Lipid metabolism disorders and bone dysfunction - interrelated and mutually regulated (Review)

Tian,Li; Yu,Xijie

doi:10.3892/mmr.2015.3472

Lipid metabolism disorders and bone dysfunction - interrelated and mutually regulated (Review)

Authors:
- Li Tian
- Xijie Yu
View Affiliations

Affiliations: Laboratory of Endocrinology and Metabolism, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: March 11, 2015 https://doi.org/10.3892/mmr.2015.3472
Pages: 783-794
Copyright: © Tian et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The association between lipid and bone metabolism has become an increasing focus of interest in recent years, and accumulating evidence has shown that atherosclerosis (AS) and osteoporosis (OP), a disorder of bone metabolism, frequently co‑exist. Fat and bone are known to share a common progenitor cell: Multipotent mesenchymal stem cells (MSC) in the bone marrow (BM), which are able to differentiate into various cell phenotypes, including osteoblasts, adipocytes and chondrocytes. Laboratory‑based and clinical trials have shown that increasing adipocytes are accompanied by a decrease in bone mineral density (BMD) and bone mass. Statins, lipid‑lowering drugs used to treat hyperlipidemia, also provide benefit in the treatment of OP. There is thus evidence that the metabolism of lipids is correlated with that of bone, and that the two are mutually regulated. The present review primarily focuses on the potential association between lipid metabolism disturbance and OP, based on biological metabolism, pathophysiological processes, results from clinical and experimental animal studies, processes involved in the differentiation of adipocytes and osteoblasts, as well as pharmacological treatments of these diseases.

View Figures

View References

1	Bagger YZ, Tankó LB, Alexandersen P, Qin G and Christiansen C: Prospective epidemiological risk factors study group: radiographic measure of aorta calcification is a site-specific predictor of bone loss and fracture risk at the hip. J Intern Med. 259:598–605. 2006. View Article : Google Scholar : PubMed/NCBI
2	Sinnott B, Syed I, Sevrukov A and Barengolts E: Coronary calcification and osteoporosis in men and postmenopausal females are independent processes associated with aging. Calcif Tissue Int. 78:195–202. 2006. View Article : Google Scholar : PubMed/NCBI
3	Yao W, Cheng Z, Busse C, Pham A, Nakamura MC and Lane NE: Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis and Rheum. 58:1674–1686. 2008. View Article : Google Scholar
4	Edwards CJ, Hart DJ and Spector TD: Oral statins and increased bone-mineral density in postmenopausal females. Lancet. 355:2218–2219. 2000. View Article : Google Scholar : PubMed/NCBI
5	Barengolts EI, Berman M, Kukreja SC, Kouznetsova T, Lin C and Chomka EV: Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal females. Calcif Tissue Int. 62:209–213. 1998. View Article : Google Scholar : PubMed/NCBI
6	Consensus development conference: diagnosis, prophylaxis and, treatment of osteoporosis. Am J Med. 94:646–650. 1993. View Article : Google Scholar
7	Bonjour JP, Ammann P and Rizzoli R: Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998. WHO guielelines. 9:379–393. 1999.
8	Mundy G, Garrett R, Harris S, et al: Stimulation of bone formation in vitro and in rodents by statins. Science. 286:1946–1949. 1999. View Article : Google Scholar : PubMed/NCBI
9	Yamaguchi T, Sugimoto T, Yano S, Yamauchi M, Sowa H, Chen Q and Chihara K: Plasma lipids and osteoporosis in postmenopausal females. Endocr J. 49:211–217. 2002. View Article : Google Scholar : PubMed/NCBI
10	Orozco P: Atherogenic lipid profile and elevated lipoprotein (a) are associated with lower bone mineral density in early postmenopausal overweight females. Eur J Epidemiol. 19:1105–1112. 2004. View Article : Google Scholar
11	Dennison EM, Syddall HE, Aihie Sayer A, Martin HJ and Cooper C: Lipid profile, obesity and bone mineral density: the Hertfordshire Cohort Study. QJM. 100:297–303. 2007. View Article : Google Scholar : PubMed/NCBI
12	Broulik PD and Kapitola J: Interrelations between body weight, cigarette smoking and spine bone mineral density in osteoporotic Czech females. Endocr Regul. 27:57–60. 1993.PubMed/NCBI
13	Tang YJ, Sheu WH, Liu PH, Lee WJ and Chen YT: Positive associations of bone mineral density with body mass index, physical activity and blood triglyceride level in men over 70 years old: a TCVGHAGE study. J Bone Miner Metab. 25:54–59. 2007. View Article : Google Scholar
14	Sivas F, Alemdaroǧlu E, Elverici E, Kuluǧ and Ozoran K: Serum lipid profile: its relationship with osteoporotic vertebrae fractures and bone mineral density in Turkish postmenopausal females. Rheumatol Int. 29:885–890. 2009. View Article : Google Scholar
15	Szulc P, Varennes A, Delmas PD, Goudable J and Chapurlat R: Men with metabolic syndrome have lower bone mineral density but lower fracture risk-the MINOS study. J Bone Miner Res. 25:1446–1454. 2010. View Article : Google Scholar : PubMed/NCBI
16	Samelson EJ, Cupples LA, Hannan MT, et al: Long-term effects of serum cholesterol on bone mineral density in females and men: the Framingham Osteoporosis Study. Bone. 34:557–561. 2004. View Article : Google Scholar : PubMed/NCBI
17	Tankó LB, Bagger YZ, Nielsen SB and Christiansen C: Does serum cholesterol contribute to vertebral bone loss in postmenopausal females? Bone. 32:8–14. 2003. View Article : Google Scholar
18	Hsu YH, Venners SA, Terwedow HA, et al: Relation of body composition, fat mass and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and females. Am J Clin Nutr. 83:146–154. 2006.PubMed/NCBI
19	Czerny B, Pawlik A, Juzyszyn Z and Myśliwiec Z: Effect of tamoxifen on bone mineral density and blood lipids in ovariectomized rats. Pol J pharmacol. 55:1137–1142. 2003.
20	Liu KJ, Wang WJ, Li DJ, Jin HF and Zhou WJ: Effect of Gengnianchun Recipe on bone mineral density, bone biomechanical parameters and serum lipid level in ovariectomized rats. Chin J Integr Med. 12:132–136. 2006. View Article : Google Scholar : PubMed/NCBI
21	Parhami F, Tintut Y, Beamer WG, Gharavi N, Goodman W and Demer LL: Atherogenic high-fat diet reduces bone mineralization in mice. J Bone Miner Res. 16:182–188. 2001. View Article : Google Scholar : PubMed/NCBI
22	Pelton K, Krieder J, Joiner D, Freeman MR, Goldstein SA and Solomon KR: Hypercholesterolemia promotes an osteoporotic phenotype. Am J Pathol. 181:928–936. 2012. View Article : Google Scholar : PubMed/NCBI
23	Parhami F, Mody N, Gharavi N, Ballard AJ, Tintut Y and Demer LL: Role of cholesterol biosynthetic pathway in osteoblastic differentiation of marrow stromal cells. J Miner Res. 17:1997–2003. 2002. View Article : Google Scholar
24	Xu S and Yu JJ: Beneath the minerals, a layer of round lipid particles was identified to mediate collagen calcification in compact bone formation. Biophys J. 91:4221–4229. 2006. View Article : Google Scholar : PubMed/NCBI
25	Wang Y, Tao Y, Hyman ME, Li J and Chen Y: Osteoporosis in China. Osteoporosis Int. 20:1651–1662. 2009. View Article : Google Scholar
26	Gimble JM, Robinson CE, Wu X, et al: Peroxisome proliferator-activated receptorgamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol Pharmacol. 50:1087–1094. 1996.PubMed/NCBI
27	Lecka-Czernik B, Moerman EJ, Grant DF, Lehman JM, Manolagas SC and Jilka RL: Divergent effects of selective peroxisome proliferators-activated receptor-gamma2 ligands on adipocyte versus osteoblast differentiation. Endocrinology. 143:2376–2384. 2002.PubMed/NCBI
28	Huang JT, Welch JS, Ricote M, et al: Interleukin-4-dependent production of PPAR gamma ligands in macrophages by 12/15-lipoxygenase. Nature. 400:378–382. 1999. View Article : Google Scholar : PubMed/NCBI
29	Kirkland JL, Tchkonia T, Pirtskhalava T, Han J and Karagiannides I: Adipogenesis and aging: does aging make fat go MAD? Exp Gerontol. 37:757–767. 2002. View Article : Google Scholar : PubMed/NCBI
30	Simonet WS, Lacey DL, Dunstan CR, et al: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 89:309–319. 1997. View Article : Google Scholar : PubMed/NCBI
31	Schoppet M, Preissner KT and Hofbauer LC: RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascularfunction. Arterioscler Thromb Vasc Biol. 22:549–553. 2002. View Article : Google Scholar : PubMed/NCBI
32	Jabbar S, Drury J, Fordham JN, Datta HK, Francis RM and Tuck SP: Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis. J Clin Pathol. 64:354–357. 2011. View Article : Google Scholar : PubMed/NCBI
33	Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT and Dunstan CR: The effect of a single dose of osteoprotegerin in postmenopausal females. J Bone Miner Res. 16:348–360. 2001. View Article : Google Scholar : PubMed/NCBI
34	Mezquita-Raya P, de la Hiquera M, García DF, et al: The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal females. Osteoporos Int. 16:1368–1374. 2005. View Article : Google Scholar : PubMed/NCBI
35	Indridason OS, Franzson L and Sigurdsson G: Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover. Osteoporos Int. 16:417–423. 2005. View Article : Google Scholar : PubMed/NCBI
36	Cummings SR, Martin JS, McClung MR, et al: Denosumab for prevention of fractures in postmenopausal females with osteoporosis. N Engl J Med. 361:756–765. 2009. View Article : Google Scholar : PubMed/NCBI
37	Qiu W, Andersen TE, Bollerslev J, Mandrup S, Abdallah BM and Kassem M: Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells. J Bone and Mineral Res. 22:1720–1731. 2007. View Article : Google Scholar
38	Abdallah BM and Kassem M: New factors controlling the balance between osteoblastogenesis and adipogenesis. Bone. 50:540–545. 2012. View Article : Google Scholar
39	Tamai K, Semenov M, Kato Y, et al: LDL-receptor related proteins in Wnt signal transduction. Nature. 407:530–535. 2000. View Article : Google Scholar : PubMed/NCBI
40	Bienz M: TCF: transcriptional activator or repressor? Curr Opin Cell Biol. 10:366–372. 1998. View Article : Google Scholar : PubMed/NCBI
41	Taipaleenmäki H, Abdallah BM, AlDahmash A, Säämänen AM and Kassem M: Wnt signaling mediates the cross-talk between bone marrow derived pre-adipocytic and pre-osteoblastic cell populations. Exp Cell Res. 317:745–756. 2011. View Article : Google Scholar
42	Kang S, Bennett CN, Gerin I, Rapp LA, Hankenson KD and Macdougald OA: Wnt signaling stimulates osteolastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferators-activated receptor gamma. J Biol Chem. 282:14515–14524. 2007. View Article : Google Scholar : PubMed/NCBI
43	Jones SE and Jomary C: Secreted frizzled-related proteins: searching for relationships and patterns. Bioessays. 24:811–820. 2002. View Article : Google Scholar : PubMed/NCBI
44	Gaur T, Rich L, Lengner CJ, et al: Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation. J Cell Physiol. 208:87–96. 2006. View Article : Google Scholar : PubMed/NCBI
45	Yao W, Cheng Z, Shahnazari M, Dai W, Johnson ML and Lane NE: Overexpression of secreted frizzled-related protein 1 inhibits bone formation and attenuates parathyroid hormone bone anabolic effects. J Bone Miner Res. 25:190–199. 2010. View Article : Google Scholar
46	Lagathu C, Christodoulides C, Tan CY, et al: Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity. Int J Obes. 34:1695–1705. 2010. View Article : Google Scholar
47	Denver RJ, Bonett RM and Boorse GC: Evolution of leptin structure and function. Neuroendocrinology. 94:21–38. 2011. View Article : Google Scholar : PubMed/NCBI
48	Thomas T: The complex effects of leptin on bone metabolism through multiple pathways. Curr Opin Pharmacol. 4:295–300. 2004. View Article : Google Scholar : PubMed/NCBI
49	Turner RT, Kalra SP, Wong CP, Philbrick KA, Lindenmaier LB, Boghossian S and Iwaniec UT: Peripheral leptin regulates bone formation. J Bone Mineral Res. 28:22–34. 2013. View Article : Google Scholar
50	Cornish J, Callon KE, Bava U, et al: Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J Endocrinol. 175:405–415. 2002. View Article : Google Scholar : PubMed/NCBI
51	Hamrick MW, Pennington C, Newton D, Xie D and Isales C: Leptin deficiency produces contrasting phenotypes in bones of the limb and spine. Bone. 34:376–383. 2004. View Article : Google Scholar : PubMed/NCBI
52	Iwaniec UT, Boghossian S, Lapke PD, Turner RT and Kalra SP: Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice. Peptides. 28:1012–1019. 2007. View Article : Google Scholar : PubMed/NCBI
53	Kalra SP, Dube MG and Iwaniec UT: Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides. 30:967–973. 2009. View Article : Google Scholar : PubMed/NCBI
54	Bartell SM, Rayalam S, Ambati S, et al: Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice. J Bone Miner Res. 26:1710–1720. 2011. View Article : Google Scholar : PubMed/NCBI
55	Ducy P, Amling M, Takeda S, et al: Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 100:197–207. 2000. View Article : Google Scholar : PubMed/NCBI
56	Holloway WR, Collier FM, Aitken CJ, et al: Leptin inhibits osteoclast generation. J Bone Miner Res. 17:200–209. 2002. View Article : Google Scholar : PubMed/NCBI
57	Thomas T, Gori F, Khosla S, Jensen MD, Burguera B and Riggs BL: Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology. 140:1630–1638. 1999.PubMed/NCBI
58	Kim GS, Hong JS, Kim SW, Koh JM, An CS, Choi JY and Cheng SL: Leptin induces apoptosis via ERK/cPLA2/cytochrome pathway in human bone marrow stromal cells. J Biol Chem. 278:21920–21929. 2003. View Article : Google Scholar : PubMed/NCBI
59	Hamrick MW and Ferrari SL: Leptin and the sympathetic connection of fat to bone. Osteoporos Int. 19:905–912. 2008. View Article : Google Scholar
60	Hamrick MW, Della-Fera MA, Hartzell D, Pennington C and Baile CA: Intrahypothalamic injections of leptin increase adipocyte apoptosis in peripheral fat pad and in bone marrow. Cell Tissue Res. 327:133–141. 2007. View Article : Google Scholar
61	Idelevich A, Sato K and Baron R: What are the effects of leptin on bone and where are they exerted? J Bone Miner Res. 28:18–21. 2013. View Article : Google Scholar
62	Farooqi IS, Jebb SA, Langmack G, et al: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 341:879–884. 1999. View Article : Google Scholar : PubMed/NCBI
63	Paz-Filho G, Mastronardi C, Delibasi T, Wong ML and Licinio J: Congenital leptin deficiency: diagnosis and effects of leption replacement therapy. Arq Bras Endocrinol Metab. 54:690–697. 2010. View Article : Google Scholar
64	Arita Y, Kihara S, Ouchi N, et al: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 257:79–83. 1999. View Article : Google Scholar : PubMed/NCBI
65	Kumada M, Kihara S, Dumitsuji S, et al: Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol. 23:85–89. 2003. View Article : Google Scholar : PubMed/NCBI
66	Hara K, Horikoshi M, Yamauchi T, et al: Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care. 29:1357–1362. 2006. View Article : Google Scholar : PubMed/NCBI
67	Oshima K, Nampei A, Matsuda M, et al: Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. Biochem Biophys Res Commun. 331:520–526. 2005. View Article : Google Scholar : PubMed/NCBI
68	Yamaguchi N, Kukita T, Li YJ, Marinez Argueta JG, Saito T, Hanazawa S and Yamashita Y: Adiponectin inhibits osteoclast formation stimulated by lipoplysaccharide from Actinobacillus actinomycetemcomitans. FEMS Immunol Med Microbiol. 49:28–34. 2007. View Article : Google Scholar
69	Kajimura D, Lee WH, Riley JK, et al: Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 17:901–915. 2013. View Article : Google Scholar : PubMed/NCBI
70	Luo XH, Guo LJ, Xie H, Yuan LQ, Wu XP, Zhou HD and Liao EY: Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway. J Bone Miner Res. 21:1648–1656. 2006. View Article : Google Scholar : PubMed/NCBI
71	Tu QS, Zhang J, Dong LQ, Saunders E, Luo E, Tang J and Chen J: Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. J Bio Chem. 286:12542–12553. 2011. View Article : Google Scholar
72	Yamaguchi N, Kukita T, Li YJ, et al: Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling. FEBS Letters. 582:451–456. 2008. View Article : Google Scholar : PubMed/NCBI
73	Luo XH, Guo LJ, Yuan LQ, Xie H, Zhou HD, Wu XP and Liao EY: Adiponectin stimulates human osteobalsts proliferation and differentiation via the MAPK signaling pathway. Exp Cell Res. 309:99–109. 2005. View Article : Google Scholar : PubMed/NCBI
74	Lee HW, Kim SY, Kim AY, Lee EJ, Choi JY and Kim JB: Adiponection stimulates osteoblast differentiation through induction of COX2 in mesenchymal progenitor cells. Stem Cells. 27:2254–2262. 2009. View Article : Google Scholar : PubMed/NCBI
75	Mitsui Y, Gotoh M, Fukushima N, et al: Hyperadiponectinemia enhances bone formation in mice. BMC Musculoskelet Disord. 12:182011. View Article : Google Scholar : PubMed/NCBI
76	Ealey KN, Kaludjerovic J, Archer M and Ward WE: Adiponectin is a negative regulator of bone mineral and bone strength in growing mice. Exp Biol Med (Maywood). 233:1546–1553. 2008. View Article : Google Scholar
77	Hotta K, Funahashi T, Bodkin NL, et al: Circulating concentrations of the adipocyte protein adiponetin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes. 50:1126–1133. 2001. View Article : Google Scholar : PubMed/NCBI
78	Bauche IB, E1 Mkadem SA, Pottier AM, et al: Overexpression of adiponectin targeted to adipose tissue in transgenic mice: impaired adipocyte differentiation. Endocrinology. 148:1539–1549. 2007. View Article : Google Scholar : PubMed/NCBI
79	Otabe S, Yuan X, Fukutani T, et al: Overexpression of human adiponectin in transgenic mice results in suppression of fat accumulation and prevention of premature death by high-calorie diet. Am J Physiol Endocrinol Metab. 293:E210–E218. 2007. View Article : Google Scholar : PubMed/NCBI
80	Williams GA, Wang Y, Callon KE, et al: In vitro and in vivo effects of adiponectin on bone. Endocrinology. 150:3603–3610. 2009. View Article : Google Scholar : PubMed/NCBI
81	Yano W, Kubota N, Itoh S, et al: Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice. Endocr J. 55:515–522. 2008. View Article : Google Scholar : PubMed/NCBI
82	Nawrocki AR, Rajala MW, Tomas E, et al: Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem. 281:2654–2660. 2006. View Article : Google Scholar
83	Kubota N, Terauchi Y, Yamauchi T, et al: Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. 277:25863–25866. 2002. View Article : Google Scholar : PubMed/NCBI
84	Maeda N, Shimomura I, Kishida K, et al: Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med. 8:731–737. 2002. View Article : Google Scholar : PubMed/NCBI
85	Kanazawa I: Does adiponectin have adverse effects on bone mass and fracture. Internal Med. View Article : Google Scholar : 2011.
86	Mohiti-Ardekani J, Soleymani-Salehabadi H, Owlia MB and Mohiti A: Relationships between serum adipocyte hormones (adiponectin, leptin, resistin), bone mineral density and bone metabolic markers in osteoporosis patients. J Bone Miner Metab. 32:400–404. 2013. View Article : Google Scholar : PubMed/NCBI
87	Wu N, Wang QP, Li H, Wu XP, Sun ZQ and Luo XH: Relationships between serum adiponectin, leptin concentrations and bone mineral density and bone biochemical markers in Chinese females. Clin Chim Acta. 411:771–775. 2010. View Article : Google Scholar : PubMed/NCBI
88	Tenta R, Kontogianni MD and Yiannakouris N: Association between circulating levels of adiponectin and indices of bone mass and bone metabolism in middle-aged post-menopausal females. J Endocrinol Invest. 35:306–311. 2012.
89	Schwartz AV, Sigurdsson S, Hue TF, et al: Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults. J Clin Endocrinol Metab. 98:2294–2300. 2013. View Article : Google Scholar : PubMed/NCBI
90	Widlansky ME, Gokce N, Keaney JF and Vita JA: The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 42:1149–1160. 2003. View Article : Google Scholar : PubMed/NCBI
91	Wang GJ, Maga DB, Richemer WG, Sweet DE, Reger SI and Thompson RC: Cortisone induced bone changes and its response to lipid clearing agents. Clin Orthop. 130:81–85. 1978.PubMed/NCBI
92	Miyanishi K, Yamamoto T, Irisa T, Yamashita A, Jingushi S, Noguchi Y and Iwamoto Y: Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis. Bone. 30:185–190. 2002. View Article : Google Scholar : PubMed/NCBI
93	Zhou Q, Li Q, Yang L and Liu F: Changes of blood vessels in glucocorticoid-induced avascular necrosis of femoral head in rabbits. Zhonghua Wai Ke Za Zhi. 38:212–215. 2000.In Chinese.
94	Kitajima M, Shigematsu I, Ogawa K, Sugihara H and Hotokebuchi T: Effects of glucocorticoid on adipocyte size in human bone marrow. Med Mol Morphol. 40:150–156. 2007. View Article : Google Scholar : PubMed/NCBI
95	Kerachian MA, Séguin C and Harvey EJ: Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action. J Steroid Biochem Mol Biol. 114:121–128. 2009. View Article : Google Scholar : PubMed/NCBI
96	Savopoulos CH, Dokos CH, Kaiafa G and Hatzitolios A: Adipogenesis and osteoblastogenesis: trans-differentiation in the pathophysiology of bone disorders. Hippokratia. 15:18–21. 2011.PubMed/NCBI
97	Tsartsalis AN, Dokos C, Kaiafa GD, Tsartsalis DN, Kattamis A, Hatzitolios AI and Savopoulos CG: Statins, bone formation and osteoporosis: hope or hype? Hormones (Athens). 11:126–139. 2012. View Article : Google Scholar
98	Esposito K, Capuano A, Sportiello L, Giustina A and Giugliano D: Should we abandon statins in the prevention of bone fractures? Endocrine. 44:326–333. 2013. View Article : Google Scholar : PubMed/NCBI
99	Borton AJ, Frederick JP, Datto MB, Wang XF and Weinstein RS: The loss of Smad3 results in a lower rate of bone formation and osteopenia through dysregulation of osteoblast differentiation and apoptosis. J Bone Miner Res. 16:1754–1764. 2001. View Article : Google Scholar : PubMed/NCBI
100	Kaji H, Kanatani M, Sugimoto T and Chihara K: Stains modulate the levels of osteoprotegerin/receptor activator of NF kappaB ligand mRNA in mouse bone-cell cultures. Horm Metab Res. 37:589–592. 2005. View Article : Google Scholar : PubMed/NCBI
101	Garrett IR and Mundy GR: The role of statins as potential targets for bone formation. Arthritis Res. 4:237–240. 2002. View Article : Google Scholar : PubMed/NCBI
102	Sugiyama M, Kodama T, Konishi K, Abe K, Asami S and Oikawa S: Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells. Biochem Biophys Res Commun. 271:688–692. 2000. View Article : Google Scholar : PubMed/NCBI
103	Maeda T, Matsunuma A, Kawane T and Horiuchi N: Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun. 280:874–877. 2001. View Article : Google Scholar : PubMed/NCBI
104	Oxlund H, Dalstra M and Andreassen TT: Statin given perorally to adult rats increases cancellous bone mass and compressive strength. Calcif Tissue Int. 69:299–304. 2001. View Article : Google Scholar
105	Uzzan B, Cohen R, Nicolas P, Cucherat M and Perret GY: Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone. 40:1581–1587. 2007. View Article : Google Scholar : PubMed/NCBI
106	Anagnostis P, Karagiannis A, Kakafika AI, Tziomalos K, Athyros VG and Mikhailidis DP: Atherosclerosis and osteoporosis: age-dependent degenerative processes or related entities? Osteoporos Int. 20:197–207. 2009. View Article : Google Scholar
107	de Nijs RN, Jacobs JW, Lems WF, et al: Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med. 355:675–684. 2006. View Article : Google Scholar : PubMed/NCBI
108	Reid DM, Devogelaer JP, Saag K, et al: Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomized controlled trial. Lancet. 373:1253–1263. 2009. View Article : Google Scholar : PubMed/NCBI
109	Saag KG, Shane E, Boonen S, et al: Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 357:2028–2039. 2007. View Article : Google Scholar : PubMed/NCBI
110	Wallach S, Cohen S, Reid DM, et al: Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int. 67:277–285. 2000. View Article : Google Scholar : PubMed/NCBI
111	Riggs BL, Khosla S and Melton LJ III: A unitary model for involutional osteoporosis: Estrogen deficiency causes both type I and type II osteoporosis in postmenopausal females and contributes to bone loss in aging men. J Bone Miner Res. 13:763–773. 1998. View Article : Google Scholar : PubMed/NCBI
112	Heaney RP, Recker RR and Saville PD: Menopausal changes in bone remodeling. J Lab Clin Med. 92:964–970. 1978.PubMed/NCBI
113	Manolagas SC and Jilka RL: Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 332:305–311. 1995. View Article : Google Scholar : PubMed/NCBI
114	Khosla S, Atkinson EJ, Melton LJ III and Riggs BL: Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in females: a population based study. J Clin Endocrinol Metab. 82:1522–1527. 1997.PubMed/NCBI
115	D’Amelio P, Grimaldi A, Di Bella S, et al: Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone. 43:92–100. 2008. View Article : Google Scholar
116	Wells G, Tugwell P, Shea B, et al: Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal females. Endocr Rev. 23:529–539. 2002. View Article : Google Scholar : PubMed/NCBI
117	Bonnet N, Gadois C, McCloskey E, Lemineur G, Lespessailles E, Courteix D and Benhamou CL: Protective effect of beta blockers in postmenopausal females: influence on fractures, bone density, micro and macroarchitecture. Bone. 40:1209–1216. 2007. View Article : Google Scholar : PubMed/NCBI
118	Bonnet N, Benhamou CL, Brunet-lmbault B, et al: Severe bone alterations under beta2 agonist treatment: bone mass, microarchitecture and strength analyses in female rats. Bone. 37:622–633. 2005. View Article : Google Scholar : PubMed/NCBI
119	Bonnet N, Benhamou CL, Malaval L, et al: Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions. J Cell Physiol. 217:819–827. 2008. View Article : Google Scholar : PubMed/NCBI
120	Pasco JA, Henry MJ, Sanders KM, Kotowicz MA, Seeman E and Nicholson GC: beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study. J Bone Miner Res. 19:19–24. 2004. View Article : Google Scholar : PubMed/NCBI
121	Schlienger RG, Kraenzlin ME, Jick SS and Meier CR: Use of beta-blockers and risk of fractures. JAMA. 292:1326–1332. 2004. View Article : Google Scholar : PubMed/NCBI
122	Ferrari SL, Demissie S, Karasik D, Cupples LA, Imamovic A, Dupuis J and Kiel DP: Beta 2 adrenergic receptor, beta-blockers and their influence on bone mass in humans: the Framingham osteoporosis study. J Bone Miner Res. 20(Suppl 1): 11–12. 2005.
123	Rejnmark L, Vestergaard P, Kassem M, Christoffersen BR, Kolthoff N, Brixen K and Mosekilde L: Fracture risk in perimenopausal females treated with beta-blockers. Calcif Tissue Int. 75:365–372. 2004. View Article : Google Scholar : PubMed/NCBI