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

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.

Full text

REVIEW
Inflammation, 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
inflammatory 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 inflam-
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-inflammatory drugs.
FRACTURES IN AS
Patients with AS have an increased risk of ver-
tebral fractures. A case–control 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 definition 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
group.bmj.com on November 2, 2015 - Published by http://rmdopen.bmj.com/Downloaded from

high risk of such fractures, because of the calcifications of
the spinal longitudinal ligaments and disuse osteoporosis
of the vertebral bodies related to immobility. They must
be carefully evaluated, as it is sometimes difficult to differ-
entiate between pain from fracture and pain from a
flare-up of the inflammatory 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 inflammatory 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 define 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 20–25%. 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 confirmation 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 (1.51–7.02), 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 identified,
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 confirmed in the Danish Health Registries.
18
In this
case–control study assessing data for the year 2000, the
age-matched and gender-matched ORs for patients with
AS were 5.4 (2.5–11.7) and 1.4 (1.1–1.7) 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
significant.
18
In one 4-year prospective study conducted in 298
patients, the incidence of vertebral fracture (according to
morphometric definition) 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 difficul-
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
(figure 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
2 Briot K, Roux C. RMD Open 2015;1:e000052. doi:10.1136/rmdopen-2015-000052
RMD Open
group.bmj.com on November 2, 2015 - Published by http://rmdopen.bmj.com/Downloaded from

limb, which is mandatory for an accurate hip BMD
measurement.
The definition 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 defined as Z ≤−2.
Recognising these different definitions, the prevalence
of low BMD measured by dual energy X-ray absorpti-
ometry is 14–27% and 4–14% at the spine and hip,
respectively, in patients with long-lasting disease.
16 21–24
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 first 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-
firmed diagnosis (N=93) had lower BMD than patients
with an unconfirmed 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
inflammatory 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 modified 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 fulfil 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 inflammation 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
Osteoporosis
group.bmj.com on November 2, 2015 - Published by http://rmdopen.bmj.com/Downloaded from

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 inflammation.
32–34
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
inflammatory 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 inflammatory 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 inflammation.
31
In a 1-year prospective
study in 30 patients with inflammatory 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 inflammation in bone
loss in SpA. Advances in pathogenesis have been provided
by a new mouse model that highlights the role of IL23 in
entheseal inflammation. Gut-derived IL23 (even in sub-
clinical gut involvement) can act on a previously unidenti-
fied 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
inflammation; 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, inflammation plays a key role in bone loss in
AS, and a beneficial effect of anti-inflammatory 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-inflammatory 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 confirmed by a nationwide case–control 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
inflammation 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
4 Briot K, Roux C. RMD Open 2015;1:e000052. doi:10.1136/rmdopen-2015-000052
RMD Open
group.bmj.com on November 2, 2015 - Published by http://rmdopen.bmj.com/Downloaded from

