Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 47

[13] Xiong DH, Shen H, Zhao LJ, et al. Robust and comprehensive analysis of 20 osteopo‐ rosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene in‐

[14] Liu YZ, Liu YJ, Recker RR, Deng HW. Molecular studies of identification of genes for

[15] Arvidson K, Abdallah BM, Applegate LA, et al. Bone regeneration and stem cells. J

[16] Valdés-Flores M, Casas-Avila L, Falcón-Ramírez E, Ponce-de-León-Suárez V. Genetic

[17] Ralston SH, de Crombrugghe B. Genetic regulation of bone mass and susceptibility

[18] Rivadeneira F, Styrkársdottir U, Estrada K, et al. Genetic Factors for Osteoporosis (GEFOS) Consortium. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 2009;41(11):1199-1206.

[19] Richards JB, Kavvoura FK, Rivadeneira F, et al. Genetic Factors for Osteoporosis Consortium. Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 2009;20;151(8):528-537.

[20] Sadat-Ali M, Al-Turki HA. Genetic influence of candidate osteoporosis genes in sau‐ di arabian population: a pilot study. J Osteoporos 2012; doi: 10.1155/2012/569145.

[21] Langdahl BL, Uitterlinden AG, Ralston SH, et al. APOSS investigators; DOPS investi‐ gators; EPOS investigators; EPOLOS investigators; FAMOS investigators; LASA in‐ vestigators; ERGO investigators; GENOMOS Study. Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene

[23] Albagha OM, Ralston SH. Genetics and osteoporosis. Rheum Dis Clin North Am

[24] Magaña JJ, Gómez R, Cisneros B, et al. Association of the CT gene (CA) polymor‐ phism with BMD in osteoporotic Mexican women. Clin Genet 2006;70(5):402-408.

[25] Gómez R, Magaña JJ, Cisneros B, et al. Association of the estrogen receptor alpha gene polymorphisms with osteoporosis in the Mexican population. Clin Genet

(TGFB1) and osteoporosis: the GENOMOS study. Bone 2008;42(5):969-981.

[22] Ralston SH. Genetics of osteoporosis. Proc Nutr Soc 2007;66(2):158-65. Review.

teraction. J Bone Miner Res 2006;21(11):1678-1695.

Cell Mol Med 2011;15(4):718-746. Review.

2006;32(4):659-680. Review.

2007;72(6):574-581.

osteoporosis: the 2002 update. J Endocrinol 2003;177(2):147-96.

aspects of osteoporosis. Rev Invest Clin 2012;64(3):294-307.

to osteoporosis. Genes Dev 2006;15:20(18):2492-2506. Review

1998;22(2):141-145.

[12] Harris M, Nguyen TV, Howard GM, Kelly PJ, Eisman JA. Genetic and environmental correlations between bone formation and bone mineral density: a twin study. Bone 1998;22(2):141-145.

**Author details**

46 Topics in Osteoporosis

**References**

178-182.

1991;6(6):561-567.

Margarita Valdés-Flores\*

\*Address all correspondence to<EMAIL_ADDRESS>
al density. J Bone Miner 1993;8(1):1-9.

docrinology 2000;166(2):235-245.

twins. J Bone Miner Res 1996;11(4):530-534.

aged 10–89 years: A twin study. Bone 1996;18(1):41-45.

Genetics Unit. National Rehabilitation Institute. Ministry of Health, Mexico

ture. Best Pract Res Clin Rheumatol 2009;23(6):769-79. Review.

of osteoporosis. Acta Med Austriaca 2000;27(1):18-22.

, Leonora Casas-Avila and Valeria Ponce de León-Suárez

[1] Kok C, Sambrook PN. Secondary osteoporosis in patients with an osteoporotic frac‐

[2] Krall EA, Dawson-Hugues B. Hereditable and life-style determinants of bone miner‐

[3] Obermayer-Pietsch B, Chararas C, Kotschan S, Walter D, Leb G. Genetic background

[4] Stewart TL, Ralston SH. Role of genetics in the pathogenesis of osteoporosis. J of En‐

[5] Slemenda CW, Turner CH, Peacock M, et al. The genetics of proximal femur geome‐ try, distribution of bone mass and bone mineral density. Osteoporos Int 1996;6(2):

[6] Arden NK, Baker J, Hogg C, Baan K, Spector TD. The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal

[7] Koller DL, Liu G, Econs MJ, et al. Genome screen for quantitative trait loci underly‐ ing normal variation in femoral structure. J Bone Miner Res 2001;16(6):985-991.

[8] Flicker L, Faulkner KG, Hopper JL, et al. Determinants of hip axis length in women

[9] Deng HW, Mahaney MC, Williams JT, et al. Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene

[10] Slemenda CW, Christian JC, Williams CJ, Norton JA, Johnston CCJr. Genetic deter‐ minants of bone mass in adult women: a reevaluation of the twin model and the po‐ tential importance of gene interaction on heritability estimates. J Bone Miner Res

[11] Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green RM, Wark JD. Bone density de‐ terminants in elderly women: A twin study. J Bone Miner Res 1995;10(11):1607-1613.

search for complex human diseases. Genet Epidemiol 2002;22(1):12-25.

[26] Magaña JJ, Gómez R, Cisneros B, Casas L, Valdés-Flores M. Association of interleu‐ kin-6 gene polymorphisms with bone mineral density in Mexican women. Arch Med Res 2008;39(6):618-624.

[41] Gong Y, Vikkula M, Boon L, et al. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 49

[42] Gardner-Medwin D. The natural history of Duchenne muscular dystrophy. In: Wise G, Blaw M, Procopis PG, (eds.) Topics in Child Neurology. New York: Spectrum;

[43] Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-

[44] Dubowitz V. Ramblings in the history of spinal muscular atrophy. Neuromuscul Dis‐

[45] Lee SJ, Lee DH, Yoo HW, Koo SK, Park ES, Park JW, Lim HG, Jung SC. Identification and functional analysis of cystathionine beta-synthase gene mutations in patients

[46] Tyagi N, Kandel M, Munjal C, et al. Homocysteine mediated decrease in bone blood flow and remodeling: role of folic acid. J Orthop Res 2011;29(10):1511-1516.

[48] Chatterjee R, Katz M, Bajoria R. Use of hormone replacement therapy for correction of high turnover bone disease in hypogonadal β-Thalassemia major patients present‐ ing with osteoporosis: comparison with idiopathic premature ovarian failure. Hemo‐

[49] Javier RM, Hachulla E, Rose C, et al. Vertebral fractures in Gaucher disease type I: data from the French "Observatoire" on Gaucher disease (FROG). Osteoporos Int

[50] Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher dis‐

[51] Germain DP, Benistan K, Boutouyrie P, Mutschler C. Osteopenia and osteoporosis: previously unrecognized manifestations of Fabry disease. Clin Genet 2005;68(1):

[52] Mersebach H, Johansson JO, Rasmussen AK, et al. Osteopenia: a common aspect of Fabry disease. Predictors of bone mineral density. Genet Med 2007;9(12):812-818. [53] Haworth CS, Selby PL, Webb AK, Adams JE. Osteoporosis in adults with cystic fibro‐

[54] Javier RM, Jacquot J. Bone disease in cystic fibrosis: what's new? Joint Bone Spine.

Am J Hum Genet 1996;59(1):146-151.

Marie-Tooth disease. Lancet Neurol 2009;8:654–667.

with homocystinuria. J Hum Genet 2005;50(12):648-654.

ease: a review. Br J Radiol 2002;75(Suppl 1):A2-12.

sis. J R Soc Med. 1998;91 Suppl 34:14-18.

[47] Cao A, Galanello R. Beta-thalassemia. Genet Med 2010;12(2):61-76.

1983. p 17–29.

ord 2009;19(1):69-73.

globin 2011;35(5-6):653-658.

2011;22(4):1255-1261.

2011;78(5):445-450.

93-95.

[41] Gong Y, Vikkula M, Boon L, et al. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet 1996;59(1):146-151.

[26] Magaña JJ, Gómez R, Cisneros B, Casas L, Valdés-Flores M. Association of interleu‐ kin-6 gene polymorphisms with bone mineral density in Mexican women. Arch Med

[27] Wang JT, Guo Y, Yang TL, et al. Polymorphisms in the estrogen receptor genes are

[28] Massart F, Marini F, Bianchi G, et al. Age-specific effects of estrogen receptors' poly‐ morphisms on the bone traits in healthy fertile women: the BONTURNO study. Re‐

[29] Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Associations between osteoprotegerin polymorphisms and bone mineral density: a meta-analysis. Mol Biol Rep 2010;37(1):

[30] Seremak-Mrozikiewicz A, Tatuśko J, Drews K, et al. Polymorphism of osteoproteger‐ in gene and osteoporosis in postmenopausal women. Ginekol Pol 2009;80(5):354-360.

[31] Jones ET, Hensinger RN. Spinal deformity in idiopathic juvenile osteoporosis. Spine

[32] Lorenc RS. Idiopathic juvenile osteoporosis. Calcif Tissue Int 2002;70(5):395-7. Re‐

[33] Van Dijk FS, Pals G, Van Rijn RR, Nikkels PG, Cobben JM. Classification of Osteo‐

[34] Zhang ZL, Zhang H, Ke YH, et al. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J

[35] Pyott SM, Schwarze U, Christiansen HE, et al. Mutations in PPIB (cyclophilin B) de‐ lay type I procollagen chain association and result in perinatal lethal to moderate os‐

[36] Meyer HJ. Atypical osteogenesis imperfecta: Lobstein's disease. Arch Pediat

[38] Beighton P, Winship I, Behari D. The ocular form of osteogenesis imperfecta: a new

[39] Frontali M, Stomeo C, Dallapiccola B. Osteoporosis-pseudoglioma syndrome: report

[40] Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone

of three affected sibs and an overview. Am J Med Genet 1985;22(1):35-47.

teogenesis imperfecta phenotypes. Hum Mol Genet 2011;20(8):1595-1609.

[37] Brude E. Ocular osteogenesis imperfecta. (Letter) Clin Genet 1986;29(2):187.

autosomal recessive syndrome. Clin Genet 1985;28(1):69-75.

accrual and eye development. Cell 2001;107(4):513-523.

genesis Imperfecta revisited. Eur J Med Genet 2010;53(1):1-5.

associated with hip fractures in Chinese. Bone 2008;43(5):910-914.

Res 2008;39(6):618-624.

227-234.

48 Topics in Osteoporosis

view.

prod Biol Endocrinol 2009;7:32.

(Phila Pa 1976). 1981;6(1):1-4.

Bone Miner Metab 2012;30(1):69-77.

1955;72(6):182-186.

[55] Paccou J, Zeboulon N, Combescure C, Gossec L, Cortet B. The prevalence of osteopo‐ rosis, osteopenia, and fractures among adults with cystic fibrosis: a systematic litera‐ ture review with meta-analysis. Calcif Tissue Int. 2010;86(1):1-7.

[68] van de Laar IM, van der Linde D, Oei EH, et al. Phenotypic spectrum of the SMAD3 related aneurysms-osteoarthritis syndrome. J Med Genet 2012;49(1):47-57.

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 51

[69] Stanitski DF, Nadjarian R, Stanitski CL, Bawle E, Tsipouras P. Orthopaedic manifes‐ tations of Ehlers-Danlos syndrome. Clin Orthop Relat Res 2000;376:213-221.

[70] Mayer K, Kennerknecht I, Steinmann B. Clinical utility gene card for: Ehlers-Danlos syndrome types I-VII and variants - update 2012. Eur J Hum Genet 2012; doi:

[71] Myllyharju J, Kivirikko KI. Collagens and collagen-related diseases. Ann Med

[72] Duan Y, De Luca V, Seeman E. Parathyroid hormone deficiency and excess: similar effects on trabecular bone but differing effects on cortical bone. J Clin Endocrinol

[73] Bastepe M. The GNAS locus and pseudohypoparathyroidism. Adv Exp Med Biol

[74] Thiele S, de Sanctis L, Werner R, et al. Functional characterization of GNAS muta‐ tions found in patients with pseudohypoparathyroidism type Ic defines a new sub‐ group of pseudohypoparathyroidism affecting selectively Gsα-receptor interaction.

[75] de Nanclares GP, Fernández-Rebollo E, Santin I, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary

[76] Cao LH, Wang LB, Wang SS, Ma HW, Ji CY, Luo Y. Identification of novel and recur‐ rent mutations in the calcium binding type III repeats of cartilage oligomeric matrix protein in patients with pseudoachondroplasia. Genet Mol Res 2011;10(2):955-963.

[77] Jackson GC, Mittaz-Crettol L, Taylor JA, et al. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their

[78] Sinnema M, Maaskant MA, van Schrojenstein Lantman-de Valk HM, et al. Physical health problems in adults with Prader-Willi syndrome. Am J Med Genet A

[79] Vestergaard P, Kristensen K, Bruun JM, et al. Reduced bone mineral density and in‐ creased bone turnover in Prader-Willi syndrome compared with controls matched for sex and body mass index--a cross-sectional study. J Pediatr 2004;144(5):614-619.

[80] Isidor B, Lindenbaum P, Pichon O, et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 2011;43(4):

osteodystrophy. J Clin Endocrinol Metab 2007;92(6):2370-2373.

relative contribution. Hum Mutat 2012;33(1):144-157.

10.1038/ejhg.2012.162.

Metab 1999;84(2):718-722.

Hum Mutat 2011;32(6):653-660.

2011;155A(9):2112-2124.

306-308.

2001;33(1):7-21.

2008;626:27-40.

[68] van de Laar IM, van der Linde D, Oei EH, et al. Phenotypic spectrum of the SMAD3 related aneurysms-osteoarthritis syndrome. J Med Genet 2012;49(1):47-57.

[55] Paccou J, Zeboulon N, Combescure C, Gossec L, Cortet B. The prevalence of osteopo‐ rosis, osteopenia, and fractures among adults with cystic fibrosis: a systematic litera‐

[56] Aris R, Lester G, Ontjes D. Treatment of bone disease in cystic fibrosis. Curr Opin

[57] Pollex RL, Hegele RA. Hutchinson-Gilford progeria syndrome. Clin Genet

[58] Iglesias BP, Guijarro AG, Civantos MS, Vega PB, Pavón PI, Monereo MS. Complicat‐ ed osteoporosis in progeroid syndrome: treatment with teriparatide. J Clin Densitom

[59] Laine CM, Koltin D, Susic M, et al. Primary osteoporosis without features of OI in children and adolescents: clinical and genetic characteristics. Am J Med Genet A

[60] Wekre LL, Eriksen EF, Falch JA. Bone mass, bone markers and prevalence of frac‐ tures in adults with osteogenesis imperfecta. Arch Osteoporos 2011;6(1-2):31-38.

