The Key Role of the Blood Supply to Bone

Abstract

The importance of the vascular supply for bone is well-known to orthopaedists but is still rather overlooked within the wider field of skeletal research. Blood supplies oxygen, nutrients and regulatory factors to tissues, as well as removing metabolic waste products such as carbon dioxide and acid. Bone receives up to about 10% of cardiac output, and this blood supply permits a much higher degree of cellularity, remodelling and repair than is possible in cartilage, which is avascular. The blood supply to bone is delivered to the endosteal cavity by nutrient arteries, then flows through marrow sinusoids before exiting via numerous small vessels that ramify through the cortex. The marrow cavity affords a range of vascular niches that are thought to regulate the growth and differentiation of hematopoietic and stromal cells, in part via gradients of oxygen tension. The quality of vascular supply to bone tends to decline with age and may be compromised in common pathological settings, including diabetes, anaemias, chronic airway diseases and immobility, as well as by tumours. Reductions in vascular supply are associated with bone loss. This may be due in part to the direct effects of hypoxia, which blocks osteoblast function and bone formation but causes reciprocal increases in osteoclastogenesis and bone resorption. Common regulatory factors such as parathyroid hormone or nitrates, both of which are potent vasodilators, might exert their osteogenic effects on bone via the vasculature. These observations suggest that the bone vasculature will be a fruitful area for future research.

References

[1] Trueta J, Harrison MH. The normal vascular anatomy of the femoral head in adult man. J Bone Joint Surg Br, 1953, 35-B: 442-461

[2] Trueta J, Morgan JD. The vascular contribution to osteogenesis. I. Studies by the injection method. J Bone Joint Surg Br, 1960, 42-B: 97-109

[3] Trueta Joseph. Blood Supply and the Rate of Healing of Tibial Fractures. Clinical Orthopaedics and Related Research, 1974, 105 1 11-26

[4] Brookes M, Harrison RG. The vascularization of the rabbit femur and tibio-fibula. J Anat, 1957, 91: 61-72

[5] Bridgeman G, Brookes M. Blood supply to the human femoral diaphysis in youth and senescence. J Anat, 1996, 188: 611-621

[6] Parfitt AM. The mechanism of coupling: a role for the vasculature. Bone, 2000, 26: 319-323

[7] Wilson JW, Sumner-Smith G. Blood supply to developing, mature, and healing bone. Bone in Clinical Orthopedics, 2002 Stuttgart New York Georg Thieme Verlag 23-116

[8] Laroche M. Intraosseous circulation from physiology to disease. Joint Bone Spine, 2002, 69: 262-269

[9] McCarthy I. The physiology of bone blood flow: a review. J Bone Joint Surg Am, 2006, 88 Suppl 3 4-9

[10] Brandi ML, Collin-Osdoby P. Vascular biology and the skeleton. J Bone Miner Res, 2006, 21: 183-192

[11] Portal-Núñez S, Lozano D, Esbrit P. Role of angiogenesis on bone formation. Histol Histopathol, 2012, 27: 559-566

[12] Brookes M. Blood supply of long bones. Br Med J, 1963, 2: 1064-1065

[13] Cumming JD, Nutt ME. Bone-marrow blood flow and cardiac output in the rabbit. J Physiol, 1962, 162: 30-34

[14] Ray RD, Kawabata M, Galante J. Experimental study of peripheral circulation and bone growth. An experimental method for the quantitative determination of bone blood flow. 3. Clin Orthop Relat Res, 1967, 54: 175-185

[15] Gross PM, Heistad DD, Marcus ML. Neurohumoral regulation of blood flow to bones and marrow. Am J Physiol, 1979, 237: H440-H448

[16] Enjolras O, Chapot R, Merland JJ. Vascular anomalies and the growth of limbs: a review. J Pediatr Orthop B, 2004, 13: 349-357

[17] Arnett TR. Acidosis, hypoxia and bone. Arch Biochem Biophys, 2010, 503: 103-109

