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Inflammation, bone loss and fracture risk in spondyloarthritis: Figure 1

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Abstract

Osteoporosis (ie, low bone mineral density) is common in ankylosing spondylitis, related to both systemic inflammation and decreased mobility. Vertebral fracture risk is increased; acute back pain in these patients is not always a flare-up of the disease, as it can be related to bone complications. Intervertebral disc fractures in the ankylosed spine are associated with severe neurological complications. As expected from pathophysiology, treatments effective against inflammation have a positive effect on bone, and prospective open studies have shown that tumour-necrosis-factor blockers can improve bone mineral density at the spine and the hip. There is so far no evidence of a decreased risk of fractures with such treatment.
REVIEW
Inammation, bone loss and fracture
risk in spondyloarthritis
Karine Briot, Christian Roux
To cite: Briot K, Roux C.
Inflammation, bone loss
and fracture risk in
spondyloarthritis. RMD Open
2015;1:e000052.
doi:10.1136/rmdopen-2015-
000052
Prepublication history for
this paper is available online.
To view these files please
visit the journal online
(http://dx.doi.org/10.1136/
rmdopen-2015-000052).
Received 16 February 2015
Revised 17 March 2015
Accepted 22 March 2015
Department of
Rheumatology, Cochin
Hospital, Epidemiology and
Biostatistics Sorbonne Paris
Cité, Research Center,
INSERM U1153, Paris
Descartes University, Paris,
France
Correspondence to
Professor Christian Roux;
christian.roux@cch.aphp.fr
ABSTRACT
Osteoporosis (ie, low bone mineral density) is common
in ankylosing spondylitis, related to both systemic
inflammation and decreased mobility. Vertebral fracture
risk is increased; acute back pain in these patients is
not always a flare-up of the disease, as it can be
related to bone complications. Intervertebral disc
fractures in the ankylosed spine are associated with
severe neurological complications. As expected from
pathophysiology, treatments effective against
inflammation have a positive effect on bone, and
prospective open studies have shown that tumour-
necrosis-factor blockers can improve bone mineral
density at the spine and the hip. There is so far no
evidence of a decreased risk of fractures with such
treatment.
INTRODUCTION
Osteoporosis is a frequent complication of
inammatory rheumatic disorders and a well-
recognised feature of ankylosing spondylitis
(AS).
1
The disease is characterised by osteo-
proliferation and spine rigidity. The anky-
losed spine is at risk of deformities and
fractures. However, low bone mineral density
(BMD) has also been observed in early dis-
eases,
2
suggesting that decreased mobility is
not the single mechanism of bone fragility.
Moreover, osteoporosis cannot be related to
the underlying characteristics of the patients
like in rheumatoid arthritis, as AS is typically
a disease of young men, and glucocorticoids
are not used in this disease. Systemic inam-
mation itself can have a deleterious effect on
bone remodelling, and this is the rationale
for studying the potential positive bone
effects of potent anti-inammatory drugs.
FRACTURES IN AS
Patients with AS have an increased risk of ver-
tebral fractures. A casecontrol study of
53 108 patients with fractures using the
Swedish National Hospital Discharge Register
concluded that the risk of fractures was
higher in AS than in rhe umatoid arthritis,
with the largest increase for vertebral fracture
(odd ratios (OR) 7.1 and 2.7 for AS and RA,
respectively).
3
The prevalence of vertebral
fractures is highly variable in different studies,
up to 30%.
45
These data are unexpected in a
disease affecting a young population, pre-
dominantly males. Actually, the denition of
a vertebral fracture varies among studies, and
three different vertebral complications must
be considered.
Spinal fractures in AS
Spinal fractures can occur in patients with an
ankylosed spine, even after a minor trauma.
They can be transdiscal through the syndes-
mophytes, or transvertebral, involving the
posterior arch.
6
They can be located at the
cervical spine, which is never involved in
typical osteoporotic vertebral fractures.
7
Neurological complications of variable
degrees, sometimes severe, are usual in these
fractures.
8
Moreover, the capacity of healing is
poor, and pseudoarthrosis with instability can
occur, leading to surgery in most of the cases.
Unstable cervical fractures are the most fre-
quent, as they are located at the junction
between the fused thoracic spine and the
mobile head. In such patients, the C7-T1
junction must be analysed carefully. The thor-
acic hyperkyphosis exposes the patients to a
hyperextension trauma of the neck in case of
a fall. Patients with a bamboo spine have a
Key messages
Osteoporosis (or low bone mineral density) is
common in ankylosing spondylitis, related to
both systemic inflammation and decreased
mobility.
Patients with ankylosing spondylitis have an
increased risk of vertebral fractures.
Effective treatments against inflammation (TNF
blockers) have a positive affect on bone mineral
density.
There is no evidence of a decreased risk of frac-
tures with the control of inflammation.
Briot K, Roux C. RMD Open 2015;1:e000052. doi:10.1136/rmdopen-2015-000052 1
Osteoporosis
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high risk of such fractures, because of the calcications of
the spinal longitudinal ligaments and disuse osteoporosis
of the vertebral bodies related to immobility. They must
be carefully evaluated, as it is sometimes difcult to differ-
entiate between pain from fracture and pain from a
are-up of the inammatory disease. A retrospective
study showed that 60% of cervical spine fractures in AS
were undetectable on initial X-rays;
9
CT is more sensitive
than radiographs. A prospective 22-year cohort study
recently showed that the occurrence of spinal fractures in
AS, mainly cervical fractures, has an increased occur-
rence. One potential explanation is that patients with a
bamboo spine can have an increasing level of physical
activity and thus a greater risk for injuries, because of
pain relief related to effective treatment (TNF blockers)
of the disease.
10
Vertebral deformities in AS
Deformities of vertebral bodies are frequent in AS, par-
ticularly at the thoracic spine, for a number of reasons:
erosions of the anterior corners, squaring, wedging sec-
ondary to inammatory lesions. These deformities are
captured by semi-automated methods of morphometry,
which use automatic positioning of points on vertebral
contours; with such methods, fractures are dene d as
any reduction of the anterior or middle height of the
vertebral body larger than 20% as compared to the pos-
terior height, or as compared to the heights of adjacent
vertebrae. These methods are very sensitive but need
expert adjudication;
11
otherwise, they increase the risk
of false positives. Short vertebral heights are frequent at
the thoracic spine and should not be considered as frac-
tures. Anterior deformities of the thoracic spine,
whether they are related to fractures or other causes-
related wedging, are responsible for hyperkyphosis, a fre-
quent complication of AS.
12
Vertebral fractures in AS
Prevalence of vertebral fractures ranged from 9% to
18% in studies published in the 1990s.
413
Higher rates
have been reported recently in studies using systematic
imaging methods of the spine (either X-rays or the ver-
tebral fracture assessment (VFA) method by dual-energy
X-ray absorptiometry). In 176 patients (79% males, aged
48.6±13.1 years) with a mean disease duration of
22 years, the prevalence of vertebral fractures was 32.4%;
82% of the fractures were at the thoracic spine, and
65% of them were mild, that is, showed a decrease in at
least one vertebral body height of 2025%. A semiauto-
mated software was used for analysis.
5
In 80 patients
(84% males, age 38.9±11.8 years) with a mean disease
duration of 10 years, the prevalence of moderate or
severe fractures (ie, a decrease in vertebral body height
of more than 25% and more than 40%, respectively) was
18.8%.
14
In early spondyloarthropathies (ie, 7 months of
disease duration, but 5.7 years of symptom duration),
15% of the 113 patients (66% males, aged 37.3
±9.0 years) had a vertebral fracture; most of them were
located at the mid-thoracic spine, half of the fractures
were moderate, and none were severe.
15
Whether or not
the severity of the vertebral fractures is a function of the
duration of the disease is unclear.
The use of large databases gives the opportunity to
assess the prevalence of VFs in a very large number of
patients but with the limits of such method, in particular
the absence of the conrmation of the fracture in most
of the cases. All the vertebral fractures are those which
come to clinical attention, which may represent a minor-
ity of them. A nested case control study has been per-
formed in the large General Practice Research Database
in the UK; 231 778 patients with fracture and the same
number of controls were analysed.
16
From medical
records, AS was diagnosed in 758 participants. These
patients had an increased risk of clinical vertebral frac-
ture: OR=3.26 (1.517.02), but no increased risk of non-
vertebral fracture, including of the wrist and hip. In a
large database in Catalonia, Spain, accounting for 80% of
the population, 6474 patients with AS were identied,
compared to controls, and followed for a median time of
5 years.
17
Among patients with AS, 0.86% and 3.4% sus-
tained a clinical vertebral and a non-vertebral fracture,
respectively. This represents a twofold increased risk of
clinical vertebral fractures, as compared to controls.
Interestingly, an increase in the non-vertebral fracture
risk (1.2 fold) was reported in this study, an observation
which has never been made previously. Such results have
been conrmed in the Danish Health Registries.
18
In this
casecontrol study assessing data for the year 2000, the
age-matched and gender-matched ORs for patients with
AS were 5.4 (2.511.7) and 1.4 (1.11.7) for vertebral
and non-vertebral fractures, respectively. The association
between AS and clinical fractures was highest in patients
diagnosed for less than 2.5 years, or for more than
12.5 years. However, after adjustment for potential con-
founders, only clinical spine fracture risk was still
signicant.
18
In one 4-year prospective study conducted in 298
patients, the incidence of vertebral fracture (according to
morphometric denition) was 4.7% at 2 years and 13.6%
at 4 years. None of the fractures were severe. The risk
factors were prevalent vertebral fractures at baseline and
increased C reactive protein (CRP) levels at 2 years.
19
RISK FACTORS FOR FRACTURES IN AS
Patients with a bamboo spine, hyperkyphosis and difcul-
ties with peripheral vision have potential impairments in
balance and coordination and a high risk of falls.
20
Disease duration and wall-occiput distance have been
reported as risk factors for vertebral fractures
5
(gure 1).
A low BMD is common in patients with AS with pro-
gressive disease. However, increased BMD can be due to
artefacts related to the presence of syndesmophytes or
other structural lesions as ankylosed posterior arch and
periosteal bone formation. Active or past hip arthritis
(coxitis) can impair the internal rotation of the lower
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limb, which is mandatory for an accurate hip BMD
measurement.
The denition of low BMD varies among studies. In
theory, T scores are used only for postmenopausal
women, and Z scores should be used in young males; an
abnormal BMD could then be dened as Z ≤−2.
Recognising these different denitions, the prevalence
of low BMD measured by dual energy X-ray absorpti-
ometry is 1427% and 414% at the spine and hip,
respectively, in patients with long-lasting disease.
16 2124
Prevalence is higher in studies using quantitative CT at
the spine, as this technique allows measurement of
central areas of vertebral bodies, avoiding the cortex
and bone constructions. The prevalence of osteoporosis
(based on dual energy X-ray absorptiometry measure-
ments) in patients within the rst decade after diagnosis
is 16% and 13% at the lumbar spine and femoral neck,
respectively.
25
In 267 patients with symptoms suggestive
of axial SpA, we showed recently that patients with a con-
rmed diagnosis (N=93) had lower BMD than patients
with an unconrmed SpA (N=74). The positive likeli-
hood ratio of low BMD for an axial SpA diagnosis was
2.60 and 3.12 at the spine and hip, respectivel y.
26
In 80
patients aged 39 years, the prevalence of osteoporosis
(T ≤−2.5 at any site) was 25%, which is higher than
expected in such a young population. Low weight and
low body mass index (BMI), long disease duration, male
gender and markers of disease activity were associated
with osteoporosis.
14
In 204 patients (57% men, mean
age 50±13 years), the prevalence of osteoporosis
(T≤−2.5) was 21% in participants aged 50 years. Low
BMD was associated with age, BMI, disease duration and
inammatory parameters.
23
Patients with vertebral frac-
tures had lower BMD than patients without, and femoral
neck was the best discriminant site in this population
where the mean modied Stoke Ankylosing spondylitis
spine score (MSASSS) was 14.2 (median 5.5).
24
There is
a debate about low BMD as a risk factor for vertebral
fracture in AS. Such a relationship has not been found
in patients with early disease.
