A comprehensive overview on osteoporosis and its risk factors

Figures & data

Table

1. Major modifiable risk factors:  Inadequate nutritional absorption  Lack of physical activity or fall risk  Weight loss  Cigarette smoking  Alcohol consumption  Air pollution  Stress 2. Major non-modifiable risk factors:  History of falls  Older age  Gender  White ethnic background  Prior fracture  Reproductive factors (family history of osteoporosis) 3. Secondary causes of osteoporosis  Chronic use of certain medications (prolonged corticosteroid use, and so on)  Hypogonadism  Hyperparathyroidism  Chronic liver disease  Inflammatory diseases (rheumatoid arthritis, and so on)  Vitamin D deficiency  Renal disease (history of kidney stones)  Cardiovascular disease  Diabetes mellitus  Dementia

Figure 1 Common osteoporosis risk factors involved in pathways associated with bone formation and osteoporotic fractures.

Note: RA, smoking, glucocorticoids, diabetes mellitus and tumors, the most common risk factors, negatively control the bone organization pathway, resulting in osteoporotic fractures.
Abbreviations: IL, interleukin; M-CSF, macrophage colony stimulating factor; OPG, osteoprotegerin; PPARγ, peroxisome proliferator-activated receptor-γ; PTH, parathyroid hormone; RA, rheumatoid arthritis; RANKL, RANK with its ligand; TNF, tumor necrosis factor; DM, diabetes mellitus; AP2, adipocyte fatty acid binding protein 2; RANK, receptor activator of nuclear factor κ.

Table 1 Candidate genes associated with osteoporosis

Candidate gene	Protein	Chromosome	Function	Reference
VDR	Vitamin D receptor	12q12-14	The nuclear hormone receptor for vitamin D3	Ferrari et al,^Citation62 Durrin et al,^Citation252 Remes et al,^Citation253 Lambrinoudaki et al,^Citation254 Wang et al,^Citation255 Pouresmaeili et al,^Citation73
ER-α	Estrogen receptor-α	6q25	An estrogen receptor	Ioannidis et al,^Citation256 Yamada et al,^Citation257 van Meurs et al,^Citation99 Tang et al,^Citation258
ER-β	Estrogen receptor-β	14q22-24	A member of the family of estrogen receptors and the superfamily of nuclear receptor transcription factors	Ogawa et al,^Citation259 Lau et al,^Citation260 Scariano et al,^Citation261 Kung et al,^Citation262
CT	Calcitonin	11p15	A peptide hormone that causes reduction in serum calcium	Miyao et al,^Citation263 Magaña et al,^Citation264
CTR	Calcitonin receptor	7q21	A high-affinity receptor for the peptide hormone calcitonin	Tural et al,^Citation265
PTH	Parathyroid hormone	11p15	This hormone elevates blood Ca^2+ level by dissolving the salts in bone and preventing their renal excretion	Hosoi et al,^Citation266
PTHR	Parathyroid hormone receptor 1	3p22-21	A receptor for PTH and for PTHLH	Minagawa et al,^Citation267
CYP19	Aromatase (cytochrome P450)	15q21	A member of the cytochrome P450 superfamily of enzymes and catalyzes the last steps of estrogen biosynthesis	Napoli et al,^Citation268
CYP17	Steroid 17-alpha- hydroxylase/17,20 lyase	10q24	A member of the cytochrome P450 superfamily of enzymes and a key enzyme in the steroidogenic pathway	Zmuda et al,^Citation269 Sharp et al,^Citation270
GCR	GC receptor	5q31	Receptor for GCs that affects inflammatory responses, cellular proliferation and differentiation in target tissues	Huizenga et al,^Citation271
CaSR	Calcium-sensing receptor	3q13-21	It senses changes in the extracellular concentration of calcium ions and maintains ion homeostasis	Tsukamoto et al,^Citation272
AR	Androgen receptor	Xq11-12	A nuclear receptor that affects IGF-1 and genes involved in the development of primary and secondary male sexual characteristics expression	Langdah et al,^Citation273
TGF-β1	Transforming growth factor-β1	19q13	Potent stimulator of osteoblastic bone formation	Langdahl et al,^Citation274
IL-6	Interleukin-6	7p21	A cytokine that functions in inflammation and also as a bone- resorbing cytokine	Murray et al,^Citation108 Tsukamoto et al,^Citation109
IGF-I	Insulin-like growth factor I	12q22-24	A physiologic regulator of [1-14C]- 2-deoxy-d-glucose transport and glycogen synthesis in osteoblasts	Rivadeneira et al,^Citation275
IL-1ra	Interleukin-1 receptor antagonist	2q14	A member of the IL-1 cytokine family which inhibits the activities of IL-1	Langdahl et al,^Citation93
OPG	Osteoprotegerin	8q24	As a potent inducer of DKK-1 can inhibit the Wnt signaling pathway	Arko et al,^Citation276 García-Unzueta et al,^Citation277 Jurado et al,^Citation278
TNF-αsw	Tumor necrosis factor-α	6p21	A multifunctional bone-resorbing cytokine	Mencej et al,^Citation279
TNFR2	Tumor necrosis factor receptor 2	1p36	A member of the TNF-receptor superfamily	Hoshino et al,^Citation280
COL1A1	Collagen type Iα1	17q21-22	A fibril-forming collagen found in most connective tissues and bone	Grant et al,^Citation281 Tural et al,^Citation265
COL1A2	Collagen type Iα2	7q22	A fibril-forming collagen found in most connective tissues and bone	Lau et al,^Citation282
BGLAP	Osteocalcin	1q22	Constitutes 1%–2% of the total bone protein and binds strongly to apatite and calcium	Chen et al,^Citation283 McGuigan et al,^Citation284
MGP	Matrix Gla protein	12p12	An inhibitor of bone formation	Zebboudj et al,^Citation285
AHSG	α-2-HS-glycoprotein	3q27	Influences the mineral phase of bone	Eichner et al,^Citation286
ApoE	Apolipoprotein E	19q13	Mediates the binding, internalization and catabolism of lipoprotein particles	Johnston et al,^Citation287 Cauley et al,^Citation288
MTHFR	Methylenetetrahydrofolate reductase	1p36	Catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine	Villadsen et al,^Citation289
P57 (KIP2)	Cyclin-dependent kinase inhibitor 1c	11p15	Regulates osteoblast proliferation and differentiation	Urano and Inoue,^Citation290
HLA-DR15	Major histocompatibility complex, class II, DR	6p21	Interacts with another gene related to bone metabolism such as TNF-α	Douroudis et al,^Citation291
PPARγ	Peroxisome proliferator- activated receptor-γ	3p25	Key regulator of adipocyte differentiation and glucose homeostasis	Altshuler et al,^Citation292
FRA-1	Fos-related antigen-1	11q13	Leucine zipper proteins that act as regulators of cell proliferation, differentiation and transformation	Albagha et al,^Citation293
RUNX-2	Runt-related transcription factor-2	6p21	Essential for osteoblastic differentiation and skeletal morphogenesis	Vaughan et al,^Citation294 Doecke et al,^Citation295
Klatho gene	Klotho protein	13q12	Involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D	Kawano et al,^Citation296
WRN (Werner syndrome gene)	Werner helicase	8p12	A DNA helicase involved in many aspects of DNA metabolism	Ogata et al,^Citation297
LRP5	Receptor related protein 5	11q12-13	A coreceptor with frizzled protein family members for transducing signals by Wnt proteins	Babij et al,^Citation298 Ai et al,^Citation299
CTSK	Cathepsin K	1q21	A lysosomal cysteine proteinase involved in bone remodeling and resorption	Giraudeau et al,^Citation300
BMP4	Bone morphogenetic protein 4	14q22	It plays an important role in the onset of endochondral bone formation in humans	Babu et al,^Citation301
CLCN7	Chloride channel 7	16p13	Slow voltage-gated channel mediating the exchange of chloride ions against protons	Pettersson et al,^Citation302 Kornak et al,^Citation303
TCIRG1	T cell immune regulator	11q13.4-q13.5	Part of the proton channel of V-ATPases	Lee et al,^Citation304
FDPS	Farnesyl pyrophosphate synthase	1q22	Key enzyme in isoprenoid biosynthesis	Marini et al,^Citation305
P2X7	Purinergic receptor P2X, ligand-gated ion channel, 7	12q24	Found in the central and peripheral nervous systems and increases the release of proinflammatory molecules such as IL-1β, IL-6 and TNF-α	Gartland et al,^Citation306

Abbreviations: GC, glucocorticoid; IGF, insulin-like growth factor; IL, interleukin; PTH, parathyroid hormone; PTHLH, parathyroid hormone-like hormone; TNF, tumor necrosis factor.

FerrariSBonjourJPRizzoliRThe vitamin D receptor gene and calcium metabolismTrends Endocrinol Metab1998925926518406281

 PubMed Web of Science ®Google Scholar

DurrinLKHaileRWInglesSACoetzeeGAVitamin D receptor 3′-untranslated region polymorphisms: lack of effect on mRNA stabilityBiochimica et Biophysica Acta (BBA)-Molecular Basis of Disease19991453331132010101249

 PubMed Web of Science ®Google Scholar

RemesTVäisänenSBMahonenABone mineral density, body height, and vitamin D receptor gene polymorphism in middle-aged menAnnals of Medicine200537538339216179274

 PubMed Web of Science ®Google Scholar

LambrinoudakiIKaparosGArmeniEBsmI vitamin D receptor’s polymorphism and bone mineral density in men and premeno-pausal women on long-term antiepileptic therapyEuropean Journal of Neurology2011181939820500803

 PubMed Web of Science ®Google Scholar

WangLMaJMansonJEBuringJEGazianoJMSessoHDA prospective study of plasma vitamin D metabolites, vitamin D receptor gene polymorphisms, and risk of hypertension in menEuropean Journal of Nutrition20135271771177923262750

 PubMed Web of Science ®Google Scholar

PouresmaeiliFJJAzargashbESamangoueeSAssociation between vitamin D receptor gene BsmI polymorphism and bone mineral density in a population of 146 Iranian womenCell J2013157882

 Web of Science ®Google Scholar

IoannidisJPRalstonSHBennettSTDifferential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomesJAMA2004292172105211415523071

 PubMed Web of Science ®Google Scholar

YamadaYAndoFNiinoNOhtaSShimokataHAssociation of polymorphisms of the estrogen receptor α gene with bone mineral density of the femoral neck in elderly Japanese womenJournal of Molecular Medicine200280745246012110951

 PubMed Web of Science ®Google Scholar

van MeursJBSchuitSCWeelAEAssociation of 5′ estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture riskHum Mol Genet2003121745175412837697

 PubMed Web of Science ®Google Scholar

TangLChengG-LXuZ-HAssociation between estrogen receptor α gene (ESR1) PvuII (C/T) and XbaI (A/G) polymorphisms and hip fracture risk: evidence from a meta-analysisPloS One2013812e8280624482673

 PubMed Web of Science ®Google Scholar

OgawaSFujitaMIshiiYImpaired estrogen sensitivity in bone by inhibiting both estrogen receptor α and β pathwaysJournal of Biological Chemistry200027528213722137910806217

 PubMed Web of Science ®Google Scholar

LauHHoALukKKungAEstrogen receptor β gene polymorphisms are associated with higher bone mineral density in premeno-pausal, but not postmenopausal southern Chinese womenBone200231227628112151079

 PubMed Web of Science ®Google Scholar

ScarianoJSimplicioSMontoyaGGarryPBaumgartnerREstrogen receptor β dinucleotide (CA) repeat polymorphism is significantly associated with bone mineral density in postmenopausal womenCalcified Tissue International200474650150815354857

 PubMed Web of Science ®Google Scholar

KungAWLaiBMNgMYChanVShamPCT-1213C polymorphism of estrogen receptor beta is associated with low bone mineral density and osteoporotic fracturesBone20063951097110616777502

 PubMed Web of Science ®Google Scholar

MiyaoMHosoiTEmiMAssociation of bone mineral density with a dinucleotide repeat polymorphism at the calcitonin (CT) locusJournal of Human Genetics200045634635011185743

 PubMed Web of Science ®Google Scholar

MaganaJGomezRCisnerosBAssociation of the CT gene (CA) polymorphism with BMD in osteoporotic Mexican womenClinical Genetics200670540240817026622

 PubMed Web of Science ®Google Scholar

TuralSKaraNAlayliGTomakLAssociation between osteoporosis and polymorphisms of the bone Gla protein, estrogen receptor 1, collagen 1-A1 and calcitonin receptor genes in Turkish postmenopausal womenGene2013515116717223137636

 PubMed Web of Science ®Google Scholar

HosoiTMiyaoMInoueSAssociation study of parathyroid hormone gene polymorphism and bone mineral density in Japanese postmenopausal womenCalcified Tissue International199964320520810024376

 PubMed Web of Science ®Google Scholar

MinagawaMYasudaTWatanabeTAssociation between AAAG repeat polymorphism in the P3 promoter of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene and adult height, urinary pyridinoline excretion, and promoter activityThe Journal of Clinical Endocrinology & Metabolism20028741791179611932319

 PubMed Web of Science ®Google Scholar

NapoliNRastelliAMaCGenetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER (+) breast cancerBone201355230931423643682

 PubMed Web of Science ®Google Scholar

ZmudaJMCauleyJAKullerLHFerrellREA common promoter variant in the cytochrome P450c17α (CYP17) gene is associated with bioavailable testosterone levels and bone size in menJournal of Bone and Mineral Research200116591191711341336

 PubMed Web of Science ®Google Scholar

SharpLCardyAHCottonSCLittleJCYP17 gene polymorphisms: prevalence and associations with hormone levels and related factors. a HuGE reviewAmerican Journal of Epidemiology2004160872974015466495

 PubMed Web of Science ®Google Scholar

HuizengaNAde LangePKoperJWHuman adrenocorticotro-pin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locusThe Journal of Clinical Endocrinology & Metabolism19988339179219506748

 PubMed Web of Science ®Google Scholar

TsukamotoKOrimoHHosoiTAssociation of bone mineral density with polymorphism of the human calcium-sensing receptor locusCalcified Tissue International200066318118310666491

 PubMed Web of Science ®Google Scholar

LangdahlBLStenkjaerLCarstensMToftengCEriksenEA CAG repeat polymorphism in the androgen receptor gene is associated with reduced bone mass and increased risk of osteoporotic fracturesCalcified Tissue International200373323724314667136

 PubMed Web of Science ®Google Scholar

LangdahlBLCarstensMStenkjærLEriksenEFPolymorphisms in the transforming growth factor beta 1 gene and osteoporosisBone200332329731012667558

 PubMed Web of Science ®Google Scholar

MurrayRMcGuiganFGrantSReidDRalstonSPolymorphisms of the interleukin-6 gene are associated with bone mineral densityBone19972189929213013

 PubMed Web of Science ®Google Scholar

TsukamotoKYoshidaHWatanabeSAssociation of radial bone mineral density with CA repeat polymorphism at the interleukin 6 locus in postmenoposal Japanese womenJ Hum Genet19994414815110319577

 PubMed Web of Science ®Google Scholar

RivadeneiraFHouwing-DuistermaatJJVaessenNAssociation between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: the Rotter-dam StudyThe Journal of Clinical Endocrinology & Metabolism20038883878388412915683

 PubMed Web of Science ®Google Scholar

LangdahlBLLøkkeECarstensMStenkjaerLLEriksenEFA TA repeat polymorphism in the estrogen receptor gene is associated with osteoporotic fractures but polymorphisms in the first exon and intron are notJ Bone Miner Res2000152222223011092403

 PubMed Web of Science ®Google Scholar

ArkoBPreželjJKocijančičAKomelRMarcJAssociation of the osteoprotegerin gene polymorphisms with bone mineral density in postmenopausal womenMaturitas200551327027915978970

 PubMed Web of Science ®Google Scholar

Garcia-UnzuetaMRianchoJZarrabeitiaMAssociation of the 163A/G and 1181G/C osteoprotegerin polymorphism with bone mineral densityHormone and Metabolic Research2008400321922418348083

 PubMed Web of Science ®Google Scholar

JuradoSNoguésXAguedaLPolymorphisms and haplo-types across the osteoprotegerin gene associated with bone mineral density and osteoporotic fracturesOsteoporosis International2010;21228729619436932

 PubMed Web of Science ®Google Scholar

MencejSAlbaghaOMPreželjJKocjanTMarcJTumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosisJournal of Molecular Endocrinology200840627327918502820

 PubMed Web of Science ®Google Scholar

HoshinoSHosoiTShirakiMOrimoHOuchiYInoueSAssociation of tumor necrosis factor receptor 1 gene polymorphism with bone mineral densityGeriatrics & Gerontology International200332101105

 Google Scholar

GrantSFReidDMBlakeGHerdRFogelmanIRalstonSHReduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I α 1 geneNature Genetics19961422038841196

 PubMed Web of Science ®Google Scholar

LauEChoyDLiMWooJChungTShamAThe relationship between COLI A1 polymorphisms (Sp 1) and COLI A2 polymorphisms (Eco R1 and Puv II) with bone mineral density in Chinese men and womenCalcified Tissue International200475213313715085313

 PubMed Web of Science ®Google Scholar

ChenHYTsaiHDChenWCWuJYTsaiFJTsaiCHRelation of polymorphism in the promotor region for the human osteocalcin gene to bone mineral density and occurrence of osteoporosis in postmenopausal Chinese women in TaiwanJournal of Clinical Laboratory Analysis200115525125511574953

 PubMed Web of Science ®Google Scholar

McGuiganFKumarJIvaskaKKObrantKJGerdhemPÅkessonKOsteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identificationJournal of Bone and Mineral Research20102561392139920200947

 PubMed Web of Science ®Google Scholar

ZebboudjAFImuraMBoströmKMatrix GLA protein, a regulatory protein for bone morphogenetic protein-2Journal of Biological Chemistry200227764388439411741887

 PubMed Web of Science ®Google Scholar

EichnerJEFriedrichCACauleyJAAlpha 2-HS glycoprotein phenotypes and quantitative hormone and bone measures in postmenopausal womenCalcified Tissue International19904763453491705475

 PubMed Web of Science ®Google Scholar

JohnstonJMCauleyJAGanguliMAPOE 4 and hip fracture risk in a community-based study of older adultsJournal of the American Geriatrics Society199947111342134510573444

 PubMed Web of Science ®Google Scholar

CauleyJAZmudaJMYaffeKApolipoprotein E polymorphism: A new genetic marker of hip fracture risk–The Study of Osteoporotic FracturesJ Bone Miner Res19991471175118110404018

 PubMed Web of Science ®Google Scholar

VilladsenMMBüngerMHCarstensMStenkjærLLangdahlBLMethylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMDOsteoporosis International200516441141615300362

 PubMed Web of Science ®Google Scholar

UranoTInoueSGenetics of osteoporosisBiochemical and Biophysical Research Communications2014452228729325139232

 PubMed Web of Science ®Google Scholar

DouroudisKTarassiKAthanassiadesTHLA alleles as predisposal factors for postmenopausal osteoporosis in a Greek populationTissue Antigens200769659259617498269

 PubMedGoogle Scholar

AltshulerDHirschhornJNKlannemarkMThe common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetesNature Genetics20002617610973253

 PubMed Web of Science ®Google Scholar

AlbaghaOMcGuiganFReidDRalstonSNovel polymorphism in the human Fos related antigen-1gene is associated with bone mineral density in women from the UKPaper presented at: Journal of Bone and Mineral Research2002

 Google Scholar

VaughanTPascoJAKotowiczMANicholsonGCMorrisonNAAlleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fractureJournal of Bone and Mineral Research20021781527153412162506

 PubMed Web of Science ®Google Scholar

DoeckeJDDayCJStephensASAssociation of functionally different RUNX2 P2 promoter alleles with BMDJournal of Bone and Mineral Research200621226527316418782

 PubMed Web of Science ®Google Scholar

KawanoKIOgataNChianoMKlotho gene polymorphisms associated with bone density of aged postmenopausal womenJournal of Bone and Mineral Research200217101744175112369777

 PubMed Web of Science ®Google Scholar

OgataNShirakiMHosoiTKoshizukaYNakamuraKKawaguchiHA polymorphic variant at the Werner helicase (WRN) gene is associated with bone density, but not spondylosis, in postmenopausal womenJournal of Bone and Mineral Metabolism200119529630111498731

 PubMed Web of Science ®Google Scholar

BabijPZhaoWSmallCHigh bone mass in mice expressing a mutant LRP5 geneJournal of Bone and Mineral Research200318696097412817748

 PubMed Web of Science ®Google Scholar

AiMHolmenSLVan HulWWilliamsBOWarmanMLReduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signalingMolecular and Cellular Biology200525124946495515923613

 PubMed Web of Science ®Google Scholar

GiraudeauFSMcginnisREGrayICCharacterization of common genetic variants in cathepsin K and testing for association with bone mineral density in a large cohort of perimenopausal women from ScotlandJournal of Bone and Mineral Research2004191314114753734

 PubMed Web of Science ®Google Scholar

BabuLRWilsonSDickIIslamFDevineAPrinceRBone mass effects of a BMP4 gene polymorphism in postmenopausal womenBone200536355556115777683

 PubMed Web of Science ®Google Scholar

PetterssonUAlbaghaOMMiroloMPolymorphisms of the CLCN7 gene are associated with BMD in womenJournal of Bone and Mineral Research200520111960196716234969

 PubMed Web of Science ®Google Scholar

KornakUOstertagABrangerSBenichouOde VernejoulM-CPolymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type IIThe Journal of Clinical Endocrinology & Metabolism2006913995100016368748

 PubMed Web of Science ®Google Scholar

LeeS-HRhoJJeongDv-ATPase V 0 subunit d2–deficient mice exhibit impaired osteoclast fusion and increased bone formationNature Medicine200612121403

 PubMed Web of Science ®Google Scholar

MariniFFalchettiASilvestriSModulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosisCurrent Medical Research and Opinion20082492609261518687167

 PubMed Web of Science ®Google Scholar

GartlandASkarrattKKHockingLJPolymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal womenEuropean Journal of Human Genetics201220555922234152

 PubMed Web of Science ®Google Scholar