[61] Sakai H, Visser R, Ikegawa S, et al. Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. Am J

[62] Villamizar C, Regalado ES, Fadulu VT, et al. Paucity of skeletal manifestations in Hispanic families with FBN1 mutations. Eur J Med Genet 2010;53(2):80-84

[63] Stheneur C, Collod-Béroud G, Faivre L, et al. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum

[64] Kirmani S, Tebben PJ, Lteif AN, et al. Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome. Am J Med

[65] Ben Amor IM, Edouard T, Glorieux FH, et al. Low bone mass and high material bone density in two patients with Loeys-Dietz syndrome caused by transforming growth

[66] Kiliç E, Alanay Y, Utine E, Ozgen-Mocan B, Robinson PN, Boduroğlu K. Arterial tor‐ tuosity and aneurysm in a case of Loeys-Dietz syndrome type IB with a mutation

[67] van de Laar IM, Oldenburg RA, Pals G, et al. Mutations in SMAD3 cause a syndrom‐ ic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet

factor beta receptor 2 mutations. J Bone Miner Res 2012;27(3):713-718.

p.R537P in the TGFBR2 gene. Turk J Pediatr 2012;54(2):198-202.

ture review with meta-analysis. Calcif Tissue Int. 2010;86(1):1-7.

Pulm Med. 2004;10(6):524-30.

2004;66(5):375-381.

50 Topics in Osteoporosis

2012;15(1):116-119.

2012;158A(6):1252-1261.

Med Genet A 2006;140(16):1719-1725.

Mutat 2008;29(11):E284-E95.

2011;43(2):121-126.

Genet A 2010;152A(4):1016-1019.

[81] Simpson MA, Irving MD, Asilmaz E, et al. Mutations in NOTCH2 cause Hajdu-Che‐ ney syndrome, a disorder of severe and progressive bone loss. Nat Genet 2011;43(4): 303-305.

[94] Stratakis CA. New genes and/or molecular pathways associated with adrenal hyper‐ plasias and related adrenocortical tumors. Mol Cell Endocrinol 2009;300(1-2):152-157.

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 53

[95] Horvath A, Boikos S, Giatzakis C, et al. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adreno‐

[96] Carney JA, Gaillard RC, Bertherat J, Stratakis CA. Familial micronodular adrenocorti‐ cal disease, Cushing syndrome, and mutations of the gene encoding phosphodiester‐

[97] Ihde LL, Forrester DM, Gottsegen CJ, et al. Sclerosing bone dysplasias: review and differentiation from other causes of osteosclerosis. Radiographics 2011;31(7):

[98] van Egmond ME, Dikkers FG, Boot AM, van Lierop AH, Papapoulos SE, Brouwer OF. A rare cause of facial nerve palsy in children: Hyperostosis corticalis generalisata (Van Buchem disease). Three new pediatric cases and a literature review. Eur J Pae‐

[99] Scopelliti D, Orsini R, Ventucci E, Carratelli D. Van Buchem disease. Maxillofacial changes, diagnostic classification and general principles of treatment. Minerva Sto‐

[100] van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone

[101] Grodum E, Gram J, Brixen K, Bollerslev J. Autosomal dominant osteopetrosis: bone mineral measurements of the entire skeleton of adults in two different subtypes.

[102] Bollerslev J, Nielsen HK, Larsen HF, Mosekilde L. Biochemical evidence of disturbed bone metabolism and calcium homeostasis in two types of autosomal dominant os‐

[103] Bénichou O, Cleiren E, Gram J, Bollerslev J, de Vernejoul MC, Van Hul W. Mapping of autosomal dominant osteopetrosis type II (Albers-Schönberg disease) to chromo‐

[104] Kantaputra PN, Thawanaphong S, Issarangporn W, et al. Long-term survival in in‐ fantile malignant autosomal recessive osteopetrosis secondary to homozygous

[105] Lahera Vargas M, da Costa CV. Prevalence, etiology and clinical findings of Cush‐

[106] Beauregard C, Dickstein G, Lacroix A. Classic and recent etiologies of Cushing's syn‐

drome: diagnosis and therapy. Treat Endocrinol 2002;1(2):79-94.

p.Arg526Gln mutation in CLCN7. Am J Med Genet A 2012;158A(4):909-916.

cortical hyperplasia. Nat Genet 2006;38(7):794-800.

diatr Neurol 2012; doi: 10.1016/j.ejpn.2012.03.002.

density. Am J Hum Genet 2003;72(3):763-771.

teopetrosis. Acta Med Scand 1988;224(5):479-483.

some 16p13.3. Am J Hum Genet 2001;69(3):647-654.

ing's syndrome. Endocrinol Nutr 2009;56(1):32-39.

1865-1882.

matol 1999;48(5):227-234.

Bone 1995;16(4):431-434.

ase 11A4 (PDE11A). Am J Surg Pathol 2010;34(4):547-555.

[94] Stratakis CA. New genes and/or molecular pathways associated with adrenal hyper‐ plasias and related adrenocortical tumors. Mol Cell Endocrinol 2009;300(1-2):152-157.

[81] Simpson MA, Irving MD, Asilmaz E, et al. Mutations in NOTCH2 cause Hajdu-Che‐ ney syndrome, a disorder of severe and progressive bone loss. Nat Genet 2011;43(4):

[82] Prié D, Beck L, Friedlander G, Silve C. Sodium-phosphate cotransporters, nephroli‐ thiasis and bone demineralization. Curr Opin Nephrol Hypertens 2004;13(6):675-681.

[83] Scheinman SJ, Tenenhouse HS. Nephrolithiasis, osteoporosis, and mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med 2003;348(3):264-265.

[84] Karim Z, Gérard B, Bakouh N, et al. NHERF1 mutations and responsiveness of renal

[85] Arrabal-Polo MA, Arrabal-Martin M, de Haro-Munoz T, et al. Mineral density and bone remodelling markers in patients with calcium lithiasis. BJU Int 2011;108(11):

[86] Arrabal-Polo MA, Arrabal-Martin M, Girón-Prieto MS, et al. Osteopenia/osteoporosis in patients with calcium nephrolithiasis. Urol Res 2012; doi:10.1007/

[87] Norton N, Siegfried JD, Li D, Hershberger RE. Assessment of LMNA copy number variation in 58 probands with dilated cardiomyopathy. Clin Transl Sci 2011;4(5):

[88] Sébillon P, Bouchier C, Bidot LD, et al. Expanding the phenotype of LMNA muta‐ tions in dilated cardiomyopathy and functional consequences of these mutations. J

[89] Basel-Vanagaite L, Dokal I, Tamary H, et al. Expanding the clinical phenotype of au‐ tosomal dominant dyskeratosis congenita caused by TERT mutations. Haematologi‐

[90] Du HY, Pumbo E, Manley P, et al. Complex inheritance pattern of dyskeratosis con‐ genita in two families with 2 different mutations in the telomerase reverse transcrip‐

[91] Sasa GS, Ribes-Zamora A, Nelson ND, Bertuch AA. Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. Clin Genet

[92] Hofer AC, Tran RT, Aziz OZ, et al. Shared phenotypes among segmental progeroid syndromes suggest underlying pathways of aging. J Gerontol A Biol Sci Med Sci

[93] Groussin L, Jullian E, Perlemoine K, et al. Mutations of the PRKAR1A gene in Cush‐ ing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J

parathyroid hormone. N Engl J Med 2008;359(11):1128-1135.

303-305.

52 Topics in Osteoporosis

1903-1908.

351-352.

s00240-012-0497-8.

Med Genet 2003;40(8):560-567.

tase gene. Blood 2008;111(3):1128-1130.

Clin Endocrinol Metab 2002;87(9):4324-4329.

ca 2008;93(6):943-934.

2012;81(5):470-478.

2005;60(1):10-20.

[107] Heimall J, Freeman A, Holland SM. Pathogenesis of hyper IgE syndrome. Clin Rev Allergy Immunol 2010;38(1):32-38.

[120] El-Gharbawy AH, Peeden JN Jr, Lachman RS, Graham JM Jr, Moore SR, Rimoin DL. Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 55

of the C-terminal region of RUNX2. Am J Med Genet A 2010;152A(1):169-174.

[121] Shao C, Tian J, Shi DH, et al. A novel mutation in TPRS1 gene caused tricho-rhinophalangeal syndrome in a Chinese patient with severe osteoporosis. Chin Med J

[122] Gai Z, Gui T, Muragaki Y. The function of TRPS1 in the development and differentia‐ tion of bone, kidney, and hair follicles. Histol Histopathol 2011;26(7):915-921.

[123] Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular bases of vitamin D-

[124] Portale AA, Miller WL. Human 25-hidroxyvitamin D-1alpha-hydroxilase: cloning,

[125] Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L. Association between iron overload and osteoporosis in patients with hereditary hemochromato‐

[126] Nakchbandi IA, van der Merwe SW. Current understanding of osteoporosis associat‐

[127] Narumi S, Numakura C, Shiihara T, et al. Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb micro‐ deletion using oligonucleotide tiling microarray. Am J Med Genet A 2010;152A(1):

[128] Laine CM, Chung BD, Susic M, et al. Novel mutations affecting LRP5 splicing in pa‐ tients with osteoporosis-pseudoglioma syndrome (OPPG). Eur J Hum Genet

[129] El Maghraoui A, Ghozlani I, Mounach A, et al. Homocysteine, folate, and vitamin b(12) levels and vertebral fracture risk in postmenopausal women. J Clin Densitom

[130] Bucciarelli P, Martini G, Martinelli I, et al. The relationship between plasma homo‐ cysteine levels and bone mineral density in post-menopausal women. Eur J Intern

[131] Takagi M, Ishii T, Barnes AM, et al. A novel mutation in LEPRE1 that eliminates only the KDEL ER- retrieval sequence causes non-lethal osteogenesis imperfecta. PLoS

[132] Willaert A, Malfait F, Symoens S, et al. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form re‐

sponsible for prolyl 3-hydroxylation. J Med Genet 2009;46(4):233-241.

One 2012;7(5):e36809. doi: 10.1371/journal.pone.0036809.

dependent rickets type I. Endocr J 2001;48(4):427-432.

mutation and gene expression. Pediatr Nefrol 2000;14(7):620-625.

ed with liver disease. Nat Rev Gastroenterol Hepatol 2009;6:660-670.

(Engl) 2011;124(10):1583-1585.

sis Osteoporos Int 2009;20(4):549–555.

133-140.

2011;19(8):875-81.

2012;15(3):328-333.

Med 2010;21(4):301-305.

[120] El-Gharbawy AH, Peeden JN Jr, Lachman RS, Graham JM Jr, Moore SR, Rimoin DL. Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion of the C-terminal region of RUNX2. Am J Med Genet A 2010;152A(1):169-174.

[107] Heimall J, Freeman A, Holland SM. Pathogenesis of hyper IgE syndrome. Clin Rev

[108] Moneret-Vautrin DA, Kanny G, Thinus G. Hyperglobulinemia E syndrome with re‐ current infections (Job's syndrome). Rev Med Interne 1999;20(2):133-140.

[109] Mani A, Radhakrishnan J, Wang H, et al. LRP6 mutation in a family with early coro‐ nary disease and metabolic risk factors. Science 2007;315(5816):1278-1282.

[110] van Meurs JB, Trikalinos TA, Ralston SH, et al. Large-scale analysis of association be‐ tween LRP5 and LRP6 variants and osteoporosis. JAMA 2008;299(11):1277-1290. [111] Ugwonali OF, Sarkissian H, Nercessian OA. Bilateral osteonecrosis of the femoral head associated with pregnancy: four new cases and a review of the literature. Or‐

[112] Zhao F, Li Z, Zhang N, et al. Differences between transient osteoporosis of the hip and bone marrow edema associated with osteonecrosis of the femoral head. Zhong‐

[113] Boyden ED, Campos-Xavier AB, Kalamajski S, et al. Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity. Am J Hum Genet 2011;89(6):767-772. Er‐

[114] Min BJ, Kim N, Chung T, et al. Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type. Am

[115] Dai J, Kim OH, Cho TJ, et al. Novel and recurrent TRPV4 mutations and their associ‐ ation with distinct phenotypes within the TRPV4 dysplasia family. J Med Genet

[116] Nishimura G, Dai J, Lausch E, et al. Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by

[117] Watanabe H, Hashimoto-Uoshima M, Goseki-Sone M, Orimo H, Ishikawa I. A novel point mutation (C571T) in the tissue-non-specific alkaline phosphatase gene in a case

[118] Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP. "Atypical femoral frac‐ tures" during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res

[119] Wang GX, Sun RP, Song FL. A novel RUNX2 mutation (T420I) in Chinese patients

TRPV4 mutations. Am J Med Genet A 2010;152A(6):1443-1449.

of adult-type hypophosphatasia. Oral Dis 2001;7(6):331-5.

with cleidocranial dysplasia. Genet Mol Res 2010;9(1):41-47.

guo Xiu Fu Chong Jian Wai Ke Za Zhi 2008;22(10):1157-1160.

ratum in: Am J Hum Genet 2012;90(1):170.

J Hum Genet 2011;89(6):760-766.

2010;47(10):704-709.

2012;27(5):987-994.

Allergy Immunol 2010;38(1):32-38.

54 Topics in Osteoporosis

thopedics 2008;31(2):183.

[133] van Dijk FS, Nesbitt IM, Zwikstra EH, et al. PPIB mutations cause severe osteogene‐ sis imperfecta. Am J Hum Genet 2009;85(4):521-527.

[146] Shastry S, Delgado MR, Dirik E, Turkmen M, Agarwal AK, Garg A. Congenital gen‐ eralized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 57

[147] Desnick JP, Kim J, He X, Wasserstein MP, Simonaro CM, Schuchman EH. Identifica‐ tion and characterization of eight novel SMPD1 mutations causing types A and B

[148] Bachor E, Knop E, Karmody CS, Northrop C, Carranza A, Schuknecht HF. Temporal bone histopathology of Niemann-Pick disease type A. Am J Otolaryngol 1997;18(5):

[149] Volders P, Van Hove J, Lories RJ, et al. Niemann-Pick disease type B: an unusual clinical presentation with multiple vertebral fractures. Am J Med Genet 2002;109(1):

[150] Brunetti-Pierri N, Corso G, Rossi M, et al. Lathosterolosis, a novel multiple-malfor‐ mation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-del‐ ta5-desaturase. Am J Hum Genet 2002;71(4):952-958. Erratum in: Am J Hum Genet

[151] Rossi M, D'Armiento M, Parisi I, et al. Am J Med Genet A 2007;143A(20):2371-2381.

IVA (Morquio A) in Spain. Mol Genet Metab 2012;106(2):196-201.

