Statins, bone formation and osteoporosis: hope or hype? 2012,126-139.pdfStatins, bone formation and...

Statins, bone formation and osteoporosis: hope or hype?

Athanasios N. Tsartsalis,1,2 Charalambos Dokos,3 Georgia D. Kaiafa,3 Dimitris N. Tsartsalis,4 Antonios Kattamis,5 Apostolos I. Hatzitolios,3,6 Christos G. Savopoulos3,6

1Department of Diabetes and Endocrinology, Whittington Hospital, London, UK, 2Department of Endocrinology Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, 31st Medical Propedeutic Dept, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 4Cardiology Department, Hippokration Hospital, Athens, 5Thalassemia Unit, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Greece, 6International Centre of Circulatory Health (ICCH) National Heart and Lung Institute (NHLI), Imperial College, London, UK

AbstrAct

Osteoporosis is a major health problem affecting both men and women. statins, besides their action as lipid-lowering agents, seem to have additional pleiotropic properties, among them a beneficial effect on bone mineral density. the entirety of experimental and the majority of clinical studies as well as the only relevant meta-analysis suggest that statins have an anabolic effect on bone metabolism. statins, osteoporosis and adipogenesis share the same pathway, rANKL/OPG. It would appear that an imbalance in this pathway could be responsible for the manifestation of some metabolic disorders such as diabetes mellitus, atherogenesis, multiple myeloma, osteoporosis. Possibly in the future, drugs which can intervene in this biochemi-cal and pathophysiological cascade, like statins, in a variety of doses, could be used for the management of ectopic ossification syndromes and other bone disorders, even as an additive treatment. Until then, further large longitudinal randomized controlled studies for each statin separately are required to confirm this hypothesis.

Key words: Adipogenesis, Bone formation, Bone mineral density, OPG, Osteoporosis, RANKL, Statins

Review

HORMONES 2012, 11(2):126-139

Address for correspondence:Christos Savopoulos, Medical School of Thessaloniki, Aristotle University, AHEPA Hospital, Thessaloniki, Greece e-mail: [email protected]

Received 25-10-11, Revised 08-01-12, Accepted 30-01-12

INTRODUCTION

Osteoporosis is a serious health problem not only because it affects the quality of life but also

and more importantly because it is associated with morbidity and mortality as well as economic burden. According to the WHO, osteoporosis is a “systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue which leads to bone fragility and susceptibility to fracture”. Bone mineral density (BMD) in osteoporotic patients is less than -2.5 SD compared with the BMD of young

Statins, bone formation and osteoporosis: hope or hype? 127

people (T-score<-2.5 SD). BMD of people without osteoporosis is usually above -1SD.1

Osteoporosis is a more frequent disease in women than in men,2 although mortality due to osteoporotic fractures is higher in men than in women.3 In addi-tion to this, post-menopausal women suffer from osteoporosis and osteoporotic fractures at a higher frequency than pre-menopausal women.4

Through adult life there is a dynamic progress which is called “bone remodeling”. Bone remodeling is well established throughout the literature and in-volves both systemic and non-systemic factors.5 It is well known that in this procedure an important role is played by the system of receptor activator of nuclear factor kappa b ligand (RANKL)-osteoprotegerin (OPG),6 some cytokines and bone morphogenetic proteins (BMPs) (Figure 1).7

On the other hand, it has been well known since the 70s that bone loss in osteoporotic patients is

associated with increase of adipose tissue in bone marrow.8 Mesenchymal stem cells are pluripotent cells with a high mitotic index and are involved in the differentiation of adipocytes under the regula-tion of genes and transcription factors. Adipose tissue is considered as a separate endocrine gland, responsible for the secretion of adipokines (leptin, adiponectin) and hormones (vitamin D3, estrogen, etc.) and is involved in the pathophysiology of some entities. Leptin controls the RANKL/OPG axis by inhibiting the expression of RANKL and inducing OPG to create pre-osteoblasts and mononuclear cells in circulation. The diversion of an adipocyte into osteoblast is considered to be a multifactorial process regulated by all these factors (Figure 2). In addition to this, it is well known that statins, osteo-porosis and adipogenesis share the same pathway, RANKL/OPG.9,10 It appears that an imbalance in this pathway could be responsible for the manifestation of some metabolic disorders such as diabetes mellitus,

Figure 1. Bone metabolism enhanced by growth factors like bone morphogenetic proteins (BMPs), transforming growth factors beta (TGF-β), insulin growth factors (IGFs), fibroblast growth factors (FGFs). Systemic factors can also enhance osteoblast differentia-tion and proliferation. Systemic factors and locally produced growth factors can also induce activation of osteoclasts. Interleukins, prostaglandins and M-CSF produced from osteoblasts also induce the formation of osteoclasts. RANKL binds its receptor RANKL and induces the formation of osteoclasts. OPG inhibits RANKL binding to RANK.

