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Mini-review

Correlation between osteoporosis and cardiovascular


disease

Delia Sprini1
Giovam Battista Rini1
Laura Di Stefano1
Luisella Cianferotti2
Nicola Napoli3

Department of Internal Medicine, University of Palermo,


Palermo, Italy
2
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
3
Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis MO, USA

Address for correspondence:


Giovam Battista Rini, MD, PhD
Department of Internal Medicine
University of Palermo
Via del Vespro 129
90127 Palermo, Italy
Phone: +39 091 6554432
Fax: +39 091 6554338
E-mail: g.battista.rini@unipa.it

Summary
Several evidences have shown in the last years a possible correlation between cardiovascular diseases and osteoporosis. Patients affected with osteoporosis, for example, have a higher risk of cardiovascular diseases
than subjects with normal bone mass. However, the heterogeneous approaches and the different populations
that have been studied so far have limited the strength
of the findings. Studies conducted in animal models
show that vascular calcification is a very complex mechanism that involves similar pathways described in the
normal bone calcification. Proteins like BMP, osteopontin, osteoprotegerin play an important role at the bone
level but are also highly expressed in the calcified vascular tissue. In particular, it seems that the OPG protect
from vascular calcification and elevated levels have
been found in patients with CVD. Other factors like oxidative stress, inflammation, free radicals, lipids metabolism are involved in this complex scenario. It is not a
case that medications used for treating osteoporosis also inhibit the atherosclerotic process, acting on blood
pressure and ventricular hypertrophy. Given the limited
amount of available data, further studies are needed to
elucidate the underlying mechanisms between osteoporosis and cardiovascular disease which may be important in the future also for preventive and therapeutic
approaches of both conditions.
Clinical Cases in Mineral and Bone Metabolism 2014; 11(2): 117-119

KEY WORDS: osteoporosis; cardiovascular disease; vascular calcification.

Cardiovascular disease and osteoporosis are important


causes of morbidity and mortality in the elderly. Traditionally
these two conditions were considered unrelated and their coexistence has been attributed to independent processes exclusively related to age. However an increasing number of
biological and epidemiological evidence has provided support for a link between the two conditions that have been
shown to share common pathophysiological and genetic risk
factors (1-5).
The possible link between cardiovascular disease and osteoporosis stimulates today to analyse not only the evidence of
a possible association, but also to identify common pathogenetic pathway.
To date studies to identify them are numerous, but the great
heterogeneity of the population makes it difficult to perform a
correct meta-analysis.
However the majority of these studies have shown that individuals with cardiovascular disease have a higher risk of experiencing bone loss and thus greater predisposition to risk
of fracture. On the other hand there is growing evidence that
individuals with low bone mass have higher mortality for cardiovascular events compared to patients with cardiovascular
disease with normal bone mass.
Vascular calcification and bone mineralization share a number of interesting anatomical and pathophysiological common features. In fact the calcification of the arterial tissue is
not just a passive process of precipitation or absorption of
phosphate and calcium but it is a highly organized and regulated by mechanisms similar to those involved in bone mineralization (6-9).
Vascular calcification is an active process, regulated by factors known to be primarily involved in the osteogenesis
process. These include the BMP (Bone morphogenetic protein), the ALP (alkaline phosphatase), the OPN (osteopontin)
and the MPG (Gla protein of matrix) (10, 11).
Calcification is a consequence of bone formation triggered
by Osteoblast-like cells. Vascular smooth muscle cells able
to differentiate into Osteoblast-like cells, were shown to form
nodules and mineralize spontaneously. In vitro, these osteoblastic cells produce hydroxyapatite, an important mineral
in bone formation.
The transformation of vascular smooth muscle cells in Osteoblast-like cells is promoted by several factors and stimuli
such as: BMP, Rank-L, oxidative stress, inflammation, oestrogen deficiency. These osteoblastic cells produce ALP,
osteocalcin and other important factors to mineralization
(10).
The BMP is a powerful growth factor on Osteoblast differentiation and also seems to be an important mediator of vascular calcification. This has been highlighted (10, 12), in the
atheromatous plaques, where the endothelial cells, foam
cells and smooth muscle cells exhibit greater BMP2 and

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D. Sprini et al.
BMP4 expression.
In vitro it has been seen that there are several factors that
can cause cardiovascular disease such as oxidative stress,
oxidized LDL, the TNF-alpha can up-regulate the expression
of BMP in endothelial cells.
The OPN is a glycoprotein which accumulates in extracellular matrix of bone tissue where it binds to calcium and hydroxyapatite. The OPN, which is expressed in the bone tissue, is also found in atherosclerotic arteries and its elevated
serum levels are associated with vascular calcifications.
The ALP is located on the osteoblasts surface and is often
used as a marker of bone turnover. It is an enzyme that catalyzes the hydrolysis of esters. Inflammation and oxidative
stress induce an increase in ALP in smooth muscle cells in
vitro. This increase is associated with an increase in mineralization.
The OPG expressed in vascular and bone tissue is produced
by osteoblasts by different factors including BMP, inflammation, estrogens, vitamin D and oxidative stress.
OPG knock-out mice shows an early onset of osteoporosis
and increased vascular calcification. In vitro studies shows
as the OPG may be important for endothelial cells survival
and inhibition of calcification; it appears that the OPG protect
from vascular calcification and elevated levels have been
found in patients with CVD.
The antibody RANK-L (Denosumab), which inhibits the OPG
in experimental animal, prevents calcium deposition at vascular level (10, 13).
Several hypotheses have been proposed to explain the link
between the two conditions.
One concerns the coexistence of osteoporosis and cardiovascular disease in relation to common etiologic factors besides age, such as smoking, physical activity, alcohol consumption, menopause, hypertension, etc., which can simultaneously promote or inhibit atherosclerosis and bone demineralization. This may partly explain the association between the two diseases, however in many epidemiological
studies, the association between osteoporosis and cardiovascular disease remains even after the removal of some of
these risk factors (14).
Involved in the progression of two conditions there are common pathophysiological mechanisms which include inflammatory cytokines, endogenous sex hormones, oxidized lipids
and dyslipidemia, vitamin K and vitamin D deficiency, low
calcium intake, oxidative stress and diabetes in both condition of insulin resistance and lack of insulin production (1517).
The role of lipids in the association between osteoporosis
and cardiovascular disease is controversial today. In mice,
the oxidized lipids cause vascular calcifications and inhibit
the differentiation of osteoblasts. In mice dyslipidemia is always associated with an increases bone resorption mediated
by osteoclasts which leads to osteoporosis (11).
Estrogen deficiency is a major risk factor for osteoporosis
and cardiovascular disease. After menopause, estrogen levels decrease dramatically resulting in formation of osteoclasts and bone turnover increase with subsequent rapid
bone loss. In addition, the decline in production of estrogen
causes secretion of pro-inflammatory cytokines such as IL-6,
IL-1, TNF-alpha (18, 19).
In postmenopausal women the risk of cardiovascular mortality, stroke-related increases for each DS decrease bone
mass (20).
Inflammation, important in the atherogenic process, involves

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the release of markers such as pro-inflammatory cytokines


and the PCR which are involved in the process and which influence atherosclerosis and bone metabolism by increasing
bone resorption through an induction of osteoclastogenesis
or even inhibiting the way of OPG (21).
Radicals have an important effect on the osteoclasts differentiation. Oxidative stress is associated with hypertension,
atherosclerosis as well as with BMD. Oxidized LDL promotes
vascular smooth muscle cells differentiation into osteoblasts,
which is inhibited by antioxidant effects.
The free radical Nitric Oxide (NO), is a powerful vasodilator
that helps keep the vascular tone and would inhibit collagen
and bone loss. Knock-out mice have low bone mass, decreased BMD and reduced the number of osteoclasts which
suggest that NO could be involved in osteogenesis (22). The
endothelial synthase eNOS, isoform, is present in high concentrations level in bone and play an active role in osteoblast
activation and inhibition of bone resorption. Patients treated
for one year with NO show an increasing bone mass. Finally
the nitroglycerin has proved to be a powerful medicine to enable the osteoclastogenesis and to increase bone mass (2224).
Atherogenesis and bone loss have in common genetic factors such as mutations in genes related to the osteoprotegerina, the Gla protein of matrix and the apolipoprotein E
(ApoE). Mice lacking the osteoprotegerina gene have a
greater ability to develop early vascular calcification, osteoporosis, increased risk of CVD and cerebral hemorrhages.
Similarly, mice lacking protein Gla of matrix gene showed
vascular calcifications, osteopenia and fractures. ApoE
genotype was associated with atherosclerosis, end stage renal disease, reduced BMD, risk fracture, hypertension and
vascular diseases (1, 11, 25).
Polymorphism in the gene for IL-6, a cytokine involved in
bone metabolism and cardiovascular diseases, has shown to
be associated with reduced bone mass in postmenopausal
women and with increase of PAO, while in men was associated with an increased incidence of cardiovascular disease.
Polymorphism of the vitamin D receptor is associated with
risk of both vertebral fractures and MI (26).
Other hypotheses suggest a causal relationship between the
two conditions. A reduced blood flow supply predisposes to
atherosclerosis and could influence the intraosseous blood
circulation. This in turn impairs bone metabolism in the joint
and results in osteoporosis. There is evidence that in the
case of asymmetrical peripheral arterial disease, the hip
bone mineral content in the affected limb is lower than that of
the contralateral limb.
Limited physical activity in patients with cardiovascular disease could be consequently responsible for bone loss.
It is also speculated that progressive bone loss is due to deposit of salts, calcium and phosphate in the arterial wall. It
has been shown than in patients with femoral neck fracture,
spraying blood vessels proximal femurs are often atherosclerotic.
Finally evidence that some medications such as statins, insulin, antihypertensives and bisphosphonates are effective
on both osteoporosis and cardiovascular disease, suggests
a common pathophysiological basis.
Experimental studies in mice have shown that bisphosphonates, widely used as treatment of osteoporosis and prevention of risk of fracture, also inhibit the atherosclerotic
process, acting on blood pressure and ventricular hypertrophy (27).
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Correlation between osteoporosis and cardiovascular disease


Raloxifene, a selective modulator of estrogen receptors, useful in preventing osteoporosis and fracture risk, seems to
have a positive effect on LDL cholesterol levels and risk of
coronary heart disease, especially in postmenopausal
women in which improves vascular endothelial function.
In this connection it should be remembered that mevalonate,
common to both diseases, leads to the synthesis of both
cholesterol and prenylated proteins which activate the osteoclast cells. His inhibition induced by statin or bisphosphonates reduces the synthesis of cholesterol and protein prenylation (18, 19, 28).
Statins reduce cardiovascular mortality by regression of atherosclerotic plaque and decrease LDL cholesterol levels in
patients with dyslipidemia, are also associated with greater
bone mineralization in rats and patients with osteoporosis in
which is also observed a reduced incidence of fractures.
In conclusion, the association between osteoporosis and cardiovascular disease, not just age dependent, could allow an
early identification of those at high risk. Further elucidation of
the mechanisms underlying the link between osteoporosis
and cardiovascular disease are crucial to understanding the
basis for preventive and therapeutic approach of both conditions (1, 17).

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