[152] Pajares S, Alcalde C, Couce ML, et al. Molecular analysis of mucopolysaccharidosis

[153] Tomatsu S, Montaño AM, Oikawa H, et al. Mucopolysaccharidosis type IVA (Mor‐ quio A disease): clinical review and current treatment. Curr Pharm Biotechnol

[154] Menkès CJ, Rondot P. Idiopathic osteonecrosis of femur in adult Morquio type B dis‐

[155] Krishnamurthy J, Dalal BS, Sunila, Gubanna MV. Juvenile hyaline fibromatosis. Indi‐

[156] El-Kamah GY, Fong K, El-Ruby M, et al. Spectrum of mutations in the ANTXR2 (CMG2) gene in infantile systemic hyalinosis and juvenile hyaline fibromatosis. Br J

[157] Oz OK, Zerwekh JE, Fisher C, et al. Bone has a sexually dimorphic response to aro‐

[158] Vandenput L, Ohlsson C. Estrogens as regulators of bone health in men. Nat Rev En‐

[159] Dwyer E, Hyland J, Modaff P, Pauli RM. Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family.

matase deficiency. J Bone Miner Res 2000;15(3):507-514.

Am J Med Genet A 2010;152A(12):3043-3050.

mutations. Am J Med Genet A 2010;152A(9):2245-2253.

Niemann-Pick disease. Mol Med 2010;16(7-8):316-321.

349-362.

42-51.

2003;73(2):445.

2011;12(6):931-945.

ease. J Rheumatol 2007;34(11):2314-2316.

an J Dermatol. 2011;56(6):731-3.

Dermatol. 2010;163(1):213-215.

docrinol 2009;5:437-443.

[146] Shastry S, Delgado MR, Dirik E, Turkmen M, Agarwal AK, Garg A. Congenital gen‐ eralized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations. Am J Med Genet A 2010;152A(9):2245-2253.

[133] van Dijk FS, Nesbitt IM, Zwikstra EH, et al. PPIB mutations cause severe osteogene‐

[134] Kraus JP, Spector E, Venezia S, et al. Mutation analysis in 54 propionic acidemia pa‐

[135] Pérez B, Angaroni C, Sánchez-Alcudia R, et al. The molecular landscape of propionic acidemia and methylmalonic aciduria in Latin America. J Inherit Metab Dis

[136] Yen JL, Lin SP, Chen MR, Niu DM. Clinical features of Ehlers-Danlos syndrome. J

[137] Uppal S, Diggle CP, Carr IM, et al. Mutations in 15-hydroxyprostaglandin dehydro‐ genase cause primary hypertrophic osteoarthropathy. Nat Genet. 2008;40(6):789-793.

[138] Shimizu C, Kubo M, Kijima Het al. A rare case of acromegaly associated with pachy‐

[139] Georgitsi M, Raitila A, Karhu A, et al. Molecular diagnosis of pituitary adenoma pre‐ disposition caused by aryl hydrocarbon receptor-interacting protein gene mutations.

[140] Minetto M, Reimondo G, Osella G, Ventura M, Angeli A, Terzolo M. Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing's syndrome.Os‐

[141] Chong B, Hegde M, Fawkner M, et al. International Hyperphosphatasia Collabora‐ tive Group. Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships

[142] Whyte MP, Singhellakis PN, Petersen MB, Davies M, Totty WG, Mumm S. Juvenile Paget's disease: the second reported, oldest patient is homozygous for the TNFRSF11B "Balkan" mutation (966\_969delTGACinsCTT), which elevates circulating

immunoreactive osteoprotegerin levels. J Bone Miner Res 2007;22(6):938-946.

[143] Yates CJ, Bartlett MJ, Ebeling PR. An atypical subtrochanteric femoral fracture from pycnodysostosis: a lesson from nature. J Bone Miner Res 2011;26(6):1377-1379. [144] Toral-López J, González-Huerta LM, Sosa B, Orozco S, González HP, Cuevas-Cova‐ rrubias SA. Familial pycnodysostosis: identification of a novel mutation in the CTSK

[145] Hayashi YK, Matsuda C, Ogawa M, et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystro‐

between phenotype and genotype. J Bone Miner Res 2003;18(12):2095-2104.

sis imperfecta. Am J Hum Genet 2009;85(4):521-527.

tients. J Inherit Metab Dis 2012;35(1):51-63.

Formos Med Assoc 2006;105(6):475-480.

Erratum in: Nat Genet 2008;40(7):927.

teoporos Int 2004;15(11):855-861.

dermoperiostosis. J Endocrinol Invest 1999;22(5):386-389.

Proc Natl Acad Sci USA 2007;104(10):4101-4105.

gene (cathepsin K). J Investig Med 2011;59(2):277-280.

phy. J Clin Invest 2009;119(9):2623-2633.

2010;33(Suppl 2):S307-S314.

56 Topics in Osteoporosis

[160] Forlino A, Piazza R, Tiveron C, et al. A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the re‐ sulting chondrodysplasia phenotype. Hum Mol Genet 2005;14(6):859-871.

[173] Cabanillas R, Cadiñanos J, Villameytide JA, et al. Néstor-Guillermo progeria syn‐ drome: a novel premature aging condition with early onset and chronic development

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 59

[174] Osorio FG, Ugalde AP, Mariño G, Puente XS, Freije JM, López-Otín C. Cell autono‐ mous and systemic factors in progeria development. Biochem Soc Trans 2011;39(6):

[175] Walne AJ, Vulliamy T, Marrone A, et al. Genetic heterogeneity in autosomal reces‐ sive dyskeratosis congenita with one subtype due to mutations in the telomerase-as‐

[176] Vulliamy TJ, Dokal I. Dyskeratosis congenita: the diverse clinical presentation of mu‐

[177] Basel-Vanagaite L, Sarig O, Hershkovitz D, et al. RIN2 deficiency results in macroce‐ phaly, alopecia, cutis laxa, and scoliosis: MACS syndrome. Am J Hum Genet

[178] Syx D, Malfait F, Van Laer L, et al. The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2).

[179] Sinibaldi L, Harifi G, Bottillo I, et al. A novel homozygous splice site mutation in the HPGD gene caused mild primary Hypertrophic osteoarthropathy. Clin Exp Rheuma‐

[180] Sajnani AK, Yiu CK, King NM. Larsen syndrome: a review of the literature and case

[181] Knoblauch H, Urban M, Tinschert S. Autosomal recessive versus autosomal domi‐ nant inheritance in Larsen syndrome: report of two affected sisters. Genet Couns

[182] Lindvall LE, Kormeili T, Chen E, et al. Infantile systemic hyalinosis: Case report and

[183] Dowling O, Difeo A, Ramirez MC, et al. Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile sys‐

[184] Lussiana C, Guani B, Mari C, Restagno G, Massobrio M, Revelli A. Mutations and polymorphisms of the FSH receptor (FSHR) gene: clinical implications in female fe‐ cundity and molecular biology of FSHR protein and gene. Obstet Gynecol Surv

[185] Doherty E, Pakarinen P, Tiitinen A, Kiilavuori A, Huhtaniemi I, Forrest S, Aittomäki K. A Novel mutation in the FSH receptor inhibiting signal transduction and causing

primary ovarian failure. J Clin Endocrinol Metab 2002;87(3):1151-1155.

review of the literature. J Am Acad Dermatol 2008;58(2):303-307.

temic hyalinosis. Am J Hum Genet 2003;73(4):957-966.

sociated protein NOP10. Hum Mol Genet 2007;16(13):1619-1629.

tations in the telomerase complex. Biochimie 2008;90(1):122-130.

caused by BANF1 mutations. Am J Med Genet A 2011;155A(11):2617-2625.

1710-1714.

2009;85(2):254-263.

tol 2010;28(2):153-157.

1999;10(3):315-320.

2008;63(12):785-795.

Hum Genet 2010;128(1):79-88.

report. Spec Care Dentist 2010;30(6):255-260.

[173] Cabanillas R, Cadiñanos J, Villameytide JA, et al. Néstor-Guillermo progeria syn‐ drome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet A 2011;155A(11):2617-2625.

[160] Forlino A, Piazza R, Tiveron C, et al. A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the re‐

[161] Faivre L, Cormier-Daire V, Young I, et al. Long-term outcome in Desbuquois dyspla‐ sia: a follow-up in four adult patients. Am J Med Genet A 2004;124A(1):54-59. [162] Faden M, Al-Zahrani F, Arafah D, Alkuraya FS. Mutation of CANT1 causes Desbu‐

[163] Mosig RA, Dowling O, DiFeo A, et al. Loss of MMP-2 disrupts skeletal and craniofa‐ cial development and results in decreased bone mineralization, joint erosion and de‐ fects in osteoblast and osteoclast growth. Hum Mol Genet 2007;16(9):1113-1123. [164] Zankl A, Bonafé L, Calcaterra V, Di Rocco M, Superti-Furga A. Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloprotei‐

[165] Newman WG, Clayton-Smith J, Metcalfe K, et al. Geroderma osteodysplastica maps to a 4 Mb locus on chromosome 1q24. Am J Med Genet A 2008;146A(23):3034-3037.

[166] Yildirim Y, Tolun A, Tüysüz B. The phenotype caused by PYCR1 mutations corre‐ sponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa

[167] Sebastio G, Sperandeo MP, Andria G. Lysinuric protein intolerance: reviewing con‐ cepts on a multisystem disease. Am J Med Genet C Semin Med Genet 2011;157(1):

[168] Gömez L, García-Cazorla A, Gutiérrez A, et al. Treatment of severe osteoporosis with alendronate in a patient with lysinuric protein intolerance. J Inherit Metab Dis

[169] Briggs TA, Abdel-Salam GM, Balicki M, et al. Cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Am J Med Genet A 2008;146A(2):182-190.

[170] Toiviainen-Salo S, Linnankivi T, Saarinen A, Mäyränpää MK, Karikoski R, Mäkitie O. Cerebroretinal microangiopathy with calcifications and cysts: characterization of the

[171] Jiao X, Ventruto V, Trese MT, Shastry BS, Hejtmancik JF. Autosomal recessive fami‐ lial exudative vitreoretinopathy is associated with mutations in LRP5. Am J Hum

[172] Qin M, Hayashi H, Oshima K, Tahira T, Hayashi K, Kondo H. Complexity of the gen‐ otype-phenotype correlation in familial exudative vitreoretinopathy with mutations

skeletal phenotype. Am J Med Genet A 2011;155A(6):1322-1328.

in the LRP5 and/or FZD4 genes. Hum Mutat 2005;26(2):104-112.

sulting chondrodysplasia phenotype. Hum Mol Genet 2005;14(6):859-871.

quois dysplasia. Am J Med Genet A 2010;152A(5):1157-1160.

nase 2. Clin Genet 2005;67(3):261-266.

54-62.

58 Topics in Osteoporosis

2006;29(5):687.

Genet 2004;75(5):878-884.

type 2. Am J Med Genet A 2011;155A(1):134-140.

[186] Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000;25(4):406-409.

[200] Cabrera-Abreu J, Crabtree NJ, Elias E, Fraser W, Cramb R, Alger S. Bone mineral density and markers of bone turnover in patients with glycogen storage disease

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 61

[201] Lee PJ, Patel JS, Fewtrell M, Leonard JV, Bishop NJ. Bone mineralisation in type 1

[202] Zaffanello M, Diomedi-Camassei F, Melzi ML, Torre G, Callea F, Emma F. Sense‐ nbrenner syndrome: a new member of the hepatorenal fibrocystic family. Am J Med

[203] Walczak-Sztulpa J, Eggenschwiler J, Osborn D, et al. Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene.

[204] Gallus GN, Dotti MT, Mignarri A, et al. Four novel CYP27A1 mutations in seven Ital‐

[205] Keren Z, Falik-Zaccai TC. Cerebrotendinous xanthomatosis (CTX): a treatable lipid

[206] Dalal A, Bhavani G SL, Togarrati et al. Analysis of the WISP3 gene in Indian families with progressive pseudorheumatoid dysplasia. Am J Med Genet A 2012; doi:10.1002/

[207] Delague V, Chouery E, Corbani S, et al. Molecular study of WISP3 in nine families originating from the Middle-East and presenting with progressive pseudorheuma‐ toid dysplasia: identification of two novel mutations, and description of a founder ef‐

[208] Penttinen M, Koillinen H, Niinikoski H, Mäkitie O, Hietala M. Genitopatellar syn‐ drome in an adolescent female with severe osteoporosis and endocrine abnormali‐

[209] Campeau PM, Kim JC, Lu JT, et al. Mutations in KAT6B, encoding a histone acetyl‐ transferase, cause Genitopatellar syndrome. Am J Hum Genet. 2012;90(2):282-289.

[210] Foulquier F, Amyere M, Jaeken J, et al. TMEM165 deficiency causes a congenital dis‐

[211] Woods AG, Woods CW, Snow TM. Congenital disorders of glycosylation. Adv Neo‐

[212] Noordam C, Funke S, Knoers NV, et al. Decreased bone density and treatment in pa‐ tients with autosomal recessive cutis laxa. Acta Paediatr 2009;98(3):490-494.

[213] Callewaert B, Su CT, Van Damme T, et al. Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. Hum Mutat 2012; doi: 10.1002/

types I, III and IX. J Inherit Metab Dis 2004;27(1):1-9.

Genet A 2006;140(21):2336-2340.

ajmg.a.35620.

Am J Hum Genet 2010;86(6):949-956.

glycogen storage disease. Eur J Pediatr 1995;154(6):483-487.

ian patients with CTX. Eur J Neurol 2010;17(10):1259-1262.

storage disease. Pediatr Endocrinol Rev 2009;7(1):6-11.

fect. Am J Med Genet A. 2005;138A(2):118-126.

ties. Am J Med Genet A 2009;149A(3):451-455.

natal Care 2012;12(2):90-95.

humu.22165.

order of glycosylation. Am J Hum Genet 2012;91(1):15-26.

[200] Cabrera-Abreu J, Crabtree NJ, Elias E, Fraser W, Cramb R, Alger S. Bone mineral density and markers of bone turnover in patients with glycogen storage disease types I, III and IX. J Inherit Metab Dis 2004;27(1):1-9.

[186] Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with

[187] Liu J, Hoppman N, O'Connell JR, Wang H, Streeten EA, McLenithan JC, Mitchell BD, Shuldiner AR. A functional haplotype in EIF2AK3, an ER stress sensor, is associated

[188] Jaakkola E, Mustonen A, Olsen P, et al. ERCC6 founder mutation identified in Fin‐

[189] Natale V. A comprehensive description of the severity groups in Cockayne syn‐

[190] Selimoglu MA, Ertekin V, Doneray H, Yildirim M. Bone mineral density of children with Wilson disease: efficacy of penicillamine and zinc therapy. J Clin Gastroenterol

[191] Hegedus D, Ferencz V, Lakatos PL, et al. Decreased bone density, elevated serum os‐ teoprotegerin, and beta-cross-laps in Wilson disease. J Bone Miner Res 2002;17(11):

[192] Ogata N, Shiraki M, Hosoi T, Koshizuka Y, Nakamura K, Kawaguchi H. A polymor‐ phic variant at the Werner helicase (WRN) gene is associated with bone density, but not spondylosis, in postmenopausal women. J Bone Miner Metab 2001;19(5):296-301.

