Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 2/2014

01-06-2014 | Muscle and Bone (L Bonewald and M Harrick, Section Editors)

Therapies for Musculoskeletal Disease: Can we Treat Two Birds with One Stone?

Authors: Christian M. Girgis, Nancy Mokbel, Douglas J. DiGirolamo

Published in: Current Osteoporosis Reports | Issue 2/2014

Login to get access

Abstract

Musculoskeletal diseases are highly prevalent with staggering annual health care costs across the globe. The combined wasting of muscle (sarcopenia) and bone (osteoporosis)—both in normal aging and pathologic states—can lead to vastly compounded risk for fracture in patients. Until now, our therapeutic approach to the prevention of such fractures has focused solely on bone, but our increasing understanding of the interconnected biology of muscle and bone has begun to shift our treatment paradigm for musculoskeletal disease. Targeting pathways that centrally regulate both bone and muscle (eg, GH/IGF-1, sex steroids, etc.) and newly emerging pathways that might facilitate communication between these 2 tissues (eg, activin/myostatin) might allow a greater therapeutic benefit and/or previously unanticipated means by which to treat these frail patients and prevent fracture. In this review, we will discuss a number of therapies currently under development that aim to treat musculoskeletal disease in precisely such a holistic fashion.
Literature
1.
2.
Connelly LB, Woolf A, Brooks P. Cost-effectiveness of interventions for musculoskeletal conditions. In: Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, et al., editors. Disease control priorities in developing countries, 2nd edn. Washington, DC: Oxford University Press and World Bank; 2006. p. 963–8.
3.
4.••
Bonewald LF, Kiel DP, Clemens TL, Esser K, Orwoll ES, O'Keefe RJ, et al. Forum on bone and skeletal muscle interactions: summary of the proceedings of an ASBMR workshop. J Bone Miner Res. 2013;28(9):1857–65. doi:10.​1002/​jbmr.​1980. This perspective article summarizes an ASBMR workshop on bone-muscle interactions, outlines current concepts in the field, and research questions to stmulate potential therapeutic strategies for musculoskeletal disorders.PubMed
5.
6.
Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, Ross RR, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998;147(8):755–63.PubMed
7.
Scott D, Hayes A, Sanders KM, Aitken D, Ebeling PR, Jones G. Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults. Osteoporos Int. 2014;25(1):187–93. doi:10.​1007/​s00198-013-2431-5.PubMed
8.••
DiGirolamo DJ, Kiel DP, Esser KA. Bone and skeletal muscle: neighbors with close ties. J Bone Miner Res. 2013;28(7):1509–18. doi:10.​1002/​jbmr.​1969. This perspective article reviews bone-muscle interactions throughout development and aging and highlights the predominant nature of muscle in this relationship.
9.
Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Chapter 8: Development of the musculoskeletal system. Larsen's human embryology 4th edition. Philadelphia: Churchill Livingstone/Elsevier; 2009.
10.•
Karasik D, Kiel DP. Evidence for pleiotropic factors in genetics of the musculoskeletal system. Bone. 2010;46(5):1226–37. doi:10.​1016/​j.​bone.​2010.​01.​382. This review covers genetic aspects of bone-muscle interactions, providing valuable insight in the common genetic etiology of osteoporosis and sarcopenia.PubMed
11.
12.
13.
Larson CM, Henderson RC. Bone mineral density and fractures in boys with Duchenne muscular dystrophy. J Pediatr Orthop. 2000;20(1):71–4.PubMed
14.
15.
Sharir A, Stern T, Rot C, Shahar R, Zelzer E. Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis. Development. 2011;138(15):3247–59. doi:10.​1242/​dev.​063768.PubMed
16.
17.
Szulc P, Beck TJ, Marchand F, Delmas PD. Low skeletal muscle mass is associated with poor structural parameters of bone and impaired balance in elderly men—the MINOS study. J Bone Miner Res. 2005;20(5):721–9. doi:10.​1359/​JBMR.​041230.PubMed
18.
Rikkonen T, Sirola J, Salovaara K, Tuppurainen M, Jurvelin JS, Honkanen R, et al. Muscle strength and body composition are clinical indicators of osteoporosis. Calcif Tissue Int. 2012;91(2):131–8. doi:10.​1007/​s00223-012-9618-1.PubMed
19.
20.••
Lebrasseur NK, Achenbach SJ, Melton III LJ, Amin S, Khosla S. Skeletal muscle mass is associated with bone geometry and microstructure and serum insulin-like growth factor binding protein-2 levels in adult women and men. J Bone Miner Res. 2012;27(10):2159–69. doi:10.​1002/​jbmr.​1666. This observational study of ~ 590 patients reported an association between appendicular muscle mass, bone cortical thickness at remote sites, and serum insulin-like growth factor (IGF) binding protein-2 (IGFBP-2) levels. This further supports the integrated nature of bone-muscle cross-talk.PubMedCentralPubMed
21.
Harry LE, Sandison A, Paleolog EM, Hansen U, Pearse MF, Nanchahal J. Comparison of the healing of open tibial fractures covered with either muscle or fasciocutaneous tissue in a murine model. J Orthop Res. 2008;26(9):1238–44. doi:10.​1002/​jor.​20649.PubMed
22.
Gopal S, Majumder S, Batchelor AG, Knight SL, De Boer P, Smith RM. Fix and flap: the radical orthopaedic and plastic treatment of severe open fractures of the tibia. J Bone Joint Surg (Br). 2000;82(7):959–66.
23.
24.
Elkasrawy MN, Hamrick MW. Myostatin (GDF-8) as a key factor linking muscle mass and bone structure. J Musculoskelet Neuronal Interact. 2010;10(1):56–63.PubMedCentralPubMed
25.
26.
27.••
DiGirolamo DJ, Clemens TL, Kousteni S. The skeleton as an endocrine organ. Nat Rev Rheumatol. 2012;8(11):674–83. doi:10.​1038/​nrrheum.​2012.​157. This review presents bone as an endocrine organ based on the discovery of unique ‘osteokines’ with effects in glucose and energy homeostasis.PubMed
28.
Christoforidis A, Maniadaki I, Stanhope R. Growth hormone / insulin-like growth factor-1 axis during puberty. Pediatr Endocrinol Rev. 2005;3(1):5–10.PubMed
29.
Perrini S, Carreira MC, Conserva A, Laviola L, Giorgino F. Metabolic implications of growth hormone therapy. J Endocrinol Invest. 2008;31(9 Suppl):79–84.PubMed
30.
Perrini S, Laviola L, Carreira MC, Cignarelli A, Natalicchio A, Giorgino F. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J Endocrinol. 2010;205(3):201–10. doi:10.​1677/​JOE-09-0431.PubMed
31.••
Mavalli MD, DiGirolamo DJ, Fan Y, Riddle RC, Campbell KS, van Groen T, et al. Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice. J Clin Invest. 2010;120(11):4007–20. doi:10.​1172/​JCI42447. This study delineates specific effects of GH signaling in muscle via the generation of 2 different mouse models. Effects of GH in muscle development depend on IGF-1, whilst effects on insulin sensitivity are IGF-1-independent.PubMedCentralPubMed
32.
Rojas Vega S, Knicker A, Hollmann W, Bloch W, Struder HK. Effect of resistance exercise on serum levels of growth factors in humans. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2010;42(13):982–6. doi:10.​1055/​s-0030-1267950.
33.
34.
35.
36.
37.
38.
Hock JM, Centrella M, Canalis E. Insulin-like growth factor I has independent effects on bone matrix formation and cell replication. Endocrinology. 1988;122(1):254–60. doi:10.​1210/​endo-122-1-254.PubMed
39.
40.
41.
Zhao HY, Liu JM, Ning G, Zhao YJ, Chen Y, Sun LH, et al. Relationships between insulin-like growth factor-I (IGF-I) and OPG, RANKL, bone mineral density in healthy Chinese women. Osteoporos Int. 2008;19(2):221–6. doi:10.​1007/​s00198-007-0440-y.PubMed
42.
Leger B, Derave W, De Bock K, Hespel P, Russell AP. Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylation. Rejuvenation Res. 2008;11(1):163–75B. doi:10.​1089/​rej.​2007.​0588.PubMed
43.
Ghiron LJ, Thompson JL, Holloway L, Hintz RL, Butterfield GE, Hoffman AR, et al. Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women. J Bone Miner Res. 1995;10(12):1844–52. doi:10.​1002/​jbmr.​5650101203.PubMed
44.
45.
Reed ML, Merriam GR, Kargi AY. Adult growth hormone deficiency - benefits, side effects, and risks of growth hormone replacement. Front Endocrinol. 2013;4:64. doi:10.​3389/​fendo.​2013.​00064.
46.
Liu H, Bravata DM, Olkin I, Nayak S, Roberts B, Garber AM, et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med. 2007;146(2):104–15.PubMed