128 A.N. TSArTSAliS ET Al

CURReNT maNagemeNT Of OsTeOpOROsIs

It is now generally accepted that first-line agents for the management of osteoporosis are the amino-biphosphonates. These drugs act to decrease bone resorption by inhibition of the farnesyl diphosphate synthase, which is a step in the mevalonic acid path-way.12 3-Hydroxy-3-Methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) inhibit the same pathway at an earlier point and may also antagonize osteoclasts by increasing expression of osteoprotegerin (Figure 3).13 In order to improve BMD and prevent osteoporosis, we have used many different drugs based on two treatment strategies: i) to inhibit the osteoclast activity and ii) to stimulate the osteoblast activity. First-line agents to avoid bone resorption are the biphosphonates like alendronate, risedronate, ibandronate and zoledronic acid.14,15 Other drugs used are teriparatide, a recombinant form of parathyroid hormone,16 selective estrogen receptor modulators (SERMs), hormone replace-ment therapy, calcitonin, calcitriol and vitamin D analogues.17-19 We also have agents with a different

atherogenesis, multiple myeloma, osteoporosis. We have also seen that fat and bone tissue interaction altered by activation or silencing of genes, signaling molecules and transcription factors.11

The purpose of our review is to investigate whether, according to the available clinical data, there is a relation between statins and osteoporosis and thus to pose queries regarding new pathways which may enhance our knowledge about the prevention and management of osteoporosis. Clinical studies, sys-tematic reviews and meta-analyses were searched for in PUBMED and EMBASE/EXCERPTA MEDICA databases. Computerized search of the databases was accomplished by using the combination of keywords and Medical Subject Heading terms such as: statins, aminobiphosphonates, osteoporosis, RANKL, OPG, BMP, HMG-CoA reductase inhibitors, BMD, adipose tissue. We limited our search to articles published between June 2007 and October 2011 that were at least accompanied by an English abstract. We have found that there is a meta-analysis including all the clinical studies until June 2007.

Figure 2. The interaction of adipose tissue and other factors in the differentiation of osteoblasts (Savopoulos 2011).


mechanism of action: bone forming through osteoblast modulation and antiresorptive through osteoclastic inhibition like strontium ranelate.20

sTaTINs aND BONes: INTRIgUINg INTeRaCTIONs

Lipid-lowering therapy and pleiotropic effects

Statins compose a drug class broadly character-ized as lipid-lowering agents.21 These agents can be subgrouped according to their hydrophobic or hy-drophilic nature. Hydrophobic statins (simvastatin, lovastatin) enter the liver by the hepatic portal vein, while the hydrophilic statins (rosuvastatin, pravas-tatin, fluvastatin) require active transport into the cell.22 Statins inhibit mevalonic acid synthesis and, as a consequence, there is a decrease in the amount of total cholesterol and decreased levels of low density lipoproteins (LDL).23 All statins have favorable effects on cardiovascular diseases, the nervous system, the immune system, the skeletal system, tumor growth.24,25 There is emerging interest in the pleiotropic effects of this class of drugs, e.g. Srivastava and colleagues26

who examined the possible action of atorvastatin in acute phase reaction in children after intravenous biphosphonate infusion, but who, however, failed to demonstrate a positive result.

Statins and bones: metabolism and clinical implications

Molecular biology and genetics reveal that both vascular and osteoblast biology have a common pathway: RANK/RANKL/OPG.27-29 With regard to this issue, there is growing interest concerning the possible mechanism and the impact of statins on bones on either the experimental or the clinical level. Mundy and colleagues in 1999 were the first to report an anabolic effect of statins in cultured mouse and human bone cells. Both simvastatin and lovastatin enhanced the expression of bone morphogenetic protein-2 (BMP-2) mRNA.30

Experimental studies

Several experimental studies illustrate the effect of statins in bone metabolism either in vitro or in vivo. Table 1 displays the main characteristics of various

Figure 3. The interaction between HMG-CoA reductase inhibitors and bIphosphonates in the mevalonate pathway.

130 A.N. TSArTSAliS ET Alt

able

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nseq

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RA

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L

depr

essi

on

tab

le 1

. (co

ntin

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Aut

hor

Met

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stat

inO

utco

me

com

men

ts

ML

W: m

iner

aliz

atio

n w

idth

; ML

V: m

iner

aliz

atio

n vo

lum

e; M

AR

: min

eral

opp

ositi

on ra

te; B

MD

: bon

e m

iner

al d

ensi

ty; S

IM: s

imva

stat

in; O

VX

: ova

riec

tom

ized

; SH

AM

: sha

m-

oper

ated

gro

up; A

CS:

ate

loco

llage

n sp

onge

; LV

: lov

asta

tin; R

A: r

heum

atoi

d ar

thri

tis; R

SN: r

osuv

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tin; A

V: a

torv

asta

tin; E

2: 1

7β-e

stra

diol

; RL

: ral

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C: c

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ne

citr

ate;

RA

NK

L: r

ecep

tor

activ

ator

of

nucl

ear

fact

or k

appa

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; M-C

SF: m

acro

phag

e cl

ony

stim

ulat

ing

fact

or; T

RA

P: t

artr

ate

resi

stan

t ac

id p

hosp

atas

e; B

AL

P: b

one

spec

ific

alka

line

phos

phat

ase;

TB

V: t

rabe

cula

r bo

ne v

olum

e; O

C: o

steo

calc

in; V

EG

F: v

ascu

lar

endo

thel

ial g

row

th fa

ctor

; TG

F: tr

ansf

orm

ing

grow

th fa

ctor

; LFB

: lef

t fem

oral

bo

ne; L

S: lu

mba

r sp

ine;

TC

P: tr

ical

cium

pho

spha

tes;

DB

BM

: dem

iner

aliz

ed b

ovin

e bo

ne m

atri

x; <

: les

s; >

: hig

her;

(+

): p

ositi

ve; (

-): n

egat

ive;

▲: i

ncre

ased

; ▼: d

ecre

ased

.


Ho

et a

l 200

94454

OV

X a

nd S

ham

ope

r-at

ed fe

mal

e ra

tsSi

mva

stat

in 1

0-20

mg/

kg/

day

for 6

wee

ksSh

am le

ss T

BV

than

OV

X, S

IM ▲

TB

V a

nd

oste

obla

st n

umbe

r, os

teob

last

ic c

ells

with

imm

une-

stai

ned

BM

P2, c

olla

gen

type

1, O

C ▲

by

SIM

20m

g

SIM

mig

ht p

rom

ote

bone

form

atio

n vi

a ▲

os

teob

last

num

bers

and

mat

rix

prot

ein

leve

ls

Paul

y et

al

2009

45Fr

actu

res p

rodu

ced

into

200

fem

ale

rats

and

st

abili

zed

intr

amed

ulla

ry.

Div

ided

into

4 g

roup

s de-

pend

ing

on th

e w

ires

and

st

atin

. 9 a

nim

als o

f eac

h gr

oup

test

ed

In se

cond

gro

up si

mva

sta-

tin lo

w d

ose

3μg/

impl

ant

and

in th

e th

ird

grou

p 50

μg

/impl

ant

Prog

ress

ed c

allu

s con

solid

atio

n in

BM

P2 a

nd st

atin

gr

oup,

hig

h do

se S

IM▲

stiff

ness

and

ele

vate

d m

axim

um lo

ad

Dos

e-de

pend

ent e

ffec

t and

impr

oved

frac

ture

he

alin

g un

der l

ocal

app

licat

ion

of S

IM

Cha

ng L

iu

et a

l 200

94648

rats

inpl

ante

d ca

rrie

rs

with

or w

ithou

t SIM

and

di

vide

d in

to 2

gro

ups

Sim

vast

atin

TG

F-β1

, BM

P-2,

VE

GF

mR

NA

▲ in

bot

h gr

oups

af

ter o

ne w

eek.

TG

F-β1

, BM

P-2

mR

NA

▲in

1 a

fter

1,

2,4

wee

ks a

nd V

EG

F m

RN

A▲

aft

er 1

,2 w

eeks

Loc

al a

dmin

istr

atio

n of

SIM

can

influ

ence

al

veol

ar b

one

rem

odel

ing

by re

gula

ting

the

expr

essi

on o

f gro

wth

fact

ors

Shun

g-H

siun

g C

hen

et a

l 20

0947

27 fe

mal

e ra

ts u

nder

wen

t bi

late

ral O

VX

div

ided

into

3

grou

ps, i

) con

trol

, ii)

A

rom

asin

gro

up, i

ii) S

IM

+ A

rom

asin

gro

up

Sim

vast

atin

6.5

mg/

kg 5

tim

es p

er w

eek

for 1

2 w

eeks

Aft

er 1

mon

th: i

) LFB

BM

D 0

.492

6±0.

0332

an

d L

S B

MD

0.2

858±

0.01

1, ii

) LFB

BM

D

0.46

084±

0.05

8 L

S B

MD

0.3

318±

0.00

56, i

ii) L

FB

BM

D 0

.452

4±0.

024

LS

BM

D 0

.303

4±0.

019.

Aft

er 3

mon

ths L

S B

MD

: i) 0

.388

3±0.

0259

, ii)

0.

3174

±0.

0071

, iii)

0.3

702±

0.00

95

Aro

mas

in c

atab

olic

eff

ect o

n sk

elet

al sy

stem

an

d SI

M m

ay h

ave

a th

erap

eutic

app

licat

ion

in

the

trea

tmen

t of o

steo

poro

sis t

o co

unte

rbal

-an

ce th

e ad

vers

e ef

fect

s of A

rom

asin

Nya

n M

et a

l 20

0948

Bila

tera

l 5-m

m-d

iam

eter

ca

lvar

ial d

efec

ts w

ere

cre-

ated

in a

dult

Wis

tar r

ats

Sim

vast

atin

0, 0

.01,

0.1

, 0.

25 a

nd 0

.5 m

g co

mbi

ned

with

alp

ha-T

CP

part

icle

s or

left

em

pty

1) 0

.25

and

0.5

mg

caus

ed in

flam

mat

ion

of th

e so

ft

tissu

e at

the

graf

t site

, con

trol

and

oth

er d

oses

did

no

t, 2)

alp

ha-T

CP

with

0.1

mg

sim

vast

atin

(TC

P-0.

1) g

roup

yie

lded

sign

ifica

ntly

> b

one

volu

mes

th

an u

ntre

ated

con

trol

gro

up a

t all

thre

e tim

e po

ints

, 3) t

he p

erce

ntag

e of

def

ect c

losu

re, b

one

min

eral

con

tent

and

bon

e m

iner

al d

ensi

ty w

ere

also

>

in th

e T

CP-

0.1

grou

p

Whe

n co

mbi

ned

with

alp

ha-T

CP

part

icle

s, 0.

1 m

g si

mva

stat

in is

the

optim

al d

ose

for s

timul

a-tio

n of

the

max

imum

bon

e re

gene

ratio

n in

rat

calv

aria

l def

ects

with

out i

nduc

ing

infla

mm

atio

n an

d it

coul

d be

app

lied

as a

n ef

fect

ive

bone

gr

aft m

ater

ial.

Wan

g et

al

2010

4930

mic

e in

two

grou

psL

ovas

tatin

10m

g/kg

onc

e at

the

time

of fr

actu

re1)

Lac

k of

Nf1

in o

steo

blas

ts d

elay

s bon

e he

alin

g,

2) la

ck o

f Nf1

in o

steo

blas

ts▼

cal

lus b

iom

echa

nica

l pr

oper

ties,

3) e

xten

sive

ost

eoid

surf

aces

and

im-

pair

ed o

steo

clas

t fun

ctio

n m

ay p

reve

nt p

rope

r cal

lus

rem

odel

ing

in N

f- /- mic

e, 4

) Lov

asta

tin m

icro

part

icle

tr

eatm

ent i

mpr

oves

bon

e he

alin

g an

d m

echa

nica

l pr

oper

ties i

n N

f- /- mic

e

i) D

ysfu

nctio

ns c

ause

d by

loss

of N

f1 in

ost

eo-

blas

ts im

pair

cal

lus m

atur

atio

n an

d w

eake

n ca

llus m

echa

nica

l pro

pert

ies,

ii) lo

cal l

ow d

ose

of lo

vast

atin

may

impr

ove

frac

ture

hea

ling

tab

le 1

. (co

ntin

ued)

Aut

hor

Met

hod

stat

inO

utco

me

com

men

ts


Goe

s P e

t al

2010

50Pe

riod

ontit

is w

as in

duce

d by

liga

ture

pla

cem

ent

arou

nd th

e up

per s

econ

d le

ft m

olar

in a

tota

l of 2

4 m

ale

Wis

tar r

ats (

± 2

00 g

)

Gro

ups o

f 6 a

nim

als

rece

ived

via

ora

l gav

age

eith

er sa

line

or A

V (1

, 3

and

9 m

g/kg

) dur

ing

11

days

.

1) A

TV

(9 m

g/kg

) cau

sed

a si

gnifi

cant

▲ o

n gr

ay

tone

var

iatio

n of

ove

r 48%

whe

n co

mpa

red

to

salin

e, in

dica

ting

grea

ter r

adio

grap

hic

dens

ity, 2

) A

V (9

mg/

kg) ▼

alv

eola

r bon

e lo

ss b

y ov

er 4

7%

(p<

0.05

), w

hen

com

pare

d to

the

grou

p of

unt

reat

ed

anim

als

AT

V w

as a

ble

to p

reve

nt a

lveo

lar b

one

loss

se

en o

n a

Slig

atur

e-in

duce

d pe

riod

ontit

is

mod

el.

Lim

a et

al

2011

5164

rats

in 4

gro

ups,

i) n

o tr

eatm

ent,

ii) D

BB

M, i

ii)

SIM

& D

BB

M, i

v) S

IM&

D

BB

M

Sim

vast

atin

2.2

mg/

50μl

in

thir

d gr

oup

and

sim

vas-

tatin

0.5

mg/

50μl

in fo

urth

gr

oup

Thi

rd g

roup

low

est B

MD

in 3

0 da

ys, i

n 60

day

s sim

-va

stat

in g

roup

s < B

MD

, on

30 d

ay se

cond

and

thir

d gr

oup

(-) i

mpa

ct o

n bo

ne fo

rmat

ion,

on

60 d

ay n

one

of th

e co

mbi

natio

ns im

pair

ed b

one

form

atio

n

Hig

h lo

cal d

oses

of s

imva

stat

in c

ause

d an

in

tens

e in

flam

mat

ory

reac

tion,

SIM

& D

BB

M

have

neg

ativ

e im

pact

on

bone

repa

ir

tab

le 1

. (co

ntin

ued)

Aut

hor

Met

hod

stat

inO

utco

me

com

men

ts

ML

W: m

iner

aliz

atio

n w

idth

; ML

V: m

iner

aliz

atio

n vo

lum

e; M

AR

: min

eral

opp

ositi

on ra

te; B

MD

: bon

e m

iner

al d

ensi

ty; S

IM: s

imva

stat

in; O

VX

: ova

riec

tom

ized

; SH

AM

: sha

m-

oper

ated

gro

up; A

CS:

ate

loco

llage

n sp

onge

; LV

: lov

asta

tin; R

A: r

heum

atoi

d ar

thri

tis; R

SN: r

osuv

asta

tin; A

V: a

torv

asta

tin; E

2: 1

7β-e

stra

diol

; RL

: ral

oxife

ne; C

C: c

lom

iphe

ne

citr

ate;

RA

NK

L: r

ecep

tor

activ

ator

of

nucl

ear

fact

or k

appa

-b li

gand

; M-C

SF: m

acro

phag

e cl

ony

stim

ulat

ing

fact

or; T

RA

P: t

artr

ate

resi

stan

t ac

id p

hosp

atas

e; B

AL

P: b

one

spec

ific

alka

line

phos

phat

ase;

TB

V: t

rabe

cula

r bo

ne v

olum

e; O

C: o

steo

calc

in; V

EG

F: v

ascu

lar

endo

thel

ial g

row

th fa

ctor

; TG

F: tr

ansf

orm

ing

grow

th fa

ctor

; LFB

: lef

t fem

oral

bo

ne; L

S: lu

mba

r sp

ine;

TC

P: tr

ical

cium

pho

spha

tes;

DB

BM

: dem

iner

aliz

ed b

ovin

e bo

ne m

atri

x; <

: les

s; >

: hig

her;

(+

): p

ositi

ve; (

-): n

egat

ive;

▲: i

ncre

ased

; ▼: d

ecre

ased

. studies performed mostly in animal models. Although Lima et al (2011)51 demonstrated controversial, and even negative, effects of statins on bone repair, the vast majority of the studies in Table 1 support the beneficial role of this group of drugs. The administra-tion of statins presents anabolic effects by promoting osteoblast activity and suppressing osteoclasts. As a result, statins act effectively on bone formation, inhi-bition of BMD decrease and, in general, on fracture healing and osteoporosis prevention. However, we should take into account that these studies refer to different animal models, they used different doses and the result was a local phenomenon, beyond the established cholesterol-lowering effect of statins. Nevertheless, certain studies underline the remarkable increase of relevant growth factors (TGFβ-1, VGF), revealing a possible explanation for the statins and bones interaction.

Further studies performed in vitro, in cell cultures (Table 2), support the previous findings, thus clarify-ing the potential mechanism of the beneficial effect of statins on bone metabolism. The expression of genes as BMP-2, COLLIA1, osteocalcin (OC) (which demonstrate an anabolic effect) and depression of others like RANKL (leading to suppression of osteo-clast activity), all stimulated by statins, may regulate the role of this class of drugs in bone formation. Hughes A et al in 200752 found that hydrophobic and hydrophylic statins can inhibit osteoclast function in vitro, thereby showing a possible class effect, although stronger evidence supports the role of lipophilic agents as simvastatin (Pagkalos et al60).

Observational studies

An interesting meta-analysis of clinical studies since 2007 by Uzzan et al61 showed that statins have a positive effect on BMD in various sites. In particular, the better effect on BMD was found by lipophylic statins (simvastatin, lovastatin). The authors pro-posed that statins could be used for the management of osteoporosis, but the minimum concentration required for the beneficial effects on bone remains to be determined.

Several clinical studies since then have demon-strated the positive effect of statins on bones. Table 3 displays the main characteristics of these studies and their effect on BMD and bone biochemical markers.

tab

le 2

. Mai

n ch

arac

teri

stic

s of s

tudi

es in

cel

l cul

ture

s inv

estig

atin

g th

e ro

le o

f sta

tins i

n bo

ne m

etab

olis

mA

utho

rM

etho

dst

atin

Out

com

ec

omm

ents

Hug

hes A

et a

l 20

0752

Mou

se m

acro

phag

e lik

e ce

lls,

oste

ocla

st li

ke c

ells

from

rab

bit

bone

mar

row

Ros

uvas

tatin

, pr

avas

tatin

, si

mva

stat

in,

ceri

vast

atin

i) O

rder

of p

oten

cy fo

r in

hibi

tion

of b

one

reso

rptio

n C

ER

>SI

M>

RSV

>PR

Aii)

PR

A in

hibi

ted

reso

rptio

n at

con

cent

ratio

ns >

50μM

iii)

Sing

le in

ject

ions

of R

SV a

nd C

ER

suff

icie

nt to

pr

enyl

ate

bone

mar

row

cel

ls

i) H

ydro

phob

ic a

nd h

ydro

phyl

ic

stat

ins c

an in

hibi

t ost

eocl

ast f

unct

ion

in v

itro

ii) >

dos

es o

f sta

tins c

an in

hibi

t pr

otei

n pr

enyl

atio

n in

ost

eocl

asts

in

vivo

iii)

> d

oses

of C

ER

or

RSV

mild

ly

prev

ent t

he b

one

loss

Rui

s-G

aspa

et

al 2

00753

Cul

ture

s of b

one

spec

imen

s of

3 po

st m

enop

ausa

l wom

en a

nd

MG

3 os

teos

arco

ma

like

cells

.Cel

ls

incu

bate

d w

ith th

e pr

esen

ce o

f st

atin

Sim

vast

atin

or

ator

vast

atin

fro

10-6M

-1

0-9M

CO

LL

IA1,

OC

, BM

P2 g

ene

expr

essi

on si

gnifi

cant

▲,

sim

ilar

effe

cts t

o M

G3

cells

SIM

and

ato

rvas

tatin

stim

ulat

ory

effe

cts i

n C

OL

LIA

1, O

C, B

MP2

ge

nes,

(+)

effe

ct in

ost

eopo

rosi

s

Ahn

KS

et a

l 20

0854

M

ouse

mac

roph

age

cells

, hum

an

brea

st a

deno

carc

inom

a an

d m

ultip

le m

yelo

ma

cells

exp

osed

to

stat

ins

and

RA

NK

L

Sim

vast

atin

i) O

steo

clas

t ▼ w

ith▲

con

cent

ratio

ns o

f sim

vast

atin

, ii)

the

inhi

bito

ry e

ffec

t▼ in

tim

e-de

pend

ent m

anne

r,

iii)i

nhib

ited

oste

ocla

stog

enes

is in

duce

d by

tum

or c

ells

Sim

vast

atin

inhi

bits

the

RA

NK

L-

indu

ced

NF-

kapp

aB a

ctiv

atio

n,

supp

ress

es o

steo

clas

toge

nesi

s, th

erap

eutic

pot

entia

l in

oste

opor

osis

an

d in

can

cer-

rela

ted

bone

loss

.

Yam

ashi

ta e

t al

2008

55C

ultu

res o

f mou

se m

yobl

ast c

ell

line

C2C

12 tr

eate

d w

ith B

MP-

2,

TN

F-a,

SIM

Sim

vast

atin

SIM

no

effe

cts o

n R

unx2

and

AL

P ac

tivity

, SIM

re

vers

ed T

NF-

a in

hibi

tion

of B

MP-

indu

ced

Smad

1,

5, 8

pho

spho

ryla

tion,

SIM

▲ e

xpre

ssio

n of

Sm

ad in

C

2C12

cel

ls e

xpos

ed to

TN

F-a,

SIM

supp

ress

ed T

NF-

a ph

osph

oryl

atio

n of

ER

K1/

2 an

d SA

RK

/JN

K, F

PP a

nd

GG

PP r

ever

sed

the

SIM

eff

ects

on

TN

F-a

indu

ced

activ

atio

n of

Ras

/Rho

/MA

RK

pat

hway

SIM

supp

orts

BM

P-in

duce

d os

teob

last

s diff

eren

tiatio

n th

roug

h an

tago

nizi

ng T

NF-

a-to

-Ras

/Rho

/M

AR

K p

athw

ay a

nd a

ugm

entin

g B

MP-

Smad

sign

alin

g su

gges

ting

pote

ntia

l usa

ge o

f SIM

to

infla

mm

ator

y bo

ne d

amag

e

Mon

jo e

t al

2010

56C

ultu

res o

f mou

se o

steo

blas

tic c

ell

line

MC

3T3-

E1

Diff

eren

t co

ncen

trat

ions

of

rosu

vast

atin

(0.

001-

10μ

Μ)

< c

once

ntra

tions

of R

SV w

ere

prot

ectiv

e ag

ains

t cel

l de

ath

and

> sh

owed

cyt

otox

icity

RSV

pro

mot

es o

steo

blas

t di

ffer

entia

tion

and

regu

late

s the

ex

pres

sion

of S

lco1

a1 w

hich

may

co

nstit

ute

the

tran

spor

t sys

tem

for

RSV

acr

oss t

he c

ell m

embr

ane

in

mat

ure

oste

obla

sts

Yam

ashi

ta e

t al

2010

57M

ouse

ost

eocl

ast l

ine

cell

ML

C-6

from

mou

se b

one

mar

row

co-

cultu

red

with

mou

se

chon

droc

ytes

Sim

vast

atin

SI

M su

ppre

ssed

ost

eocl

astic

act

ivity

and▲

RA

NK

, T

RA

P an

d ca

thep

sin

K e

xpre

ssio

n, S

IM a

ctiv

ated

ER

K,

SAR

K/J

NK

, AK

T p

athw

ays a

nd in

activ

ated

Ras

, Src

ph

osph

oryl

atio

n su

ppre

ssed

by

SIM

SIM

inhi

bits

ost

eocl

astic

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ffer

entia

tion

thro

ugh

inhi

bitin

g Sr

c an

d en

hanc

ing

MA

RK

/AK

T

path

way

s

Che

n et

al

2010

58C

ell c

ultu

res o

f mic

e os

teob

last

lik

e ce

lls a

fter

3 d

ays e

xam

ined

the

mito

chon

dria

ost

eobl

astic

act

ivity

w

ith v

ario

us c

once

ntra

tions

of S

IM

Sim

vast

atin

W

ith 1

0-6M

SIM

AL

P en

hanc

ed a

nd B

MP-

2, A

LP,

si

alop

rote

in, t

ype

I col

lage

n up

-reg

ulat

ed, R

asG

RF1

an

d ph

osph

oRas

GR

F1 ▼

i) S

IM c

an p

rom

ote

oste

obla

st

viab

ility

and

diff

eren

tiatio

n vi

a Sm

ad/

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path

way

, ii)

stat

ins

stim

ulat

e os

teob

last

diff

eren

tiatio

n in

vitr

o


CE

R: c

eriv

asta

tin; S

IM: s

imva

stat

in; P

RA

: pra

vast

atin

; RSV

: ros

uvas

tatin

, CO

LL

IA1:

col

lage

n ty

pe I

a 1

; BM

P-2:

bon

e m

orph

ogen

etic

pro

tein

-2; O

C: o

steo

calc

in; R

AN

KL

: re

cept

or a

ctiv

ator

of n

ucle

ar fa

ctor

kap

pa-b

liga

nd; T

NF-

a: tu

mor

nec

rosi

s fa

ctor

alp

ha, F

PP: f

arne

syl p

yrop

hosp

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, GG

PP: g

eran

ylge

rany

l pyr

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te, T

RA

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rtra

te

resi

stan

t ac

id p

hosp

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se, A

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ecta

ble

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gine

ered

bon

e, h

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SCs:

hum

an a

dipo

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ed c

ells

; h P

RP:

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an p

late

let

rich

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sma;

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bfa1

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e bi

ndin

g fa

ctor

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ha 1

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vas

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r en

doth

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row

th fa

ctor

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s: e

mbr

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ells

; >: h

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r; <

: low

er, (

+):

pos

itive

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: inc

reas

ed; ▼

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reas

ed.

Zho

u et

al

2010

59A

n IT

B c

ompo

sed

of h

AD

SCs

and

hPR

P w

as p

relim

inar

ily

cons

truc

ted,

but

its o

steo

geni

c ca

pabi

lity

need

s im

prov

ing

Sim

vast

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rom

, 0.1

mic

rom

, and

1 m

icro

m S

IM

indu

ce h

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SCs’

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obla

stic

diff

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tiatio

n in

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o ac

com

pani

ed w

ith n

on-in

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on c

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>

AL

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tivity

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e m

iner

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posi

tion

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mor

e ex

pres

sion

of o

steo

blas

t-re

late

d ge

nes s

uch

as O

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a1 ,

BM

P-2,

VE

GF,

and

bas

ic F

GF

1) S

imva

stat

in a

t 1 m

Icro

m se

emed

th

e m

ost o

ptim

al c

once

ntra

tion

due

to it

s hig

h os

teoc

alci

n se

cret

ion

in

med

ia, 2

) si

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stat

in a

t opt

imal

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ncen

trat

ions

can

be

used

to

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ote

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ITB

’s os

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enes

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alos

et a

l 20

1060

ESC

s, de

rive

d fr

om th

e in

ner

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vast

atin

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ces m

urin

e E

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iffer

entia

tion

tow

ard

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ic li

neag

e in

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abse

nce

of o

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indu

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e su

pple

men

ts, 2

) si

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in

conc

entr

atio

n in

the

mic

rom

olar

ran

ge a

nd >

was

toxi

c to

the

cells

and

that

an

effe

ctiv

e co

ncen

trat

ion

for

oste

oind

uctio

n is

0.1

nM

Lip

ophi

lic si

mva

stat

in m

ay p

rovi

de a

no

vel p

harm

acol

ogic

age

nt fo

r bo

ne

tissu

e en

gine

erin

g ap

plic

atio

ns

tab

le 2

. (co

ntin

ued)

Aut

hor

Met

hod

stat

inO

utco

me

com

men

tsStatins, bone formation and osteoporosis: hope or hype? 135

All these studies found a significant change either in BMD or in bone markers, except for three studies which found no statistically significant correlation.

Among these studies, there are four controlled studies, one cross-sectional, three open-label, one open randomized and one cohort study. Although not all of them are characterized by a strictly con-trolled study design, the vast majority reveal a posi-tive effect on BMD and bone biochemical markers. Furthermore, as shown in Table 1 the controlled studies, even though not establishing the effects on BMD, showed significant changes in bone markers, which corroborates the hypothesis of the correlation between statins and bone formation.

DIsCUssION

The pleiotropic effect of statins has led clinicians to investigate their potential use among other enti-ties, such as bone metabolism. Uzzan et al,61 in their aforementioned meta-analysis, found that statins have a positive effect on BMD in various sites. Although the authors concluded that there was a modest but statistically significant favorable effect of statins on BMD, thus confirming the results of previous studies, we are as yet far from an evidence-based recommen-dation of statins as a useful therapeutic modality in osteoporotic patients, even as a complementary one. In addition, more data are needed to support the use of statins for prevention of bone fracture.

This perception has mainly been developed by experimental studies, there being a lack of obser-vational studies to clarify the field. The majority of the literature showed an increase in BMD or in bone markers. Several reasons might be advocated to explain the discrepancies. In fact, the doses used in experimental models which provided a favorable effect were much higher than the doses used in clinical practice. In addition, implementation of treatment was in a short-term perspective. Although obesity and physical activity were associated with prevention of fracture risk, they were neither controlled nor quantified. Thus, the control groups in most of the studies were small, thereby not reflecting an equal, comparative population and thus leading to bias.

On the other hand, statins could be prescribed

tab

le 3

. Mai

n ch

arac

teri

stic

s of

the

stud

ies s

how

ing

effe

ct e

ither

in B

MD

or

in b

one

mar

kers

with

the

use

of st

atin

s

Aut

hor

stud

y de

sign

stat

inPe

riod

of u

se

of s

tati

nsPa

tien

tsA

geE

ffec

t on

bM

Db

one

mar

kers

Uys

al e

t al

2007

62C

ross

-se

ctio

nal

Sim

vast

atin

;37

wom

en w

ith ty

pe

2 di

abet

esN

o av

aila

ble

da

taB

orde

rlin

e, n

o si

gnifi

cant

incr

ease

No

data

ava

ilabl

e

Maj

ima

et a

l 20

0763

Ope

n la

bel

Ato

rvas

tatin

10

mg/

day

3 m

onth

s22

hy

perc

hole

ster

olem

ic

Japa

nese

mal

es

62.3

6±10

.1N

o da

ta a

vaila

ble

Ca

9.58

-9.4

4B

AL

P 22

.42-

21.7

6N

TX

15.

84-1

2.20

Maj

ima

et a

l 20

0764

Ope

n co

ntro

lPi

tava

stat

in

1mg/

day

3 m

onth

s10

1 hy

pech

oles

tero

lem

ic

Japa

nese

(57

men

, 44

wom

en, 6

3 us

ers,

35 n

on-u

sers

)

58.6

±12

No

data

ava

ilabl

eC

a 9.

56-9

.44

P 3.

38-3

.38

BA

LP

23.3

9-23

.09

NT

X 1

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-12.

52

Safa

ei H

et a

l 20

0765

Ope

n la

bel

clin

ical

tria

lL

ovas

tatin

20

mg/

day

18 m

onth

s55

dia

betic

pos

t-m

enop

ausa

l wom

en54

-67

LS

0.94

6-0.

978

War

d’s t

rian

gle

0.

685-

0.78

0

No

avai

labl

e da

ta

Bon

e G

H e

t al

2007

66Pr

ospe

ctiv

e ra

ndom

ized

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uble

-blin

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ebo-

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rolle

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dose

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ging

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mpa

rativ

e

Plac

ebo,

at

orva

stat

in 1

0,

20, 4

0, 8

0mg/

day

52 w

eeks

626

dysl

ipid

emic

po

stpm

enop

ausa

l w

omen

with

T-s

core

0

to -2

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40-7

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gnifi

cant

ch

ange

No

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ifica

nt c

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e

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z-C

astr

illón

JL

et

al 2

00867

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tatin

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-20m

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d 40

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ient

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m

ales

, 27

fem

ales

)60

GG

gen

otyp

eL

S 1.

107-

1.12

9 (p

=0.

0001

)

No

data

ava

ilabl

e

Patil

S e

t al

2009

68Pr

ospe

ctiv

e do

uble

-blin

d R

CT

Sim

vast

atin

20

mg/

day

12 w

eeks

62 p

atie

nts (

31

user

s, 31

non

-use

rs)

25-8

1N

o si

gnifi

cant

ch

ange

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LP

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-28.

2O

C 1

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18.9

P1N

P 61

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CT

X 0

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0.21

Yav

uz B

et a

l 20

0969

Pros

pect

ive

coho

rtR

osuv

asta

tin

10-2

0mg/

day

8 w

eeks

91 h

yper

lipid

emic

pa

tient

s59

±12

.5 N

o av

aila

ble

data

25(O

H)D

14-

36.3

1.2

5(O

H)2

D 2

2.9-

26.6

OC

3.5

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BA

LP

17.7

-9.5

Ca

9.4-

9.3

P 3.

1-3.

1

Kan

azaw

a et

al

2009

70O

pen

labe

l ra

ndom

ized

Ros

uvas

tatin

2.

5mg/

day

36 J

apan

ese

60.1

±7.

4 (u

sers

), 64

.7±

2.7

(non

-us

ers)

No

data

ava

ilabl

eB

AL

P 29

.7-3

3.1

NT

X 4

6.4-

51.6

DPD

5.8

-6.4

Che

ungs

amar

n et

al 2

01071

Pros

pect

ive

RC

TSi

mva

stat

in

40-8

0mg/

day

18 m

onth

s21

2 pa

tient

s (10

6 us

ers,

106

non-

user

s, 63

mal

e, 1

49 fe

mal

e)

>40

BM

D in

crea

sed

(p<

0.01

)B

one

form

atio

n in

crea

sed

(p <

-.000

1) b

one

reso

rptio

n re

duce

d (p

=0.

017)

BM

D m

easu

red

in g

r/cm

3; L

S|: l

umba

r sp

ine;

FN

: fem

oral

nec

k; T

H: t

otal

hip

; Tro

ch: t

roch

ante

r; O

R: o

pens

ran

dom

ized

; RC

T: r

ando

miz

ed c

ontr

ol tr

ial.



in people with lower risk for fractures. Moreover, most of the studies attribute the interaction of statins with bone metabolism to a class-effect mechanism rather than to an individual drug effect. We have to stress here that we do not have extensive data on the pharmacological effects of statins in non-hypercholesterolemic patients.

All the available data from the literature, including evidence from experimental studies as well as from the vast majority of observational studies and the results of a single meta-analysis, suggested that there is a positive effect of statins on BMD, although another meta-analysis by Bauer et al72 showed evidence that the beneficial effects on BMD and on fracture risk are observational, while many limitations and the placebo-controlled trials did not demonstrate any clear-cut benefit. However, the in vitro and some clinical studies (Chuengsamarn et al71) suggest that statins inhibit bone resorption and stimulate bone formation, having a dual action on bone metabolism. Therefore, in the future statins might gain a position among drugs used for the prevention and management of osteoporosis, taking into account that clinicians already have a good deal of experience in prescribing statins, for other indications, and feel familiar with this drug family. Their anabolic and anti-resorptive effects on bone make them an ideal candidate for osteoporosis treatment.

In conclusion, statins, osteoporosis and adipogen-esis share a major pathway, that of RANKL/RANK/OPG. Moreover, fat and bone tissue interaction is altered by activation or silencing of genes signaling molecules and transcription factors. Possibly in the future drugs which intervene in this biochemical and pathophysiological cascade, like statins, in a variety of doses, could be used for the management of ectopic ossification syndromes and other bone disorders like osteoporosis and multiple myeloma, even as an adjuvant therapy. Until then, further large longitu-dinal randomized controlled studies for each statin separately are required to confirm this hypothesis.

aCkNOwleDgemeNTs

We are indebted to Dr Michael Schachter MD, PhD, Senior Lecturer at the International Centre for Circulatory Health and the National Heart &

Lung Institute, Imperial College London. His lecture inspired us to produce this review.

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