Jou nal o
Clinical Medicine
A icle
F agili y F ac u es and Imminen F ac u e Risk in he Spanish
Popula ion: A Re ospec i e Obse a ional Coho S udy
Ma ia-JoséMon oya-Ga cía1, Me cèGine 2,* , Rod igo Ma cos 3, Da id Ga cía-Rome o 3,
F ancisco-Jesús Olmo-Mon es 4, Mª JoséMi anda 4, Blanca He nández-C uz 5, Miguel-Angel Colmene o 4
and Mª Angeles Vázquez-Gámez 1


Ci a ion: Mon oya-Ga cía, M.-J.;
Gine , M.; Ma cos, R.; Ga cía-Rome o,
D.; Olmo-Mon es, F.-J.; Mi anda, M.J.;
He nández-C uz, B.; Colmene o,
M.-A.; Vázquez-Gámez, M.A.
F agili y F ac u es and Imminen
F ac u e Risk in he Spanish
Popula ion: A Re ospec i e
Obse a ional Coho S udy. J. Clin.
Med. 2021,10, 1082. h ps://doi.o g/
10.3390/jcm10051082
Academic Edi o : Hein ich Resch
Recei ed: 5 Feb ua y 2021
Accep ed: 2 Ma ch 2021
Published: 5 Ma ch 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
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A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
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1Depa amen o de Medicina, Uni e sidad de Se illa, A da. D . Fed iani s/n, 41009 Se illa, Spain;
[email p o ec ed] (M.-J.M.-G.); [email p o ec ed] (M.A.V.-G.)
2
Depa amen o de Ci ología e His ología No mal y Pa ológica, Uni e sidad de Se illa, A da. D . Fed iani s/n,
41009 Se illa, Spain
3
O hopedic Su ge y and T auma ology Se ice, Vi gen Maca ena Uni e si y Hospi al, A da Sánchez Pizjuán
s/n, 41009 Se ille, Spain; od i.ma [email p o ec ed] (R.M.); ga cia ome [email p o ec ed] (D.G.-R.)
4Se icio de Medicina In e na, HUV Maca ena, A da Sánchez Pizjuán s/n, 41009 Se illa, Spain;
[email p o ec ed] (F.-J.O.-M.); [email p o ec ed] (M.J.M.);
[email p o ec ed] (M.-A.C.)
5
Rheuma ology Se ice, Vi gen Maca ena Uni e si y Hospi al, A da Sánchez Pizjuán s/n, 41009 Se ille, Spain;
[email p o ec ed]
*Co espondence: [email p o ec ed]
Abs ac :
F agili y ac u es cons i u e a majo public heal h p oblem wo ldwide, causing impo an
high mo bidi y and mo ali y a es. The aim was o p esen he epidemiology o agili y ac u es
and o assess he imminen isk o a subsequen ac u e and mo ali y. This is a e ospec i e
popula ion-based coho s udy (n = 1369) wi h a agili y ac u e. We es ima ed he incidence a e o
index agili y ac u es and ob ained in o ma ion on he subsequen ac u es and dea h du ing a
ollow-up o up o h ee yea s. We assessed he e ec o age, sex, and skele al si e o index ac u e as
independen isk ac o s o u he ac u es and mo ali y. Incidence a e o index agili y ac u es
was 86.9/10,000 pe son-yea s, wi h highes a es o hip ac u es in women aged
≥
80 yea s. The isk
o ac u e was highe in subjec s wi h a ecen ac u e (Rela i e Risk(RR), 1.80; p< 0.01). Highe age
was an independen isk ac o o u he ac u e e en s. Signi ican excess mo ali y was ound in
subjec s aged
≥
80 yea s and wi h a p e ious hip ac u e (haza d a io, 3.43 and 2.48, espec i ely). I
is he i s s udy in Spain o e alua e he incidence o majo os eopo o ic ac u es, no only o he
hip, and he a e o imminen ac u e. Ou esul s p o ide u he e idence highligh ing he need
o ea ly ea men .
Keywo ds: os eopo osis; agili y ac u e; ac u e isk; imminen ac u e isk
1. In oduc ion
F agili y ac u es caused by os eopo osis cons i u e a majo public heal h p oblem
wo ldwide. The annual cos s a ibu able o agili y ac u es in he Eu opean Union (EU)
cu en ly equa e o
€
37 billion, and hese numbe s a e expec ed o ise due o popula ion
aging [
1
]. F agili y ac u es a e an impo an cause o disabili y, mo bidi y, and mo ali y
in he popula ion [
2
]. Such massi e bu den highligh s he impo ance o isk assessmen o
agili y ac u es and he need o adap p e en ion s a egies o indi idual isk pa e ns.
A la ge numbe o isk ac o s o agili y ac u e ha e been iden i ied [
3
]. Among
hem, a p e ious agili y ac u e has been gene ally ecognized as an assessmen c i e ia
o ac u e isk in os eopo osis, ega dless o bone mine al densi y (BMD) [
4
]. Al hough
i is gene ally ecognized ha he isk o ac u e inc eases h oughou li e wi h a p e i-
ous ac u e, a ecen os eopo o ic ac u e inc eases e en mo e he isk o an imminen
ac u e [
5
–
7
], and he magni ude o his isk and he con ibu ion o o he clinical isk
J. Clin. Med. 2021,10, 1082. h ps://doi.o g/10.3390/jcm10051082 h ps://www.mdpi.com/jou nal/jcm
J. Clin. Med. 2021,10, 1082 2 o 11
ac o s s ill demand u he esea ch. P e ious e idence sugges s ha he isk is no con-
s an bu a he luc ua es o e ime, being g ea es wi hin he i s ew yea s o he ini ial
ac u e [
5
,
8
–
11
]. The p edic i e impo ance o imminen (12 o 24 mon hs) ac u e isk
is widely accep ed. Howe e , he signi icance o he ea ly yea s a e an index ac u e
need o be u he explo ed. A e a i s agili y ac u e, he skele al loca ion o he index
ac u e may also in luence he magni ude o imminen ac u e isk. Howe e , only a ew
s udies ha e measu ed i s e ec on he le el o u he ac u e isk, and conclusions do no
hold o solid gene aliza ion. [
12
–
14
]. Olde age is also a well-de ined clinical isk ac o
o ac u es [
15
]. Howe e , he e is con o e sy be ween s udies o e i s con ibu ion on
he isk o u he ac u e e en s. Some au ho s ha e obse ed a ma ked inc ease by age
in he isk o a second majo agili y ac u e [
11
,
16
], whe eas he associa ion be ween
age and subsequen ac u e was no con i med by o he epo s [
3
,
17
]. As wi h age, he
p edic i e alue o sex in he isk o u he ac u e e en s is also con o e sial. O iginally,
women we e conside ed a highe isk o bo h ini ial and subsequen ac u e and, indeed,
some au ho s con i med his hypo hesis [
11
,
16
]. Howe e , o he s udies ha e no epo ed
di e ences in he isk o subsequen ac u e e en s be ween men and women [18,19].
The p ima y objec i e o he p esen s udy was o explo e he epidemiology o agili y
ac u es in sou he n Spain by using da a om a popula ion-based coho o women and
men, aged 50 o olde , admi ed o he eme gency uni a Vi gen Maca ena Uni e si y
Hospi al. Ou s udy also p o ides an es ima ion o he incidence a e o subsequen
ac u es o e 1–3 yea s ollowing an index ac u e. As seconda y objec i es, he s udy
e alua ed mo ali y o e h ee yea s ollowing an index ac u e, analyzing he ole o
subsequen ac u es as an independen isk ac o .
2. Ma e ials and Me hods
This s udy was designed as a e ospec i e obse a ional popula ion-based coho
s udy in ol ing men and women aged
≥
50 yea s wi h an index agili y ac u e (caused
by an inju y ha would be insu icien o ac u e no mal bone; he esul o a/o esis ance
o bone o sion [20]) occu ing be ween 1 Janua y 2014 and 31 Decembe 2014.
Eligible s udy pa icipan s we e ollowed un il 31 Decembe 2016, o ob ain in o ma-
ion on he ou comes: subsequen agili y ac u es and dea hs e en s. Age, sex, ime
om index ac u e, and skele al si e we e assessed as po en ial independen isk ac o s.
Pa ien s we e iden i ied using he eme gency uni ’s medical eco ds a Vi gen Maca ena
Uni e si y Hospi al in Spain. Vi gen Maca ena Uni e si y Hospi al is a public e ia y
hospi al and i s Eme gency Uni se es up o 481,879 inhabi an s, o whom 157,428 subjec s
a e aged
≥
50 yea s, wi hin he heal hca e a ea o No h Se ille. Fu he mo e, his is he
single e e ence hospi al o he heal hca e a ea including eme gency ca e a en ion. Gene al
medical eco ds (Di aya) we e also used o collec any ele an in o ma ion on he s udy
ou comes including demog aphic in o ma ion, index ac u e ype, and causali y as well
as any ele an adiological con i ma o y indings. Eligible inciden al agili y ac u e
loca ions included axial (hip, pel is, do sal, and lumba e eb ae) as well as appendicu-
la bones (p oximal hume us and w is ), acco ding o he In e na ional Classi ica ion o
Diseases, ICD-9 codes (Supplemen a y Table S1). Diagnosis was based on symp oms bu
mus ha e included a adiologic con i ma ion o he ac u e. Non-clinical adiog aphic
e eb al ac u es as well as o he pa hological o auma ic ac u es we e excluded. The
iden i ica ion o subsequen ac u es equi ed a simila main diagnosis o ac u e. To
dis inguish subsequen ac u es om p e ious e en s eco ded a ollow-up isi s and/o
pa ien his o y, he ollowing c i e ia we e applied: (1) F ac u es in he same skele al si e
o index ac u e we e only cap u ed i a minimum o ou mon hs had elapsed since he
index ac u e; (2) hip ac u es we e only cap u ed i an inpa ien hospi al admission was
equi ed; (3) all medical isi s iden i ied as ollow-up examina ion o a p e ious ac u e
we e excluded as u he ac u e e en s; (4) pa ien s who died ollowing a ac u e we e
cap u ed as ha ing bo h ou comes; and (5) i he index ac u e in ol ed mo e han one
skele al si es, o a oid double coun ing, he ac u e was assigned o he si e o highes
J. Clin. Med. 2021,10, 1082 3 o 11
se e i y. Time a isk o subsequen ac u e e en s began he day a e he da e o he
index ac u e and con inued un il ou come occu ence, ei he ac u e o pa ien dea h.