[18] Harrison JS, Rameshwar P, Chang V, Bandari P. Oxygen saturation in the bone marrow of healthy volunteers. Blood, 2002, 99: 394

[19] Schipani E, Maes C, Carmeliet G, Semenza GL. Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J Bone Miner Res, 2009, 24: 1347-1353

[20] Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell, 2011, 9: 298-310

[21] Arnett TR, Gibbons DC, Utting JC, Orriss IR, Hoebertz A, Rosendaal M, Meghji S. Hypoxia is a major stimulator of osteoclast formation and bone resorption. J Cell Physiol, 2003, 196: 2-8

[22] Utting JC, Flanagan AM, Brandao-Burch A, Orriss IR, Arnett TR. Hypoxia stimulates osteoclast formation from human peripheral blood. Cell Biochem Funct, 2010, 28: 374-380

[23] Dandajena TC, Ihnat MA, Disch B, Thorpe J, Currier GF. Hypoxia triggers a HIF-mediated differentiation of peripheral blood mononuclear cells into osteoclasts. Orthod Craniofac Res, 2012, 15: 1-9

[24] Hadi HA, Smerdon GR, Fox SW . Hyperbaric oxygen therapy suppresses osteoclast formation and bone resorption. J Orthop Res. 2013 July 22. [Epub ahead of print]

[25] Utting JC, Robins SP, Brandao-Burch A, Orriss IR, Behar J, Arnett TR. Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts. Exp Cell Res, 2006, 312: 1693-1702

[26] Roche B, David V, Vanden-Bossche A, Peyrin F, Malaval L, Vico L, Lafage-Proust M-H. Structure and quantification of micro-vascularisation within mouse long bones: what and how should we measure? Bone, 2012, 50: 390-399

[27] Chow DC, Wenning LA, Miller WM, Papoutsakis ET. Modeling pO(2) distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys J, 2001, 81: 685-696

[28] Eliasson P, Jönsson JI. The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol, 2010, 222: 17-22

[29] Yang DC, Yang MH, Tsai CC, Huang TF, Chen YH, Hung SC. Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST. PloS One, 2011, 6: e23965

[30] Xu N, Liu H, Qu F, Fan J, Mao K, Yin Y, Liu J, Geng Z, Wang Y. Hypoxia inhibits the differentiation of mesenchymal stem cells into osteoblasts by activation of Notch signaling. Exp Mol Pathol, 2013, 94: 33-39

[31] Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res, 2001, 16: 1575-1582

[32] Eriksen EF, Eghbali-Fatourechi GZ, Khosla S. Remodeling and vascular spaces in bone. J Bone Miner Res, 2007, 22: 1-6

[33] Kristensen HB, Andersen TL, Marcussen N, Rolighed L, Delaisse JM. Increased presence of capillaries next to remodeling sites in adult human cancellous bone. J Bone Miner Res, 2013, 28: 574-585

[34] Maes C, Carmeliet G, Schipani E. Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol, 2012, 8: 358-366

[35] Brighton CT, Krebs AG. Oxygen tension of healing fractures in the rabbit. J Bone Joint Surg Am, 1972, 54: 323-332

[36] Aro H, Eerola E, Aho AJ, Niinikoski J. Tissue oxygen tension in externally stabilized tibial fractures in rabbits during normal healing and infection. J Surg Res, 1984, 37: 202-207

[37] Wang Y, Wan C, Deng L, Liu X, Cao X, Gilbert SR, Bouxsein ML, Faugere M-C, Guldberg RE, Gerstenfeld LC, Haase VH, Johnson RS, Schipani E, Clemens TL. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest, 2007, 117: 1616-1626

[38] Wang Y, Wan C, Gilbert SR, Clemens TL. Oxygen sensing and osteogenesis. Ann N Y Acad Sci, 2007, 1117: 1-11

[39] Wan C, Gilbert SR, Wang Y, Cao X, Shen X, Ramaswamy G, Jacobsen KA, Alaql ZS, Eberhardt AW, Gerstenfeld LC, Einhorn TA, Deng L, Clemens TL. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci U S A, 2008, 105: 686-691

