Mini-Review Article

Osteoblast-n-Osteoclast: Making Headway to Osteoporosis Treatment

Author(s): Malkiet Kaur, Manju Nagpal* and Manjinder Singh

Volume 21, Issue 16, 2020

Page: [1640 - 1651] Pages: 12

DOI: 10.2174/1389450121666200731173522

Price: $65


Background: Bone is a dynamic tissue that continuously undergoes the modeling and remodeling process to maintain its strength and firmness. Bone remodeling is determined by the functioning of osteoblast and osteoclast cells. The imbalance between the functioning of osteoclast and osteoblast cells leads to osteoporosis. Osteoporosis is divided into primary and secondary osteoporosis. Generally, osteoporosis is diagnosed by measuring bone mineral density (BMD) and various osteoblast and osteoclast cell markers.

Methods: Relevant literature reports have been studied and data has been collected using various search engines like google scholar, scihub, sciencedirect, pubmed, etc. A thorough understanding of the mechanism of bone targeting strategies has been discussed and related literature has been studied and compiled.

Results: Bone remodeling process has been described in detail including various approaches for targeting bone. Several bone targeting moieties have been stated in detail along with their mechanisms. Targeting of osteoclasts and osteoblasts using various nanocarriers has been discussed in separate sections. The toxicity issues or Biosafety related to the use of nanomaterials have been covered.

Conclusion: The treatment of osteoporosis targets the inhibition of bone resorption and the use of agents that promote bone mineralization to slow disease progression. Current osteoporosis therapy involves the use of targeting moieties such as bisphosphonates and tetracyclines for targeting various drugs. Nanotechnology has been used for targeting various drug molecules such as RANKLinhibitors, parathyroid hormone analogues, estrogen agonists and antagonists, Wnt signaling enhancer and calcitonin specifically to bone tissue (osteoclast and osteoblasts). So, a multicomponent treatment strategy targeting both the bone cells will be more effective rather than targeting only osteoclasts and it will be a potential area of research in bone targeting used to treat osteoporosis. The first section of the review article covers various aspects of bone targeting. Another section comprises details of various targeting moieties such as bisphosphonates, tetracyclines; and various nanocarriers developed to target osteoclast and osteoblast cells and summarized data on in vivo models has been used for assessment of bone targeting, drawbacks of current strategies and future perspectives.

Keywords: Osteoporosis, bone targeting, osteoblast, osteoclast, bone remodeling, metastasis.

Graphical Abstract
Low SA, Kopeček J. Targeting polymer therapeutics to bone. Adv Drug Deliv Rev 2012; 64(12): 1189-204.
[] [PMID: 22316530]
Rockville. Bone health and Osteoporosis- A report of the surgeon general, U.S.A. department of Health and Human services, Office of Surgeon general 2004.
Khadilkar AV, Mandlik RM. Epidemiology and treatment of osteoporosis in women: an Indian perspective. Int J Womens Health 2015; 7: 841-50.
[] [PMID: 26527900]
Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002; 359(9319): 1761-7.
[] [PMID: 12049882]
Masi L. Epidemiology of osteoporosis. Clin Cases Miner Bone Metab 2008; 5(1): 11-3.
[PMID: 22460840]
Coe FL, Favus MJ. Disorders of bone and mineral metabolism. Lippincott Williams & Wilkins 2002.
Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis 2016; 8(6): 225-35.
[] [PMID: 28255336]
Bilezikian JP, Matsumoto T, Bellido T, et al. Targeting bone remodeling for the treatment of osteoporosis: summary of the proceedings of an ASBMR workshop. J Bone Miner Res 2009; 24(3): 373-85.
[] [PMID: 19260805]
Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science 2000; 289(5484): 1508-14.
[] [PMID: 10968781]
Sözen T, Özışık L, Başaran NÇ. An overview and management of osteoporosis. Eur J Rheumatol 2017; 4(1): 46-56.
[] [PMID: 28293453]
Barry M, Pearce H, Cross L, Tatullo M, Gaharwar AK. Advances in Nanotechnology for the treatment of osteoporosis. Curr Osteoporos Rep 2016; 14(3): 87-94.
[] [PMID: 27048473]
Paspaliaris V, Kolios G. Stem cells in osteoporosis: from biology to new therapeutic approaches. Stem Cells Int 2019; •••20191730978
[] [PMID: 31281368]
Tu KN, Lie JD, Wan CKV, et al. Osteoporosis: a review of treatment options. P&T 2018; 43(2): 92-104.
[PMID: 29386866]
Mazziotti G, Bilezikian J, Canalis E, Cocchi D, Giustina A. New understanding and treatments for osteoporosis. Endocrine 2012; 41(1): 58-69.
[] [PMID: 22180055]
Lewiecki EM. Osteoporosis: Treat-to-Target. Curr Osteoporos Rep 2017; 15(2): 103-9.
[] [PMID: 28236035]
Dobbs MB, Buckwalter J, Saltzman C. Osteoporosis: the increasing role of the orthopaedist. Iowa Orthop J 1999; 19: 43-52.
[PMID: 10847516]
Premier orthopaedics The different types of osteoporosis
Newman MR, Benoit DS. Local and targeted drug delivery for bone regeneration. Curr Opin Biotechnol 2016; 40: 125-32.
[] [PMID: 27064433]
Cosman F, de Beur SJ, LeBoff MS, et al. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 2014; 25(10): 2359-81.
[] [PMID: 25182228]
Jean-Louis M, Claudia CY, Jean-Marie R, Patrick C. Simulating pharmaceutical treatment effects on osteoporosis via a bone remodeling algorithm targeting hypermineralized sites. Med Eng Phys 2020; 76: 56-68.
[] [PMID: 31870544]
Chen JS, Sambrook PN. Antiresorptive therapies for osteoporosis: a clinical overview. Nat Rev Endocrinol 2011; 8(2): 81-91.
[] [PMID: 21894214]
Mora Raimundo P, Manzano García M, Vallet Regí M. Nanoparticles for the treatment of osteoporosis. AIMS Bioeng 2017; 4(2): 259-74.
Rosen CJ, Bilezikian JP. Clinical review 123: Anabolic therapy for osteoporosis. J Clin Endocrinol Metab 2001; 86(3): 957-64.
[] [PMID: 11238469]
Cheng H, Chawla A, Yang Y, et al. Development of nanomaterials for bone-targeted drug delivery. Drug Discov Today 2017; 22(9): 1336-50.
[] [PMID: 28487069]
Modi A, Sajjan S, Gandhi S. Challenges in implementing and maintaining osteoporosis therapy. Int J Womens Health 2014; 6: 759-69.
[] [PMID: 25152632]
Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol 2017; 5(11): 898-907.
[] [PMID: 28689769]
Tanaka Y, Nakayamada S, Okada Y. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy 2005; 4(3): 325-8.
[] [PMID: 16101541]
Gu W, Wu C, Chen J, Xiao Y. Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration. Int J Nanomedicine 2013; 8: 2305-17.
[] [PMID: 23836972]
Chan CK, Mason A, Cooper C, Dennison E. Novel advances in the treatment of osteoporosis. Br Med Bull 2016; 119(1): 129-42.
[] [PMID: 27558130]
Alencastre IS, Sousa DM, Alves CJ, et al. Delivery of pharmaceutics to bone: Nanotechnologies, high-throughput processing and in silico mathematical models. Eur Cell Mater 2016; 31: 355-81.
[] [PMID: 27232664]
Stapleton M, Sawamoto K, Alméciga-Díaz CJ, et al. Development of bone targeting drugs. Int J Mol Sci 2017; 18(7): 1345.
[] [PMID: 28644392]
Deal C. Future therapeutic targets in osteoporosis. Curr Opin Rheumatol 2009; 21(4): 380-5.
[] [PMID: 19461517]
International osteoporosis foundation Osteoporosis musculoskeletal disorders January 15, 2020)
Bonnelye E, Aubin JE. Estrogen receptor-related receptor α: a mediator of estrogen response in bone. J Clin Endocrinol Metab 2005; 90(5): 3115-21.
[] [PMID: 15713703]
Pilbeam CC, Harrison JR, Raisz LG. Prostaglandins and bone metabolism in principles of bone biology. San Diego: Academic Press 2002; pp. 979-95.
Marie PJ, Kassem M. Osteoblasts in osteoporosis: past, emerging, and future anabolic targets. Eur J Endocrinol 2011; 165(1): 1-10.
[] [PMID: 21543379]
Gong Y, Slee RB, Fukai N, et al. Osteoporosis-Pseudoglioma Syndrome Collaborative Group. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001; 107(4): 513-23.
[] [PMID: 11719191]
Bucay N, Sarosi I, Dunstan CR, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12(9): 1260-8.
[] [PMID: 9573043]
Carano A, Teitelbaum SL, Konsek JD, Schlesinger PH, Blair HC. Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J Clin Invest 1990; 85(2): 456-61.
[] [PMID: 2105340]
Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008; 83(9): 1032-45.
[] [PMID: 18775204]
Canalis E. Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol 2013; 9(10): 575-83.
[] [PMID: 23938284]
Coxon FP, Thompson K, Rogers MJ. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 2006; 6(3): 307-12.
[] [PMID: 16650801]
Farrell KB, Karpeisky A, Thamm DH, Zinnen S. Bisphosphonate conjugation for bone specific drug targeting. Bone Rep 2018; 9: 47-60.
[] [PMID: 29992180]
Doschak MR, Kucharski CM, Wright JE, Zernicke RF, Uludağ H. Improved bone delivery of osteoprotegerin by bisphosphonate conjugation in a rat model of osteoarthritis. Mol Pharm 2009; 6(2): 634-40.
[] [PMID: 19718808]
Morioka M, Kamizono A, Takikawa H, et al. Design, synthesis, and biological evaluation of novel estradiol-bisphosphonate conjugates as bone-specific estrogens. Bioorg Med Chem 2010; 18(3): 1143-8.
[] [PMID: 20071185]
Bhandari KH, Newa M, Uludag H, Doschak MR. Synthesis, characterization and in vitro evaluation of a bone targeting delivery system for salmon calcitonin. Int J Pharm 2010; 394(1-2): 26-34.
[] [PMID: 20412845]
Yang Y, Bhandari KH, Panahifar A, Doschak MR. Synthesis, characterization and biodistribution studies of (125)I-radioiodinated di-PEGylated bone targeting salmon calcitonin analogue in healthy rats. Pharm Res 2014; 31(5): 1146-57.
[] [PMID: 24357414]
Yewle JN, Puleo DA, Bachas LG. Bifunctional bisphosphonates for delivering PTH (1-34) to bone mineral with enhanced bioactivity. Biomaterials 2013; 34(12): 3141-9.
[] [PMID: 23369219]
Arns S, Gibe R, Moreau A, Monzur Morshed M, Young RN. Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis. Bioorg Med Chem 2012; 20(6): 2131-40.
[] [PMID: 22341574]
Dang L, Liu J, Li F, et al. Targeted delivery systems for molecular therapy in skeletal disorders. Int J Mol Sci 2016; 17(3): 428.
[] [PMID: 27011176]
Wang H, Liu J, Tao S, et al. Tetracycline-grafted PLGA nanoparticles as bone-targeting drug delivery system. Int J Nanomedicine 2015; 10: 5671-85.
[PMID: 26388691]
Chen LR, Ko NY, Chen KH. Medical treatment for osteoporosis: From molecular to clinical opinions. Int J Mol Sci 2019; 20(9): 2213.
[] [PMID: 31064048]
Ansboro S, Greiser U, Barry F, Murphy M. Strategies for improved targeting of therapeutic cells: implications for tissue repair. Eur Cell Mater 2012; 23: 310-8.
[] [PMID: 22522285]
Luhmann T, Germershaus O, Groll J, Meinel L. Bone targeting for the treatment of osteoporosis. J Control Release 2012; 161(2): 198-213.
[] [PMID: 22016072]
Rochefort GY. The osteocyte as a therapeutic target in the treatment of osteoporosis. Ther Adv Musculoskelet Dis 2014; 6(3): 79-91.
[] [PMID: 24891879]
Corrado A, Sanpaolo ER, Di Bello S, Cantatore FP. Osteoblast as a target of anti-osteoporotic treatment. Postgrad Med 2017; 129(8): 858-65.
[] [PMID: 28770650]
Rawadi G, Roman-Roman S. Wnt signalling pathway: a new target for the treatment of osteoporosis. Expert Opin Ther Targets 2005; 9(5): 1063-77.
[] [PMID: 16185158]
Wang D, Miller SC, Kopecková P, Kopeček J. Bone-targeting macromolecular therapeutics. Adv Drug Deliv Rev 2005; 57(7): 1049-76.
[] [PMID: 15876403]
Wang HH, Hsu YH, Chang MS. IL-20 bone diseases involvement and therapeutic target potential. J Biomed Sci 2018; 25(1): 38.
[] [PMID: 29690863]
Brommage R. New Targets and Emergent Therapies for Osteoporosis. Handb Exp Pharmacol 2019.
[] [PMID: 31820174]
Asafo-Adjei TA, Chen AJ, Najarzadeh A, Puleo DA. Advances in controlled drug delivery for treatment of osteoporosis. Curr Osteoporos Rep 2016; 14(5): 226-38.
[] [PMID: 27502334]
Taipaleenmäki H, Bjerre Hokland L, Chen L, Kauppinen S, Kassem M. Mechanisms in endocrinology: micro-RNAs: targets for enhancing osteoblast differentiation and bone formation. Eur J Endocrinol 2012; 166(3): 359-71.
[] [PMID: 22084154]
Huang Y, Ren K, Yao T, et al. MicroRNA-25-3p regulates osteoclasts through nuclear factor I X. Biochem Biophys Res Commun 2020; 522(1): 74-80.
[] [PMID: 31740002]
Sun Y, Ye X, Cai M, et al. Osteoblast-targeting-peptide modified nanoparticle for siRNA/microRNA delivery. ACS Nano 2016; 10(6): 5759-68.
[] [PMID: 27176123]
Qadir A, Gao Y, Suryaji P, et al. Non-viral delivery system and targeted bone disease therapy. Int J Mol Sci 2019; 20(3): 565.
[] [PMID: 30699924]
Liang C, Guo B, Wu H, et al. Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference-based bone anabolic strategy. Nat Med 2015; 21(3): 288-94.
[] [PMID: 25665179]
Houschyar KS, Tapking C, Borrelli MR, et al. Wnt pathway in bone repair and regeneration. Front Cell Dev Biol 2019; 6: 170.
[] [PMID: 30666305]
Khosla S, Westendorf JJ, Oursler MJ. Building bone to reverse osteoporosis and repair fractures. J Clin Invest 2008; 118(2): 421-8.
[] [PMID: 18246192]
Cho M, Han S, Kim H, Kim KS, Hahn SK. Hyaluronate - parathyroid hormone peptide conjugate for transdermal treatment of osteoporosis. J Biomater Sci Polym Ed 2018; 29(7-9): 793-804.
[] [PMID: 29115187]
Mora-Raimundo P, Lozano D, Manzano M, Vallet-Regí M. Nanoparticles to Knockdown osteoporosis-related gene and promote osteogenic marker expression for osteoporosis treatment. ACS Nano 2019; 13(5): 5451-64.
[] [PMID: 31071265]
Yu AX, Xu ML, Yao P, et al. Corylin, a flavonoid derived from Psoralea Fructus, induces osteoblastic differentiation via estrogen and Wnt/β-catenin signaling pathways. FASEB J 2020; 34(3): 4311-28.
[] [PMID: 31965654]
Zhang Y, Jiang Y, Luo Y, Zeng Y. Interference of miR-212 and miR-384 promotes osteogenic differentiation via targeting RUNX2 in osteoporosis. Exp Mol Pathol 2020; •••113104366
[] [PMID: 31891679]
Khajuria DK, Razdan R, Mahapatra DR. Drugs for the management of osteoporosis: a review. Rev Bras Reumatol 2011; 51(4): 365-371, 379-382.
[PMID: 21779712]
Xie H, Chen G, Young RN. Design, synthesis, and pharmacokinetics of a bone-targeting dual-action prodrug for the treatment of osteoporosis. J Med Chem 2017; 60(16): 7012-28.
[] [PMID: 28699744]
Bi H, Chen X, Gao S, et al. Key triggers of osteoclast-related diseases and available strategies for targeted therapies: A review. Front Med (Lausanne) 2017; 4: 234.
[] [PMID: 29326938]
Pignatello R, Sarpietro MG, Castelli F. Synthesis and biological evaluation of a new polymeric conjugate and nanocarrier with osteotropic properties. J Funct Biomater 2012; 3(1): 79-99.
[] [PMID: 24956517]
Schem C, Tower RJ, Kneissl P, et al. Pharmacologically inactive bisphosphonates as an alternative strategy for targeting osteoclasts: in vivo assessment of 5‐fluorodeoxyuridine‐alendronate in a preclinical model of breast cancer bone metastases. J Bone Miner Res 2017; 32(3): 536-48.
[] [PMID: 27714838]
Tanaka S. RANKL is a therapeutic target of bone destruction in rheumatoid arthritis. F1000 Res 2019; 8: 8.
[] [PMID: 31069051]
Nardone V, D’Asta F, Brandi ML. Pharmacological management of osteogenesis. Clinics (São Paulo) 2014; 69(6): 438-46.
[] [PMID: 24964310]
Brömme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin Investig Drugs 2009; 18(5): 585-600.
[] [PMID: 19388876]
Kim HY, Kim KS, Kim MJ, Kim HS, Lee KY, Kang KW. Auranofin Inhibits RANKL-Induced Osteoclastogenesis by Suppressing Inhibitors of κB Kinase and Inflammasome-Mediated Interleukin-1β Secretion Oxidative med cell Longev 2019.
Duan X, Yang S, Zhang L, Yang T. V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics 2018; 8(19): 5379-99.
[] [PMID: 30555553]
Kawai VK, Stein CM, Perrien DS, Griffin MR. Effects of anti-tumor necrosis factor α agents on bone. Curr Opin Rheumatol 2012; 24(5): 576-85.
[] [PMID: 22810364]
Babanejad N, Farhadian A, Omrani I, Nabid MR. Design, characterization and in vitro evaluation of novel amphiphilic block sunflower oil-based polyol nanocarrier as a potential delivery system: Raloxifene-hydrochloride as a model. Mater Sci Eng C 2017; 78: 59-68.
[] [PMID: 28576026]
Ye Y, Zhang T, Li W, et al. Glucose-based mesoporous carbon nanospheres as functional carriers for oral delivery of amphiphobic raloxifene: Insights into the bioavailability enhancement and lymphatic transport. Pharm Res 2016; 33(3): 792-803.
[] [PMID: 26553355]
Sun X, Wei J, Lyu J, et al. Bone-targeting drug delivery system of biomineral-binding liposomes loaded with icariin enhances the treatment for osteoporosis. J Nanobiotechnology 2019; 17(1): 10.
[] [PMID: 30670021]
Saini D, Fazil M, Ali MM, Baboota S, Ali J. Formulation, development and optimization of raloxifene-loaded chitosan nanoparticles for treatment of osteoporosis. Drug Deliv 2015; 22(6): 823-36.
[] [PMID: 24725026]
Khajuria DK, Razdan R, Mahapatra DR. Development, in vitro and in vivo characterization of zoledronic acid functionalized hydroxyapatite nanoparticle based formulation for treatment of osteoporosis in animal model. Eur J Pharm Sci 2015; 66: 173-83.
[] [PMID: 25444840]
Fazil M, Hassan MQ, Baboota S, Ali J. Biodegradable intranasal nanoparticulate drug delivery system of risedronate sodium for osteoporosis. Drug Deliv 2016; 23(7): 2428-38.
[PMID: 25625496]
Cai Y, Gao T, Fu S, Sun P. Development of zoledronic acid functionalized hydroxyapatite loaded polymeric nanoparticles for the treatment of osteoporosis. Exp Ther Med 2018; 16(2): 704-10.
[] [PMID: 30116324]
Elnaggar YSR, Omran S, Hazzah HA, Abdallah OY. Anionic versus cationic bilosomes as oral nanocarriers for enhanced delivery of the hydrophilic drug risedronate. Int J Pharm 2019; 564: 410-25.
[] [PMID: 31029657]
Cai M, Yang L, Zhang S, Liu J, Sun Y, Wang X. A bone-resorption surface-targeting nanoparticle to deliver anti-miR214 for osteoporosis therapy. Int J Nanomedicine 2017; 12: 7469-82.
[] [PMID: 29075114]
Lee D, Heo DN, Kim HJ, et al. Inhibition of osteoclast differentiation and bone resorption by bisphosphonate-conjugated gold nanoparticles. Sci Rep 2016; 6(1): 27336.
[] [PMID: 27251863]
Tan H, Zhao C, Zhu Q, et al. Ursolic Acid Isolated from the Leaves of Loquat (Eriobotrya japonica) Inhibited Osteoclast Differentiation through Targeting Exportin 5. J Agric Food Chem 2019; 67(12): 3333-40.
[] [PMID: 30827108]
Yu T, Witten PE, Huysseune A, Buettner A, To TT, Winkler C. Live imaging of osteoclast inhibition by bisphosphonates in a medaka osteoporosis model. Dis Model Mech 2016; 9(2): 155-63.
[] [PMID: 26704995]
Abdelsamie AS, Salah M, Siebenbürger L, et al. Design, Synthesis, and Biological Characterization of Orally Active 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors Targeting the Prevention of Osteoporosis. J Med Chem 2019; 62(15): 7289-301.
[] [PMID: 31343176]
Mao Z, Zhu Y, Hao W, Chu C, Su H. MicroRNA-155 inhibition up-regulates LEPR to inhibit osteoclast activation and bone resorption via activation of AMPK in alendronate-treated osteoporotic mice. IUBMB Life 2019; 71(12): 1916-28.
[] [PMID: 31317664]
Liu Y, Yu P, Peng X, et al. Hexapeptide-conjugated calcitonin for targeted therapy of osteoporosis. J Control Release 2019; 304: 39-50.
[] [PMID: 31054990]
Wang Q, Yan J, Yang J, Li B. Nanomaterials promise better bone repair. Mater Today 2016; 19(8): 451-63.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy