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https://t.me/med1917

IMPORTANCE OF GENETICS IN

OSTEOPOROSIS

Genetic factors play an important role in regu-

lating several phenotypes revelant to the patho-

genesis of osteoporosis. Data from twin and fam-

ily studies have shown that between 50 and 85%

of the variance in bone mass is genetically deter-

mined

1–4

. Other determinants of osteoporotic

fracture risk such as quantitative ultrasound

properties of bone

, femoral neck geometry

muscle strength

, bone turnover markers

and

age at menopause

have also been shown to be

genetically determined. Genetic factors play a

less important role in the pathogenesis of frac-

ture itself. Whilst family history of fracture has

been shown to be an independent risk factor for

fracture in several studies

9,10

, twin studies have

shown that environmental factors such as falls

are a more important determinant of fracture

than are genetic factors

IDENTIFYING GENES WHICH

PREDISPOSE TO OSTEOPOROSIS

Several approaches have been employed to iden-

tify the genes which contribute to the regulation

of bone mass and the pathogenesis of fragility

fractures. These include: linkage studies in fami-

lies; linkage studies in experimental crosses of

inbred strains of mice; and association studies of

candidate genes in unrelated subjects.

Human linkage studies

Linkage studies are a tried and tested way of

identifying genes responsible for monogenic dis-

eases, and these have more recently been applied

to the identification of chromosomal regions

which contain genes that regulate quantitative

traits such as bone mineral density. These regions

are called quantitative trait loci (QTL). Linkage

studies involve genotyping a large number of

polymorphic markers, typically spread at

5–10 cM (million base pair) intervals throughout

the genome and relating inheritance of these

marker alleles to the inheritance of bone mass.

An advantage of linkage studies is that they are

statistically robust and unlikely to give false-

positive results. A disadvantage is that they have

limited power to detect genes of modest effect,

such as those that have been implicated in the

pathogenesis of osteoporosis.

Linkage studies have been used with greatest

effect in the identification of genes responsible

for monogenic bone diseases (Table 1). For exam-

ple, mutations in the lipoprotein related receptor

5 (LRP5) gene have been shown to be respon-

sible for two monogenic bone disease syndromes

with opposing effects on bone mineral density

(BMD): the high bone mass (HBM) syndrome,

in which bone density is increased

18,19

, and the

osteoporosis pseudoglioma syndrome (OPPS), in

which bone density is reduced

. It turns out that

OPPS is caused by a variety of homozygous in-

activating mutations in LRP5, whereas HMB is

caused by heterozygous activating mutations in a

specific region of the gene. Mutations in the

latency-activating peptide domain of the trans-

forming growth factor

β1 (TGFβ1) gene have

been shown to be responsible for Camaruti–

Engelmann disease – a condition characterized

by osteosclerosis mainly affecting the diaphysis of

long bones

, whereas inactivating mutations

affecting the sclerostin (SOST) gene have been

found to cause the syndromes of sclerosteosis and

van Buchem disease

, both of which are charac-

terized by increased bone mass and generalized

Genetic regulation of bone mass

S. H. Ralston

https://t.me/med1917

osteosclerosis. Osteopetrosis is a disease charac-

terized by defects in osteoclast function

, and

positional cloning studies have identified muta-

tions in several genes as the cause of this condi-

tion. These include the TCIRG1 gene which

encodes a subunit of the osteoclast proton

pump

, the CLCN7 gene which encodes the

osteoclast chloride channel

and the CATK gene

which encodes a protease that is essential for the

degradation of bone matrix

Although the above-mentioned conditions

are rare, it turns out that polymorphic variation

in several of these genes contributes to regula-

tion of bone mass in the normal population. For

example, polymorphisms in the TGF

β1 gene

have been found by several groups to be

associated with BMD in the normal popula-

tion

, as have polymorphisms in the LRP5

gene

, TCIRG1 gene

; SOST gene

and

CLCN7 gene

Linkage studies have also been performed in

families with osteoporosis and in population-

based cohorts of individuals to identify QTL for

regulation of BMD in subjects who do not have

monogenic bone diseases (reviewed by Liu and

colleagues

). These studies have yielded mixed

results, with little replication of QTL in different

studies. At the present time, only one gene has

been identified by this approach, and that is

BMP2, which was shown to account (at least in

part) for the osteoporosis susceptibility locus

identified on chromosome 20p12 in the Icelandic

population

Linkage studies in experimental

animals

Linkage studies in experimental animals have

long been used in the identification of genes

responsible for complex traits

, and, over recent

years, many such studies have been performed

to identify loci involved in the regulation of

BMD and bone geometry in mice. These studies

involve setting up crosses of inbred strains of

mice with low and high bone density to create

an F1 generation of mice that have intermediate

levels of BMD due to inheritance of alleles with

opposing effects on BMD from the parents. By

interbreeding offspring from the F1 generation,

a second generation of mice (F2) is established

with varying levels of BMD, because of segre-

gation of BMD-regulating alleles in the off-

spring. A genome-wide search can then be per-

formed in the F2 generation and the inheritance

of specific alleles related to the inheritance of

BMD. Mice have several advantages as an exper-

imental model: environment can be carefully

controlled, thus minimizing the influence of

confounding factors; large numbers of progeny

can be generated, giving excellent statistical

power; and fine mapping can be achieved by

repeated back-crosses onto the parental strain.

Table 1 Monogenic bone disease genes

Gene Disease Function Implicated in osteoporosis?

TCIRG1 recessive osteopetrosis subunit of osteoclast proton pump yes

LRP5 high bone mass, osteoporosis, regulates osteoblast growth and yes

pseudoglioma syndrome bone formation

CLCN7 recessive osteopetrosis, osteoclast chloride pump yes

dominant osteopetrosis

CaII recessive osteopetrosis with catalyzes formation of protons from not studied

renal tubular acidosis CO

and H

O in osteoclasts

CatK pyknodysostosis degrades bone matrix no

SOST sclerosteosis, van Buchem disease inhibitor of BMP action yes

COLIA1 osteogenesis imperfecta major protein of bone matrix yes

BMP, bone morphogenetic protein

POSTMENOPAUSAL OSTEOPOROSIS

https://t.me/med1917

GENETIC REGULATION OF BONE MASS

There are some limitations of this approach. So

far, it has proved difficult to move from identifi-

cation of QTL to gene discovery, since the

regions of linkage are typically large and can

only be narrowed by the time-consuming

process of repeated back-crossing. It is also

uncertain whether the genes that are found to

regulate BMD in mice will also be relevant to

the regulation of BMD in humans.

Multiple QTL for peak bone mass have now

been identified by linkage analysis in mice

, and

some of these QTL have also been shown to act

as determinants of bone strength, structure and

biomechanical responsiveness

32,33

. To date, how-

ever, only one gene has been identified as the

result of positional cloning studies in mice, and

that is Alox15 which is situated within a BMD

QTL identified by Klein and colleagues on

mouse chromosome 11

. The Alox15 gene was

discovered by a microarray experiment which

showed a 20-fold increase in Alox15 mRNA

levels in the low BMD-associated DBA2 mouse

strain used to identify the QTL. Subsequent

studies of Alox15 knock-out mice and pharmaco-

logic inhibitors of Alox15 activity confirmed the

importance of the Alox15 gene as a regulator of

bone metabolism and bone mass. Further studies

are now in progress to determine whether

genetic variation in the human homolog con-

tributes to the regulation of bone mass in

humans.

Candidate gene association studies

In the case of candidate gene studies, the inves-

tigator selects a gene that is thought to play a

role in the regulation of bone turnover or bone

mass and identifies polymorphisms in that gene,

either by performing mutation screening or by

analyzing online databases that hold information

on polymorphic variations in genes throughout

the genome. These polymorphisms (or groups of

linked polymorphisms termed haplotypes) are

then investigated for an association with BMD,

fractures or other phenotypes of interest in pop-

ulation-based studies or in case–control studies.

Candidate gene-association studies are relatively

easy to perform, and can detect genetic variants

which have modest effects on the phenotype of

interest. Disadvantages of these studies include

the possibility of false-positive (or false-negative)

results due to confounding factors and popula-

tion stratification. Moreover, demonstration of

an association between a candidate gene poly-

morphism and a trait does not necessarily mean

that the polymorphism is causally responsible for

the effect observed. Another explanation is that

the effect could be mediated by a linked poly-

morphism in the same gene or in a gene nearby.

Mention should be made of the transmission

disequilibrium test (TDT), which is a special

type of association study that examines the fre-

quency with which individuals inherit putative

susceptibility alleles from a heterozygous par-

ent

. The transmitted allele in the TDT acts as

the ‘case’ and the non-transmitted allele acts as

the ‘control’, thus circumventing the problem of

population stratification. The TDT is statisti-

cally robust, but lacks power when the polymor-

phism of interest is uncommon. Another disad-

vantage is that it can only be used where

parental samples are available, thus limiting its

applicability to the study of late-onset diseases

such as osteoporosis.

Individual candidate genes that have been

implicated in the regulation of bone mass or

osteoporotic fractures by association studies are

discussed in more detail below.

Vitamin D receptor (VDR)

Vitamin D, by interacting with its receptor, plays

an important role in calcium homeostasis by reg-

ulating bone cell growth and differentiation,

intestinal calcium absorption and parathyroid

hormone secretion. Morrison identified three

common polymorphisms in the 3

′ region of the

VDR gene situated between exons 8 and 9,

which are recognized by the restriction enzymes

BsmI, ApaI and TaqI. These were found to be

associated with circulating levels of the

osteoblast-specific protein osteocalcin and bone

mass in twin studies and a population-based

study

. Other studies of VDR in relation to bone

mass have yielded conflicting results, but a

recent meta-analysis concluded that the VDR

BsmI genotype is associated with modest effects

on bone mass

. There is evidence to suggest that

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POSTMENOPAUSAL OSTEOPOROSIS

VDR genotype could influence the skeletal

response to both calcium intake and vitamin D

intake, although many of the studies on this

topic have been small with rather inconclusive

results.

Another polymorphism affecting exon 2 of

VDR has been described which creates an alter-

native translation start site, potentially resulting

in the production of two isoforms of the VDR

protein, which differ in length by three amino

acids

. This has been associated with BMD in

some, but not all, populations. A functional

polymorphism has been identified in the pro-

moter of VDR at a binding site for the transcrip-

tion factor Cdx-2, which has been associated

with BMD in Japanese subjects

and with frac-

ture in Caucasians

. The mechanisms by which

these polymorphisms modulate VDR function

are incompletely understood. There is evidence

to suggest that the 3

′ polymorphisms may act as

markers for RNA stability. Evidence has also

been presented to suggest that the isoforms of

VDR encoded by the different Fok-1 alleles differ

in terms of function, although other groups have

failed to confirm these findings.

Type I collagen

The genes encoding type I collagen (COLIA1 and

COLIA2) are important candidates for the patho-

genesis of osteoporosis. Grant and colleagues

described a common polymorphism affecting a

binding site for the transcription factor Sp1 in

the first intron of COLIA1, which was more

prevalent in osteoporotic patients than in con-

trols. Positive associations between the COLIA1

Sp1 polymorphism and bone mass or osteo-

porotic fractures were subsequently reported in

several populations, and a meta-analysis showed

that the COLIA1 genotype conferred differences

in BMD of approximately 0.15 Z score units per

copy of the ‘s’ allele and an increase in fracture

risk of approximately 62% per copy of the ‘s’

allele

. Significant ethnic differences have been

reported in population prevalence of COLIA1

Sp1 alleles: the polymorphism is common in

Caucasian populations, but is rare in Africans

and Chinese

. The mechanism by which the Sp1

polymorphism predisposes to osteoporosis has

been investigated by Mann and colleagues

who found that the ‘s’ allele had increased affin-

ity for Sp1 protein binding and was associated

with elevated allele-specific transcription in het-

erozygotes. These abnormalities were accompa-

nied by increased production of the

αI chain of

collagen by osteoblasts cultured from ‘Ss’ het-

erozygotes, resulting in an increased ratio of

α1/α2 chains, reflecting the presence of α1

homotrimer formation. Biomechanical testing of

bone samples from ‘Ss’ heterozygotes showed

reduced bone strength compared with ‘SS’

homozygotes and impairment in the mineraliza-

tion of bone

. Overall, the data suggest that the

COLIA1 Sp1 polymorphism is a functional vari-

ant which has adverse effects on bone composi-

tion and mechanical strength.

Estrogen receptor α

The estrogen receptor α gene (ESR1) is a strong

functional candidate for osteoporosis susceptibil-

ity. Most studies of ESR1 have focused on a TA

repeat polymorphism in the ESR1 promoter

and two other polymorhisms within intron 1 of

the ESR1, recognized by the restriction enzymes

PvuII and XbaI

. Most studies of ESR1 alleles in

osteoporosis have been small, but a meta-analy-

sis of these studies has suggested that polymor-

phic variation at the XbaI site may act as a

determinant of bone mass

. Recently, a large

association study involving nearly 19 000 sub-

jects showed that the XbaI polymorphism is

associated with osteoporotic fracture independ-

ent of differences in BMD

. The TA repeat poly-

morphism in the ESR1 promoter is in strong

linkage disequlibrium with the XbaI and PvuII

polymorphisms

, and it is currently uncertain

which (if any) of these polymorphisms is func-

tional. There is some evidence to suggest that the

PvuII polymorphism affects a Myb binding site,

and that polymorphic variations at this site alter

ESR1 transcription in vitro

. This does not

exclude the possibility that the XbaI and TA

repeat polymorphisms also have functional con-

sequences, or indeed the possibility that other

linked polymorphisms at the ESR1 locus may be

responsible for the associations with osteoporosis

phenotypes that have been observed.

https://t.me/med1917

GENETIC REGULATION OF BONE MASS

Other genes

Polymorphisms of several other candidate genes

have been associated with bone mass and/or

osteoporotic fracture, and this subject has

recently been reviewed

28,50

. Polymorphisms in

the TGF

β1 gene have been associated with

BMD, osteoporotic fracture and circulating

TGF

β levels in various studies

, although the

mechanisms by which these influence TGF

β1

function are unclear. Polymorphisms in the 3

′

untranslated region of the TNFRS1B gene have

been associated with femoral neck bone mass in

women, and there is evidence to suggest that this

might be mediated by an effect on RNA stabil-

ity

. The TNFRSF1B gene is a functional candi-

date for regulation of BMD because it encodes

the tumor necrosis factor (TNF) type 2 receptor,

and is a positional candidate since it lies within a

linkage region for BMD regulation on chromo-

some 1p36

. Another gene that lies close to

TNFRSF1B on chromosome 1p36 is the methy-

lene tetrahydrofolate reductase (MTHFR) gene,

which plays a role in folate metabolism. A func-

tional polymorphism affecting codon 667 of

MTHFR has been associated with BMD and

fracture in various studies

53,54

, and it is thought

that this effect may be mediated by altering

homocysteine metabolism. Associations have

been described between polymorphisms in the

promoter of the interleukin-6 (IL-6) gene and

BMD, and it appears that these polymorphisms

affect transcriptional regulaton of IL-6 and influ-

ence bone turnover

. Other investigators have

looked at possible associations between apolipo-

protein E (apo E) alleles and osteoporosis. In

Japanese women, the apo E4 allele was found to

be associated with low bone mass, and, in

another study of US women, the same allele was

associated with osteoporotic fractures independ-

ent of bone mass. The mechanism by which apo

E alleles influence susceptibility to osteoporosis

are unclear, but may involve differences in

hydroxylation of the osteoblast-specific protein

osteocalcin. Other candidate genes which have

been studied in relation to BMD include those

for the calcitonin receptor, osteocalcin, parathy-

roid hormone, the parathyroid hormone receptor,

the androgen receptor, aromatase, interleukin-1

and the interleukin-1 receptor antagonist

(IL-1ra).

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ciation of a common allelic polymorphism

(C677T) in the methylene tetrahydrofolate

https://t.me/med1917

POSTMENOPAUSAL OSTEOPOROSIS

reductase gene with a reduced risk of osteo-

porotic fractures. A case control study in Danish

postmenopausal women. Calcif Tissue Int 2002;

71: 386–92

54. Miyao M, Morita H, Hosoi T, et al. Association of

methylenetetrahydrofolate reductase (MTHFR)

polymorphism with bone mineral density in

postmenopausal Japanese women. Calcif Tissue Int

2000; 66: 190–4

55. Ferrari SL, Garnero P, Emond S, et al. A func-

tional polymorphic variant in the interleukin-6

gene promoter associated with low bone resorp-

tion in postmenopausal women. Arthritis Rheum

2001; 44: 196–201

https://t.me/med1917

THE CONCEPT OF PEAK BONE

MASS

Peak bone mass (PBM) is defined as the highest

level of bone mass achieved as a result of normal

growth

. PBM represents a main determinant of

osteoporotic fracture risk in adulthood, together

with the maintenance of bone mass in adulthood,

and the rate of bone loss in late adulthood

In both sexes, the timing of PBM has been

considered to occur from ages as early as 16–18

years

1,3,4

. Lumbar spine and femoral bone min-

eral density (BMD) show a rapid decline after the

attainment of PBM

5,6

, whereas radial, skull and

total body BMD show a minimal increase until

50 years as a result of continuous periosteal

expansion with age

. Matkovic and colleagues

showed that the timing of cessation of linear

growth is 1–7 years earlier than cessation of the

accumulation of bone mass at various skeletal

sites, suggesting that a rapid consolidation of

skeletal density occurs after the bulk of bone

modeling has been completed. Nevertheless,

mostly, PBM is reached in late adolescence

within the second decade of life. Differences in

examined skeletal sites and/or in densitometric

techniques used to assess bone mineral status, as

well as racial, genetic or environmental factors,

may influence the pattern of bone mass accumu-

lation and the value of PBM.

ACQUISITION OF BONE MASS

DURING CHILDHOOD AND

ADOLESCENCE

Before puberty, no consistent gender difference

in bone mineral status assessed at the axial or

appendicular skeleton has been reported. More-

over, there is no evidence for a gender difference

in bone mass at birth. This lack of difference in

bone mass between sexes is maintained up to the

onset of puberty

In both sexes, lumbar spine BMD, assessed

by dual-energy X-ray absorptiometry (DXA),

increases progressively during childhood and

adolescence, and reaches a plateau around the

ages of 15 and 17 years in girls and boys, respec-

tively

3,4,8,9

. Subsequently, BMD values remain

stable

or decline slightly

. BMD is higher in

men than in women because the former have

bigger bones, partly because prepubertal longi-

tudinal growth continues for 2 years more in

males than in females

At the femoral neck, BMD values measured

by DXA show a peak at the age of 14.5 years in

females and 16.5 years in males; thereafter, BMD

values remain stable

4,10

or decline slightly

At the distal one-third of the radius, BMD

values measured by single-photon absorptio-

metry increase progressively up to 18–19 years

in males and 15–16 years in females

At the proximal phalanges of the hand, stud-

ies using quantitative ultrasound have shown

that PBM is reached at around 30 years

12–14

The pattern of BMD values at the lumbar

spine and femur during childhood and adoles-

cence indicates that puberty has a crucial role in

the acquisition of bone mass; indeed, a signifi-

cant gain in skeletal mass occurs during the

pubertal years, when approximately 40% of bone

mass is accumulated

1,3,4

. In both sexes, maximal

BMD accumulation at the lumbar spine and

femoral neck occurs in the last stages of puberty,

mainly in males

3,15

Bone mineral acquisition during infancy and

adolescence

G. Saggese and G. I. Baroncelli

https://t.me/med1917

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