[40] Chen D, Li Y, Zhou Z, Wu C, Xing Y, Zou X, Tian W, Zhang C. HIF-1a Inhibits Wnt Signaling Pathway by Activating Sost Expression in Osteoblasts. PloS One, 2013, 8: e65940

[41] Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI, Mackem S, Carmeliet G, Kronenberg HM. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell, 2010, 19: 329-344

[42] Muir P, Sample SJ, Barrett JG, McCarthy J, Vanderby R Jr., Markel MD, Prokuski LJ, Kalscheur VL. Effect of fatigue loading and associated matrix microdamage on bone blood flow and interstitial fluid flow. Bone, 2007, 40: 948-956

[43] Boerckel JD, Uhrig BA, Willett NJ, Huebsch N, Guldberg RE. Mechanical regulation of vascular growth and tissue regeneration in vivo. Proc Natl Acad Sci U S A, 2011, 108: E674-E680

[44] Chim SM, Tickner J, Chow ST, Kuek V, Guo B, Zhang G, Rosen V, Erber W, Xu J. Angiogenic factors in bone local environment. Cytokine Growth Factor Rev, 2013, 24: 297-310

[45] Gerber HP, Ferrara N. Angiogenesis and bone growth. Trends Cardiovasc Med, 2000, 10: 223-228

[46] Maes C, Goossens S, Bartunkova S, Drogat B, Coenegrachts L, Stockmans I, Moermans K, Nyabi O, Haigh K, Naessens M, Haenebalcke L, Tuckermann JP, Tjwa M, Carmeliet P, Mandic V, David J-P, Behrens A, Nagy A, Carmeliet G, Haigh JJ. Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones. EMBO J, 2010, 29: 424-441

[47] Gherghe CM, Duan J, Gong J, Rojas M, Klauber-Demore N, Majesky M, Deb A. Wnt1 is a proangiogenic molecule, enhances human endothelial progenitor function, and increases blood flow to ischemic limbs in a HGF-dependent manner. FASEB, 2011, 25: 1836-1843

[48] Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R, Ferrara N, Olsen BR. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest, 2012, 122: 3101-3113

[49] Riddle RC, Khatri R, Schipani E, Clemens TL. Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling. J Mol Med Berl Ger, 2009, 87: 583-590

[50] Prisby R, Guignandon A, Vanden-Bossche A, Mac-Way F, Linossier MT, Thomas M, Laroche N, Malaval L, Langer M, Peter ZA, Peyrin F, Vico L, Lafage-Proust MH. Intermittent PTH (1–84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites. J Bone Miner Res, 2011, 26: 2583-2596

[51] Prisby R, Menezes T, Campbell J. Vasodilation to PTH (1–84) in bone arteries is dependent upon the vascular endothelium and is mediated partially via VEGF signaling. Bone, 2013, 54: 68-75

[52] Alagiakrishnan K, Juby A, Hanley D, Tymchak W, Sclater A. Role of vascular factors in osteoporosis. J Gerontol A BiolSci Med Sci, 2003, 58: 362-366

[53] Dinenno FA, Jones PP, Seals DR, Tanaka H. Limb blood flow and vascular conductance are reduced with age in healthy humans: relation to elevations in sympathetic nerve activity and declines in oxygen demand. Circulation, 1999, 100: 164-170

[54] Dinenno FA, Tanaka H, Stauffer BL, Seals DR. Reductions in basal limb blood flow and vascular conductance with human ageing: role for augmented alpha-adrenergic vasoconstriction. J Physiol, 2001, 536: 977-983

[55] Griffith JF, Yeung DKW, Tsang PH, Choi KC, Kwok TCY, Ahuja AT, Leung KS, Leung PC. Compromised bone marrow perfusion in osteoporosis. J Bone Miner Res, 2008, 23: 1068-1075

[56] Bloomfield SA, Hogan HA, Delp MD. Decreases in bone blood flow and bone material properties in aging Fischer-344 rats. Clin Orthop Relat Res, 2002, 396: 248-257