We es ima ed he incidence a e o e 12 mon hs o (index) agili y ac u es in he gen-
e al popula ion aged
≥
50 yea s (based on a o al es ima ed popula ion o
157,428 indi iduals
aged 50 o o e se ed in Vi gen Maca ena Hospi al ca chmen a ea on 1 Janua y 2014).
Then, we es ima ed he incidence a e o u he ac u e e en s du ing he s udy pe iod
among hose who had a p e ious agili y ac u e in 2014. Time a isk o subsequen
ac u e e en s began he day a e he da e o he index ac u e and con inued un il
ou come occu ence, ei he ac u e o pa ien dea h. F ac u e incidence a es pe 10,000
pe son-yea s we e calcula ed by age g oup, sex, and ac u e ype. The 95% con idence
in e als (CIs) we e calcula ed assuming a Poisson dis ibu ion. The excess isk o u he
ac u es was compa ed o he gene al popula ion using a Poisson eg ession model in-
cluding age, sex, and loca ion o p e ious ac u e as co a ia es. Nelson–Aalen cumula i e
haza d es ima es we e plo ed o analyze he ime o a subsequen ac u e e en [
21
]. The
isk o subsequen ac u e was analyzed using a Cox p opo ional haza ds eg ession
model, as well as he model p oposed by Fine and G ay [
22
], using dea h as a compe ing
isk. All-cause mo ali y was also analyzed using he Cox haza d model. Fu he mo e, we
included a ime-dependen a iable in his model o es ima e he isk o all-cause dea h
associa ed wi h he occu ence o subsequen ac u e e en s du ing he s udy pe iod.
Es ima es wi h p alues < 0.05 we e conside ed s a is ically signi ican . No impu a ion o
missing da a was necessa y. All s a is ical analyses we e pe o med using S a a so wa e
(STATA Co p., College S a ion, TX, USA).
3. Resul s
3.1. Pa ien Baseline Cha ac e is ics
Among a o al popula ion o 157,428 Caucasian indi iduals aged 50 o o e se ed
by Vi gen Maca ena Uni e si y Hospi al, 1068 women and 301 men (3.5 emale/male
a io), wi h mean o age 75.1 and 72.1 yea s, espec i ely, egis e ed eligible index agili y
ac u es in 2014 and we e included in he analyses. Only 14 subjec s we e excluded
due o miscoding o ac u es (3/14) o auma ic (8/14) o pa hological ac u es (3/14),
(Figu e 1)
. The mos equen index ac u e si e in women was w is (405 [37.9%]), whe eas
in men hip ac u es we e he mos common (111 [36.9%]). Mean du a ion o ollow-up
was 2.3 yea s o all subjec s, 2.2 yea s in males and 2.3 in emales.
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 4 o 12
Figu e 1. Flow diag am o s udy pa icipan s based on he S obe s a emen . A o al o 1383 subjec s we e assessed o
eligibili y, among a s udy popula ion o 157,428 inhabi an s. F ac u e miscoding o auma ic o pa hological causes o
ac u es we e he causes o he exclusion o 14 subjec s. Subjec s we e en olled om Janua y 2014 o Decembe 2014 and
ollowed up un il Decembe 2016. Mean du a ion o ollow-up was 2.3 yea s o all subjec s, 2.2 yea s in males and 2.3 in
emales. The mos equen ypes o index ac u e we e w is (N = 506, 37.0%) and hip (N = 431, 31.5%), ollowed closely
by p oximal hume us (N = 264, 19.3%). O e all, 99 subjec s egis e ed a subsequen ac u e, wi h 120 e en s o dea h
occu ing h oughou ollow-up. Fx: ac u e. SsFx: subsequen ac u e.
3.2. Incidence Ra e o Index F ac u e in he Gene al Popula ion
An o e all incidence a e o 86.9 ac u es/10,000 pe son-yea s was ound in he gen-
e al popula ion aged ≥50 yea s (Table 1). The equency o agili y ac u es was signi i-
can ly highe among women as compa ed o men: 123.9 (CI 95% 116.6–131.6) e sus 42.3
(CI95% 37.7–47.4), espec i ely. Also, ma ked inc ease in he equency was also obse ed
wi h inc easing age. The highes o e all equency was obse ed o w is ac u es. De-
spi e his, hip ac u es we e he mos equen among women and men aged ≥80 yea s.
On he o he hand, he skele al si es wi h he lowes incidence a e o agili y ac u es
we e he pel is and he spine.
Table 1. Incidence a e o index ac u e in he gene al popula ion aged ≥50 yea s, by index ac u e si e, sex, and age
g oup. The o al popula ion alues o males and emales a e ma ked in bold. The shading indica es ha hey a e o al
alues o he popula ion, o di e en ia e hem om he es ha a e sepa a ed by gende and age.
Index F ac u e Si e
Age * All Si es Hip Pel is Ve eb al P ox.
Hume us W is
All subjec s 50+ yea s 86.9 (82.4–91.6) 27.5 (25.0–30.2) 4.6 (3.6–5.8) 6.0 (4.8–7.3) 16.8 (14.8–
18.9) 32.1 (29.4–35.0)
Males
All males 42.3 (37.7–47.4) 15.6 (12.8–18.8) 1.8 (0.0–3.1) 2.4 (1.4–3.8) 8.3 (6.3–10.7) 14.2 (11.6–17.3)
50–59 yea s 23.4 (18.3–29.5) 2.3 (0.9–4.8) 0.0 (NA) 1.3 (0.4–3.4) 7.3 (4.5–11.0) 12.5 (8.9–17.2)
60–69 yea s 24.7 (18.5–32.3) 4.7 (2.2–8.6) 0.9 (0.1–3.4) 0.9 (0.1–3.4) 6.1 (3.2–10.4) 12.1 (7.9–17.8)
70–79 yea s 56.4 (44.1–71.0) 18.8 (12.1–28.0) 2.4 (0.5–6.9) 3.1 (0.9–8.0) 11.8 (6.6–19.4) 20.4 (13.3–29.8)
80+ yea s 157.7 (129.0–
190.9)
105.1 (82.0–
132.8) 12.0 (5.2–23.7) 10.5 (4.2–21.7) 13.5 (6.2–25.7 16.5 (8.25–29.6)
Females All emales 123.9 (116.6–
131.6) 37.1 (33.2–41.4) 7.1 (5.4–9.1) 8.9 (7.1–11.2) 23.8 (20.6–
27.3) 47.0 (42.5–51.8)
50–59 yea s 48.3 (41.00–6.5) 3.7 (1.9–6.5) 0.6 (0.1 -2.3) 4.4 (2.4–7.3) 12.2 (8.6–16.6) 27.4 (22.0–33.8)
Figu e 1.
Flow diag am o s udy pa icipan s based on he S obe s a emen . A o al o 1383 subjec s we e assessed o
eligibili y, among a s udy popula ion o 157,428 inhabi an s. F ac u e miscoding o auma ic o pa hological causes o
ac u es we e he causes o he exclusion o 14 subjec s. Subjec s we e en olled om Janua y 2014 o Decembe 2014 and
ollowed up un il Decembe 2016. Mean du a ion o ollow-up was 2.3 yea s o all subjec s, 2.2 yea s in males and 2.3 in
emales. The mos equen ypes o index ac u e we e w is (N = 506, 37.0%) and hip (N = 431, 31.5%), ollowed closely by
p oximal hume us (N = 264, 19.3%). O e all, 99 subjec s egis e ed a subsequen ac u e, wi h 120 e en s o dea h occu ing
h oughou ollow-up. Fx: ac u e. SsFx: subsequen ac u e.
J. Clin. Med. 2021,10, 1082 4 o 11
3.2. Incidence Ra e o Index F ac u e in he Gene al Popula ion
An o e all incidence a e o 86.9 ac u es/10,000 pe son-yea s was ound in he
gene al popula ion aged
≥
50 yea s (Table 1). The equency o agili y ac u es was
signi ican ly highe among women as compa ed o men: 123.9 (CI 95% 116.6–131.6) e sus
42.3 (CI95% 37.7–47.4), espec i ely. Also, ma ked inc ease in he equency was also
obse ed wi h inc easing age. The highes o e all equency was obse ed o w is
ac u es. Despi e his, hip ac u es we e he mos equen among women and men aged
≥
80 yea s. On he o he hand, he skele al si es wi h he lowes incidence a e o agili y
ac u es we e he pel is and he spine.
Table 1.
Incidence a e o index ac u e in he gene al popula ion aged
≥
50 yea s, by index ac u e si e, sex, and age g oup.
The o al popula ion alues o males and emales a e ma ked in bold. The shading indica es ha hey a e o al alues o
he popula ion, o di e en ia e hem om he es ha a e sepa a ed by gende and age.
Index F ac u e Si e
Age * All Si es Hip Pel is Ve eb al P ox.
Hume us W is
All subjec s 50+ yea s 86.9
(82.4–91.6)
27.5
(25.0–30.2) 4.6 (3.6–5.8) 6.0 (4.8–7.3) 16.8
(14.8–18.9)
32.1
(29.4–35.0)
Males
All males 42.3
(37.7–47.4)
15.6
(12.8–18.8) 1.8 (0.0–3.1) 2.4 (1.4–3.8) 8.3 (6.3–10.7) 14.2
(11.6–17.3)
50–59 yea s 23.4
(18.3–29.5) 2.3 (0.9–4.8) 0.0 (NA) 1.3 (0.4–3.4) 7.3 (4.5–11.0) 12.5
(8.9–17.2)
60–69 yea s 24.7
(18.5–32.3) 4.7 (2.2–8.6) 0.9 (0.1–3.4) 0.9 (0.1–3.4) 6.1 (3.2–10.4) 12.1
(7.9–17.8)
70–79 yea s 56.4
(44.1–71.0) 18.8
(12.1–28.0) 2.4 (0.5–6.9) 3.1 (0.9–8.0) 11.8
(6.6–19.4) 20.4
(13.3–29.8)
80+ yea s 157.7
(129.0–190.9) 105.1
(82.0–132.8) 12.0
(5.2–23.7) 10.5
(4.2–21.7) 13.5 (6.2–25.7 16.5
(8.25–29.6)
Females
All emales 123.9
(116.6–131.6)
37.1
(33.2–41.4) 7.1 (5.4–9.1) 8.9 (7.1–11.2) 23.8
(20.6–27.3)
47.0
(42.5–51.8)
50–59 yea s 48.3
(41.00–6.5) 3.7 (1.9–6.5) 0.6 (0.1 -2.3) 4.4 (2.4–7.3) 12.2
(8.6–16.6) 27.4
(22.0–33.8)
60–69 yea s 77.9
(67.1–89.9) 5.8 (3.2–9.8) 2.5 (0.9–5.4) 2.9 (1.2–6.0) 19.6
(14.4–26.0) 47.1
(38.8–56.6)
70–79 yea s 150.2
(132.4–169.7) 38.0
(29.3–48.4) 8.2 (4.5–13.7) 13.4
(8.5–20.2) 31.6
(23.7–41.2) 59.0
(48.1–71.7)
80+ yea s 359.5
(327.7–393.6) 175.5
(153.5–199.8) 29.9
(21.3–40.9) 25.3
(17.4–35.5) 49.8
(38.5–63.5) 79.0
(64.4–95.8)
Da a a e incidence a e pe 10,000 pe son-yea s (95% con idence in e al). * Age is desc ibed as o index da e.
3.3. Incidence o Subsequen F ac u es
The equency o clinical subsequen ac u e e en s was 318.2/10,000 pe son-yea s.
Incidence a e o subsequen ac u es was highe in women han in men. Howe e , he
o e all di e ences did no each s a is ical signi icance (Table 2). By con as , he equency
o clinical ac u e e en s inc eased wi h age, wi h ma kedly highe incidences a es in
men and women aged 70 yea s o olde (Table 2). O e all, no signi ican di e ences in he
equency o subsequen ac u e e en s we e obse ed by index ac u e ype. Howe e ,
a sligh end was obse ed owa d inc eased incidence among subjec s wi h pel is and
hip index ac u es (Table 2). The a e o u he ac u e e en s was highes wi hin he
≥
80 yea s’ age g oup, in women wi h a p e ious ac u e in he pel is and men wi h a
p e ious w is index ac u e. The mos equen skele al loca ions o u he ac u es we e
hip and w is . The incidence a e o u he ac u e e en s du ing he i s yea a e he
index agili y ac u e was no highe han he a es obse ed du ing he ollowing second
and hi d yea s o ollow-up, ega dless o sex and age (Figu e 2). Simila ly, no ma ked
di e ences among ollow-up pe iods we e obse ed by si e o index ac u e. Howe e , a
sligh end was obse ed o w is ac u es (Supplemen a y Table S2).
J. Clin. Med. 2021,10, 1082 5 o 11
Table 2.
Incidence a e o subsequen ac u es (any si e) among pa ien s wi h an index ac u e, by index ac u e si e, sex,
and age g oup. The o al popula ion alues o males and emales a e ma ked in bold. The shading indica es ha hey a e
o al alues o he popula ion, o di e en ia e hem om he es ha a e sepa a ed by gende and age.
Index F ac u e
Si e
Age * All Si es Hip Pel is Ve eb al P ox.