patients wit h an indication for TNF blocker treatment,
without prevalent non-traumatic fracture, it seems
logical to assess first the benefit 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 defined.
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 inflammation.
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/
REFERENCES
1. Roux C. Osteoporosis in inflammatory joint diseases. Osteoporos Int
2011;22:421–33.
2. Will R, Palmer R, Bhalla AK, et al. Osteoporosis in early ankylosing
spondylitis. A primary pathological event ? Lancet 1989;2:1483–5.
3. Weiss RJ, Wick MC, Ackermann PW, et al. Incresed fracture risk in
patients with rheumatic disorders and other inflammatory diseases.
A case-control study with 53,108 patients with fracture. J Rheumatol
2010;37:2247–50.
4. Cooper C, Carvone L, Michet CJ, et al. Fracture risk in patients with
ankylosing spondylitis: a population based study. J Rheumatol
1994;21:1877–82.
5. Montala N, Juanola X, Collantes E, et al. Prevalence of vertebral
fractures by semiautomatedmortphometry in patients with ankylosing
spondylitis. J Rheumatol 2011;38:893–7.
6. Campagna R, Pessis E, Feydy A, et al. Fractures of the
ankylosedspine: MDCT and MRI with emphasis of individual
anatomic spinal structures. Am J Roentgenol 2009;192:987–95.
7. Stenhouse G, Ulbricht C, Khanna M. Spinal injury in ankylosing
spondylitis. BMJ 2014;348:g3849.
8. Vosse D, Feldtkeller E, Erlendsson J, et al. Clinical vertebral
fractures in patients with ankylosing spondylitis. J Rheumatol
2004;31:1981–5.
9. Anwar F, Al-Khayer A, Joseph G, et al. Delayed presentation and
diagnosis of cervical spine injuries in long-standing ankylosing
spondylitis. Eur Spine J 2011;20:403–7.
10. Robinson Y, Sanden B, Olerud C. Increased occurrence of spinal
fractures related to ankylosing spondylitis: a prospective 22-year
cohort study in 17,764 patients from a national registry in Sweden.
Patient Saf Surg 2013;7:2.
11. Vosse D, Heijckmann C, Landewé R, et al. Comparing
morphometric X-ray absorptiometry and radiography in defining
vertebral wedge fractures in patients with ankylosing spondylitis.
Rheumatology 2007;46:1667–71.
12. Geusens P, Vosse D, Van der Heijde DM, et al. High prevalence of
thoracic vertebral deformities and discal wedging in ankylosing
spondylitis patients with hyperkyphosis. J Rheumatol
2001;28:1856–61.
13. Raltson SH, Urquhart GDK, Bzeski M, et al. Prevalence of vertebral
compression fractures due to osteoporosis in ankylosing spondylitis.
Br Med J 1990;300:563–5.
14. Ghozlani I, Ghazi M, Nouijai A, et al. Prevalence and risk factors of
osteoporosis and vertebral fractures in patients with ankylosing
spondylitis. Bone 2009;44:772–6.
15. Van der Weijden MAC, Van der Horst-Bruinsma IE, van Denderen
JC,
et al.
High frequency of vertebral fractures in early
spondylarthropathies. Osteoporos Int 2012;23:1683–90.
16. Vosse D, Landewé R, van der Heijde D, et al. Ankylosing spondylitis
and the risk of fracture: results from a large primary care-based
nested case control study. Ann Rheum Dis 2009;68:1839–42.
17. Munoz-Ortego J, Vestergaard P, Rubio JB, et al. Ankylosing
spondylitis is associated with an increased risk of vertebral and
non-vertebral clinical fractures: a populations based cohort study.
J Bone Miner Res 2014;29:1770–6.
18. Prieto-Alhambra D, Munoz-Ortego J, De Vries F, et al. Ankylosing
spondylitis confers substantially increased risk of clinical spine
fractures: a nationwide case-control study. Osteoporos Int
2015;26:85–91.
19. Kang KY, Kim IJ, Jung SM, et al. Incidence and predictors of
morphometric vertebral fractures in patients with ankylosing
spondylitis. Arthr Res Therap 2014;16:R124.
20. Fatemi G, Gensler LS, Learch TJ, et al. Spine fractures in
ankylosing spondylitis: a case report and review of imaging as well
as predisposing factors to falls and fractures. Semin Arthritis Rheum
2014;44:20–4.
21. Jun JAE, Joo KB, Her MY, et al. Femoral bone mineral denstity is
associated with vertebral fractures in patients with ankylosing
spondylitis: a cross-sectional study. J Rheumatol 2006;33:1637–41.
22. El Maghraoui A, Borderie D, Edouard R, et al. Osteoporosis, body
composition and bone turnover in ankylosing spondylitis.
J Rheumatol 1999;26:2205–9.
23. Klingberg E, Geijer M, Göthlin J, et al. Vertebral fractures in ankylosing
spondylitis are associated with lower bone mineral density in both
central and peripheral skeleton. J Rheumatol 2012;39:1987–95.
24. Klingberg E, Lorentzon M, Mellström D, et al. Osteoporosis in
ankylosing spondylitis: prevalence, risk factors and methods of
assessment. Arthr Res Therap 2012;14:R108.
25. Van der Weijden MAC, Claushuis TAM, Nazari T, et al. High
prevalence of low bone mineral density in patients within 10 years of
onset of ankylosing spondylitis: a systematic review. Clin Rheumatol
2012;31:1529–35.
26. Forien M, Molto A, Etcheto A, et al. Bone mineral density in patients
with symptoms suggestive of spondyloarthritis. Osteoporos Int
2015;26:1647–53.
27. Mitra D, Elvins DM, Speden DJ, et al . The prevalence of vertebral
fractures in mild ankylosing spondylitis and their relationship to bone
mineral density. Rheumatology (Oxford) 2000;39:85–9.
28. Van Der Weijden MAC, Van Denderen JC, Lems WF, et al.Low
bone mineral density is related to male gender and decreased
functio
nal capacity in early spondylarthopathies. Clin Rheumatol
2011;30:497–503.
29. Karberg K, Zochling J, Sieper J, et al. Bone loss is detected more
frequently in patients with ankylosing spondylitis with
syndesmophytes. J Rheumatol 2005;32:1290–8.
30. Klingberg E, Lorentzon M, Göthlin J, et al. Bone microarchitecture in
ankylosing spondylitis and the association with bone mineral density,
fractures, and syndesmophytes. Arthr Therap 2013;15:R179.
31. Briot K, Durnez A, Paternotte S, et al. Bone oedema on MRI is
highly associated with low bone mineral density in patients with early
inflammatory back pain: results from the DESIR cohort. Ann Rheum
Dis 2013;72:1914–19.
32. Lange U, Teichmann J, Strunk J, et al. Association of 1.25 vitamin
D3 deficiency, disease activity and low bone mass in ankylosing
spondylitis. Osteoporos Int 2005;16:1999–2004.
33. Obermayer-Pietsch BM, Lange U, Tauber G, et al. Vitamin D
receptor initiation codon polymorphism, bone density and
inflammatory activity of patients with ankylosing spondylitis.
Osteoporos Int 2003;14:995–1000.
34. Arends S, Spoorenberg A, Bruyn GAW, et al. The relation between
bone mineral density, bone turnover markers, and vitamin D status
in ankylosing spondylitis patients with active disease: a cross-
sectional analysis. Osteoporos Int 2011;22:1431–9.
35. Rauner M, Stupphann D, Haas M, et al. The HLA-B27 transgenic
rat, a model of spondyloarthritis, has decreased bone mineral
density and increased RANK L to osteoproteogerin in RNA ratio.
J Rheumatol 2009;36:120–6.
36. Gratacos J, Collado A, Pons F, et al. Significant loss of bone mass
in patients with early, active ankylosing spondylitis. A follow-up
study. Arthritis Rheum 1999;42:2319–24.
37. Maillefert JF, Aho S, El Maghraoui A, et al. Changes in bone density
in patients with ankylosing spondylitis: a 2 year follow-up study.
Osteoporos Int 2001;12:605–9.
Briot K, Roux C. RMD Open 2015;1:e000052. doi:10.1136/rmdopen-2015-000052 5
Osteoporosis
group.bmj.com on November 2, 2015 - Published by http://rmdopen.bmj.com/Downloaded from

38. Haugeberg G, Bennett AN, McGonagle D, et al. Bone loss in very
early inflammatory back pain in undifferentiated spondyloarthropathy:
a 1-year observational study. Ann Rheum Dis 2010;69:1364–6.
39. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces
spondyloarthropathy by acting on
ROR-γt
+
CD3
+
CD4
−
CD8
−
entheseal resident T cells. Nat Med
2012;18:1069–76.
40. Briot K, Gossec L, Kolta S, et al. Prospective assessment of body
weight, body composition, and bone density changes in patients
with spondyloarthropathy receiving anti-tumor necrosis factor-alpha
treatment. J Rheumatol 2008;35:855–61.
41. Syrbe U, Callhoff J, Conrad K, et al. Serum adipokine levels in
patients with ankylosing spondylitis and their relationship to clinical
parameters and radiographic spinal progression. Arthritis Rheumatol
2015;67:678–85.
42. Allali F, Breban M, Porcher R, et al. Increase in bone mineral density
of patients with spondyloarthropathy treated with anti-tumour
necrosis factor alpha. Ann Rheum Dis 2003;62:347–9.
43. Durnez A, Paternotte S, Fechtenbaum J, et al. Increase in bone
density in patients with spondyloarthritis during anti-tumor necrosis
factor therapy: 6-year follow-up study. J Rheumatol 2013;40:1712–18.
44. Haroon NN, Sriganthan J, Al Ghanim N, et al. Effect of TNF-alpha
inhibitor treatment on bone mineral density in patients with
ankylosing spondylitis: a systematic review and meta-analysis.
Semin Arthritis Rheum 2014;44:155–61.
45. Lam J, Takeshita S, Barker JE, et al. TNF-alpha induces
osteoclastogenesis by direct stimulation of macrophages
exposed to permissive levels of RANK ligand. J Clin Invest
2000;143:1108–18.
46. Glantsching H, Fisher JE, Wesolowski G, et al. M-CSF, TNF-alpha
and RANK ligand promote osteoclast survival by signaling through
mTOR/S6 kinase. Cell Death Differ 2003;10:1165–77.
47. Heiland GR, Zwerina K, Baum W, et al. Neutralisation of Dkk-1
protects from systemic bone loss during inflammation and reduces
sclerostin expression. Ann Rheum Dis 2010;69:2152–9.
48. Gengenbacher M, Sebald HJ, Villiger PM, et al. Infliximab inhibits
bone resorption by circulating osteoclast precursor cells in patients
with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis
2008;67:620–4.
49. Visvanathan S, van der Heijde D, Deodhar A, et al. Effects of
infliximab on markers of inflammation and bone turnover and
associations with bone mineral density in patients with ankylosing
spondylitis. Ann Rheum Dis 2009;68:175–82.
50. Hmamouchi I, Roux C, Paternotte S, et al. Early increase of abdominal
adiposity in patients with spondyloarthritis receiving anti-tumor necrosis
factor-α treatment. J Rheumatol 2014;41:1112–17.
51. Kawai VK, Grijalva CG, Arbogast PG, et al. Initiation of tumor
necrosis factor α
antagonists and risk of fractures in patients with
selected
rheumatic and autoimmune diseases. Arthritis Care Res
2013;65:1085–94.
52. Masiero S, Bonaldo L, Pigatto M, et al. Rehabilitation treatment in
patients with ankylosing spondylitis stabilized with tumor necrosis
factor inhibitor therapy. A randomized controlled trial. Arthritis Care
Res 2012;64:101–7.
6 Briot K, Roux C. RMD Open 2015;1:e000052. doi:10.1136/rmdopen-2015-000052
RMD Open
group.bmj.com on November 2, 2015 - Published by http://rmdopen.bmj.com/Downloaded from

spondyloarthritis
Inflammation, bone loss and fracture risk in
Karine Briot and Christian Roux
doi: 10.1136/rmdopen-2015-000052
2015 1: RMD Open
http://rmdopen.bmj.com/content/1/1/e000052
Updated information and services can be found at:
These include:
References
#BIBLhttp://rmdopen.bmj.com/content/1/1/e000052
This article cites 52 articles, 22 of which you can access for free at:
Open Access
http://creativecommons.org/licenses/by-nc/4.0/non-commercial. See:
provided the original work is properly cited and the use is
non-commercially, and license their derivative works on different terms,
permits others to distribute, remix, adapt, build upon this work
Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
This is an Open Access article distributed in accordance with the Creative
service
Email alerting
box at the top right corner of the online article.
Receive free email alerts when new articles cite this article. Sign up in the
Notes
http://group.bmj.com/group/rights-licensing/permissions
To request permissions go to:
http://journals.bmj.com/cgi/reprintform
To order reprints go to:
http://group.bmj.com/subscribe/
To subscribe to BMJ go to:
group.bmj.com on November 2, 2015 - Published by http://rmdopen.bmj.com/Downloaded from