47.
Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schambelan M, et al. Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med. 1996;124(8):708–16.PubMed
48.
Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA. 2002;288(18):2282–92.PubMed
49.
50.
Human Body Size and the Laws of Scaling: Physiological, Performance, Growth, Longevity and Ecological Ramifications. In: Samaras T, editor. New York: Nova Science Publishers; 2007.
51.
52.
Holt LJ, Turner N, Mokbel N, Trefely S, Kanzleiter T, Kaplan W, et al. Grb10 regulates the development of fiber number in skeletal muscle. FASEB. 2012;26(9):3658–69. doi:10.​1096/​fj.​11-199349.
53.
54.
Veldhuis JD, Patrie JM, Frick K, Weltman JY, Weltman AL. Administration of recombinant human GHRH-1,44-amide for 3 months reduces abdominal visceral fat mass and increases physical performance measures in postmenopausal women. Eur J Endocrinol. 2005;153(5):669–77. doi:10.​1530/​eje.​1.​02019.PubMed
55.
Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell Jr FE, Clasey JL, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008;149(9):601–11.PubMedCentralPubMed
56.
White HK, Petrie CD, Landschulz W, MacLean D, Taylor A, Lyles K, et al. Effects of an oral growth hormone secretagogue in older adults. J Clin Endocrinol Metab. 2009;94(4):1198–206. doi:10.​1210/​jc.​2008-0632.PubMed
57.
58.
59.••
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–59. doi:10.​1210/​jc.​2009-2354. These guidelines published by the Endocrine Society outline reccomendations for testing and treating androgen deficiency.PubMed
60.
Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, et al. Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab. 2006;2(3):146–59. doi:10.​1038/​ncpendmet0120.PubMedCentralPubMed
61.
Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, Cauley JA, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab. 2006;91(10):3908–15. doi:10.​1210/​jc.​2006-0173.PubMed
62.
Tracz MJ, Sideras K, Bolona ER, Haddad RM, Kennedy CC, Uraga MV, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. 2006;91(6):2011–6. doi:10.​1210/​jc.​2006-0036.PubMed
63.
Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol. 2005;63(3):280–93. doi:10.​1111/​j.​1365-2265.​2005.​02339.​x.
64.
Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95(2):639–50. doi:10.​1210/​jc.​2009-1251.PubMed
65.•
Spitzer M, Huang G, Basaria S, Travison TG, Bhasin S. Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol. 2013;9(7):414–24. doi:10.​1038/​nrendo.​2013.​73. This review summarizes benefits of testosterone therapy, its indications and risks in older men, particularly relating to cardiovascular disease, prostate conditions, and erythrocytosis.PubMed
66.
Testosterone and aging: clinical research directions. Institute of Medicine TNAP. In: Liverman CT, Blazer, DG, editors. Washington, D.C.: National, Academies Press; 2004.
67.•
Zhang X, Sui Z. Deciphering the selective androgen receptor modulators paradigm. Expert Opin Drug Discov. 2013;8(2):191–218. doi:10.​1517/​17460441.​2013.​741582. This review covers pharmacologic aspects in the development of SARMs and summarizes preclinical and clinical data.PubMed
68.
Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, et al. Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009;52(12):3597–617. doi:10.​1021/​jm900280m.PubMed
69.
Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachex Sarcopenia Muscle. 2011;2(3):153–61. doi:10.​1007/​s13539-011-0034-6.
70.•
Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14(4):335–45. doi:10.​1016/​S1470-2045(13)70055-X. This clinical trial of enobosarm, a nonsteroidal SARM, showed significant increases in lean body mass but no effect in bone mineral density in patients with cancer cachexia. A phase 3 trial is currently underway.PubMed
71.
Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J Gerontol A Biol Sci Med Sci. 2013;68(1):87–95. doi:10.​1093/​gerona/​gls078.PubMed
72.•
Papanicolaou DA, Ather SN, Zhu H, Zhou Y, Lutkiewicz J, Scott BB, et al. A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. J Nutr Health Aging. 2013;17(6):533–43. doi:10.​1007/​s12603-013-0335-x. The steroidal SARM, MK-0773, resulted in significant increases in lean body mass in frail elderly women but this did not translate to improvements in muscle strength.PubMed
73.•
Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE. The roles of Vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev. 2013;34:33–83. doi:10.​1210/​er.​2012-1012. This review summarizes effects of vitamin D in skeletal muscle from animal, cell and human studies.PubMed
74.
Amling M, Priemel M, Holzmann T, Chapin K, Rueger JM, Baron R, et al. Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology. 1999;140(11):4982–7.PubMed
75.
76.•
Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys. 2012;523(1):123–33. doi:10.​1016/​j.​abb.​2012.​04.​001. This article examines the tissue distribution of VDR, including organs where its presence is controversial such as liver and skeletal muscle.PubMed
77.
Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P, et al. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest. 2012;122(5):1803–15. doi:10.​1172/​JCI45890.PubMedCentralPubMed
78.
Yamamoto Y, Yoshizawa T, Fukuda T, Shirode-Fukuda Y, Yu T, Sekine K, et al. Vitamin D receptor in osteoblasts is a negative regulator of bone mass control. Endocrinology. 2013;154(3):1008–20. doi:10.​1210/​en.​2012-1542.PubMed
79.
Lam NN, Triliana R, Sawyer RK, Atkins GJ, Morris HA, O'Loughlin PD, et al. Vitamin D receptor overexpression in osteoblasts and osteocytes prevents bone loss during vitamin D-deficiency. J Steroid Biochem Mol Biol. 2014. doi:10.​1016/​j.​jsbmb.​2014.​01.​002.PubMed
80.
Endo I, Inoue D, Mitsui T, Umaki Y, Akaike M, Yoshizawa T, et al. Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology. 2003;144(12):5138–44. doi:10.​1210/​en.​2003-0502.PubMed
81.
Girgis CM, Clifton-Bligh RJ, Mokbel N, Cheng K, Gunton JE. Vitamin D signaling regulates proliferation, differentiation and myotube size in C2C12 skeletal muscle cells. Endocrinology. 2014;155(2):347–57. doi:10.​1210/​en.​2013-1205.PubMed
82.
Lee SG, Lee YH, Kim KJ, Lee W, Kwon OH, Kim JH. Additive association of vitamin D insufficiency and sarcopenia with low femoral bone mineral density in noninstitutionalized elderly population: the Korea National Health and Nutrition Examination Surveys 2009–2010. Osteoporos Int. 2013;24(11):2789–99. doi:10.​1007/​s00198-013-2378-6.PubMed
83.
Snijder MB, van Schoor NM, Pluijm SM, van Dam RM, Visser M, Lips P. Vitamin D status in relation to one-year risk of recurrent falling in older men and women. J Clin Endocrinol Metab. 2006;91(8):2980–5. doi:10.​1210/​jc.​2006-0510.PubMed
84.
85.
Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293(18):2257–64. doi:10.​1001/​jama.​293.​18.​2257.PubMed
86.
87.
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669–83. doi:10.​1056/​NEJMoa055218.PubMed
88.
89.•
Ceglia L, Niramitmahapanya S, Morais MD, Rivas DA, Harris SS, Bischoff-Ferrari H, et al. A randomized study on the effect of vitamin D3 supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women. J Clin Endocrinol Metab. 2013. doi:10.​1210/​jc.​2013–2820. This RCT of 21 older women showed an increase in myonuclear VDR and muscle fiber size amongst those receiving vitamin D supplementation (4000 IU d for 4 months). However, functional parameters were unchanged, possibly due to the small sample size.
90.•
Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815–22. doi:10.​1001/​jama.​2010.​594. This well-known RCT of 2256 community-dwelling older women reported an increased risk of falls and fractures in the 3 months following vitamin D mega-supplementation (500,000 IU oral).PubMed
91.•
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–8. doi:10.​1210/​jc.​2010-2704. This article summarizes the IOM recommendations for 25OHD target levels (50 nmol/L) and daily vitamin D doses (800 IU in adults >70years). Extra-skeletal benefits of vitamin D were reportedly “not yet compelling”.PubMedCentralPubMed
92.•