25 27
In a study of 113
patients with a disease duration of 7 months, aged
37 years on average, the majority of patients with verte-
bral fractures do not full the densitometry-based cri-
teria for osteoporosis.
25
The proportion of patients with
low BMD varies with time. In 130 patients (66% males)
with an early disease (time since diagnosis 6.6 months,
and disease duration 6.3 years), 9% of these patients
aged 38±9 years had osteoporosis (ie, T score ≤−2.5 at
the spine and or hip).
28
In patients within 5 years of
onset of AS, the prevalence of osteoporosis was 11% and
15% at the hip and spine, respectively; these rates were
30% and 4%, respectively, in patients with a disease dur-
ation higher than 10 years.
28
There is an association
between the presence of syndesmophytes and a low hip
BMD,
29
suggesting the role of both the severity of the
disease and the reduced mobility of the patients.
Attention has been paid recently to bone microarchi-
tecture changes in patients with AS
30
measured by high-
resolution peripheral quantitative CT of the ultradistal
radius and tibia. Patients with AS have lower cortical
BMD at peripheral sites, a result which is in accordance
with the role of systemic inammation and thus a sys-
temic bone effect in this disease. In contrast, the pres-
ence of syndesmophytes was not associated with any sign
Figure 1 Bone fragility in
ankylosing spondylitis.
Briot K, Roux C. RMD Open 2015;1:e000052. doi:10.1136/rmdopen-2015-000052 3
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of hyperostosis in the peripheral microarchitecture, sug-
gesting that osteoproliferation is not a systemic process.
30
PHYSIOPATHOLOGY OF BONE FRAGILITY IN AS
Osteoporosis can occur in AS because of reduced phys-
ical activity, and decreased functional capacity related to
pain, stiffness and ankylosis.
28
However, low BMD is
found in patients with early disease, before any struc-
tural changes.
26 28 31
Vitamin D receptor gene may contribute to BMD dif-
ferences in patients with AS, and some polymorphisms
are also linked to inammation.
3234
The HLA B27 transgenic rat, a validated model of
spondyloarthritis, having colitis, skin lesions, peripheral
arthritis and spondylitis, exhibits a decreased bone
strength, without any defect in the mineralisation
process; histomorphometric indices indicate a decrease
in bone volume, trabecular number and trabecular
thickness, that is, an osteoporosis.
35
Two prospective studies have shown that spine and hip
BMD decrease predominantly in patients with active
disease.
36 37
In 332 (52% males) patients with early
inammatory back pain suggestive of spondyloarthropa-
thies (disease duration of symptoms 1.6 years), we found
that male gender, either increased erythrocyte sedimen-
tation rateor CRP, and presence of bone marrow
oedema on MRI were associated with a low BMD.
Interestingly, bone inammatory lesions on MRI were
one of the determinants of low spine BMD, and the
single determinant of low hip BMD, suggesting the sys-
temic effect of inammation.
31
In a 1-year prospective
study in 30 patients with inammatory back pain, there
was no change in hip and spine BMD; however, in a post
hoc analysis, hip bone loss (not of the spine) was found
to be associated with raised baseline CRP and sacroiliitis
diagnosed by MRI.
38
All these data support the role of inammation in bone
loss in SpA. Advances in pathogenesis have been provided
by a new mouse model that highlights the role of IL23 in
entheseal inammation. Gut-derived IL23 (even in sub-
clinical gut involvement) can act on a previously unidenti-
ed subpopulation of entheseal resident T cells, which, in
reaction, produce cytokines such as IL22 and IL17,
involved in osteoproliferation and bone loss, respectively.
39
Patients with active and long-lasting AS are at risk of
muscle loss because of reduced physical activity and
inammation; tumour-necrosis-factor (TNF) increases
resting energy expenditure, stimulates muscle protein
breakdown and downregulates the systemic and local
expression of anabolic hormones and growth factors.
40
Adipokines, produced by adipocytes from fat tissue, can
have immune regulatory function and affect bone
metabolism; some of them (resistin, visfatin) may be
involved in radiographic damage in patients with AS.
41
Thus, inammation plays a key role in bone loss in
AS, and a benecial effect of anti-inammatory drugs
on bone is expected, not only through the increased
mobility related to pain relief, but also through a direct
effect on bone.
EFFECT OF PHARMACOLOGICAL TREATMENTS ON
OSTEOPOROSIS
NSAIDs
In a primary care-based nested case control study, the
risk of any clinical fracture was decreased in patients
with AS taking non-steroidal anti-inammatory drugs
(NSAIDs) (OR: 0.65 (0.50, 0.84)), after adjustments.
16
In a population-based cohort study, the increased risk of
fractures in patients with AS was apparent only in those
not on regular NSAIDs treatment.
17
However, this result
was not conrmed by a nationwide casecontrol study:
after stratifying by NSAID use, the excess risk of any clin-
ical fracture in patients with AS is higher in NSAID
users, which may be related to a higher utilisation of
NSAIDs in patients with a more severe disease.
18
All
these data should thus be interpreted with caution.
TNF blockers
Prospective open studies in patients with AS receiving
TNF blockers show a positive effect on BMD.
42
In a
2-year follow-up study of 106 patients, we observed 5.8%
and 2.3% increases in the lumbar spine and hip BMD,
respectively.
40
Over 6 years of continuous administration
of such treatment in 59 patients, the increase in BMD
was 11.8 and 3.6% at these two sites, even after exclusion
of patients with prevalent and/or incident syndesmo-
phytes.
43
A systematic review of eight studies (including
1 randomised control trial) with a total of 568 patients
with AS showed an average of 8.6% and 2.5% increases
in BMD at the lumbar spine and hip, respectively.
44
There is a strong biological rationale beyond these
results, as TNFα plays a key role in bone resorption and
formation. Osteoclastogenesis and osteocla st activity are
enhanced by TNFα, which also inhibits osteoclast apop-
tosis.
45 46
On the other hand, excess TNFα inhibits the
bone formation process, and sclerostin is over expressed
in TNFα transgenic mice.
47
As expected, changes in
bone remodelling markers in patients treated with TNFα
blockers are those expected with a treatment having an
antiresorptive activity.
40 48 49
An increase in body weight
is observed in patients receiving TNF blockers, mostly
due to a gain in fat mass,
40
with an early increase in
abdominal (both visceral and subcutaneous) fat.
50
As a consequence, the bone effect of anti-TNF treat-
ment should be taken into account before introducing
antiosteoporotic treatment in patients with AS with
osteoporosis. However, there is so far no evidence of an
anti-fracture effect of TNF blockers in AS.
51
In a pro-
spective study conducted in 298 patients, markers of
inammation were associated with incident vertebral
fracture; among 26 patients with new vertebral fracture,
6 were on TNF inhibitors and the study was not powered
to identify a protective effect of this treatment.
19
There
are no guidelines for treatment of osteoporosis in AS. In
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patients wit h an indication for TNF blocker treatment,
without prevalent non-traumatic fracture, it seems
logical to assess rst the benet of this treatment.
However, in patients with severe osteoporosis and preva-
lent fractures, available guidelines in osteoporotic parti-
cipants and male osteoporosis must be applied.
Rehabilitation treatments have been reported to
improve management of patients with AS receiving TNF
blockers, but which exercise protocols should be recom-
mended is not yet dened.
52
CONCLUSION
Ankylosing spondylitis raises a paradox: patients have
both osteoporosis and an excess of bone formation.
Local changes and systemic bone loss are underlined by
different mechanisms. AS is an appropriate model for
studies of bone effect of inammation.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
Data sharing statement No additional data are available.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/4.0/
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6 Briot K, Roux C. RMD Open 2015;1:e000052. doi:10.1136/rmdopen-2015-000052
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Inflammation, bone loss and fracture risk in
Karine Briot and Christian Roux
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... The characteristics of the AS patients are similar to those in other studies with respect to sex, age, BMI, and fractures 16,17 . Few studies have used dedicated QCT measurements to determine the bone mass in AS, which may have implications for treatment 18 . The major findings in this study indicate that 3DQCT can be effectively used to acquire bone mass measurements that differ significantly from measurements acquired by other bone densitometric methods, in both the trabecular and cortical bone. ...
... In the pathophysiology of bone loss in AS, proposed mechanisms 1,18,19 have included subclinical inflammatory bowel disease with malabsorption of calcium and vitamin D 18,20,21 and secondary hyperparathyroidism, which may induce intracortical bone loss. Once there, the appendicular skeleton (rich in cortical bone) is more likely to be offended by changes in parathyroid hormone due to the malabsorption of calcium. ...
... In the pathophysiology of bone loss in AS, proposed mechanisms 1,18,19 have included subclinical inflammatory bowel disease with malabsorption of calcium and vitamin D 18,20,21 and secondary hyperparathyroidism, which may induce intracortical bone loss. Once there, the appendicular skeleton (rich in cortical bone) is more likely to be offended by changes in parathyroid hormone due to the malabsorption of calcium. ...
Article
Full-text available
Objective: The aim of this study was to investigate if there is a bias in bone mineral density measurements among major densitometric techniques across multiple skeletal sites. Methods: In 25 advanced ankylosing spondylitis patients, bone mineral density measurements were acquired in the lumbar spine, the hip, and the forearm. Results: In total, 60% of patients had a bone mineral density Z-score of -2 or less at one or more skeletal sites. Dedicated loss of cortical bone was identified at the distal forearm (60% of patients). Differences in bone mineral density measurements across all densitometric techniques were highly significant (p≤0.001). Bone loss was more striking in spinal trabecular bone by three-dimensional quantitative computed tomography [Z-score -2.1] versus dual-energy X-ray absorptiometry [Z-score 0]. A trabecular bone loss quantified by quantitative computed tomography was about twice as much as a cortical bone loss by single-energy X-ray absorptiometry (p=0.001). Conclusions: Low bone mineral density is prevalent in advanced ankylosing spondylitis patients, predominating in the spine. Bone mineral density measurements have systematic differences when compared to each other. Knowledge of these offsets is useful for improved diagnosis of regional bone loss that allows for targeted treatment of osteoporosis. Three-dimensional quantitative computed tomography is more suitable for evaluating spinal osteoporosis in advanced ankylosing spondylitis than dual-energy X-ray absorptiometry, which rather underestimates bone loss.
... Patients with ankylosing spondylitis (AS) have a 7.1-fold increased risk of vertebral fracture than the general population, and that risk is elevated further in the presence of other inflammatory arthritis or autoimmune diseases [14]. The increased risk of osteoporosis and related fracture in axSpA is related not only to known risk factors for osteoporosis but also systemic inflammation [15]. Bisphosphonate is the most commonly used anti-osteoporotic agent and inhibits osteoclasts and monocyte/macrophage lineage cells [16]. ...
... The anti-arthritic effects of anti-osteoporotic agents could be useful in patients with inflammatory arthritis, including SpA, which are linked to increased osteoclast activity and an increased risk of osteoporosis [12]. The latter could be explained by increased systemic inflammation [15]; moreover, IL-1β, IL-6, IL-17, and TNF-α promote osteoclastogenesis in inflammatory arthritis [25]. Therefore, additional antiarthritic effects of anti-osteoporotic agent can be attractive therapy in patients with inflammatory arthritis, because it could expect dual therapeutic effects, preventing osteoporosis and additional anti-arthritic effects. ...
Article
Full-text available
Purpose Spondyloarthritis (SpA) is a systemic inflammatory arthritis mediated mainly by interleukin (IL)-17. The vitronectin-derived bioactive peptide, VnP-16, exerts an anti-osteoporotic effect via β1 and αvβ3 integrin signaling. SpA is associated with an increased risk of osteoporosis, and we investigated the effect of VnP-16 in mice with SpA. Methods SpA was induced by curdlan in SKG ZAP-70 W163C mice, which were treated with vehicle, celecoxib, VnP-16, or VnP-16+celecoxib. The clinical score, arthritis score, spondylitis score, and proinflammatory cytokine expression of the spine were evaluated by immunohistochemical staining. Type 17 helper T cell (Th17) and regulatory T cell (Treg) differentiation in the spleen was evaluated by flow cytometry and in the spine by confocal staining. Splenocyte expression of signal transducer and activator of transcription (STAT) 3 and p STAT3 was evaluated by in vitro Western blotting. Results The clinical score was significantly reduced in the VnP16+celecoxib group. The arthritis and spondylitis scores were significantly lower in the VnP-16 and VnP16+celecoxib groups than the vehicle group. In the spine, the levels of IL-1β, IL-6, tumor necrosis factor-α, and IL-17 expression were reduced and Th17/Treg imbalance was regulated in the VnP-16 alone and VnP-16+celecoxib groups. Flow cytometry of splenocytes showed increased polarization of Tregs in the VnP-16+celecoxib group. In vitro , VnP-16 suppressed p STAT3. Conclusions VnP-16 plus celecoxib prevented SpA progression in a mouse model by regulating the Th17/Treg imbalance and suppressing the expression of proinflammatory cytokines.
... Instead, RNA demethylase ALKBH5 downregulated the combination of circ_0008542 with miRNA-185-5p to rescue excessive bone resorption (Wang et al., 2021). In addition, several studies have shown that m6A has a regulatory effect on intracellular inflammatory factors such as interleukin-1β (IL-1β), IL-6, interferon-gamma (IFN-γ), and tumor necrosis factor-α (TNF-α), leading to bone loss through the bone immune system (Neurath and Finotto, 2011;Briot and FIGURE 1 | The molecular mechanism and physiological regulation roles of m6A modification in bone. M6A is mainly catalyzed by the METTL3-METTL14-WTAP methyltransferase complex, and the demethylases ALKBH5 and FTO remove the methyl group of m6A off RNAs. ...
... Frontiers in Cell and Developmental Biology | www.frontiersin.org December 2021 | Volume 9 | Article 783322 Roux, 2015;van Bodegraven and Bravenboer, 2019). Estrogen deficiency also increases inflammatory cytokines (Tsangari et al., 2004), followed by the activation of osteoclasts, increased bone resorption, and osteoporosis . ...
Article
Full-text available
Osteoporosis is a prevalent bone disease of the aging population, which is characterized by a decrease in bone mass because of the imbalance of bone metabolism. Although the prevention and treatment of osteoporosis have been explored by different researchers, the mechanisms underlying osteoporosis are not clear exactly. N6 methyladenosine (m6A) is a methylated adenosine nucleotide, which functions through its interaction with the proteins called “writers,” “readers” and “erasers.” The epigenetic regulation of m6A has been demonstrated to affect mRNA processing, nuclear export, translation, and splicing. At the cellular level, m6A modification has been known to affect cell proliferation, differentiation, and apoptosis of bone-related cells, such as bone marrow mesenchymal stem cells (BMSC), osteoblasts, and osteoclasts by regulating the expression of ALP, Runx2, Osterix, VEGF, and other related genes. Furthermore, PTH/Pth1r, PI3K‐Akt, Wnt/β‐Catenin, and other signaling pathways, which play important roles in the regulation of bone homeostasis, are also regulated by m6A. Thus, m6A modification may provide a new approach for osteoporosis treatment. The key roles of m6A modification in the regulation of bone health and osteoporosis are reviewed here in this article.
... The exact mechanisms and causes of bone loss and fractures in AS have not yet been fully elucidated. Various factors have been suggested as possible explanations, including systemic inflammation, decreased physical activity, use of non-steroidal antiinflammatory drugs, and smoking [33][34][35][36]. In our data, menopause, ESR, CRP level, HLA-B27 positivity, glucocorticoid use, and PPI use were associated with an increased prevalence of osteoporosis and a high risk of osteoporotic fractures. ...
Article
Full-text available
Background: We investigated the prevalence of and the factors associated with a high risk of osteoporotic fractures in Korean patients with ankylosing spondylitis (AS). Methods: This was a multicenter, retrospective study including 219 AS patients from five university hospitals; the control group was selected by matching age and sex with those of the AS patients. The fracture risk was evaluated based on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry and the fracture risk assessment tool (FRAX) with/without BMD. Results: The mean age of the patients was 47.6 years, and 144 (65.8%) patients were men. According to the WHO criteria and FRAX with/without BMD, the candidates for pharmacological treatment were 44 (20.1%), 20 (13.2%), and 23 (15.1%) patients, respectively, significantly more than those in the healthy control group. Among them, the proportion of patients receiving osteoporosis treatment was 39.1-75%. In logistic regression analysis, menopause was an independent factor for the high risk of fracture according to the WHO criteria and FRAX with/without BMD. C-reactive protein level (odds ratio (OR) 3.8 and OR 6) and glucocorticoid use (OR 1.5 and OR 1.7) were associated with a high risk of osteoporotic fracture based on FRAX without BMD and osteoporosis diagnosed according to the WHO criteria. Conclusions: Our study suggests that both FRAX and WHO criteria may be complementary for treatment decisions to reduce osteoporotic fractures in patients with AS.
... Proinflammatory cytokines (such as TNF-α and IL-17) are involved in the bone remodeling process of SpA [99]. Extensive experimental and clinical evidence has linked TNF-α to osteoclast development, but the role of osteoblast formation has remained somewhat controversial [100]. Surprisingly, the unique bone phenotype that occurs in PsA and AS coexists with both systemic bone destruction and new bone formation, which is likely to be the result of the actions of IL-23 and/or IL-17 on osteocytes [101,102]. ...
Article
Full-text available
Inflammatory arthritis has been reported to be associated with the development of osteoporosis. Recent research has investigated the mechanisms of bone metabolism in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Progress in both animal and clinical studies has provided a better understanding of the osteoclastogenesis-related pathways regarding the receptor activator of nuclear factor-κB ligand (RANKL), anti-citrullinated protein antibodies (ACPAs), and Wnt signaling and Dickkopf-related protein 1 (Dkk-1). The complex interplay between inflammatory cytokines and bone destruction has been elucidated, especially that in the interleukin-17/23 (IL-17/23) axis and Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling. Moreover, advances in biological and targeted therapies have achieved essential modifications to the bone metabolism of these inflammatory arthritis types. In this narrative review, we discuss recent findings on the pathogenic effects on bone in RA and SpA. Proinflammatory cytokines, autoantibodies, and multiple signaling pathways play an essential role in bone destruction in RA and SpA patients. We also reviewed the underlying pathomechanisms of bone structure in biological and targeted therapies of RA and SpA. The clinical implications of tumor necrosis factor inhibitors, abatacept, rituximab, tocilizumab, Janus kinase inhibitors, and inhibitors of the IL-17/23 axis are discussed. Since these novel therapeutics provide new options for disease improvement and symptom control in patients with RA and SpA, further rigorous evidence is warranted to provide a clinical reference for physicians and patients.
... There is an elevated fracture risk in AS due to pathological spinal remodeling and osteoporosis [1][2]. Ectopic bone forms with unusual osteoproliferative processes leading to a ligamentous ossification progressively bridging the whole spine and simultaneously develops osteopenia -in part resulting from a stress shielding of the cancellous vertebral parts [3]. The fractures are usually associated with low-energy trauma. ...
Article
The objective of this case report is to describe the substantial sagittal correction of spinal hyperkyphosis alongside fracture fixation. In advanced ankylosing spondylitis (AS), the spine is usually fused, hyperkyphotic, and due to deformity, as well as improper bone remodeling, predisposed to fractures. These fractures, mostly unstable, require surgical treatment. The authors present fracture management with concomitant deformity correction at the fracture site and pedicle subtraction osteotomy (PSO) below the fracture, showing the benefits of performing the procedures with the patient in a sitting position. A 58-year-old male with AS was diagnosed with a fracture of C6 and referred to the department of neurosurgery, Wroclaw University Hospital. For the last week, he had complained of worsening neck pain and exacerbation of spinal kyphosis, with no neurological deficits. The patient had a fully fused spine, significant hyperkyphosis prior to the injury, and a fracture with an additionally exacerbated deformity. The patient was offered operative treatment - spinal fusion and fracture reduction with hyperkyphosis correction. The procedure consisted of 1) partial, mostly closed correction at the fracture site, 2) PSO of C7 and C2-T3 pedicular fixation and fusion while sitting in the posterior approach. To enable closed reduction at the fracture site and avoid difficulties with positioning a prone patient with very severe hyperkyphosis and an unstable spine, the authors performed surgical procedures with the patient in a sitting position. The authors obtained significant correction during the procedure by 740, from 53.40 of kyphosis to 24.30 of lordosis measured between C2 and T1. The patient had several complications (transient weakness of the upper limb, pleural effusion, and delayed wound healing); however, all resolved and the patient was discharged within two weeks post the operation. In patients with spinal hyperkyphosis with AS who sustain spinal fractures requiring operative treatment, it is worth considering simultaneous correction of the spinal deformity during surgical management of the fracture.
... In addition, osteopenia was independently associated with a longer disease duration in our study. It has been reported that patients with long-standing axSpA have a higher risk of muscle loss because of reduced physical activity, immobilisation and inflammation [25,26]. Consistent with these reports, we found that both low BMD and osteopenia in either the total hip or femoral neck were associated with radiographic sacroiliitis, which may, in part, be a reflection of patients with a more severe disease and lower mobility, although no direct association was found with the UCOASMI. ...
Article
Full-text available
Studies on osteoporosis in axial spondyloarthritis (axSpA) have focused on the lumbar segment, and few studies have assessed bone mineral density (BMD) in the hip and femoral neck in these patients. The aim of this study was to evaluate the prevalence of low BMD and osteopenia in the total hip or femoral neck and the factors associated with these conditions in axSpA patients. This was a single-centre, observational, cross-sectional study among consecutive patients with axSpA according to the ASAS criteria from the CASTRO registry. All patients underwent total hip and femoral neck DXA BMD measurements. Low BMD was defined as a Z-score less than -1, and osteopenia was defined as a T-score less than -1. Multivariate logistic and generalised linear regressions were used to evaluate factors independently associated with low BMD and osteopenia in the hip or femoral neck and those associated with variability in BMD, respectively. A total of 117 patients were included, among which 30.8% were female and the mean age was 45 years. A total of 36.0% of patients had low BMD (28.1% in the total hip and 27.4% in the femoral neck), and 56.0% of patients had osteopenia (44.7% in the total hip and 53.8% in the femoral neck). A multivariate logistic regression showed that age, radiographic sacroiliitis and ASAS-HI were independently associated with low BMD in the total hip or femoral neck. Factors that were independently associated with osteopenia were Body Mass Index, disease duration, radiographic sacroiliitis and ASAS-HI. In conclusion, 36% of the patients with axSpA had low BMD in the total hip or femoral neck. A younger age and radiographic sacroiliitis were the most important factors associated with decreased BMD.
... The me chanisms of spinal fracture in axial SpA/AS[83]. ...
Article
Axial Spondyloarthritis (axial SpA) is an inflammatory arthritis primarily affecting the sacroiliac joints (SIJ) and spine and a spectrum of disease which includes the more commonly known Ankylosing Spondylitis. Axial SpA is often missed in musculoskeletal assessments and mismanaged/treated as chronic low back pain. Early diagnosis and intervention is essential to improve outcomes and so is it essential that people presenting with back pain are screened for axial SpA. This masterclass aims improve clinicians’ understanding and awareness of axial SpA, including screening, recognition and when to refer to rheumatology. This article will familiarise clinicians with typical clinical features, appropriate investigation and interpretation, referral pathways in line with NICE guidelines and advise on best practice for clinicians managing axial SpA.
Article
Objective: The aim: To evaluate osteocalcin and PINP levels in men suffering from AS and to compare them with structural and functional state of bone tissue and clinical course of illness. Patients and methods: Materials and methods: The study included 82 patients suffering from AS with an average age of 40,9±0,9 years. Osteocalcin level was determined in 82 patients, and PINP level was determined in 79 patients. Control group included 22 apparently healthy persons. Disease activity was assessed through CRP level, ASDAS and BASDAI scores, while functional ability was assessed through the BASFI score. Osteocalcin and PINP levels were determined by immunoenzymatic method for the purpose of evaluating the metabolic state of bone tissue. Results: Results: Average osteocalcin and PINP levels were not significantly different in patients suffering from AS and patients in the control group and did not show any significant correlation with ASDAS, BASDAI, BASFI and CRP scores. In patients with spinal ankylosis, average osteocalcin values (14,3 ng\ml) and PINP (747,2 pg\ml) were higher compared to patients with single syndesmophytes (11,0 ng\ml; 711,8 pg\ml) and patients without syndesmophytes (10,4 ng\ml; 537,7 pg\ml respectively). Conclusion: Conclusions: Osteocalcin and PINP levels are not related to age, disease duration, BMI, glucocorticoids load and inflammatory process activity, however, they are closely related to the presence of bone growths.