[57] Prisby RD, Ramsey MW, Behnke BJ, Dominguez JM 2nd, Donato AJ, Allen MR, Delp MD. Aging reduces skeletal blood flow, endothelium-dependent vasodilation, and NO bioavailability in rats. J Bone Miner Res, 2007, 22: 1280-1288

[58] Griffith JF, Wang Y-XJ, Zhou H, Kwong WH, Wong WT, Sun Y-L, Huang Y, Yeung DKW, Qin L, Ahuja AT. Reduced bone perfusion in osteoporosis: likely causes in an ovariectomy rat model. Radiology, 2010, 254: 739-746

[59] London GM. Soft bone — hard arteries: a link? Kidney Blood Press Res, 2011, 34: 203-208

[60] De Schutter TM, Neven E, Persy VP, Behets GJ, Postnov AA, De Clerck NM, D'Haese PC. Vascular calcification is associated with cortical bone loss in chronic renal failure rats with and without ovariectomy: the calcification paradox. Am J Nephrol, 2011, 34: 356-366

[61] Thompson B, Towler DA. Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol, 2012, 8: 529-543

[62] Mizuno Y, Jacob RF, Mason RP. Advances in pharmacologic modulation of nitric oxide in hypertension. Curr Cardiol Rep, 2010, 12: 472-480

[63] Tsuda K, Nishio I, Masuyama Y. Bone mineral density in women with essential hypertension. Am J Hypertens, 2001, 14: 704-707

[64] Gotoh M, Mizuno K, Ono Y, Takahashi M. High blood pressure, bone-mineral loss and insulin resistance in women. Hypertens Res, 2005, 28: 565-570

[65] Giallauria F, Ling SM, Schreiber C, Maggio M, Shetty V, Muller D, Vigorito C, Ferrucci L, Najjar SS. Arterial stiffness and bone demineralization: the Baltimore longitudinal study of aging. Am J Hypertens, 2011, 24: 970-975

[66] Zhang Y-F, Wang Y-XJ, Griffith JF, Kwong WKM, Ma HT, Qin L, Kwok TCY. Proximal femur bone marrow blood perfusion indices are reduced in hypertensive rats: a dynamic contrast-enhanced MRI study. J Magn Reson Imaging, 2009, 30: 1139-1144

[67] Vestergaard P, Rejnmark L, Mosekilde L. Hypertension is a risk factor for fractures. Calcif Tissue Int, 2009, 84: 103-111

[68] Rejnmark L. Cardiovascular drugs and bone. Curr Drug Saf, 2008, 3: 178-184

[69] Wiens M, Etminan M, Gill SS, Takkouche B. Effects of antihypertensive drug treatments on fracture outcomes: a meta-analysis of observational studies. J Intern Med, 2006, 260: 350-362

[70] Reid IR. Effects of beta-blockers on fracture risk. J Musculoskelet Neuronal Interact, 2008, 8: 105-110

[71] Song HJ, Lee J, Kim Y-J, Jung S-Y, Kim HJ, Choi N-K, Park B-J. β1 selectivity of β-blockers and reduced risk of fractures in elderly hypertension patients. Bone, 2012, 51: 1008-1015

[72] Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res, 2007, 22: 1317-1328

[73] Oikawa A, Siragusa M, Quaini F, Mangialardi G, Katare RG, Caporali A, van Buul JD, van Alphen FPJ, Graiani G, Spinetti G, Kraenkel N, Prezioso L, Emanueli C, Madeddu P. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol, 2010, 30: 498-508

[74] Ohara T, Hirai T, Muro S, Haruna A, Terada K, Kinose D, Marumo S, Ogawa E, Hoshino Y, Niimi A, Chin K, Mishima M. Relationship between pulmonary emphysema and osteoporosis assessed by CT in patients with COPD. Chest, 2008, 134: 1244-1249

[75] Ferguson GT, Calverley PMA, Anderson JA, Jenkins CR, Jones PW, Willits LR, Yates JC, Vestbo J, Celli B. Prevalence and progression of osteoporosis in patients with COPD: results from the towards a revolution in COPD health study. Chest, 2009, 136: 1456-1465

[76] Regan E, Jaramillo J. It's the fracture that matters -bone disease in COPD patients. COPD, 2012, 9: 319-321

[77] Miller RG, Segal JB, Ashar BH, Leung S, Ahmed S, Siddique S, Rice T, Lanzkron S. High prevalence and correlates of low bone mineral density in young adults with sickle cell disease. Am J Hematol, 2006, 81: 236-241

[78] Toumba M, Skordis N. Osteoporosis syndrome in thalassaemia major: an overview. J Osteoporos, 2010, 2010: 537673

[79] Kanis JA, Johansson H, Oden A, McCloskey EV. Assessment of fracture risk. Eur J Radiol, 2009, 71: 392-397

[80] Yoon V, Maalouf NM, Sakhaee K. The effects of smoking on bone metabolism. Osteoporos Int, 2012, 23: 2081-2092

[81] Spier SA, Delp MD, Meininger CJ, Donato AJ, Ramsey MW, Muller-Delp JM. Effects of ageing and exercise training on endothelium-dependent vasodilatation and structure of rat skeletal muscle arterioles. J Physiol, 2004, 556: 947-958

[82] Dominguez JM 2nd, Prisby RD, Muller-Delp JM, Allen MR, Delp MD. Increased nitric oxide-mediated vasodilation of bone resistance arteries is associated with increased trabecular bone volume after endurance training in rats. Bone, 2010, 46: 813-819

[83] Yao Z, Lafage-Proust M-H, Plouët J, Bloomfield S, Alexandre C, Vico L. Increase of both angiogenesis and bone mass in response to exercise depends on VEGF. J Bone Miner Res, 2004, 19: 1471-1480

[84] Leblanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM. Bone mineral loss and recovery after 17 weeks of bed rest. J Bone Miner Res, 1990, 5: 843-850

[85] Colleran PN, Wilkerson MK, Bloomfield SA, Suva LJ, Turner RT, Delp MD. Alterations in skeletal perfusion with simulated microgravity: a possible mechanism for bone remodeling. J Appl Physiol, 2000, 89: 1046-1054

[86] Ding WG, Yan WH, Wei ZX, Liu JB. Difference in intraosseous blood vessel volume and number in osteoporotic model mice induced by spinal cord injury and sciatic nerve resection. J Bone Miner Metab, 2012, 30: 400-407

[87] Tu X, Rhee Y, Condon KW, Bivi N, Allen MR, Dwyer D, Stolina M, Turner CH, Robling AG, Plotkin LI, Bellido T. Sost down-regulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone, 2012, 50: 209-217

[88] Kwon RY, Meays DR, Meilan AS, Jones J, Miramontes R, Kardos N, Yeh JC, Frangos JA. Skeletal adaptation to intramedullary pressure-induced interstitial fluid flow is enhanced in mice subjected to targeted osteocyte ablation. PloS One, 2012, 7: e33336

[89] Qin YX, Kaplan T, Saldanha A, Rubin C. Fluid pressure gradients, arising from oscillations in intramedullary pressure, is correlated with the formation of bone and inhibition of intracortical porosity. J Biomech, 2003, 36: 1427-1437

[90] Kwon RY, Meays DR, Tang WJ, Frangos JA. Microfluidic enhancement of intramedullary pressure increases interstitial fluid flow and inhibits bone loss in hindlimb suspended mice. J Bone Miner Res, 2010, 25: 1798-1807

[91] Qin YX, Lam H, Ferreri S, Rubin C. Dynamic skeletal muscle stimulation and its potential in bone adaptation. J Musculoskelet Neuronal Interact, 2010, 10: 12-24

[92] Bergula AP, Huang W, Frangos JA. Femoral vein ligation increases bone mass in the hindlimb suspended rat. Bone, 1999, 24: 171-177

[93] Bergula AP, Haidekker MA, Huang W, Stevens HY, Frangos JA. Venous ligation-mediated bone adaptation is NOS 3 dependent. Bone, 2004, 34: 562-569

[94] Kelly PJ, Bronk JT. Venous pressure and bone formation. Microvasc Res, 1990, 39: 364-375

[95] Zorbas YG, Federenko YF, Naexu KA. Effect of hyperhydration on bone mineralization in physically healthy subjects after prolonged restriction of motor activity. Acta Astronaut, 1991, 25: 727-731

[96] Schneider V, Oganov V, LeBlanc A, Rakmonov A, Taggart L, Bakulin A, Huntoon C, Grigoriev A, Varonin L. Bone and body mass changes during space flight. Acta Astronaut, 1995, 36: 463-466

[97] Hanley DA, Brown JP, Tenenhouse A, Olszynski WP, Ioannidis G, Berger C, Prior JC, Pickard L, Murray TM, Anastassiades T, Kirkland S, Joyce C, Joseph L, Papaioannou A, Jackson SA, Poliquin S, Adachi JD. Associations among disease conditions, bone mineral density, and prevalent vertebral deformities in men and women 50 years of age and older: cross-sectional results from the Canadian Multicentre Osteoporosis Study. J Bone Miner Res, 2003, 18: 784-790

[98] Fritton SP, Weinbaum S. Fluid and Solute Transport in Bone: Flow-Induced Mechanotransduction. Annu Rev Fluid Mech, 2009, 41: 347-374

[99] Gurkan UA, Akkus O. The mechanical environment of bone marrow: a review. Ann Biomed Eng, 2008, 36: 1978-1991

[100] Wang L, Fritton SP, Weinbaum S, Cowin SC. On bone adaptation due to venous stasis. J Biomech, 2003, 36: 1439-1451

[101] Li W, Gardinier JD, Price C, Wang L. Does blood pressure enhance solute transport in the bone lacunar-canalicular system? Bone, 2010, 47: 353-359

[102] Caulkins C, Ebramzadeh E, Winet H. Skeletal muscle contractions uncoupled from gravitational loading directly increase cortical bone blood flow rates in vivo. J Orthop Res, 2009, 27: 651-656

[103] Winet H. A bone fluid flow hypothesis for muscle pump-driven capillary filtration: II. Proposed role for exercise in erodible scaffold implant incorporation. Eur Cell Mater, 2003, 6: 1-10

[104] Brinker MR, Lippton HL, Cook SD, Hyman AL. Pharmacological regulation of the circulation of bone. J Bone Joint Surg Am, 1990, 72: 964-975

[105] Tran MA. Effect of dopamine and apomorphine on bone circulation. J Pharmacol, 1981, 12: 417-426

[106] Tran MA, Géral JP. The influence of some vasoactive drugs on bone circulation. Eur J Pharmacol, 1978, 52: 109-114

[107] Dean MT, Wood MB, Vanhoutte PM. Antagonist drugs and bone vascular smooth muscle. J Orthop Res, 1992, 10: 104-111

[108] Li H, Förstermann U. Nitric oxide in the pathogenesis of vascular disease. J Pathol, 2000, 190: 244-254

[109] Fitzgerald SM, Bashari H, Cox JA, Parkington HC, Evans RG. Contributions of endothelium-derived relaxing factors to control of hindlimb blood flow in the mouse in vivo. Am J Physiol Heart Circ Physiol, 2007, 293: H1072-H1082

[110] Wimalawansa SJ, De Marco G, Gangula P, Yallampalli C. Nitric oxide donor alleviates ovariectomy-induced bone loss. Bone, 1996, 18: 301-304

[111] Wimalawansa SJ. Rationale for using nitric oxide donor therapy for prevention of bone loss and treatment of osteoporosis in humans. Ann N Y Acad Sci, 2007, 1117: 283-297

[112] Jamal SA, Hamilton CJ, Eastell R, Cummings SR. Effect of nitroglycerin ointment on bone density and strength in post-menopausal women: a randomized trial. JAMA, 2011, 305: 800-807

[113] Jamal SA, Browner WS, Bauer DC, Cummings SR. Intermittent use of nitrates increases bone mineral density: the study of osteoporotic fractures. J Bone Miner Res, 1998, 13: 1755-1759

[114] Jamal SA, Hamilton CJ, Black D, Cummings SR. The effects of organic nitrates on osteoporosis: a randomized controlled trial [ISRCTN94484747]. Trials, 2006, 7: 10

[115] Jamal SA, Cummings SR, Hawker GA. Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial. J Bone Miner Res, 2004, 19: 1512-1517

[116] Khosla S. Is nitroglycerin a novel and inexpensive treatment for osteoporosis? JAMA, 2011, 305: 826-827

[117] Jamal SA, Reid LS, Hamilton CJ. The effects of organic nitrates on osteoporosis: a systematic review. Osteoporos Int, 2013, 24: 763-770

[118] Van't Hof RJ, Ralston SH. Nitric oxide and bone. Immunology, 2001, 103: 255-261

[119] Bakker AD, Huesa C, Hughes A, Aspden RM, van't Hof RJ, Klein-Nulend J, Helfrich MH. Endothelial nitric oxide synthase is not essential for nitric oxide production by osteoblasts subjected to fluid shear stress in vitro. Calcif Tissue Int, 2013, 92: 228-239

[120] Chow JW, Fox SW, Lean JM, Chambers TJ. Role of nitric oxide and prostaglandins in mechanically induced bone formation. J Bone Miner Res, 1998, 13: 1039-1044

[121] Das-Gupta V, Williamson RA, Pitsillides AA. Expression of endothelial nitric oxide synthase protein is not necessary for mechanical strain-induced nitric oxide production by cultured osteoblasts. Osteoporos Int, 2012, 23: 2635-2647

[122] Pérez-Castrillón JL, De Luis DA, Duenas-Laita A. Are beta-blockers useful in the prevention of osteoporotic fractures? Eur Rev Med Pharmacol Sci, 2009, 13: 157-162

[123] Histing T, Marciniak K, Scheuer C, Garcia P, Holstein JH, Klein M, Matthys R, Pohlemann T, Menger MD. Sildenafil accelerates fracture healing in mice. J Orthop Res, 2011, 29: 867-873

[124] Gulhan I, Kebapcilar L, Alacacioglu A, Bilgili S, Kume T, Aytac B, Gunaydin R. Postmenopausal women with osteoporosis may be associated with high endothelin-1. Gynecol Endocrinol, 2009, 25: 674-678

[125] Mestek ML, Weil BR, Greiner JJ, Westby CM, DeSouza CA, Stauffer BL. Osteopenia and endothelin-1-mediated vascons-trictor tone in postmenopausal women. Bone, 2010, 47: 542-545

[126] Zheng LW, Ma L, Cheung LK. Changes in blood perfusion and bone healing induced by nicotine during distraction osteogenesis. Bone, 2008, 43: 355-361

[127] Ma L, Zheng LW, Sham MH, Cheung LK. Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing. J Bone Miner Res, 2010, 25: 1305-1313

[128] Wang HH, Drugge ED, Yen YC, Blumenthal MR, Pang PK. Effects of synthetic parathyroid hormone on hemodynamics and regional blood flows. Eur J Pharmacol, 1984, 97: 209-215

[129] Boushel R, Langberg H, Risum N, Kjaer M. Regulation of blood flow by prostaglandins. Curr Vasc Pharmacol, 2004, 2: 191-197

[130] Roche B, van den Bossche A, Normand M, Malaval L, Vico L, Lafage-Proust MH. Validated doppler measurement of mouse bone blood perfusion-response to age or ovariectomy differs with genetic background. Bone, 2013, 55: 418-426

[131] Moraes AN, Gouvêa SA, Gonçalves WLS, Romero WG, Moyses MR, Bissoli NS, Pires JGP, Abreu GR. Raloxifene reduces blood pressure in hypertensive animals after ovarian hormone deprivation. Basic Clin Pharmacol Toxicol, 2011, 109: 334-338

[132] Weinstein RS, Wan C, Liu Q, Wang Y, Almeida M, O'Brien CA, Thostenson J, Roberson PK, Boskey AL, Clemens TL. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell, 2010, 9: 147-161

[133] Weinstein RS. Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab Clin North Am, 2012, 41: 595-611

[134] Collip JB, Clark EP. Further studies on the physiological action of parathyroid hormone. J Biol Chem, 1925, 64: 485-507

[135] Charbon GA. A rapid and selective vasodialtor effect of parathyroid hormone. Eur J Pharmacol, 1968, 3: 275-278

[136] Mok LL, Nickols GA, Thompson JC, Cooper CW. Parathyroid hormone as a smooth muscle relaxant. Endocr Rev, 1989, 10: 420-436

[137] Qian J, Lorenz JN, Maeda S, Sutliff RL, Weber C, Nakayama T, Colbert MC, Paul RJ, Fagin JA, Clemens TL. Reduced blood pressure and increased sensitivity of the vasculature to parathyroid hormone-related protein (PTHrP) in transgenic mice overexpressing the PTH/PTHrP receptor in vascular smooth muscle. Endocrinology, 1999, 140: 1826-1833

[138] Yang R, Thomas GR, Bunting S, Ko A, Ferrara N, Keyt B, Ross J, Jin H. Effects of vascular endothelial growth factor on hemo-dynamics and cardiac performance. J Cardiovasc Pharmacol, 1996, 27: 838-844

[139] Gohin S, Chenu C, Pitsillides A, Arnett T, Marenzana M . Inhibition of PTH-induced vasorelaxation modulates its anabolic action. Presented at the European Calcified Tissue Society Conference ECTS 2013, Lisbon, Portugal. Bone Abstr. 2013;1: OC6.4.

[140] Jee WS, Ma YF. The in vivo anabolic actions of prostaglandins in bone. Bone, 1997, 21: 297-304

[141] Vescini F, Grimaldi F. PTH 1–84: bone rebuilding as a target for the therapy of severe osteoporosis. Clin Cases Miner Bone Metab, 2012, 9: 31-36

[142] Poole KES, Reeve J. Parathyroid hormone-a bone anabolic and catabolic agent. Curr Opin Pharmacol, 2005, 5: 612-617

[143] Robling AG, Kedlaya R, Ellis SN, Childress PJ, Bidwell JP, Bellido T, Turner CH. Anabolic and catabolic regimens of human parathyroid hormone 1–34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology, 2011, 152: 2963-2975

[144] Tian XY, Zhang Q, Zhao R, Setterberg RB, Zeng QQ, Iturria SJ, Ma YF, Jee WSS. Continuous PGE₂ leads to net bone loss while intermittent PGE₂ leads to net bone gain in lumbar vertebral bodies of adult female rats. Bone, 2008, 42: 914-920

[145] Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med, 1999, 340: 1801-1811

[146] White RE. Estrogen and vascular function. Vascul Pharmacol, 2002, 38: 73-80

[147] Mekraldi S, Lafage-Proust M-H, Bloomfield S, Alexandre C, Vico L. Changes in vasoactive factors associated with altered vessel morphology in the tibial metaphysis during ovariectomy-induced bone loss in rats. Bone, 2003, 32: 630-641

[148] Prisby RD, Dominguez JM 2nd, Muller-Delp J, Allen MR, Delp MD. Aging and estrogen status: a possible endothelium-dependent vascular coupling mechanism in bone remodeling. PloS One, 2012, 7: e48564

[149] Ruifrok WP, De Boer RA, Iwakura A, Silver M, Kusano K, Tio RA, Losordo DW. Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia. Vasc Med, 2009, 14: 29-36

[150] Chan YC, Leung FP, Wong WT, Tian XY, Yung LM, Lau CW, Tsang SY, Yao X, Chen ZY, Huang Y. Therapeutically relevant concentrations of raloxifene dilate pressurized rat resistance arteries via calcium-dependent endothelial nitric oxide synthase activation. Arterioscler Thromb Vasc Biol, 2010, 30: 992-999