[193] Uhrhammer NA, Lafarge L, Dos Santos L, et al. Werner syndrome and mutations of

[194] Mohaghegh P, Hickson ID. Premature aging in RecQ helicase-deficient human syn‐

[195] Mehollin-Ray AR, Kozinetz CA, Schlesinger AE, Guillerman RP, Wang LL. Radio‐ graphic abnormalities in Rothmund-Thomson syndrome and genotype-phenotype correlation with RECQL4 mutation status. AJR Am J Roentgenol 2008;191(2):W62-

[196] Stum M, Davoine CS, Vicart S, et al. Spectrum of HSPG2 (Perlecan) mutations in pa‐ tients with Schwartz-Jampel syndrome. Hum Mutat 2006;27(11):1082-1091.

[197] Mallineni SK, Yiu CK, King NM. Schwartz-Jampel syndrome: a review of the litera‐

[198] Pierce SB, Walsh T, Chisholm KM, et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome.

[199] Jenkinson EM, Clayton-Smith J, et al. Perrault syndrome: further evidence for genetic

the WRN and LMNA genes in France. Hum Mutat 2006;27(7):718-719.

dromes. Int J Biochem Cell Biol 2002;34(11):1496-1501.

ture and case report. Spec Care Dentist 2012;32(3):105-111.

Am J Hum Genet 2010;87(2):282-288.

heterogeneity. J Neurol 2012;259(5):974-976.

with lower bone mineral density. J Bone Miner Res 2012;27(2):331-341.

nish patients with COFS syndrome. Clin Genet. 2010;78(6):541-547.

Wolcott-Rallison syndrome. Nat Genet 2000;25(4):406-409.

drome. Am J Med Genet A 2011;155A(5):1081-1095.

2008;42(2):194-198.

1961-1967.

60 Topics in Osteoporosis

W66.

[214] Reversade B, Escande-Beillard N, Dimopoulou A, et al. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet 2009;41(9):1016-1021.

[228] Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 63

[229] Goseki-Sone M, Sogabe N, Fukushi-Irie M, et al. Functional analysis of the single nu‐ cleotide polymorphism (787T>C) in the tissue-nonspecific alkaline phosphatase gene

[230] Girschick HJ, Schneider P, Kruse K, Huppertz HI. Bone metabolism and bone miner‐

[231] Grünert SC, Schwab KO, Pohl M, Sass JO, Santer R. Fanconi-Bickel syndrome: GLUT2 mutations associated with a mild phenotype. Mol Genet Metab 2012;105(3):

[232] Pena L, Charrow J. Fanconi-Bickel syndrome: Report of life history and successful pregnancy in an affected patient. Am J Med Genet A 2011; 155(2):415-417.

[233] Obermayer-Pietsch BM, Gugatschka M, Reitter S, et al. Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption? Os‐

[234] Honkanen R, Pulkkinen P, Järvinen R, et al. Does lactose intolerance predispose to low bone density? A population-based study of perimenopausal Finnish women.

[235] Hartley JL, Zachos NC, Dawood B, et al. Mutations in TTC37 cause trichohepatoen‐ teric syndrome (phenotypic diarrhea of infancy). Gastroenterology 2010;138(7):

[236] Fabre A, Martinez-Vinson C, Roquelaure B, et al. Novel mutations in TTC37 associat‐ ed with tricho-hepato-enteric syndrome. Hum Mutat 2011;32(3):277-281.

[237] Digilio MC, Sarkozy A, Capolino R, et al. Costello syndrome: clinical diagnosis in the

[238] White SM, Graham JM Jr, Kerr B, et al. The adult phenotype in Costello syndrome. Am J Med Genet A 2005;136(2):128-135. Erratum in: Am J Med Genet A 2005;139(1):

[239] Bachelot A, Chakhtoura Z, Samara-Boustani D, Dulon J, Touraine P, Polak M. Bone health should be an important concern in the care of patients affected by 21 hydroxy‐

[240] Arlt W, Willis DS, Wild SH, et al. United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab 2010;95(11):

first year of life. Eur J Pediatr 2008;167(6):621-628.

lase deficiency. Int J Pediatr Endocrinol 2010;2010: 326275.

became omnipotent. Thromb Haemost 2007;98(1):120-125.

associated with BMD. J Bone Miner Res 2005;20(5):773-782.

433-437.

teoporos Int 2007;18(4):445-451.

Bone 1996;19(1):23-28.

2388-2398, 2398.e1-2.

55.

5110-5121.

al density in childhood hypophosphatasia. Bone 1999;25(3):361-367.

[228] Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost 2007;98(1):120-125.

[214] Reversade B, Escande-Beillard N, Dimopoulou A, et al. Mutations in PYCR1 cause

[215] Lin DS, Yeung CY, Liu HL, et al. A novel mutation in PYCR1 causes an autosomal recessive cutis laxa with premature aging features in a family. Am J Med Genet A.

[216] Rodríguez-Pascau, L., Gort, L., Schuchman, et al. Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. Hum.

[217] Lambert WC, Gagna CE, Lambert MW. Trichothiodystrophy: Photosensitive, TTD-P,

[218] Hashimoto S, Egly JM. Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. Hum Mol Genet 2009;18(R2):R224-R230.

[219] Fukutake T. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke

[220] Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial is‐ chemic cerebral small-vessel disease. N Engl J Med 2009;360(17):1729-1739.

[221] Giordano N, Senesi M, Battisti E, Mattii G, Gennari C. Weill-Marchesani syndrome:

[222] Dagoneau N, Benoist-Lasselin C, Huber C, et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet 2004;75(5):801-806.

[223] Eshed V, Benbassat CA, Laron Z. Effect of alendronate on bone mineral density in adult patients with Laron syndrome (primary growth hormone insensitivity).Growth

[224] Benbassat CA, Eshed V, Kamjin M, Laron Z. Are adult patients with Laron syndrome osteopenic? A comparison between dual-energy X-ray absorptiometry and volumet‐

[225] Agarwal AK, Kazachkova I, Ten S, Garg A. Severe mandibuloacral dysplasia-associ‐ ated lipodystrophy and progeria in a young girl with a novel homozygous

[226] Kosho T, Takahashi J, Momose T, et al. Mandibuloacral dysplasia and a novel LMNA mutation in a woman with severe progressive skeletal changes. Am J Med Genet A

[227] Cranenburg EC, VAN Spaendonck-Zwarts KY, Bonafe L, et al. Circulating matrix γcarboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a

new case of Keutel syndrome. J Thromb Haemost 2011;9(6):1225-1235.

Arg527Cys LMNA mutation. J Clin Endocrinol Metab 2008;93(12):4617-4623.

cutis laxa with progeroid features. Nat Genet 2009;41(9):1016-1021.

TTD, Tay syndrome. Adv Exp Med Biol 2010;685:106-110.

report of an unusual case. Calcif Tissue Int 1997;60(4):358-360.

ric bone densities. J Clin Endocrinol Metab 2003;88(10):4586-4589.

Cerebrovasc Dis 2011 Mar-Apr;20(2):85-93.

Horm IGF Res 2006;16(2):119-124.

2007;143A(21):2598-2603.

2011;155A(6):1285-1289.

62 Topics in Osteoporosis

Mutat 2009;30:1117–1122.

[241] Francis F, Hennig S, Korn B, et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X−linked hypophosphatemic rickets. Nature Genet 1995;11(2):130-136.

[255] Goswami D, Conway GS. Premature ovarian failure. Horm Res 2007;68(4):196-202.

2010;45(6):405.

1994; 53:108-40.

1995;96:119-29.

2007;157:345-350.

syndrome. Int J Androl 2009a;32:1-8.

Metab 2012;23(11):576-581.

nology 2009;150(10):4463-4472.

2010;152A(7):1825-1831.

[256] Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian fail‐ ure. J Mol Endocrinol 2010;45(5):257-79. Review. Erratum in: J Mol Endocrinol

Genetic Diseases Related with Osteoporosis http://dx.doi.org/10.5772/55546 65

[257] Brunetti-Pierri N, Lachman R, Lee K, et al. Terminal osseous dysplasia with pigmen‐ tary defects (TODPD): Follow-up of the first reported family, characterization of the radiological phenotype, and refinement of the linkage region. Am J Med Genet A

[258] Sun Y, Almomani R, Aten E, et al. Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. Am J Hum Genet 2010;87(1):146-153.

[259] Hsu LY. Phenotype/karyotype correlations of Y chromosome aneuploidy with em‐ phasis on structural aberrations in postnatally diagnosed cases. Am J Med Genet

[260] Tuck-Muller CM, Chen H, Martinez JE, et al. Isodicentric Y chromosome: cytogenet‐ ic, molecular and clinical studies and review of the literature. Hum Genet

[261] Ksglaede L, Petersen JH, Main KM, Skakkebaek NE, Juul A. High normal Testoster‐ one levels in infants with non-mosaic Klinefelter's syndrome. Eur J Endocrinol

[262] Corona G, Petrone L, Paggi F, et al. Sexual dysfunction in subjects with Klinefelter's

[263] Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol

[264] Delhon I, Gutzwiller S, Morvan F, et al. Absence of estrogen receptor-related-alpha increases osteoblastic differentiation and cancellous bone mineral density. Endocri‐

[255] Goswami D, Conway GS. Premature ovarian failure. Horm Res 2007;68(4):196-202.

[241] Francis F, Hennig S, Korn B, et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X−linked hypophosphatemic rickets. Nature Genet

[242] Sato K, Tajima T, Nakae J, et al. Three novel PHEX gene mutations in Japanese pa‐ tients with X-linked hypophosphatemic rickets. Pediatr Res 2000;48(4):536-40. [243] Boehmer AL, Brinkmann O, Brüggenwirth H, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 2001;86(9):

[244] Melo KF, Mendonca BB, Billerbeck AE, et al. Clinical, hormonal, behavioral, and ge‐ netic characteristics of androgen insensitivity syndrome in a brazilian cohort: five novel mutations in the androgen receptor gene. J Clin Endocrinol Metab

[245] D'Hulst C, Kooy RF. Fragile X syndrome: from molecular genetics to therapy. J Med

[246] Hjalgrim H, Fisher Hansen B, Brondum-Nielsen K, Nolting D, Kjaer I. Aspects of skeletal development in fragile X syndrome fetuses. Am J Med Genet 2000;95(2):

[247] Bazzocchi A, Femia R, Feraco P, Battista G, Canini R, Guglielmi G. Occipital horn syndrome in a woman: skeletal radiological findings. Skeletal Radiol 2011;40(11):

[248] Dagenais SL, Adam AN, Innis JW, Glover TW. A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease.

[249] Gérard-Blanluet M, Birk-Møller L, Caubel I, Gélot A, Billette de Villemeur T, Horn N. Early development of occipital horns in a classical Menkes patient. Am J Med Genet A 2004;130A(2):211-213. Review. Erratum in: Am J Med Genet A 2005;134(3):346. [250] Kanumakala S, Boneh A, Zacharin M. Pamidronate treatment improves bone mineral density in children with Menkes disease. J Inherit Metab Dis 2002;25(5):391-398. [251] Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet

[252] Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Gen‐

[253] Scherleue A, Greenberg F, McCabe ERB. Dysmorphic features in patients with glyc‐

[254] Walker AP, Muscatelli F, Stafford AN, et al. Mutations and phenotype in isolated

glycerol kinase deficiency. Am J Hum Genet 1996;58(6):1205-1211.

4151-4160. Erratum in: J Clin Endocrinol Metab 2002;87(7):3109.

1995;11(2):130-136.

64 Topics in Osteoporosis

2003;88:3241-3250.

123-129.

1491-1494.

2011;204(12):635-645.

et 1998;19(1):32-38.

Genet 2009;46(9):577-584.

Am J Hum Genet 2001;69(2):420-427.

erol-kinase deficiency. J Pediatr 1995;126:764-767.

**Chapter 3**

**Serum Leptin and Bone Turnover Markers in**

Osteoporosis is a very important health problem worldwide. It is defined as a disease charac‐ terized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk [1]. Osteoporosis is a silent disease and the health and financial impact of the disease result from fracture, particularly hip fracture, for which subjects with osteoporosis are at an increased risk [2]. In the UK, one in two women and one in five men suffer a fracture after the age of 50, with an annual cost to the

In 1990, the number of osteoporotic fractures estimated in Europe was 2.7 million, with an estimated direct cost in 2004 of €36 billion (£24.5 billion), of which €24.3 billion (£16.6 billion) were accounted for by hip fracture. Costs are expected to rise to €76.8 billion (£52.4 billion) by the year 2050 [5]. Similar projections are made for many other regions of the world because of the increasing numbers of the elderly. In the USA, the annual cost of incident fractures due to osteoporosis or low bone mass is predicted to rise from \$16.9 billion in 2006 to around \$25.3 billion by the year 2025 [4]. The direct costs of medical care of hip fractures were over \$65

There are many hormones involved in bone and mineral metabolism, such as oestrogens, testosterone and parathormone (PTH). The adipocyte also plays an important role in regulat‐ ing bone metabolism by releasing estrogens, and the adipokines, like leptin, resistin, adipo‐ nectin, and many others. After the discovery of leptin receptors in bone many studies have been done to explore its involvement in bone metabolism. Some studies have shown that leptin is expressed and secreted from primary cultures of human osteoblasts during the mineraliza‐ tion period, and that it may stimulate osteogenesis in human bone marrow in vitro [7,8].

> © 2013 Lateef et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Postmenopausal Osteoporosis**

Mehreen Lateef, Mukhtiar Baig and Abid Azhar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54527

health services of around £2 billion [3,4].

**1. Introduction**

million in 2004 [6].

### **Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis**

Mehreen Lateef, Mukhtiar Baig and Abid Azhar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54527

### **1. Introduction**

Osteoporosis is a very important health problem worldwide. It is defined as a disease charac‐ terized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk [1]. Osteoporosis is a silent disease and the health and financial impact of the disease result from fracture, particularly hip fracture, for which subjects with osteoporosis are at an increased risk [2]. In the UK, one in two women and one in five men suffer a fracture after the age of 50, with an annual cost to the health services of around £2 billion [3,4].

In 1990, the number of osteoporotic fractures estimated in Europe was 2.7 million, with an estimated direct cost in 2004 of €36 billion (£24.5 billion), of which €24.3 billion (£16.6 billion) were accounted for by hip fracture. Costs are expected to rise to €76.8 billion (£52.4 billion) by the year 2050 [5]. Similar projections are made for many other regions of the world because of the increasing numbers of the elderly. In the USA, the annual cost of incident fractures due to osteoporosis or low bone mass is predicted to rise from \$16.9 billion in 2006 to around \$25.3 billion by the year 2025 [4]. The direct costs of medical care of hip fractures were over \$65 million in 2004 [6].