Article
Full-text available
Since March 11, coronavirus infection has become an intercontinental problem – a pandemic has developed.Ukraine (until December 2019) ranks 17th in the world in the number of Covid-19 cases. Although according to statistics, the children are the least vulnerable group for coronavirus infection, unfortunately, severe and serious complications such as pneumonia, Kawasaki disease and Kawasaki-like syndrome, Multisystem inflammatory syndrome in children, toxic shock syndrome, myocarditis occur in children, too. As of the end of November, according to the Ministry of Health in Ukraine, 732,625 cases of coronavirus were laboratory- confirmed, including 13,720 children. According to the Lviv Regional Laboratory Center of the Ministry of Health, in the Lviv region since the beginning of the Covid-19 pandemic, among 46078 of all infected were about 5-6% of children. To analyze clinical, laboratory features of severe coronavirus infection complicated by bilateral pneumonia with acute respiratory distress syndrome (ARDS) in a three-year-old girl who was on V-V ECMO for one week and mechanical ventilation of the lungs for 28 days.The diagnosis was confirmed by detection of SARS-CoV-2 virus RNA by PCR, X-ray and ultrasound examination of the lungs.The disease had a dramatic course but a successful outcome. Life-threatening conditions associated with COVID-19 in children are much less common than in adult patients. However, in some cases, when critical hypoxemia is not eliminated by traditional methods of respiratory support, ECMO can become a life-saving technology and with its timely usage in pediatric patients.
Article
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Introduction Ankylosing spondylitis (AS) is associated with an increased incidence of vertebral fractures (VFs); however the actual incidence and predictors of morphometric VFs are unknown. The present study examined the incidence and predictors of new VFs in a large AS cohort. Methods In total, 298 AS patients who fulfilled the modified New York criteria were enrolled and spinal radiographs were evaluated biennially. Clinical and laboratory data and radiographic progression were assessed according to the Bath AS Disease Activity Index, erythrocyte sedimentation rate, C-reactive protein (CRP), and the Stoke AS spine score (SASSS). VF was defined according to the Genant criteria. The incidence of VFs at 2 and 4 years was evaluated using the Kaplan-Meier method. The age-specific standardized prevalence ratio (SPR) for AS patients in comparison with the general population was calculated. Results Of 298 patients, 31 (10.8%) had previous VFs at baseline. A total of 30 new VFs occurred in 26 patients over 4 years. The incidence of morphometric VFs was 4.7% at 2 years and 13.6% at 4 years. Multivariate logistic regression analysis showed that previous VFs at baseline and increased CRP levels at 2 years were predictors of new VFs (odds ratio (OR) =12.8, 95% confidence interval (CI) = 3.6-45.3 and OR = 5.4, 95% CI = 1.4–15.9). The age-specific specific standardized prevalence ratio of morphometric VFs in AS was 3.3 (95% CI 2.1–4.5). Conclusions The incidence of morphometric VFs increased in AS. Previous VFs and increased CRP levels predicted future VFs. Further studies are needed to identify the effects of treatment interventions on the prevention of new VFs.
Article
Patients with axial spondyloarthritis (axSpA) have an increased risk of osteoporosis related to inflammation. We evaluate the performance of low bone mineral density (BMD) in diagnosis of axSpA for patients with symptoms suggestive of the disease. A low BMD (T ≤ -2) could be an additional tool for the diagnosis of axSpA. Diagnosis of axial spondyloarthritis (axSpA) can be challenging, especially in the absence of radiographic abnormalities. Patients with axSpA have an increased risk of osteoporosis related to inflammation. This study evaluated the performance of low bone mineral density (BMD) in diagnosis of axSpA for patients with symptoms suggestive of the disease. Medical files of patients that visited a tertiary centre for symptoms suggestive of axSpA were reviewed. Two hundred and sixty-seven patients were classified in confirmed axSpA or unconfirmed axSpA according to the diagnosis of a senior rheumatologist. BMD measurements results and percentage of patients with a low BMD (T ≤ -2) at either spine or hip were compared between the two groups. Diagnostic performances of low BMD (specificity, sensitivity, positive, negative predictive values and positive likelihood ratio (LR+)) were assessed. Compared to patients with unconfirmed axSpA (n = 74), patients with confirmed axSpA (n = 193) had similar age, were more frequently male, with positive HLA B27, higher disease duration and higher C-reactive protein (CRP). Low BMD was more frequent at spine and hip, in patients with confirmed (40.3 %) than unconfirmed axSpA (24.6 %, p = 0.021). The LR+ of low BMD for an axSpA diagnosis was 2.60 and 3.12 at the spine and hip. In the subgroup of patients without any radiographic abnormalities (n = 128), the LR+ of low BMD for an axSpA diagnosis was 2.90 and 2.54 at the spine and hip. In patients with symptoms suggestive of axSpA, a low BMD (T ≤ -2) could be an additional tool for the diagnosis of axSpA.
Article
Objective Adipokines have metabolic and inflammatory functions but can also affect bone metabolism. The purpose of this study was to determine the relationship between serum levels of adiponectin, resistin, and visfatin and markers of inflammation, disease activity, and radiographic spinal progression in patients with ankylosing spondylitis (AS).Methods Levels of adiponectin, resistin, and visfatin in the serum of 86 AS patients and 25 healthy controls were measured by enzyme-linked immunosorbent assay at baseline. Radiographic spinal progression was determined by the scoring of radiographs of the spine obtained at baseline and after 2 years.ResultsMean (±SD) baseline levels of resistin and visfatin were significantly higher in AS patients than in healthy controls (11.6 ± 10.6 ng/ml versus 6.6 ± 3.2 ng/ml [P = 0.01] for resistin, and 20.9 ± 48.3 ng/ml versus 3.4 ± 2.6 ng/ml [P = 0.001] for visfatin). Adipokine serum levels did not correlate with disease activity or functional indices. Only resistin serum levels correlated with markers of inflammation. Baseline levels of visfatin, but not resistin or adiponectin, were significantly higher in patients with worsening of the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) by ≥2 units after 2 years (n = 19) as compared to patients without mSASSS worsening (37.7 ± 57.8 ng/ml versus 16.1 ± 44.6 ng/ml; P = 0.029) and in patients with syndesmophyte formation/progression (n = 22) as compared to patients without such progression (37.1 ± 55.3 ng/ml versus 15.3 ± 44.8 ng/ml; P = 0.023). Visfatin levels of >8 ng/ml at baseline were predictive of subsequent radiographic spinal progression (adjusted odds ratio 3.6 for mSASSS progression and 5.4 for syndesmophyte formation/progression).Conclusion Serum levels of resistin and visfatin are elevated in AS patients. Elevated visfatin levels at baseline are predictive of subsequent progression of radiographic damage in AS patients.
Article
Unlabelled: Ankylosing spondylitis (AS) leads to osteopenia/osteoporosis and spine rigidity. We conducted a case-control study and found that AS-affected patients have a 5-fold and 50% increased risk of clinical spine and all clinical fractures, respectively. Excess risk of both is highest in the first years and warrants an early bone health assessment after diagnosis. Introduction: Ankylosing spondylitis (AS) is related to spine rigidity and reduced bone mass, but data on its impact on fracture risk are scarce. We aimed to study the association between AS and clinical fractures using a case-control design. Methods: From the Danish Health Registries, we identified all subjects who sustained a fracture in the year 2000 (cases) and matched up to three controls by year of birth, gender and region. Clinically diagnosed AS was identified using International Classification of Diseases, 8th revision (ICD-8; 71249), and International Classification of Diseases, 10th revision (ICD-10; M45) codes. We also studied the impact of AS duration. Conditional logistic regression was used to estimate crude and adjusted odds ratios (ORs) for non-traumatic fractures (any site, clinical spine and non-vertebral) according to AS status and time since AS diagnosis. Multivariate models were adjusted for fracture history, socio-economic status, previous medical consultations, alcoholism and use of oral glucocorticoids. Results: We identified 139/124,655 (0.11%) AS fracture cases, compared to 271/373,962 (0.07%) AS controls. Unadjusted (age- and gender-matched) odds ratio (OR) were 1.54 [95% confidence interval (95%CI) 1.26-1.89] for any fracture, 5.42 [2.50-11.70] for spine and 1.39 [1.12-1.73] for non-vertebral fracture. The risk peaked in the first 2.5 years following AS diagnosis: OR 2.69 [1.84-3.92] for any fracture. Conclusions: Patients with AS have a 5-fold higher risk of clinical spine fracture and a 35% increased risk of non-vertebral fracture. This excess risk peaks early, in the first 2.5 years of AS disease. Patients should be assessed for fracture risk early after AS diagnosis.
Article
Objectives: Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with an increased risk of osteoporosis and fractures. TNF inhibitors have been used to treat AS, but their effect on bone is unclear. Thus, we conducted a meta-analysis to study the effect of TNF inhibitors on spine and hip BMD in patients with AS. Methods: Two authors independently searched MEDLINE and PubMed for longitudinal studies that had assessed the effect of TNF inhibitors on BMD in patients with AS. Studies with a minimum follow-up period of 1 year were included. Results: Seven longitudinal studies and one randomized control trial were included, with a total of 568 AS patients (mean age range of 36-48 years and disease duration of 9-17 years). Lumbar spine BMD increased by 5.1% (95% CI: 4.0-6.1%, p = 0.00000) after 1 year of treatment with TNF inhibitors and by 8.6% (95% CI: 6.8-10.3%, p < 0.00001) after 2 years. Significant improvements in total hip BMD were also noted after 1 [1.8% (1.0-2.5%)] and 2 years [2.5% (1.9-3.0%)]. Compared to baseline, femoral neck BMD remained stable after 1 year [0.7% (-0.8% to 2.2%), p = 0.34]. No significant heterogeneity was noted amongst the included studies. Conclusions: TNF inhibitors can increase lumbar spine and total hip BMD and maintain femoral neck BMD for up to 2 years in patients with AS. More research is needed to assess the effect of TNF inhibitors on bone quality and fracture risk.
Article
Patients with spondyloarthritis (SpA) receiving anti-TNF-α treatment have an increase in fat mass. This may be relevant to cardiovascular risk. The aim of this study was to estimate visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) changes by dual-energy x-ray absorptiometry (DEXA) in patients with SpA under anti-TNF-α therapy. We used an ancillary protocol to an open, prospective 2-year followup study of patients with SpA. Waist circumference (WC), body weight, body mass index, VAT, and SAT were measured at baseline, 6 months, and 1 and 2 years. Univariate and multivariate analyses were performed to assess variables associated with VAT and SAT changes. A total of 85 patients were analyzed. Patients were 39.3 ± 11.4 years old and mean baseline Bath Ankylosing Spondylitis Disease Activity Index was 55.0 ± 20.2. Treatment was effective according to clinical and biological variables, and body weight increased by 0.9 ± 1.7 kg over 2 years. There was a significant gain in VAT after 6 months (13.7 ± 20.6 cm(2), p < 0.0001), 1 year (21.0 ± 26.6 cm(2), p < 0.0001), and after 2 years (29.1 ± 33.4 cm(2), p < 0.0001); and in SAT after 6 months (12.5 ± 27.4 cm(2), p < 0.0001), 1 year (27.1 ± 38.2 cm(2), p < 0.0001), and after 2 years (31.9 ± 53.2 cm(2), p < 0.0001). We could not find any determinant of these changes by multivariate analysis. In patients with SpA receiving anti-TNF-α therapy, there is an early significant increase in abdominal obesity with significant increase in both VAT and SAT after 1 and 2 years of treatment. Prospective studies are required to investigate the relationship between these changes and cardiovascular risk.