Hume us W is
All subjec s 50+ yea s 318.2
(261.3–387.5)
406.8
(294.7–561.4)
425.8
(203.1–893.1)
364.5
(182.3–728.9)
306.0
(195.2–479.8)
234.0
(161.6–338.9)
Males
All males 180.4
(93.2–315.1)
228.8
(74.3–534.0) 0.0 (NA) 504.4
(61.1–1821.9) 69.7 (1.8–388.5) 171.4
(46.7–438.8)
50–59 yea s 56.4 (1.4–314.2) 0.0 (NA) 0.0 (NA) 1014.3
(25.7–5651.3) 0.0 (NA) 0.0 (NA)
60–69 yea s 0.0 (NA) 0.0 (NA) 0.0 (NA) 0.0 (NA) 0.0 (NA) 0.0 (NA)
70–79 yea s 259.4
(70.7–664.1) 464.9
(56.3–1679.4) 0.0 (NA) 0.0 (NA) 0.0 (NA) 359.8
(43.6–1299.5)
80+ yea s 333.0
(133.9–686.2) 218.9
(45.2–639.8) 0.0 (NA) 665.4
(16.9–3707.5) 473.4
(12.0–2637.8) 1048.8
(127.0–3788.7)
Females
All emales 355.7
(284.9–438.8)
463.0
(316.7–653.6)
521.8
(209.8–1075.1)
333.7
(122.4–726.2)
377.0
(223.4–595.8)
249.1
(159.6–370.7)
50–59 yea s 131.2
(42.6–306.3) 0.0 (NA) 0.0 (NA) 275.8
(7.0–1536.8) 107.0
(2.7–596.1) 137.7
(28.4–402.4)
60–69 yea s 131.5
(48.3–286.2) 0.0 (NA) 0.0 (NA) 0.0 (NA) 0.0 (NA) 217.8
(79.9–474.0)
70–79 yea s 352.4
(218.1–538.6) 414.11
(152.0–901.3) 0.0 (NA) 571.2
(117.8–1669.2) 658.4
(284.3–1297.3) 163.5
(44.5–418.6)
80+ yea s 543.2
(409.2–707.0) 540.6
(353.1–792.1) 852.6
(342.8–1756.7) 262.7
(31.8–948.8) 607.8
(277.9–1153.8) 488.3
(243.8–873.7)
Da a a e incidence a e pe 10,000 pe son-yea s (95% con idence in e al). * Age is desc ibed as o index da e.
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 6 o 12
80+ yea s 543.2 (409.2–
707.0)
540.6 (353.1–
792.1)
852.6 (342.8–
1756.7) 262.7 (31.8–948.8) 607.8 (277.9–
1153.8)
488.3 (243.8–
873.7)
Da a a e incidence a e pe 10,000 pe son-yea s (95% con idence in e al). * Age is desc ibed as o index da e.
Figu e 2. Nelson–Aalen cumula i e haza d o subsequen ac u e e en s a e an index ac u e in
men and women aged ≥50 yea s o e a pe iod o h ee yea s o ollow-up. Cumula i e isk o sub-
sequen ac u e inc eased o e he yea s ollowing ini ial ac u e. Howe e , no signi ican di e -
ences we e ound in he incidence a e o subsequen ac u es o e 1, 2, and 3 yea s, ega dless o
sex and age. Do ed line ep esen s he cumula i e incidence o subsequen ac u es in all sub-
jec s. Solid line ep esen s he cumula i e incidence o subsequen ac u e e en s in emales.
Dashed line ep esen s he cumula i e incidence o subsequen ac u e e en s in males. SsFx: sub-
sequen ac u e. The Y-axis ep esen s he cumula i e haza d unc ion. The X-axis ep esen s ol-
low-up yea s a e he i s ac u e.
3.4. Risk Fac o s o Subsequen Clinical F ac u e
O e all, he incidence a e o ac u es was highe o subjec s wi h a p e ious index
agili y ac u e a any si e compa ed wi h he gene al popula ion ( ela i e isk [RR] 1.80,
p < 0.01) (Figu e 3 and Supplemen a y Table S3). Independen isk ac o s o subsequen
ac u e, as iden i ied by mul i a ia e analysis using Cox as well as Fine and G ay eg es-
sion models, Highe age (≥70 yea s) was an independen isk ac o o u he ac u e
e en s, wi h a ≥1.5 inc ease in haza d isk (HR) obse ed o each decade om 60 yea s o
age (Table 3). Mul i a ia e analysis using Fine and G ay model e ealed an inc eased isk
o subsequen ac u es in women. No e ec o index ac u e si e on he le el o isk o
u he ac u es was obse ed (Table 3).
Figu e 2.
Nelson–Aalen cumula i e haza d o subsequen ac u e e en s a e an index ac u e
in men and women aged
≥
50 yea s o e a pe iod o h ee yea s o ollow-up. Cumula i e isk
o subsequen ac u e inc eased o e he yea s ollowing ini ial ac u e. Howe e , no signi ican
di e ences we e ound in he incidence a e o subsequen ac u es o e 1, 2, and 3 yea s, ega dless
o sex and age. Do ed line ep esen s he cumula i e incidence o subsequen ac u es in all subjec s.
Solid line ep esen s he cumula i e incidence o subsequen ac u e e en s in emales. Dashed
line ep esen s he cumula i e incidence o subsequen ac u e e en s in males. SsFx: subsequen
ac u e. The Y-axis ep esen s he cumula i e haza d unc ion. The X-axis ep esen s ollow-up yea s
a e he i s ac u e.

J. Clin. Med. 2021,10, 1082 6 o 11
3.4. Risk Fac o s o Subsequen Clinical F ac u e
O e all, he incidence a e o ac u es was highe o subjec s wi h a p e ious index
agili y ac u e a any si e compa ed wi h he gene al popula ion ( ela i e isk [RR] 1.80,
p< 0.01) (Figu e 3and Supplemen a y Table S3). Independen isk ac o s o subsequen
ac u e, as iden i ied by mul i a ia e analysis using Cox as well as Fine and G ay eg ession
models, Highe age (
≥
70 yea s) was an independen isk ac o o u he ac u e e en s,
wi h a
≥
1.5 inc ease in haza d isk (HR) obse ed o each decade om 60 yea s o age
(Table 3). Mul i a ia e analysis using Fine and G ay model e ealed an inc eased isk
o subsequen ac u es in women. No e ec o index ac u e si e on he le el o isk o
u he ac u es was obse ed (Table 3).
J. Clin. Med. 2021, 10, x FOR PEER REVIEW 7 o 12
Figu e 3. Rela i e isk o subsequen ac u es among subjec s wi h a p e ious ac u e compa ed
wi h he gene al popula ion by sex (g een box and squa e), age g oup ( ed box and ci cle), and
index ac u e si e (blue box and iangle). Adjus ed a e a io es ima ed using Poisson eg ession
models ha included age, sex, and index ac u e si e as co a ia es. Co esponding da a a e p e-
sen ed in Supplemen a y Table S3. * p < 0.05, ** p < 0.01.
Table 3. Haza d a io (Cox) and subhaza d a io (Fine and G ay) o subsequen ac u e e en s
associa ed o sex, age, and index ac u e si e.
Risk Fac o HR
†
95% CI p > |z| SHR
‡
95% CI p > |z|
Sex
Male * 1 1
Female 1.73 (0.94–3.17) 0.08 1.87 (1.01–3.46) 0.05
Age g oup
50–59 yea s * 1 1
60–69 yea s 0.92 (0.30–2.86) 0.88 0.91 (0.30–2.78) 0.87
70–79 yea s 2.94 (1.20–7.22) 0.02 2.88 (1.18–7.05) 0.02
80+ yea s 4.41 (1.85–10.51) <0.01 4.15 (1.74–9.89) <0.01
Index ac u e si e
Hip 1.05 (0.62–1.77) 0.85 0.98 (0.58–1.66) 0.94
Pel is 1.14 (0.49–2.64) 0.77 1.12 (0.49–2.57) 0.79
Ve eb al 1.14 (0.52–2.53) 0.74 1.14 (0.51–2.53) 0.75
P ox. hume us 1.20 (0.67–2.15) 0.54 1.22 (0.68–2.18) 0.51
W is * 1 1
Index ac u e ype
†
Appendicula 1 1
Cen al 1 (0.66–1.53) 0.99 0.95 (0.61–1.46) 0.80
* Baseline ca ego y;
†
haza d a io (HR) and 95% con idence in e al (CI) es ima es adjus ed o all
a iables in he able using a Cox p opo ional haza ds model.
‡
Subhaza d a io (SHR) and 95%
Figu e 3.
Rela i e isk o subsequen ac u es among subjec s wi h a p e ious ac u e compa ed
wi h he gene al popula ion by sex (g een box and squa e), age g oup ( ed box and ci cle), and index
ac u e si e (blue box and iangle). Adjus ed a e a io es ima ed using Poisson eg ession models
ha included age, sex, and index ac u e si e as co a ia es. Co esponding da a a e p esen ed in
Supplemen a y Table S3. * p< 0.05, ** p< 0.01.
Table 3.
Haza d a io (Cox) and subhaza d a io (Fine and G ay) o subsequen ac u e e en s
associa ed o sex, age, and index ac u e si e.
Risk Fac o HR †95% CI p> |z| SHR ‡95% CI p> |z|
Sex
Male * 1 1
Female 1.73 (0.94–3.17) 0.08 1.87 (1.01–3.46) 0.05
Age g oup
50–59 yea s * 1 1
60–69 yea s 0.92 (0.30–2.86) 0.88 0.91 (0.30–2.78) 0.87
70–79 yea s 2.94 (1.20–7.22) 0.02 2.88 (1.18–7.05) 0.02
80+ yea s 4.41 (1.85–10.51) <0.01 4.15 (1.74–9.89) <0.01
J. Clin. Med. 2021,10, 1082 7 o 11
Table 3. Con .