There are many hormones involved in bone and mineral metabolism, such as oestrogens, testosterone and parathormone (PTH). The adipocyte also plays an important role in regulat‐ ing bone metabolism by releasing estrogens, and the adipokines, like leptin, resistin, adipo‐ nectin, and many others. After the discovery of leptin receptors in bone many studies have been done to explore its involvement in bone metabolism. Some studies have shown that leptin is expressed and secreted from primary cultures of human osteoblasts during the mineraliza‐ tion period, and that it may stimulate osteogenesis in human bone marrow in vitro [7,8].

© 2013 Lateef et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Furthermore, leptin may reduce ovariectomy-induced osteoporosis in rats and may also be involved in foetal and growing bone metabolism [9, 10].

port which has shown that when leptin injected into the brain of animals it will inhibit bone formation at doses lower than those that cause loss of body weight [24]. A lot of studies have been done to explore the relationship of serum leptin with bone mass den‐ sity and biochemical bone markers in osteoporosis. In this chapter, the mechanism of ac‐ tion of leptin on bone is reviewed and role of serum leptin in postmenopausal females is discussed with respect to its relation with bone mass density and biochemical bone

Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis

http://dx.doi.org/10.5772/54527

69

Leptin acts on bone by two different mechanisms. The first is the indirect mechanism revealed by Ducy et al (2000) in mutant mice and rats that either cannot produce or cannot respond to leptin [25]. Leptin secreted from fat cells is carried by the ObRa receptors of vascular endo‐ thelial cells across the blood-brain-barrier where it activates ObRb receptors in the hypothal‐ amus. These signals then stimulate expression of HOBIF (hypothalamic osteoblast inhibitory factor) which when released, lowers the matrix-making ability of osteoblasts [25-29] and because of this reason obese Ob (Lep)–/– mice, which should have low bone mass due to lack

The second direct mechanism of leptin action is by promoting differentiation of bone marrow stromal cells into osteoblasts [8] and by inhibiting osteoclast generation [30]. Bone marrow stromal cells (BMSC) can differentiate into either adipocytes or osteoblast cell lineage. Bone marrow adipocytes may serve as a direct source of leptin, which can inhibits adipogenesis differentiation of BMSC and stimulates differentiation of osteoblasts [31] while Kim et al. (2003) have shown that very high leptin levels led to BMSC apopto‐ sis [32]. Reseland et al. (2001) have found that human osteoblasts start making and se‐ creting leptin when they are either in the late, matrix-mineralizing stage or when changing to osteocytes [7]. Leptin has also stimulates the proliferation of cultured human osteoblasts [33], and it has been shown to cause human bone marrow stromal cells to ex‐ press alkaline phosphatase, collagen-I, and osteocalcin and to mineralize matrix [8]. These tissue culture experiments support the dual effect of leptin within the bone micro‐

In the last decade Ducy et al. (2000a,b) [25,27] have not found any long isoforms of the leptin receptors (Ob-R) on osteoblasts, so they assumed that leptin acted centrally as a very potent inhibitor of bone formation. Although the long isoform of Ob-R is abundant‐ ly expressed in the hypothalamus, and in a large number of peripheral tissues [14]. BMSC, osteoblasts, osteoclasts and chondrocytes also express leptin receptors [8]. In os‐ teoblasts, leptin acts through the osteoprotegerin (OPG)/RANKL (Receptor Activator for Nuclear factor κB Ligand) signaling pathway. Treatment with leptin changes the OPG/ RANKL expression profile favoring OPG [30]. Consequently, osteoclastogenesis is very likely suppressed by leptin through the OPG/RANKL pathway. In agreement with the previous findings, Burguera et al [10] have also confirmed the previous findings that ad‐

**2. Leptin and its mechanism of action on bone**

environment depending on the local leptin concentration.

of leptin, and thus estrogen, actually have an abnormally high bone mass.

markers.

Leptin, a fat-derived cytokine-like hormone, was discovered in 1994 by Friedman and colleagues [11]. A 16-kDa hormone, encoded by the OB gene, is predominantly expressed in adipose tissue [12] and circulates as a free and as a protein-bound entity. According to structural studies leptin belongs to the growth hormone four-helical cytokine subfamily. The leptin receptor was identified in the db locus of mouse chromosome 4. As a member of the IL-6 receptor family, the leptin receptor contains an extracellular-binding domain, a single transmembrane domain and a cytoplasmatic signaling domain [13]. Intracellular signaling is mediated through a non-covalently associated tyrosine kinase of the JAK kinase family [14]. Alternate gene splicing results in five known isoforms of the leptin receptor. The longest form of the receptor (ObR) is the only isoform capable of complete signal transduction. Conversely, the shorter isoforms of the leptin receptor have been suggested to participate in leptin clearance and/or to facilitate transport of leptin across the blood-brain barrier [14]. Circulating levels of leptin correlate with BMI and the content of fat mass. After crossing the blood–brain barrier, leptin reaches the hypothalamus, where it acts as a crucial regulator of feeding. Leptin is mainly regarded as a ''starvation-hormone'' signaling from the adipose tissue (AT) to the brain, indicating the size of the AT-stores [15].

Food intake and energy expenditure are controlled by leptin through an interaction with various neuropeptides in the hypothalamus. Neuropeptide Y (NPY) and agouti-related peptide (AGRP) expressions are inhibited, whereas pro-opiomelanocortin (POMC) expression is stimulated by leptin with increased food intake [16, 17]. Moreover, leptin interacts with neuromedin U (NMU); a novel and recently identified hypothalamic neuropeptide involved also in the regulation of appetite and locomotor activity [18]. Besides energy metabolism, leptin demonstrates pleiotropic effects in such areas as hematopoesis, blood pressure, T lymphocyte function, reproduction and bone mass regulation [14, 19]. Several endocrine and paracrine factors play a role in the fat-bone relationship. A number of local cytokines secreted by the adipose tissue, including leptin, have also been related to BMD variations [20]. Leptin because of its diverse role in bone is being considered one of the main functional connections between fat and bone.

Leptin, known to regulate appetite & energy expenditure may also contribute to mediate the effects of fat mass on bone. Interestingly, obesity seems to protect from osteoporosis. This observation led to researchers at bone formation in mouse models of obesity. Much effort has been dedicated to the relationship between leptin and bone. This interest stems from the well-founded knowledge that body weight is a major determinant of bone den‐ sity [21]. It is known that obesity is generally accompanied by increased bone strength. Obese persons have stronger bones and lose bone tissue at a slower pace [22]. Leptin has been proposed to regulate increased body weight as well as increased bone density. Mice that have congenital absence of leptin (ob/ob) have been shown to be obese and have very high bone density.  The bone mass phenotype of ob/ob mice can be rescued by intracerebroventricular (ICV) infusion of leptin, suggesting that leptin exerts an indirect influence on bone mass. There is a re‐ port which has shown that when leptin injected into the brain of animals it will inhibit bone formation at doses lower than those that cause loss of body weight [24]. A lot of studies have been done to explore the relationship of serum leptin with bone mass den‐ sity and biochemical bone markers in osteoporosis. In this chapter, the mechanism of ac‐ tion of leptin on bone is reviewed and role of serum leptin in postmenopausal females is discussed with respect to its relation with bone mass density and biochemical bone markers.

### **2. Leptin and its mechanism of action on bone**

Furthermore, leptin may reduce ovariectomy-induced osteoporosis in rats and may also be

Leptin, a fat-derived cytokine-like hormone, was discovered in 1994 by Friedman and colleagues [11]. A 16-kDa hormone, encoded by the OB gene, is predominantly expressed in adipose tissue [12] and circulates as a free and as a protein-bound entity. According to structural studies leptin belongs to the growth hormone four-helical cytokine subfamily. The leptin receptor was identified in the db locus of mouse chromosome 4. As a member of the IL-6 receptor family, the leptin receptor contains an extracellular-binding domain, a single transmembrane domain and a cytoplasmatic signaling domain [13]. Intracellular signaling is mediated through a non-covalently associated tyrosine kinase of the JAK kinase family [14]. Alternate gene splicing results in five known isoforms of the leptin receptor. The longest form of the receptor (ObR) is the only isoform capable of complete signal transduction. Conversely, the shorter isoforms of the leptin receptor have been suggested to participate in leptin clearance and/or to facilitate transport of leptin across the blood-brain barrier [14]. Circulating levels of leptin correlate with BMI and the content of fat mass. After crossing the blood–brain barrier, leptin reaches the hypothalamus, where it acts as a crucial regulator of feeding. Leptin is mainly regarded as a ''starvation-hormone'' signaling from the adipose tissue (AT) to the brain,

Food intake and energy expenditure are controlled by leptin through an interaction with various neuropeptides in the hypothalamus. Neuropeptide Y (NPY) and agouti-related peptide (AGRP) expressions are inhibited, whereas pro-opiomelanocortin (POMC) expression is stimulated by leptin with increased food intake [16, 17]. Moreover, leptin interacts with neuromedin U (NMU); a novel and recently identified hypothalamic neuropeptide involved also in the regulation of appetite and locomotor activity [18]. Besides energy metabolism, leptin demonstrates pleiotropic effects in such areas as hematopoesis, blood pressure, T lymphocyte function, reproduction and bone mass regulation [14, 19]. Several endocrine and paracrine factors play a role in the fat-bone relationship. A number of local cytokines secreted by the adipose tissue, including leptin, have also been related to BMD variations [20]. Leptin because of its diverse role in bone is being considered one of the main functional connections between

Leptin, known to regulate appetite & energy expenditure may also contribute to mediate the effects of fat mass on bone. Interestingly, obesity seems to protect from osteoporosis. This observation led to researchers at bone formation in mouse models of obesity. Much effort has been dedicated to the relationship between leptin and bone. This interest stems from the well-founded knowledge that body weight is a major determinant of bone den‐ sity [21]. It is known that obesity is generally accompanied by increased bone strength. Obese persons have stronger bones and lose bone tissue at a slower pace [22]. Leptin has been proposed to regulate increased body weight as well as increased bone density. Mice that have congenital absence of leptin (ob/ob) have been shown to be obese and have very high bone density.  The bone mass phenotype of ob/ob mice can be rescued by intracerebroventricular (ICV) infusion of leptin, suggesting that leptin exerts an indirect influence on bone mass. There is a re‐

involved in foetal and growing bone metabolism [9, 10].

indicating the size of the AT-stores [15].

fat and bone.

68 Topics in Osteoporosis

Leptin acts on bone by two different mechanisms. The first is the indirect mechanism revealed by Ducy et al (2000) in mutant mice and rats that either cannot produce or cannot respond to leptin [25]. Leptin secreted from fat cells is carried by the ObRa receptors of vascular endo‐ thelial cells across the blood-brain-barrier where it activates ObRb receptors in the hypothal‐ amus. These signals then stimulate expression of HOBIF (hypothalamic osteoblast inhibitory factor) which when released, lowers the matrix-making ability of osteoblasts [25-29] and because of this reason obese Ob (Lep)–/– mice, which should have low bone mass due to lack of leptin, and thus estrogen, actually have an abnormally high bone mass.

The second direct mechanism of leptin action is by promoting differentiation of bone marrow stromal cells into osteoblasts [8] and by inhibiting osteoclast generation [30]. Bone marrow stromal cells (BMSC) can differentiate into either adipocytes or osteoblast cell lineage. Bone marrow adipocytes may serve as a direct source of leptin, which can inhibits adipogenesis differentiation of BMSC and stimulates differentiation of osteoblasts [31] while Kim et al. (2003) have shown that very high leptin levels led to BMSC apopto‐ sis [32]. Reseland et al. (2001) have found that human osteoblasts start making and se‐ creting leptin when they are either in the late, matrix-mineralizing stage or when changing to osteocytes [7]. Leptin has also stimulates the proliferation of cultured human osteoblasts [33], and it has been shown to cause human bone marrow stromal cells to ex‐ press alkaline phosphatase, collagen-I, and osteocalcin and to mineralize matrix [8]. These tissue culture experiments support the dual effect of leptin within the bone micro‐ environment depending on the local leptin concentration.

In the last decade Ducy et al. (2000a,b) [25,27] have not found any long isoforms of the leptin receptors (Ob-R) on osteoblasts, so they assumed that leptin acted centrally as a very potent inhibitor of bone formation. Although the long isoform of Ob-R is abundant‐ ly expressed in the hypothalamus, and in a large number of peripheral tissues [14]. BMSC, osteoblasts, osteoclasts and chondrocytes also express leptin receptors [8]. In os‐ teoblasts, leptin acts through the osteoprotegerin (OPG)/RANKL (Receptor Activator for Nuclear factor κB Ligand) signaling pathway. Treatment with leptin changes the OPG/ RANKL expression profile favoring OPG [30]. Consequently, osteoclastogenesis is very likely suppressed by leptin through the OPG/RANKL pathway. In agreement with the previous findings, Burguera et al [10] have also confirmed the previous findings that ad‐ ministration of leptin reduced ovariectomy induced bone loss in rats by increasing osteo‐ protegerin mRNA in osteoblasts. Cornish et al in 2001 have found that leptin given peripherally increased bone strength in mice and also increased proliferation of osteo‐ blasts in vitro [34]. The results of these studies showed that direct peripheral action of leptin on bone is to enhance the strength of the bone in contrast to its central effect.

in women but not in men [31]. Sato et al. (2001) have found a positive correlation between serum leptin and calcaneus BMD in men, but the relationship became inverse when adjusted for body weight [18]. Pasco et al. (2001) have demonstrated a significant positive association between BMD and serum leptin in non-obese women [55]. Results of Blain et al (2002) reported that leptin is an independent predictor of whole body and femoral neck BMD in postmeno‐ pausal women [56]. Nagy et al. (2001) found a negative correlation between serum leptin levels and radial and femoral BMD in postmenopausal women [57]. Hadji et al. (2001) reported that bone mass is not correlated with the serum leptin level in pre or postmenopausal women [58]. Rauch et al. (1998) also reported no correlation between bone mass and serum leptin levels by examining total and trabecular bone density at the distal radius in adult women [59]. In leptin literature, several studies have examined the relationship between serum leptin and BMD in various cohorts, but the results remain contradictory. This fact reflects the intricacy of the

Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis

http://dx.doi.org/10.5772/54527

71

A study by Hamrick and Ferrari (2008) has documented that the effect of leptin is re‐ duced with increased age and higher BMI in both humans and laboratory animals in spite of high serum leptin levels [60]. It has been postulated that the under-responsive‐ ness to leptin, or leptin resistance, is mediated either by impaired transport of leptin through the blood-brain barrier, lower expression of leptin receptors and/or by the inhib‐ ition of the intracellular leptin signaling [61]. In plasma, leptin is bound to soluble lep‐ tin receptor (SLR), the product of an alternate splicing of leptin receptor mRNA or proteolytic cleavage [14]. Whereas serum leptin levels correlate positively with BMI, SLR is correlated negatively [14,62]. The inverse relationship between SLR and BMI reflects a feedback regulation between the body weight and leptin or leptin receptor expressions. It is observed in a study by Welt et al. (2004) when low serum leptin levels in women with hypothalamic amenorrhea (induced either by exercise or by low body weight) were treated with recombinant human leptin for three months, it led to an increase of osteo‐ calcin, bone alkaline phosphates and IGF-1, whereas urinary N-telopeptide did not change [63].They have demonstrated that leptin administration in individuals with lep‐ tin deficiency appeared to improve the growth hormone axis and markers of bone for‐

Bone markers are product derived from the bone remodeling process. During this process, compounds are released either from bone or from the cells involved in the bone remodeling process (osteoblasts and osteoclasts.) Markers of bone turnover are biochemical products measured usually in blood or urine that reflect the metabolic activity of bone but which themselves have no function in controlling skeletal metabolism [64]. Biochemical markers of bone turnover are broadly divided into two categories: markers of bone resorption, which reflect osteoclast activity and are for the most part degradation products of type I collagen; markers of bone formation, which reflect osteoblast activity and are byproducts of collagen

**4. Osteoporosis and bone turnover markers (BTMs)**

synthesis, matrix proteins or osteoblastic enzymes (Table 1) [65].

relationship of leptin and bone.

mation [63].

In order to evaluate its central effect, leptin was injected into the brain in the form of an intra-cerebelo-ventricular infusion [25, 27, 35]. Bone loss occurred in both wild-type mice and leptin deficient mice confirming that bone mass is partly regulated via the central, hypothalamic relay [25]. However, bone formation was inhibited at lower doses of leptin than those necessary to cause the loss of body weight. Ob/ob mice have low sympathetic activity, which led to the assumption that the central effect of leptin on bone is mediated by the sympathetic nervous system (SNS) [36]. The effect of leptin on the sympathetic nervous system is an important aspect in the regulation of energy homeostasis as well as several other physiological functions [37].

### **3. Serum leptin and Bone Mass Density (BMD)**

It is widely recognized that BMD measurement can predict fracture risk in the same way as cholesterol predicts cardiovascular disease [38]. In fact, the strength of BMD measurement to predict fracture is approx 3 fold higher than strength of serum cholesterol to predict cardio‐ vascular disease [39]. Bone mass measurement has been found to be a single best predictor of fracture risk and is required to the early diagnosis of osteoporosis [37,38,39].

It is observed in a study by Lateef et al 2010 that BMD is found to be significantly lower in postmenopausal females with and without osteoporosis as compared to premenopausal females [40] and there is a negative correlation between age and BMD found in post meno‐ pausal ostreoporotic females indicating bone loss with age and menopause [41]. A rapid bone loss is commonly seen in elderly individuals and tends to worsen with advancing age. The aging population is inevitably proven to be more osteoporotic unless it is intervened first with diagnostic tools and after preventive therapy [42].

Another study of Lateef et al 2011 showed that plasma leptin levels were positively correlated with bone mineral density (BMD) values in osteoporotic females [43]. Some reports have suggested a correlation between serum leptin concentration and BMD while other showed no such association [44-48]. It has been shown that plasma leptin levels are positively correlated with BMD at all skeleton sites measured in postmenopausal osteoporosis [49]. It is interesting to note that the obese are usually protected against osteoporosis and have increased bone mineral density [50]. This has been attributed to the mechanical effects of their excessive weight on bone tissue. It has been shown that obese postmenopausal women have a tendency to have increased bone mineral density compared with lean women [51-53]. The study of Di Carlo et al. (2007) documented a significant correlation between serum leptin and BMD in early postmenopausal women but the correlation was lost during progression of the postmeno‐ pausal period [54]. Thomas et al. (2001) have observed that serum leptin correlated with BMD in women but not in men [31]. Sato et al. (2001) have found a positive correlation between serum leptin and calcaneus BMD in men, but the relationship became inverse when adjusted for body weight [18]. Pasco et al. (2001) have demonstrated a significant positive association between BMD and serum leptin in non-obese women [55]. Results of Blain et al (2002) reported that leptin is an independent predictor of whole body and femoral neck BMD in postmeno‐ pausal women [56]. Nagy et al. (2001) found a negative correlation between serum leptin levels and radial and femoral BMD in postmenopausal women [57]. Hadji et al. (2001) reported that bone mass is not correlated with the serum leptin level in pre or postmenopausal women [58]. Rauch et al. (1998) also reported no correlation between bone mass and serum leptin levels by examining total and trabecular bone density at the distal radius in adult women [59]. In leptin literature, several studies have examined the relationship between serum leptin and BMD in various cohorts, but the results remain contradictory. This fact reflects the intricacy of the relationship of leptin and bone.

ministration of leptin reduced ovariectomy induced bone loss in rats by increasing osteo‐ protegerin mRNA in osteoblasts. Cornish et al in 2001 have found that leptin given peripherally increased bone strength in mice and also increased proliferation of osteo‐ blasts in vitro [34]. The results of these studies showed that direct peripheral action of leptin on bone is to enhance the strength of the bone in contrast to its central effect.

In order to evaluate its central effect, leptin was injected into the brain in the form of an intra-cerebelo-ventricular infusion [25, 27, 35]. Bone loss occurred in both wild-type mice and leptin deficient mice confirming that bone mass is partly regulated via the central, hypothalamic relay [25]. However, bone formation was inhibited at lower doses of leptin than those necessary to cause the loss of body weight. Ob/ob mice have low sympathetic activity, which led to the assumption that the central effect of leptin on bone is mediated by the sympathetic nervous system (SNS) [36]. The effect of leptin on the sympathetic nervous system is an important aspect in the regulation of energy homeostasis as well as

It is widely recognized that BMD measurement can predict fracture risk in the same way as cholesterol predicts cardiovascular disease [38]. In fact, the strength of BMD measurement to predict fracture is approx 3 fold higher than strength of serum cholesterol to predict cardio‐ vascular disease [39]. Bone mass measurement has been found to be a single best predictor of

It is observed in a study by Lateef et al 2010 that BMD is found to be significantly lower in postmenopausal females with and without osteoporosis as compared to premenopausal females [40] and there is a negative correlation between age and BMD found in post meno‐ pausal ostreoporotic females indicating bone loss with age and menopause [41]. A rapid bone loss is commonly seen in elderly individuals and tends to worsen with advancing age. The aging population is inevitably proven to be more osteoporotic unless it is intervened first with

Another study of Lateef et al 2011 showed that plasma leptin levels were positively correlated with bone mineral density (BMD) values in osteoporotic females [43]. Some reports have suggested a correlation between serum leptin concentration and BMD while other showed no such association [44-48]. It has been shown that plasma leptin levels are positively correlated with BMD at all skeleton sites measured in postmenopausal osteoporosis [49]. It is interesting to note that the obese are usually protected against osteoporosis and have increased bone mineral density [50]. This has been attributed to the mechanical effects of their excessive weight on bone tissue. It has been shown that obese postmenopausal women have a tendency to have increased bone mineral density compared with lean women [51-53]. The study of Di Carlo et al. (2007) documented a significant correlation between serum leptin and BMD in early postmenopausal women but the correlation was lost during progression of the postmeno‐ pausal period [54]. Thomas et al. (2001) have observed that serum leptin correlated with BMD

fracture risk and is required to the early diagnosis of osteoporosis [37,38,39].

several other physiological functions [37].

70 Topics in Osteoporosis

**3. Serum leptin and Bone Mass Density (BMD)**

diagnostic tools and after preventive therapy [42].

A study by Hamrick and Ferrari (2008) has documented that the effect of leptin is re‐ duced with increased age and higher BMI in both humans and laboratory animals in spite of high serum leptin levels [60]. It has been postulated that the under-responsive‐ ness to leptin, or leptin resistance, is mediated either by impaired transport of leptin through the blood-brain barrier, lower expression of leptin receptors and/or by the inhib‐ ition of the intracellular leptin signaling [61]. In plasma, leptin is bound to soluble lep‐ tin receptor (SLR), the product of an alternate splicing of leptin receptor mRNA or proteolytic cleavage [14]. Whereas serum leptin levels correlate positively with BMI, SLR is correlated negatively [14,62]. The inverse relationship between SLR and BMI reflects a feedback regulation between the body weight and leptin or leptin receptor expressions. It is observed in a study by Welt et al. (2004) when low serum leptin levels in women with hypothalamic amenorrhea (induced either by exercise or by low body weight) were treated with recombinant human leptin for three months, it led to an increase of osteo‐ calcin, bone alkaline phosphates and IGF-1, whereas urinary N-telopeptide did not change [63].They have demonstrated that leptin administration in individuals with lep‐ tin deficiency appeared to improve the growth hormone axis and markers of bone for‐ mation [63].

### **4. Osteoporosis and bone turnover markers (BTMs)**

Bone markers are product derived from the bone remodeling process. During this process, compounds are released either from bone or from the cells involved in the bone remodeling process (osteoblasts and osteoclasts.) Markers of bone turnover are biochemical products measured usually in blood or urine that reflect the metabolic activity of bone but which themselves have no function in controlling skeletal metabolism [64]. Biochemical markers of bone turnover are broadly divided into two categories: markers of bone resorption, which reflect osteoclast activity and are for the most part degradation products of type I collagen; markers of bone formation, which reflect osteoblast activity and are byproducts of collagen synthesis, matrix proteins or osteoblastic enzymes (Table 1) [65].

**5.2. Bone specific alkaline phosphatase**

indicate estrogen deficiency [69,70].

**5.3. Osteocalcin**

have been reported [72].

Bone specific alkaline phosphatase (BALP) is one of several isoenzymes of the alkaline phosphatase (ALP) family. The entire family is encoded by four gene loci, three tissue specific genes (bone,kidney,liver and other tissues). Although the nonspecific ALPs are the products of a single gene, the ioenzymes present in tissues such as bone, kidney or liver vary greatly because of variations in their carbohydrate side chains. These post translational modifications are exploited to distinguish the various ALP-isoforms from each other, employing methods including gel electrophoresis, heat denaturation, chemical inhibition or binding through specific monoclonal antibodies [68]. For therapeutic monitoring of patients, B-ALP measure‐ ments are good indicators of the metabolic activity of bone. Rising ALP concentrations may

Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis

http://dx.doi.org/10.5772/54527

73

Osteocalcin (OC) is a small, hydroxyapetite-binding protein synthesized by osteoblasts and to a lesser extent by hypertrophic chondrocytes. It contains three gamma- carboxyglutamic acid (Gla) residues which are responsible for calcium binding properties of protein. The precise function of osteocalcin has yet to be determined but recent studies suggest that OC is involved in bone remodeling via a negative mechanism. Serum osteocalcin is considered as a specific marker of osteoblast function, as its levels correlate with bone formation rates. However, the peptide is rapidly degraded in serum and both intact peptides and OC fragments of various sizes coexist in the circulation [70]. Osteocalcin is normally considered as bone formation marker. However, because it is released during bone formation from bone forming cells and during bone resorption from bone matrix, it reflects the overall turnover of bone. Assays have been developed to detect the intact protein and or the main breakdown product called N-mid fragment. OC serum levels follow a circadian rhythm with high values in early morning, but usually not influenced by food intake. Serum osteocalcin levels reportedly vary significantly

during the menstrual cycle with the highest level observerd during luteal phase [71].

The amino and carboxy terminal procollagen propeptides of type I collagen (PINP, PICP) are cleaved by specific extracellular endopeptidases from newly translated collagen type I pepetide. As these extension peptides are generated in a stoichiometric relationship with collagen biosynthesis, they are considered quantitative measures of newly formed type I collagen. However, because type I collagen is also a component of several soft tissues (fibro‐ cartilage, tendon, skin, gingival, intestine, heart valve, and large vessels) there is potential contribution to circulating procollagens from soft tissue synthesis of type I collagen. Both PICP and PINP demonstrate a cardian rhythm with peak values in the early morning, and are usually not influenced by food intake. Serum levels of amino and carboxy terminal procollagen propeptides of type I collagen (PINP, PICP) are measured by type and site specific immuno‐ assays [66]. Moderate correlations between serum PICP levels and the rate of bone formation

**5.4. Amino & carboxyterminal procollagen propeptides of type I collagen**

**Table 1.** List of important biochemical markers of bone turnover

### **5. Markers of bone formation**

Bone formation markers are direct or indirect products of active osteoblasts expressed during different phases of osteoblast development and reflecting different aspects of osteoblast function and bone formation. All markers are measured in serum or plasma [66].

### **5.1. Alkaline phosphatase**

Alkaline phosphatase (ALP) is a ubiquitous enzyme that plays an important role in osteoid formation and mineralization. The total ALP serum pool consists of several dimeric isoforms which originate from various tissues such as liver, bone, intestine, spleen, kidney and placenta. In adults with normal liver function, approximately 50% of the total ALP activity in serum arises from liver and 50% arise from bone [67].

### **5.2. Bone specific alkaline phosphatase**

Bone specific alkaline phosphatase (BALP) is one of several isoenzymes of the alkaline phosphatase (ALP) family. The entire family is encoded by four gene loci, three tissue specific genes (bone,kidney,liver and other tissues). Although the nonspecific ALPs are the products of a single gene, the ioenzymes present in tissues such as bone, kidney or liver vary greatly because of variations in their carbohydrate side chains. These post translational modifications are exploited to distinguish the various ALP-isoforms from each other, employing methods including gel electrophoresis, heat denaturation, chemical inhibition or binding through specific monoclonal antibodies [68]. For therapeutic monitoring of patients, B-ALP measure‐ ments are good indicators of the metabolic activity of bone. Rising ALP concentrations may indicate estrogen deficiency [69,70].

### **5.3. Osteocalcin**

Bone formation Detected in

Procollagen type I C-terminal propeptides (P1CP) Serum

Procollagen type I N-terminal propeptides (PINP) Serum/Plasma

Osteocalcins (OC) Serum/Plasma

Bone alkaline phosphatases (BALP) Serum

Hydroxyprolin Urine Pyridinolin(PYD) Urine Deoxypyridinoline (DPD) Urine

N-terminal cross-linked telopeptide (NTX) Urine and serum/plasma C-terminal cross-linked telopeptide (CTX) Urine and serum/plasma

Bone formation markers are direct or indirect products of active osteoblasts expressed during different phases of osteoblast development and reflecting different aspects of osteoblast

Alkaline phosphatase (ALP) is a ubiquitous enzyme that plays an important role in osteoid formation and mineralization. The total ALP serum pool consists of several dimeric isoforms which originate from various tissues such as liver, bone, intestine, spleen, kidney and placenta. In adults with normal liver function, approximately 50% of the total ALP activity in serum

Tartrate-resistant acid phosphatases (TRACP) Serum

function and bone formation. All markers are measured in serum or plasma [66].

Bone resorption Detected in

Byproducts of collagen synthesis

**Collagen degradation products**

Cross-linked telopeptides of type I collagen

Matrix protein

72 Topics in Osteoporosis

Osteoblast enzyme

Osteoclast enzymes

**5. Markers of bone formation**

**5.1. Alkaline phosphatase**

**Table 1.** List of important biochemical markers of bone turnover

arises from liver and 50% arise from bone [67].