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–30. doi:10.​1210/​jc.​2011-0385. In contrast to the IOM recommendations, the Endocrine society advocated a higher 25OHD target level of 75 nmol/L and daily doses of at least 1500–2000 IU in the older age-group.PubMed
93.
Korpelainen R, Keinanen-Kiukaanniemi S, Heikkinen J, Vaananen K, Korpelainen J. Effect of impact exercise on bone mineral density in elderly women with low BMD: a population-based randomized controlled 30-month intervention. Osteoporos Int. 2006;17(1):109–18. doi:10.​1007/​s00198-005-1924-2.PubMed
94.
95.
Winters-Stone KM, Dobek J, Nail L, Bennett JA, Leo MC, Naik A, et al. Strength training stops bone loss and builds muscle in postmenopausal breast cancer survivors: a randomized, controlled trial. Breast Cancer Res Treat. 2011;127(2):447–56. doi:10.​1007/​s10549-011-1444-z.PubMedCentralPubMed
96.
97.
Gilsanz V, Wren TA, Sanchez M, Dorey F, Judex S, Rubin C. Low-level, high-frequency mechanical signals enhance musculoskeletal development of young women with low BMD. J Bone Miner Res. 2006;21(9):1464–74. doi:10.​1359/​jbmr.​060612.PubMed
98.
Dudley-Javoroski S, Shields RK. Muscle and bone plasticity after spinal cord injury: review of adaptations to disuse and to electrical muscle stimulation. J Rehabil Res Dev. 2008;45(2):283–96.PubMedCentralPubMed
99.
Serrano-Urrea R, Garcia-Meseguer MJ. Malnutrition in an elderly population without cognitive impairment living in nursing homes in Spain: study of prevalence using the Mini Nutritional Assessment test. Gerontology. 2013;59(6):490–8. doi:10.​1159/​000351763.PubMed
100.
101.
Houston DK, Nicklas BJ, Ding J, Harris TB, Tylavsky FA, Newman AB, et al. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study. Am J Clin Nutr. 2008;87(1):150–5.PubMed
102.
103.
Milne AC, Potter J, Vivanti A, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst Rev. 2009(2):CD003288. doi:10.​1002/​14651858.CD003288.pub3.
104.
Miller CT, Fraser SF, Levinger I, Straznicky NE, Dixon JB, Reynolds J, et al. The effects of exercise training in addition to energy restriction on functional capacities and body composition in obese adults during weight loss: a systematic review. PLoS One. 2013;8(11):e81692. doi:10.​1371/​journal.​pone.​0081692.PubMedCentralPubMed
105.
106.
Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007;370(9588):657–66. doi:10.​1016/​S0140-6736(07)61342-7.PubMed
107.
108.
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83–90. doi:10.​1038/​387083a0.PubMed
109.
Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350(26):2682–8. doi:10.​1056/​NEJMoa040933.PubMed
110.
111.
Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, Sinha-Hikim I, Ma K, Ezzat S, et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proc Natl Acad Sci U S A. 1998;95(25):14938–43.PubMedCentralPubMed
112.
113.
114.
115.
Zhang ZL, He JW, Qin YJ, Hu YQ, Li M, Zhang H, et al. Association between myostatin gene polymorphisms and peak BMD variation in Chinese nuclear families. Osteoporos Int. 2008;19(1):39–47. doi:10.​1007/​s00198-007-0435-8.PubMed
116.
117.
118.•
Digirolamo D SV, Clemens T, Lee S-J. Systemic administration of soluble 483 activin receptors produces differential anabolic effects in muscle and bone in mice. J Bone Miner Res. 2011;1167 (Suppl.). This abstract presented at ASBMR meeting 2011 reported direct effects of activin receptor signaling in osteoblasts. Mice treated with ActRII-Fc fusion proteins showed both increases in muscle (15%–40%) and trabecular (~13%) bone over 4 weeks.
119.•
Bowser M, Herberg S, Arounleut P, Shi X, Fulzele S, Hill WD, et al. Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells. Exp Gerontol. 2013;48(2):290–7. doi:10.​1016/​j.​exger.​2012.​11.​004. This study examined age-related differences in the expression and activity of myostatin, activin A, and follistatin in mice. Myostatin was particularly important in the impaired proliferative capacity of aged muscle and bone cells, making it an appropriate therapeutic target in treating sarcopenia-osteoporosis.PubMedCentralPubMed
120.
Koncarevic A, Cornwall-Brady M, Pullen A, Davies M, Sako D, Liu J, et al. A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health. Endocrinology. 2010;151(9):4289–300. doi:10.​1210/​en.​2010-0134.PubMed
121.
Bogdanovich S, Krag TO, Barton ER, Morris LD, Whittemore LA, Ahima RS, et al. Functional improvement of dystrophic muscle by myostatin blockade. Nature. 2002;420(6914):418–21. doi:10.​1038/​nature01154.PubMed
122.
123.•
Chiu CS, Peekhaus N, Weber H, Adamski S, Murray EM, Zhang HZ, et al. Increased muscle force production and bone mineral density in ActRIIB-Fc-treated mature rodents. J Gerontol A Biol Sci Med Sci. 2013;68(10):1181–92. doi:10.​1093/​gerona/​glt030. Aged mice treated with ActRIIB-Fc fusion protein showed enhanced muscle size and function after 3 days. Similar features were observed in hypogonadal male mice (ie, orchidectomized) and improvements in bone mineral density were also reported.PubMed
124.
Lotinun S, Pearsall RS, Davies MV, Marvell TH, Monnell TE, Ucran J, et al. A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone. 2010;46(4):1082–8. doi:10.​1016/​j.​bone.​2010.​01.​370.PubMed
125.•
Arounleut P, Bialek P, Liang LF, Upadhyay S, Fulzele S, Johnson M, et al. A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength. Exp Gerontol. 2013;48(9):898–904. doi:10.​1016/​j.​exger.​2013.​06.​004. Aged mice injected with a myostatin inhibitor (propeptide-Fc) showed increases in muscle mass but not bone volume. This raised questions about the precise role of myostatin signaling in bone density in aged animals.PubMedCentralPubMed
126.
Wagner KR, Fleckenstein JL, Amato AA, Barohn RJ, Bushby K, Escolar DM, et al. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008;63(5):561–71. doi:10.​1002/​ana.​21338.PubMed
127.
Krivickas LS, Walsh R, Amato AA. Single muscle fiber contractile properties in adults with muscular dystrophy treated with MYO-029. Muscle Nerve. 2009;39(1):3–9. doi:10.​1002/​mus.​21200.PubMed
128.•
Attie KM, Borgstein NG, Yang Y, Condon CH, Wilson DM, Pearsall AE, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve. 2013;47(3):416–23. doi:10.​1002/​mus.​23539. This RCT reported increases in muscle mass and serum markers of bone formation in healthy postmenopausal women receiving a single dose of ACE-031, a soluble ActRIIB decoy receptor. Although side-effects were minor—nose bleeds, skin telangiectasia and transient drop in FSH levels—they highlight an incomplete understanding of systemic effects of activin signaling.PubMed
129.•
Lach-Trifilieff E, Minetti GC, Sheppard K, Ibebunjo C, Feige JN, Hartmann S, et al. An antibody blocking Activin Type II Receptor induces strong skeletal muscle hypertrophy and protects from atrophy. Mol Cell Biol. 2014;34(4):606–18. doi:10.​1128/​MCB.​01307-13. Mice injected with a novel anti ActRII antibody (BYM338) had greater increases in muscle mass than mice receiving a myostatin inhibitor alone. This agent also protected muscles from glucocorticoid-induced atrophy and has potential therapeutic implications.PubMedCentralPubMed
130.
Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481–9. doi:10.​1038/​nm.​2513.PubMed
Metadata
Title
Therapies for Musculoskeletal Disease: Can we Treat Two Birds with One Stone?
Authors
Christian M. Girgis
Nancy Mokbel
Douglas J. DiGirolamo
Publication date
01-06-2014
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 2/2014
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-014-0204-5

Other articles of this Issue 2/2014

Current Osteoporosis Reports 2/2014 Go to the issue

Biomechanics (M Silva and P Zysset, Section Editors)

Diabetes, Collagen, and Bone Quality

Hot Topic

Clinical Considerations of Regenerative Medicine in Osteoporosis

Biomechanics (M Silva and P Zysset, Section Editors)

Characterization of Complex, Co-Adapted Skeletal Biomechanics Phenotypes: A Needed Paradigm Shift in the Genetics of Bone Structure and Function

Nutrition, Exercise, and Lifestyle in Osteoporosis (C Weaver and S Ferrari, Section Editors)

The Effects of Flavonoids on Bone

Muscle and Bone (L Bonewald and M Harrick, Section Editors)

Endocrine Crosstalk Between Muscle and Bone

INVITED COMMENTARY

Bone Density Testing: Science, the Media, and Patient Care