A Systematic Review on the Relation between use of Statins and Osteoporosis
Pooneh Salari Sharif
The association between cardiovascular diseases and senile chronic diseases has been thought from many years ago. Osteoporosis is one of the major senile and chronic disease which accounts for high morbidity and mortality as well as high cost among elderly patients. Concerning the importance of prevention and treatment of cardiovascular disease as well as osteoporosis, and the pleiotropic effects of statins, the theory of the beneficial effects of statins on bone was proposed from different aspects such as the effect of statins on bone formation, bone resorption, bone mineral density and fracture risk. The probable link between cholesterol synthesis and bone metabolism has been also suggested. Regarding the link between cardiovascular disease and osteoporosis, in vitro studies show beneficial effects of statins on bone formation, however, most of clinical trials do not completely confirm the issue. Meanwhile, some investigators believe in the impact of statins on bone turnover. However, there is no conclusive data and agreement yet to recommend use of statins neither as a treatment nor prevention of osteoporosis. More longitudinal studies in different ethnicities with large sample sizes are suggested.
Received: November 23, 2010;
Accepted: November 24, 2010;
Published: March 16, 2011
Skeleton composed of bone tissue which faces with multiple mechanical and metabolic activities. Bone consists of an organic and mineralized matrix. The main deposited mineral components of bone are calcium and phosphate which are under cellular control. The cellular component contains two distinct cell types specifically osteoblasts and osteoclasts. Bone health depends on the balance between the bone formation activity of osteoblasts and bone resorption activity of osteoclasts.
The process is named remodeling. Several bone diseases cause imbalance between
bone formation and bone resorption such as osteoporosis, hyperparathyroidism,
metastatic bone disease, hypercalcemia of malignancies, hyperhomocysteinemia
(Salari et al., 2008a) or use of drugs (Salari-Sharif
and Abdollahi, 2010; Salari and Abdollahi, 2009).
Reduction in bone mass results in bone fragility and susceptibility to fracture.
The important thing which has to be noticed principally is that in most bone
disorders, increased bone resorption is the main reason for osteoporosis. Therefore
inhibition of bone resorption can be considered as the mainstay of osteoporosis
prevention and treatment and this is possible by reducing either osteoclast
generation or its activity (Woo et al., 2008).
Bone resorption by osteoclasts mediates via several stages as follows: changes
of progenitor cells to precursor cells, differentiation of preosteoclasts from
hematopoietic cells, maturation of osteoclasts, conjunction of osteoclasts to
mineralized bone surface, excretion of acids and lysosomal enzymes. Several
compounds have known to affect osteoclastic bone resorption via this process
such as genistein, vitamin K2, tyrosine kinase inhibitors and some other compounds
which are under investigation such as statins, cyclosporine A, FK506, etc. (Woo
et al., 2008). Nowadays strong evidences put special attention on
oxidative stress as the major causative agent (Abdollahi
et al., 2005; Yousefzadeh et al., 2006).
Many inflammatory mediators are related to the formation of osteoclasts including
tumor necrosis factor-a (TNF-a), receptor activator of nuclear factor κB
ligand (RANKL), interleukin-1 (IL-1), interleukin-6 (IL-6) and macrophage-colony
stimulating factor (M-CSF) (Ahn et al., 2008;
Cao et al., 2003; Kong
et al., 1999). In the recent statins are considered as the main stay
in treating cardiovascular diseases which are in the center of attention.
||The pleiotropic effects of statins. May the triangle be true?
While the beneficial effects of statins on lipids, inflammation, angiogenesis,
and platelet aggregation have been demonstrated; the benefits of statins
on bone are under question. In this triangle (the relationship between statins,
CVD, and osteoporosis) two sides are well known, while the third one (the
link between statin use and osteoporosis) is not truly clear. Plt: Platelet;
T cells: T lymphocytes; Aβ: β-amyloid peptide; CVD: Cardiovascular
In addition to some of their pleiotropic effects (decreasing platelet aggregation,
promoting angiogenesis, decreasing α-amyloid peptide and suppressing T-lymphocyte
activation) (Horiuchi and Maeda, 2006), recently statins
are considered as bone anabolic agents which motivated a great deal of interests
into basic and clinical investigations (Fig. 1). On the other
hand, several investigators have theorized the association between brittle bone
and cardiovascular diseases as two common chronic diseases affecting elderly
population (McFarlane et al., 2004).
Theoretically numerous activities of statins enable them to inhibit production
of inflammatory mediators such as TNF-a, IL-6, C-Reactive Protein (CRP), etc.
(Rosenson et al., 1999; Ikeda
and Shimada, 1999; Strandberg et al., 1999).
Based on these theories and their high usage and the concerns about their safety,
several investigations were performed in order to find their net effect and
mechanisms of action. Therefore the goal of this review is to evaluate the most
relevant studies in this issue and make a conclusion if possible.
MATERIALS AND METHODS
Concerning this area of investigation, all published papers from 2000-2009 were searched by different search engines such as Web of Sciences, Pubmed, Scopus, and Google Scholar. The selected search terms were as osteoporosis, bone, bone markers, statins, and HMG CoA inhibitors. Only articles with accessible abstract were reviewed. Due to the controversies between the results of human and animal studies, animal studies, and letter to editor articles were excluded.
Relevant studies have been summarized in Table 1.
The link between lipids and osteoporosis: It has been claimed that the
inverse correlation between low BMD and cardiovascular mortality is stronger
than blood pressure and serum cholesterol (McFarlane et
al., 2004; Tanko et al., 2003). Also
the link between low triglycerides and vertebral fractures strengthens the possibility
of interrelation between lipids and bone mass (Yamaguchi
et al., 2002). The association between cardiovascular diseases and
osteoporosis was considered from many points of views such as matrix proteins
and factors shared by bone and arterial wall which were known to be the 12-15
lipoxygenase system and peroxisome proliferator-activated receptor (PPARγ),
osteopontin, osteocalcin, osteoprotegerin, the low-density Lipoprotein Receptor-related
Protein (LRP), NF-κB, leptin and adiponectin (Hamerman,
Some other scientists proposed the byproducts of cholesterol biosynthetic pathway
substantial for differentiation of marrow stromal cells into functional osteoblastic
cells (Parhami et al., 2002), while Solomon
et al. (2005a) could not find any relationship between lipid levels
and bone mineral density.
|| The summarized results of the relevant studies
|CC: Case control; RCT: Randomized clinical trial; IHD: Ischemic
heart disease; CSS: Cross-sectional study; RCS: Retrospective cohort study;
CV: Cardiovascular; CT: Clinical trial; BMP-2: Bone matrix protein-2; HOS:
Human osteoblasts; OC: Osteocalcin; PS: Prospective study; HP: Hypercholesterolemic
patients; BALP: Bone alkaline phosphatase; NTx: Cross-linked N-telopeptides
of type I collagen ; Dpyd: Desoxypyridinoline; PMOW: Postmenopausal osteoporotic
women; PMW: Postmenopausal women; PMHW: Postmenopausal hypercholesterolemic
women; HM: Hypercholesterolemic men; CTX: C-telopeptide; IL-6:Interleukine-6;
TNF-α: Tumor necrosis- α; NF-κB: Nuclear factor- κB;
PCS: Prospective cohort study; RS: Retrospective study; BMD: Bone mineral
density; HRT: Hormone replacement therapy; BP: Biphosphonate.
Omoigui (2005) stated that the trigger and the common
causative factor and therapeutic target for atherosclerotic vascular disease
and osteoporosis are cholesterol synthesis and isoprenoid dependent interleukin-6
(IL-6) mediated inflammation, while IL-6 promotes bone remodeling by activating
osteoclastogenesis and osteoclasts (Manolagas and Jilka,
Aminobyphosphonates, as the potent anti-resorptive agents, affect cholesterol
pathway and similar to statins influence mevalonate pathway (Jadhav
and Jain, 2006). It has been known that prostaglandin (PG) synthesis has
a substantial role in bone healing. As essential fatty acids influence PG synthesis,
each affecting agent in this pathway may have an important impact such as non-steroidal
anti-inflammatory drugs (NSAIDs), and statins as well (Salari
and Abdollahi, 2009). Das (2001) considered the
essential fatty acids (EFAS) and their metabolites as the second messengers
of the actions of statins, while there is no conclusive data about the anabolic
effects of EFAS on bone (Salari-Sharif et al., 2010;
Salari et al., 2008b).
STATINS AND BONE METABOLISM
Statins and bone formation: Bone formation is the result of various
functional factors such as growth factors [fibroblast growth factor-1 (FGF-1)]
(Fromihue et al., 2004), transcription factors
[core binding factor (cbfa 1)] (Komori, 2000) which
have a substantial role in the development of osteoblasts (Manolagas,
2000). Among these, bone morphogenic proteins (BMPs) by enhancing osteoblast
differentiation play critical role (Mathews, 2005) and
can be considered as a target for treating osteoporosis (Kugimiya
et al., 2005). Previously it was hypothesized that statin use may
influence bone formation. The hypothesis was supported by in vivo and in vitro
animal studies as well as experimental investigations on cell lines. Mundy
et al. (1999) found that lovastatin and simvastatin intensify bone formation
by increasing expression of BMP-2. Sugiyama et al.
(2000) showed the impact of simvastatin but not pravastatin on bone morphogenic
protein-2 (BMP-2). Ohnaka et al. (2001) found
that pitavastatin not only enhances BMP-2 but also augments osteoclacin expression
in human osteoblasts. The anabolic effects of simvastatin on bone as a result
of advancement of osteoblastic differentiation led to the recommendation of
it as a treatment of common metabolic bone diseases by Maeda
et al. (2001) who observed increasing bone formation by statins via
acting on osteoblasts.
The positive impact of statins on bone formation was also shown by studying
on bone biomarkers. Chan et al. (2001) observed
increased osteocalcin (OC) levels in non-osteoporotic subjects treated with
simvastatin for 4 weeks in a prospective study, whereas no change was detected
in the other bone markers such as bone-specific alkaline phosphatase activity
(BALP), deoxypyridinoline (Dpyd) and cross-linked N-telopeptides of type I collagen
(NTx). Bjarnason et al. (2001) could not show
significant effect of fluvastatin on bone remodeling markers. In another study,
more than 2 years treatment with a statin could not affect bone mineral density
while could lower bone turnover markers in postmenopausal women (Rejnmark
et al., 2002). Tikiz et al. (2004)
observed significant increase in OC and BALP as markers of bone formation after
3 months treatment with simvastatin in addition to significant decrease in serum
level of TNF-α, although the negative correlation between TNF-α and
anabolic bone markers was found in hypercholestrolemic postmenopausal women.
Mediating the effect of statins on bone by affecting vitamin D synthesis is
the other theoretical action of statins on bone. In the study of Perez-Castrillon
et al. (2007), atorvastatin increased vitamin D levels in 12 months;
this effect was formerly reported by simvastatin and lovastatin in two small
studies (Wilczek et al., 1989; Wilczek
et al., 1994). In contrast, Aloia et al.
(2007) could not find a significant relationship between total cholesterol
and vitamin D levels.
Significant decrease in NTx was found in hypercholesterolemic patients on pitavastatin
after 3 months by Majima et al. (2007b) while
no significant changes were found in BALP. They also observed similar results
in men on atorvastatin (Majima et al., 2007a).
Statins and bone resorption: Aminobyphosphonates and statins share their
capability in inhibiting geranylgeranyl diphosphate (GGPP) formation which results
in suppressing osteoclasts function and reducing their number (Horiuchi
and Maeda, 2006). Also other investigations demonstrated the effect of statins
via affecting osteoclasts (Grasser et al., 2003).
Ahn et al. (2008) found that the process of nuclear
factor-κB (NF-κB) activation by RANKL can be suppressed by simvastatin.
In addition, simvastatin inhibited RANKL-induced NF-κB degradation, and
phosphorylation. Furthermore it blocked osteoclastogenesis induced by RANKL
or tumor cells.
Staal et al. (2003) assumed that the inhibitory
effect of statins on osteoclast activity is related directly to their potency
in inhibiting HMG-CoA reductase activity.
Statins and BMD: Regardless of the mechanism of action of statins on
bone, the net effect of an anabolic agent on bone can be increasing BMD. A 4.5
year cohort study showed lack of protective effect of statin use in early postmenopausal
bone loss (Sirola et al., 2002). Lupattelli
et al. (2004) compared BMD in two groups of patients in a longitudinal
study. In contrast to control group, a significant increase was seen in the
patients treated with simvastatin. De Leo et al.
(2003) observed higher bone mineral density in postmenopausal women on statins
and HRT comparing with HRT alone. In a 1-year longitudinal study, Montagnani
et al. (2003) found significant changes in BMD of patients treated
with simvastatin in comparison with control group as well as in BALP level.
In a one year double-blind controlled trial no substantial change was found
in BMD or bone markers in healthy postmenopausal women (Rejnmark
et al., 2004a). Nakashima et al. (2004)
showed a significant smaller annual decrease of BMD in statin users comparing
to non-users in diabetic patients. Some other cross-sectional surveys in postmenopausal
women using statins for hypercholesterolemia support the association between
statin use and higher BMD, however it is unknown whether the link is by chance
(Solomon et al., 2005b). The modest additive
effects of statins to biphosphonates in recovering BMD in hypercholestrolemic
postmenopausal women with confirmed osteoporosis-osteopenia was demonstrated
by Tanriverdi et al. (2005). In a double-blind
placebo-controlled trial in hypercholesterolemic postmenopausal women, Bone
et al. (2007) found no significant differences between atorvastatin
and placebo groups in BMD.
Statins and fracture risk: The inverse association between risk of fracture
and statin use was uncovered many years ago in some observational studies (Mundy
et al., 1999; Chan et al., 2000; Meier
et al., 2000; Wang et al., 2000; Rejnmark
et al., 2004b). Chan et al. (2000)
reported decreased risk of non-pathological fractures (odds ratio 0.48 [95%
CI, 0.27-0.83]) in a population-based case-control study in statin users. While
Reid et al. (2001) could not find support for
the meaningful impact of statins on risk of fracture, Pasco
et al. (2002) stated that the reduction of fracture risk with statin
use is more than presumed from increases in BMD alone. Also there are some other
researches which suggest that the observed protective effect of statins on fracture
risk may be justified by unmeasured confounding factors (Ray
et al., 2002). Results of 4 prospective studies and cumulative meta-analysis
of observational studies and controlled trials and post hoc analysis of cardiovascular
trials could not add any further proof to this theory (Bauer
et al., 2004; Reid et al., 2005; Scranton
et al., 2005). Of these, Bauer et al.
(2004) determined odds ratio of 0.87 (95%CI, 0.48-1.58) for hip fracture
and odds ratio of 1.02 (95% CI, 0.83-1.26) for nonspine fracture, however Nguyen
et al. (2007) supported the link between hip fracture and statin
use according to Bayesian model.
While nearly most of In vitro studies disclosed promising effects of
statins on bone, several in-vivo studies presented controversial results. In
fact by suggesting the link between cardiovascular diseases and osteoporosis
as two chronic senile diseases, there is no unique treatment modalities affecting
both. Not only there are controversial results from several studies investigated
the association between statin usage and bone formation or resorption but also
the surveys on their impact on BMD or fracture risk is misleading. The probable
reasons for these inconsistencies are as below:
||Unmeasured confounders such as hyperlipidemia may explain
the discrepancies while to date no conclusive data is available about the
relationship between hyperlipidemia and low bone mineral density
||In many studies, the patients status from functional, drug history,
alcohol intake, and smoking points were not assessed. Omission of these
variables may help more accurate findings
||Most of the studies are cross-sectional, while longitudinal studies would
give us information about the changes over time and can be more applicable
||Genetic heritage is the other factor which has to be considered seriously
||Osteoclastic overcoming the inhibition of HMG-CoA reductase must be considered
||Obvious differences in the sites of action of statins and aminobiphosphonates
is the other issue (Horiuchi and Maeda, 2006)
||The optimum concentration of statins in bone context is questionable,
while their liver specificity and low oral bioavailability is a major problem
and may be solved by special drug delivery systems which were investigated
in an in-vivo study by Gutierrez et al. (2001).
They compared transdermal administration of statins with oral administration
and showed a larger effect on bone metabolism
||Lack of radiologic evaluation could not provide information about subclinical
||Small number of patients and short duration of study can be modified as
||Measuring bone specific biomarkers for bone formation and bone resorption
is more sensitive in exposing slight changes in bone metabolism, while case-control
epidemiological studies consider BMD or calculate fracture risk as odds
ratio. However the sensitivity and specificity of each bone marker has to
||In most of the retrospective studies, the subjects were on statin treatment,
therefore this type of data analysis do not give us obvious conclusion about
the usefulness of statins in osteoporosis
||Furthermore the effect of statin use on bone markers in osteoporotic patients
with normal lipid levels has to be surveyed
||In addition, difference in body weight has been proposed to be another
possible confounder (Ray et al., 2002; Van
Staa et al., 2001)
||Randomization technique is of great significance especially in preventive
medicine. Thus it has to be noticed more precisely in the future investigations
||In different studies different statins were used, while the effects of
reductase inhibitors on bone may vary with each statin. Also their effective
concentration is different. Although lovastatin and simvastatin contribute
in in-vitro osteoblastic differentiation and BMP-2 induction in human cells
at micromolar concentrations (Mundy et al., 1999),
simvastatin showed its influence in osteoblastic differentiation in mouse
calvarial cells at nanomolar concentrations (Maeda et
||Additionally it has to be noted that culture conditions and cell types
may change in vitro findings
||Most of the hyperlipidemic patients are taking more cardiovascular drugs
which may affect bone turnover
Considering conflicting results, although use of statins seem hopeful but at present they cannot be recommended for osteoporosis. This is because of publication bias, heterogeneity among observational studies, and lack of association in randomized trial. Prospective large placebo-controlled trials are needed. Further investigations warrants powerful results about the relationship between statin use and bone mineral density and the possible mechanism of action of statins on bone.
This study is the outcome of an in-house non-financially supported study.
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