Osteocalcin (OC) is a small, hydroxyapetite-binding protein synthesized by osteoblasts and to a lesser extent by hypertrophic chondrocytes. It contains three gamma- carboxyglutamic acid (Gla) residues which are responsible for calcium binding properties of protein. The precise function of osteocalcin has yet to be determined but recent studies suggest that OC is involved in bone remodeling via a negative mechanism. Serum osteocalcin is considered as a specific marker of osteoblast function, as its levels correlate with bone formation rates. However, the peptide is rapidly degraded in serum and both intact peptides and OC fragments of various sizes coexist in the circulation [70]. Osteocalcin is normally considered as bone formation marker. However, because it is released during bone formation from bone forming cells and during bone resorption from bone matrix, it reflects the overall turnover of bone. Assays have been developed to detect the intact protein and or the main breakdown product called N-mid fragment. OC serum levels follow a circadian rhythm with high values in early morning, but usually not influenced by food intake. Serum osteocalcin levels reportedly vary significantly during the menstrual cycle with the highest level observerd during luteal phase [71].

### **5.4. Amino & carboxyterminal procollagen propeptides of type I collagen**

The amino and carboxy terminal procollagen propeptides of type I collagen (PINP, PICP) are cleaved by specific extracellular endopeptidases from newly translated collagen type I pepetide. As these extension peptides are generated in a stoichiometric relationship with collagen biosynthesis, they are considered quantitative measures of newly formed type I collagen. However, because type I collagen is also a component of several soft tissues (fibro‐ cartilage, tendon, skin, gingival, intestine, heart valve, and large vessels) there is potential contribution to circulating procollagens from soft tissue synthesis of type I collagen. Both PICP and PINP demonstrate a cardian rhythm with peak values in the early morning, and are usually not influenced by food intake. Serum levels of amino and carboxy terminal procollagen propeptides of type I collagen (PINP, PICP) are measured by type and site specific immuno‐ assays [66]. Moderate correlations between serum PICP levels and the rate of bone formation have been reported [72].

### **5.5. Markers of bone resorption**

Most biochemical markers of bone resorption are degradation products of bone collagen, but noncollagenous proteins such as bone sialoprotein or tartarate resistant acid phosphatase have also been investigated [73].

The use of biochemical markers of bone remodeling in the monitoring of patients on treatment for osteoporosis is generally well-recognized [81,82]. However, optimum treatment targets specific to various therapies and the benefits of monitoring in terms of improvement in fracture

Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis

http://dx.doi.org/10.5772/54527

75

The changes in BMD and BTMs following the initiation of osteoporosis treatment independ‐ ently correlate with fracture risk reduction [84]. The advantage of BTM over BDM is that the change in BTMs following treatment explains a greater proportion of treatment as compared to BMD does, in terms of fracture risk reduction [85,86]. Also, the change in BMD is small and slow whereas the changes in BTMs are large and occur early after initiation of therapy. Repeat BMD is not advocated within 12 months after initiation of therapy as the changes do not generally attain significance within that time, and in fact 18-24 months may be appropriate for repeat BMD measurements [87]. BTMs on the other hand show significant change by 3-6 months. For example, bone resorption markers can be measured 3 months after initiation of oral bisphosphonates, and bone formation markers 6 months after start of therapy [88, 89). Changes in BTMs may be useful in monitoring osteoporosis treatment to confirm compliance

There are many studies which have demonstrated BTMs and their contribution to fracture risk, but the results of these studies have been inconsistent [91-95]. Many studies which have shown positive results with BTMs included bone resorption markers, with increased resorption marker predicting an increased fracture risk. While for BTMs to predict fracture risk inde‐ pendently of BMD, it is needed to clarify their relationships to other established risk factors.

The changes in BTMs following therapy are well documented. There is a decrease in BTMs following initiation of anti-resorptive therapy, reflecting inhibition of osteoclastic activity [96-100]. For example, with bisphosphonate treatment, there is a decrease in bone resorption markers within days following intravenous therapy, and within weeks following oral therapy.

Vasikaran et al [83] supports the role of BTMs in the management of patients with osteoporosis and also emphasized on the adoption of international reference standards for enhancing

The problem in BTMs use is their wide biological and analytical variability, Glover et al [101] emphasized that reference ranges should be defined and standardized with emphasis on sample size and age range of the population. Sandhu & Hampson (2011) describe that the best established clinical use for BTMs is in monitoring treatment efficacy and compliance [102]. In a study by Kim et al observed that BMT can be used to determine BMD response to antire‐

The Scientific Advisory Council of Osteoporosis Canada including multidisciplinary working group stated about the bone turnover markers in the management of postmenopausal osteoporosis that as far as potential uses of bone turn over markers (BTMs) are concerned, they can be used to predict bone loss and fracture in untreated postmenopausal women. They can also be used to monitor osteoporosis therapy, and up to some extent enhance the adherence to therapy but BTMs should not be used for diagnosis of osteoporosis as s separate and

laboratory consistency and to facilitate their inclusion in routine clinical practice.

sorptive therapy in Korean postmenopausal osteoporotic females [103].

outcomes or in adherence to oral therapies are not established [83].

with oral therapies and efficacy of treatment [90].

### **5.6. Hydroxy proline**

Hydroxyproline is an amino acid common to and characteristic of all forms of collagen, and urinary hydroxyproline excretion is the oldest test of bone resorption. However, this test lacks specificity for bone resorption because excreted hydroxyproline also comes from other tissues, particularly from skin collagen (which can turn over rapidly in certain disorders), from newly synthesized collagen that is not incorporated into tissue, and from dietary collagen and gelatin. Because it is less specific than newer tests, it is no longer widely used [74].

### **5.7. Pyridinoline (Pyr) and Deoxypyridinoline (DPD)**

The pyridinum crosslinks pyridinoline (PYD) and deoxypyridinolin (DPD) are the main crosslinks in skeletal tissues but act as stabilizers of mature croslinks in type I, II & III collagens of all major connective tissues (bone, dentin, ligaments, tendons, vascular walls, muscle and intestine) except skin. While PYD predominates in most tissues, DPD is most abundant in bone and therefore is considered the more specific marker [75].

### **5.8. Crosslinked Telopeptides**

The term "crosslinked telopeptides" refers to the measurement of collagen degradation products associated with the crosslink regions in type I collagen. Fragments derived from the C terminus are also released into circulation as a result of the osteoclast-mediated degradation of type I collagen and can be measured by various assays [76, 77]. The immuno reactive epitopes are located on peptide fragments derived from the N terminal (NTX-1) and C terminal (CTX-1 and ICTP) telopeptides of the collagen type I molecule. The NTX-1 and CTX-1 epitopes can be measured in both serum and in urine [78, 79].

### **6. Tatartarate Resistant Acid Phosphatase (TRACP)**

Tartarate resistant acid phosphate is synthesized and secreted by osteoclasts during active bone resorption. The process of resorption occurs after the attachment of osteoclasts to the bone surface and follows the secretion of acid and enzymes into a space created between the osteoclast and the bone. The acidic environment is produced by the action of carbonic anhydrase and an H-ATPase proton pump. TRACP, one of the enzymes secreted into this space, has been located in the adjacent osteoclast membrane (known as the ruffled border) [80]. Its activity in serum reflects bone resorption rates and more recently it has been possible to measure the isoenzyme by very specific immunoassays

The use of biochemical markers of bone remodeling in the monitoring of patients on treatment for osteoporosis is generally well-recognized [81,82]. However, optimum treatment targets specific to various therapies and the benefits of monitoring in terms of improvement in fracture outcomes or in adherence to oral therapies are not established [83].

**5.5. Markers of bone resorption**

also been investigated [73].

**5.8. Crosslinked Telopeptides**

**5.6. Hydroxy proline**

74 Topics in Osteoporosis

Most biochemical markers of bone resorption are degradation products of bone collagen, but noncollagenous proteins such as bone sialoprotein or tartarate resistant acid phosphatase have

Hydroxyproline is an amino acid common to and characteristic of all forms of collagen, and urinary hydroxyproline excretion is the oldest test of bone resorption. However, this test lacks specificity for bone resorption because excreted hydroxyproline also comes from other tissues, particularly from skin collagen (which can turn over rapidly in certain disorders), from newly synthesized collagen that is not incorporated into tissue, and from dietary collagen and gelatin.

The pyridinum crosslinks pyridinoline (PYD) and deoxypyridinolin (DPD) are the main crosslinks in skeletal tissues but act as stabilizers of mature croslinks in type I, II & III collagens of all major connective tissues (bone, dentin, ligaments, tendons, vascular walls, muscle and intestine) except skin. While PYD predominates in most tissues, DPD is most abundant in bone

The term "crosslinked telopeptides" refers to the measurement of collagen degradation products associated with the crosslink regions in type I collagen. Fragments derived from the C terminus are also released into circulation as a result of the osteoclast-mediated degradation of type I collagen and can be measured by various assays [76, 77]. The immuno reactive epitopes are located on peptide fragments derived from the N terminal (NTX-1) and C terminal (CTX-1 and ICTP) telopeptides of the collagen type I molecule. The NTX-1 and CTX-1 epitopes

Tartarate resistant acid phosphate is synthesized and secreted by osteoclasts during active bone resorption. The process of resorption occurs after the attachment of osteoclasts to the bone surface and follows the secretion of acid and enzymes into a space created between the osteoclast and the bone. The acidic environment is produced by the action of carbonic anhydrase and an H-ATPase proton pump. TRACP, one of the enzymes secreted into this space, has been located in the adjacent osteoclast membrane (known as the ruffled border) [80]. Its activity in serum reflects bone resorption rates and more recently it has been possible to

Because it is less specific than newer tests, it is no longer widely used [74].

**5.7. Pyridinoline (Pyr) and Deoxypyridinoline (DPD)**

and therefore is considered the more specific marker [75].

can be measured in both serum and in urine [78, 79].

measure the isoenzyme by very specific immunoassays

**6. Tatartarate Resistant Acid Phosphatase (TRACP)**

The changes in BMD and BTMs following the initiation of osteoporosis treatment independ‐ ently correlate with fracture risk reduction [84]. The advantage of BTM over BDM is that the change in BTMs following treatment explains a greater proportion of treatment as compared to BMD does, in terms of fracture risk reduction [85,86]. Also, the change in BMD is small and slow whereas the changes in BTMs are large and occur early after initiation of therapy. Repeat BMD is not advocated within 12 months after initiation of therapy as the changes do not generally attain significance within that time, and in fact 18-24 months may be appropriate for repeat BMD measurements [87]. BTMs on the other hand show significant change by 3-6 months. For example, bone resorption markers can be measured 3 months after initiation of oral bisphosphonates, and bone formation markers 6 months after start of therapy [88, 89). Changes in BTMs may be useful in monitoring osteoporosis treatment to confirm compliance with oral therapies and efficacy of treatment [90].

There are many studies which have demonstrated BTMs and their contribution to fracture risk, but the results of these studies have been inconsistent [91-95]. Many studies which have shown positive results with BTMs included bone resorption markers, with increased resorption marker predicting an increased fracture risk. While for BTMs to predict fracture risk inde‐ pendently of BMD, it is needed to clarify their relationships to other established risk factors.

The changes in BTMs following therapy are well documented. There is a decrease in BTMs following initiation of anti-resorptive therapy, reflecting inhibition of osteoclastic activity [96-100]. For example, with bisphosphonate treatment, there is a decrease in bone resorption markers within days following intravenous therapy, and within weeks following oral therapy.

Vasikaran et al [83] supports the role of BTMs in the management of patients with osteoporosis and also emphasized on the adoption of international reference standards for enhancing laboratory consistency and to facilitate their inclusion in routine clinical practice.

The problem in BTMs use is their wide biological and analytical variability, Glover et al [101] emphasized that reference ranges should be defined and standardized with emphasis on sample size and age range of the population. Sandhu & Hampson (2011) describe that the best established clinical use for BTMs is in monitoring treatment efficacy and compliance [102]. In a study by Kim et al observed that BMT can be used to determine BMD response to antire‐ sorptive therapy in Korean postmenopausal osteoporotic females [103].

The Scientific Advisory Council of Osteoporosis Canada including multidisciplinary working group stated about the bone turnover markers in the management of postmenopausal osteoporosis that as far as potential uses of bone turn over markers (BTMs) are concerned, they can be used to predict bone loss and fracture in untreated postmenopausal women. They can also be used to monitor osteoporosis therapy, and up to some extent enhance the adherence to therapy but BTMs should not be used for diagnosis of osteoporosis as s separate and independent factor. Similarly it must not be used to select the most appropriate type of osteoporotic therapy for the treatment. [104].

occurring in responses to weight loss and weight regain. The drop in leptin levels was strongly related to the increase in bone resorption marker occurring in response to weight loss. Similarly, after weight regain the rise in leptin levels was associated with a concomitant

Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis

http://dx.doi.org/10.5772/54527

77

The relationship of leptin and bone turnover markers in post menopausal osteoporosis has not yet been clarified. Although several studies have been done but still there is need to explore their exact connection. Many studies have recommended that in the treatment of the post-men‐ opausal women, biochemical markers of bone turnover may be useful as adjuncts to BMD and other diagnostic tests. They can be mainly used to monitor response to treatment and also used as relatively economical tools for studying bone metabolism. The exact roles of BTM need to be established in clinical practice. It is suggested that repeated measurements of bone markers during anti-resorptive therapy may help to improve the management of osteoporotic patients. Both a peripheral and a central action of leptin on bone metabolism have been suggested. Pe‐ ripherally, leptin is thought to exert positive effects on bone formation, whereas it is thought to reduce bone formation via a central control mechanism when binding to its specific receptors located on the hypothalamic nuclei [26]. It has been suggested that circulating leptin may act positively to maintain bone mass but these effects of serum leptin are not mediated due to these biochemical markers. Despite a preliminary understanding of leptin–bone mass interactions,

The role of BTMs in monitoring osteoporosis treatment to confirm compliance with oral therapies, and efficacy of treatment has been established. Further studies with reference to serum leptin and BTMs in post menopausal osteoporotic females are needed to clarify their association and significance of that association in treatment targets for various therapies and

and Abid Azhar3

\*Address all correspondence to<EMAIL_ADDRESS><EMAIL_ADDRESS>
1 Pharmaceutical Research Centre, Pakistan Council of Scientific and Industrial Research

2 Department of Biochemistry, Bahria University Medical and Dental College (BUMDC),

3 Karachi Institute of Biotechnology and Genetic Engineering (KIBGE), Karachi, Pakistan

decrease in bone resorption. The reasons for these discrepancies need to be clarified.

the exact roles of leptin on bone metabolism have not yet been elucidated.

**8. Conclusion**

optimal monitoring regimes.

Mehreen Lateef1\*, Mukhtiar Baig2

Complex Laboratories Complex, PCSIR, Karachi, Pakistan

<EMAIL_ADDRESS>
**Author details**

Karachi, Pakistan

### **7. Relationship of leptin with bone markers in post menopausal osteoporotic females**

Data in the literature are inconsistent and conflicting about the relationship of leptin with bone markers in post menopausal osteoporotic females. The study of Goulding & Taylor (1998) was the first to examine relationships among plasma levels of leptin, and dynamic bi‐ ochemical markers of bone cell activity in postmenopausal women [46]. This study demon‐ strated no association between circulating plasma levels of leptin and biochemical markers of either osteoclastic or osteoblastic activity. They concluded that leptin itself does not play any significant direct role in controlling bone cell activity in postmenopausal women.

Scariano et al reported positive association between serum leptin and bone specific alkaline phosphatase in postmenopausal women and elderly men after adjustment for BMD, age and BMI [105]. The association of circulating leptin levels with bAP, a specific marker of osteo‐ blast activity suggests that leptin levels influence osteoblast activity in vivo in elderly wom‐ en and men. In a cross sectional study by Filip R & Raszewski G (2009) a positive association between leptin and osteocalcin in older patients with hip fracture [106]. Rauch et al. and La‐ teef et al also found no relationship between plasma leptin level and bone turnover markers in adult women and postmenopausal osteoporotic females respectively [40,59]. Filip & Ras‐ zewski et al, found no correlations of serum leptin with lumber spine BMD, femoral neck BMD, biochemical markers of bone turnover with leptin, in overweight and obese postme‐ nopausal women, even after stratification of the study group by BMI ratio value (25–29 9, 30–39 9 and ≥ 40), or by waist: hip ratio (WHR), ratio value (< 0 85 and ≥ 0 85) [106]. In a small study, Iwamoto et al. (2000) found correlations between serum leptin and bone re‐ modelling markers only in premenopausal women [107]. Peng et al (2008) reported no asso‐ ciation between serum leptin and bone turnover biochemical markers in men [108].

In postmenopausal osteoporotic patients with increased bone turnover, serum leptin con‐ centration is not correlated with BMD or with the biomarkers of bone formation or bone re‐ sorption [109]. According to few studies performed in China no correlation found between serum leptin and bone turnover biochemical markers in post-menopausal Chinese women [110-112]. Similarly, no correlation observed between leptin and bone turnover markers in Chinese adolescent dancers and control group in one more study (101) Blain, et al (2002) re‐ ported that serum leptin level was positively correlated with weight, fat mass, BMI, E2, crea‐ tinine clearance, and BAP level and inversely correlated with urine CTx [56]. They supported the suggestion that circulating leptin exerts its protective effect on bone through limiting the excessive bone resorption coupled with bone formation that is associated with bone loss after menopause.

Prouteau et al (2006) suggested a regulatory role of leptin on type I collagen metabolism [113]. The negative association between bone resorption (CTx levels) and serum leptin levels observed at baseline (stable body weight) was further confirmed by the biochemical changes occurring in responses to weight loss and weight regain. The drop in leptin levels was strongly related to the increase in bone resorption marker occurring in response to weight loss. Similarly, after weight regain the rise in leptin levels was associated with a concomitant decrease in bone resorption. The reasons for these discrepancies need to be clarified.

### **8. Conclusion**

independent factor. Similarly it must not be used to select the most appropriate type of

Data in the literature are inconsistent and conflicting about the relationship of leptin with bone markers in post menopausal osteoporotic females. The study of Goulding & Taylor (1998) was the first to examine relationships among plasma levels of leptin, and dynamic bi‐ ochemical markers of bone cell activity in postmenopausal women [46]. This study demon‐ strated no association between circulating plasma levels of leptin and biochemical markers of either osteoclastic or osteoblastic activity. They concluded that leptin itself does not play any significant direct role in controlling bone cell activity in postmenopausal women.

Scariano et al reported positive association between serum leptin and bone specific alkaline phosphatase in postmenopausal women and elderly men after adjustment for BMD, age and BMI [105]. The association of circulating leptin levels with bAP, a specific marker of osteo‐ blast activity suggests that leptin levels influence osteoblast activity in vivo in elderly wom‐ en and men. In a cross sectional study by Filip R & Raszewski G (2009) a positive association between leptin and osteocalcin in older patients with hip fracture [106]. Rauch et al. and La‐ teef et al also found no relationship between plasma leptin level and bone turnover markers in adult women and postmenopausal osteoporotic females respectively [40,59]. Filip & Ras‐ zewski et al, found no correlations of serum leptin with lumber spine BMD, femoral neck BMD, biochemical markers of bone turnover with leptin, in overweight and obese postme‐ nopausal women, even after stratification of the study group by BMI ratio value (25–29 9, 30–39 9 and ≥ 40), or by waist: hip ratio (WHR), ratio value (< 0 85 and ≥ 0 85) [106]. In a small study, Iwamoto et al. (2000) found correlations between serum leptin and bone re‐ modelling markers only in premenopausal women [107]. Peng et al (2008) reported no asso‐

ciation between serum leptin and bone turnover biochemical markers in men [108].

In postmenopausal osteoporotic patients with increased bone turnover, serum leptin con‐ centration is not correlated with BMD or with the biomarkers of bone formation or bone re‐ sorption [109]. According to few studies performed in China no correlation found between serum leptin and bone turnover biochemical markers in post-menopausal Chinese women [110-112]. Similarly, no correlation observed between leptin and bone turnover markers in Chinese adolescent dancers and control group in one more study (101) Blain, et al (2002) re‐ ported that serum leptin level was positively correlated with weight, fat mass, BMI, E2, crea‐ tinine clearance, and BAP level and inversely correlated with urine CTx [56]. They supported the suggestion that circulating leptin exerts its protective effect on bone through limiting the excessive bone resorption coupled with bone formation that is associated with

Prouteau et al (2006) suggested a regulatory role of leptin on type I collagen metabolism [113]. The negative association between bone resorption (CTx levels) and serum leptin levels observed at baseline (stable body weight) was further confirmed by the biochemical changes

**7. Relationship of leptin with bone markers in post menopausal**

osteoporotic therapy for the treatment. [104].

**osteoporotic females**

76 Topics in Osteoporosis

bone loss after menopause.

The relationship of leptin and bone turnover markers in post menopausal osteoporosis has not yet been clarified. Although several studies have been done but still there is need to explore their exact connection. Many studies have recommended that in the treatment of the post-men‐ opausal women, biochemical markers of bone turnover may be useful as adjuncts to BMD and other diagnostic tests. They can be mainly used to monitor response to treatment and also used as relatively economical tools for studying bone metabolism. The exact roles of BTM need to be established in clinical practice. It is suggested that repeated measurements of bone markers during anti-resorptive therapy may help to improve the management of osteoporotic patients.

Both a peripheral and a central action of leptin on bone metabolism have been suggested. Pe‐ ripherally, leptin is thought to exert positive effects on bone formation, whereas it is thought to reduce bone formation via a central control mechanism when binding to its specific receptors located on the hypothalamic nuclei [26]. It has been suggested that circulating leptin may act positively to maintain bone mass but these effects of serum leptin are not mediated due to these biochemical markers. Despite a preliminary understanding of leptin–bone mass interactions, the exact roles of leptin on bone metabolism have not yet been elucidated.

The role of BTMs in monitoring osteoporosis treatment to confirm compliance with oral therapies, and efficacy of treatment has been established. Further studies with reference to serum leptin and BTMs in post menopausal osteoporotic females are needed to clarify their association and significance of that association in treatment targets for various therapies and optimal monitoring regimes.

### **Author details**

Mehreen Lateef1\*, Mukhtiar Baig2 and Abid Azhar3

\*Address all correspondence to<EMAIL_ADDRESS><EMAIL_ADDRESS><EMAIL_ADDRESS>
1 Pharmaceutical Research Centre, Pakistan Council of Scientific and Industrial Research Complex Laboratories Complex, PCSIR, Karachi, Pakistan

2 Department of Biochemistry, Bahria University Medical and Dental College (BUMDC), Karachi, Pakistan

3 Karachi Institute of Biotechnology and Genetic Engineering (KIBGE), Karachi, Pakistan

### **References**

[1] Consensus Development Conference Diagnosis, prophylaxis and treatment of osteo‐ porosis. American Journal of Medical Sciences 1993; 94:646–65.

[16] Wardlaw SL. Obesity as a neuroendocrine disease: lessons to be learned from proo‐ piomelanocortin and melanocortin receptor mutations in mice and men.Journal of‐

Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis

http://dx.doi.org/10.5772/54527

79

[17] Patel MS, Elefteriou F. The new field of neuroskeletal biology. CalcifedTissue Inter‐

[18] Sato S, Hanada R, Kimura A, et al. Central control of bone remodelling by neurome‐

[19] Sirotkin AV, Mlynček M, Makarevich AV, et al. Leptin affects proliferation-, apopto‐ sis- and protein kinase A-related peptides in human ovarian granulosa cells. Physio‐

[20] Reid I. Relationships among body mass, its components, and bone. Bone 2002; 13:

[21] Mazess RB, Barden, HS, Ettinger M, Johnston C, Dawson-Hughes B, Baran D, Powell, M. &Notelovitz, M. Spine and femur density using dual-photon absorptiometry in

[22] Tremollieres F, Pouilles JM,Ribot C.Vertebral postmenopausal bone loss is reduced in overweight women: a longitudinal study in 155 early postmenopausal women.

[23] Elias CF, Purohit D. Leptin signaling and circuits in puberty and fertility. Cellular and Molecular Life Sciences 2012.DOI 10.1007/s00018-012-1095-1(Accessed 12 August

[24] Mundy GR. Secondary osteoporosis: the potential relevance of leptin and low body

[25] Ducy P, Amling M, Takeda S. Leptin inhibits bone formation through a hypothala‐

[26] Amling M, Takeda S, Karsenty GA. Neuro(endo)crine regulation of bone remodel‐

[27] Ducy P, Schinke T, Karsenty G. The osteoblast: a sophisticated fibroblast under cen‐

[28] Karsenty G. Leptin controls bone formation through a hypothalamic relay. Recent

[29] Takeda S &Karsenty G. Central control of bone formation. Journal ofBone& Mineral‐

[30] Holloway WR, Collier FM, Aitken CJ, Myers DE, Hodge JM, Malakellis M, et al.. Lep‐ tin inhibits osteoclast generation. Journal of Bone and Mineral Research 2002; 17:200–

US white women. Journal of Bone and Mineral Research 1987; 2: 211-219.

Journal of ClinicalEndocrinology & Metabolism 1993; 77: 683-686.

weight. Annals of Internal Medicine 2000; 21: 828-830.

ClinicalEndocrinology andMetabolism 2001; 86: 1442.

din U. NaturalMedicine 2007; 13: 1234-1240.

national 2007; 80: 337-347.

logicalResearch 2008; 57:437-442.

mic relay. Cell 2000; 100:197–207.

ing. Bioessays 2000; 22: 970–975.

ProgHorm Res 56:401–415, 2001.

Metabolism 2001;19:195–198.

tral surveillance. Science 2000; 289:1501–1504.

547-555.

2012).

209.

[16] Wardlaw SL. Obesity as a neuroendocrine disease: lessons to be learned from proo‐ piomelanocortin and melanocortin receptor mutations in mice and men.Journal of‐ ClinicalEndocrinology andMetabolism 2001; 86: 1442.

**References**

78 Topics in Osteoporosis

[1] Consensus Development Conference Diagnosis, prophylaxis and treatment of osteo‐

[2] Davey DA. Osteoporosis, osteopenia and fracture risk: Widening the therapeutic ho‐

[3] Dennison E, Cole Z, Cooper C, et al. Diagnosis and epidemiology of osteoporosis.

[4] Burge RT. The cost of osteoporotic fractures in the UK: Projections for 2000-2020.

[5] Kanis JA, Johnell O. Requirements for DXA for the management of osteoporosis in

[6] Lim S, Koo BK, Lee EJ, Park JH, Kim MH, Shin KH, et al. Incidence of hip fractures in

[7] Reseland J, Syversen U, Bakke I. et al. Leptin is expressed in and secreted from pri‐ mary cultures of human osteoblasts and promotes bone mineralization. Journal of

[8] Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL. Leptin acts on human marrow stromal cells to enhance diff erentiation to osteoblasts and to inhibit differ‐

[9] Steppan CM, Crawford DT, Chidsey-Fink KL, et al.Leptin is a potent stimulator of

[10] Burguera B, Hofbauer LC, Thomas, T. et al. Leptin reduces ovariectomy-induced

[11] Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and

[13] Tartaglia LA, Dembski M, Weng X,et al. Identification and expression cloning of a

[14] Zhang F, Chen Y., Heiman M, et al. Leptin: structure, function and biology. Vitamins

[15] Krysiak R, Handzlik-Orlik G, Okopien B. The role of adipokines in connective tissue

[12] Coen G. Leptin and bone metabolism. Journal of Nephrology 2004;17: 187-189.

porosis. American Journal of Medical Sciences 1993; 94:646–65.

rizons. South African Medical Journal 2012; 102: 285-288.

CurrentOpinion ofRheumatology 2005; 17:456-461.

Europe. Osteoporosis International 2005; 16:229–238.

Korea. Journal of Bone & Mineral Metabolism 2008; 26: 400-405.

entiation to adipocytes. Endocrinology 1999; 140:1630–1638.

bone loss in rats. Endocrinology 2001; 142, 3546–3553.

its human homologue. Nature 1994; 372: 425-432.

leptin receptor, OB-R. Cell 1995; 83: 1263-1271.

diseases. European Journal of Nutrition 2012;51:513–528.

& Hormones 2005; 71: 345-365.

bone growth in ob/ob mice. Regulatory Peptides 2000; 92, 73–78.

Journal of Medical Economics 2001;4: 51.

Bone & Mineral Research 2001;16:1426–1433.

[31] Thomas T, Burguera B, Melton LJ. Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women.Bone 2001; 29:114–120.

longitudinal results from the study of osteoporotic fractures. Journal of Bone and

Serum Leptin and Bone Turnover Markers in Postmenopausal Osteoporosis

http://dx.doi.org/10.5772/54527

81

[45] Miller PD,Zapalowski, C, Kulak CA. &Bilezikian JP.Bone Densitometry: the best way to detect osteoporosis and to monitor therapy. Journal of Clinical Endocrinologyand

[46] GouldingA,Taylor RW. Plasma Leptin values in relation to bone mass and density and to dynamic biochemical markers of bone resorption and formation in postmeno‐

[47] Rouch F, Blum WF, Klein K. Allolio, B. &Schonau, E. Does leptin have an effect on

[48] Iwamoto I, Douchi T, Kosha S, Murakami, M. Fujino T. & Nagata Y. Relationship be‐ tween serum leptin level and regional bone mineral density, bone metabolic markers in healthy women. ActaObstetriciaetGynecologicaScandinavica 2000; 79: 1060-1064. [49] Yamauchi M, Sugimoto T, Yamaguchi T. Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal