone supplementation increases muscle mass, strength, and leg power in men. These anabolic effects are related to the administered dose and to prevailing testosterone concentrations. Compared to younger men, older men are equally responsive to the anabolic effects of graded doses of testosterone, but experience a higher frequency of adverse effects.
IS16 VEGF in bone development and homeostasis B.R. Olsen⁎1 1 Harvard School of Dental Medicine, Boston, United States Vascular endothelial growth factor-A (VEGF) serves to couple endochondral bone formation and vascularization. In addition, it plays an important role in chondrocyte differentiation and survival, osteoblast and osteoclast differentiation, and osteoclast recruitment. During skeletal development blood vessel invasion into primary ossification centers within the cartilage models of future bones is preceded by VEGF-dependent sprouting angiogenesis into the perichondrium. Subsequent unregulated expression of VEGF in hypertrophic chondrocytes provides the chemotactic stimulus for migration of vascular endothelial cells, osteoclasts/chondroclasts and