Risk Fac o HR †95% CI p> |z| SHR ‡95% CI p> |z|
Index ac u e si e
Hip 1.05 (0.62–1.77) 0.85 0.98 (0.58–1.66) 0.94
Pel is 1.14 (0.49–2.64) 0.77 1.12 (0.49–2.57) 0.79
Ve eb al 1.14 (0.52–2.53) 0.74 1.14 (0.51–2.53) 0.75
P ox. hume us 1.20 (0.67–2.15) 0.54 1.22 (0.68–2.18) 0.51
W is * 1 1
Index ac u e ype +
Appendicula 1 1
Cen al 1 (0.66–1.53) 0.99 0.95 (0.61–1.46) 0.80
* Baseline ca ego y;
†
haza d a io (HR) and 95% con idence in e al (CI) es ima es adjus ed o all a iables in
he able using a Cox p opo ional haza ds model.
‡
Subhaza d a io (SHR) and 95% con idence in e al (CI)
es ima es adjus ed o all a iables in he able using a Fine and G ay compe ing isks model using dea h as
compe ing isk.
+
Appendicula ac u es: w is and p oximal hume us. Cen al ac u es: e eb al, pel is, and
hip ac u es.
3.5. Risk o Dea h Following Ini ial F ac u e
A o al o 120 dea hs occu ed du ing he s udy ollow-up pe iod in pa ien s aged
≥
50 yea s wi h an index agili y ac u e, wi h o e all mo ali y a es eaching 37.20/1000
pe son-yea s (29.09 and 67.42 pe 1000 pe son-yea s in women and men, espec i ely).
Mo ali y a es we e highe among men as compa ed o women (HR, 0.41; p< 0.01)
(Table 4)
.
Age was he s onges de e minan o mo ali y wi h signi ican excess isk o subjec s aged
80 o olde (HR, 3.43 p< 0.01). Mo ali y isk was also signi ican ly highe among pa ien s
p esen ing an index agili y ac u e in he hip (HR, 2.48; p< 0.01). Lowe mo ali y a es
we e obse ed in subjec s wi h index ac u es loca ed in pe iphe al bone posi ions (w is
and p oximal hume us). Mo ali y isk also inc eased a e a subsequen ac u e occu ed,
al hough his associa ion did no each s a is ical signi icance (HR, 2.14; p= 0.06) (Table 4).
Table 4.
Mo ali y haza d a io associa ed o sex, age, ype o index ac u e, and p esence o
subsequen ac u e e en s.
Risk Fac o MR ×1000 PY ‡HR †95% CI p> |z|
Sex
Male * 67.42 1
Female 29.09 0.41 (0.28–0.60) <0.01
Age g oup
50–59yea s * 12.42 1
60–69yea s 17.04 1.43 (0.54–3.77) 0.47
70–79yea s 29.30 2.00 (0.84–4.73) 0.12
80+yea s 62.00 3.43 (1.51–7.77) <0.01
Index ac u e si e
Hip 73.50 2.48 (1.47–4.19) <0.01
Pel is 52.60 1.95 (0.88–4.35) 0.10
Ve eb al * 22.07 1.01 (0.38–2.68) 0.99
P oximal hume us 21.83 1.13 (0.58–2.21) 0.73
W is 17.82 1
P esence o SsFX
no SsFX * 36.32 1
SsFX 60.89 2.14 (0.97–4.70) 0.06
* Baseline ca ego y.
†
Mo ali y haza d a io (HR) and 95% con idence in e al (CI) es ima es adjus ed o all
a iables in he able using a Cox p opo ional haza ds model.
‡
Mo ali y a e (MR) pe 1000 pe son-yea s (PY).
SsFx: subsequen ac u e.
4. Discussion
This s udy p esen s he i s epo o he incidence a e o index o majo agili y
ac u es and he isk o imminen ac u es in a Spanish coho o 1369 subjec s (1068
women and 301 men) aged
≥
50 yea s, by age g oup and ac u e si e. Ou s udy con i med
J. Clin. Med. 2021,10, 1082 8 o 11
ma kedly highe a es in women, as well as an age- ela ed inc ease in he isk, wi h highes
equency a es ound in women aged
≥
80 yea s. The p e alence o os eopo osis and
os eopo osis ac u e a es is highe in women compa ed o men. This is due o di e ences
in BMD, bone size, bone geome y, and bone s eng h [
23
,
24
]. Es ogen dep i a ion a e
menopause is a majo con ibu ing ac o , which could be he eason o he obse ed
gende - ela ed di e ences [
25
]. Age, on he o he hand, is a well-s udied isk ac o o
index agili y ac u es, con ibu ing o isk independen ly o bone mass densi y [
26
].
P e ious in o ma ion on he incidence a e o agili y ac u es in Spain is sca ce. As a
i s app oach, using he Q-FRACTURE ool, González López-Valcá cel e al. [
27
] es ima ed
a le el o isk anging om 1.8–21.5% in women and 0.7–10.8% in men. Acco ding o
ou indings, he equency o os eopo o ic ac u es in Spain may be sensi i ely highe
han epo ed. Con e sely, ou numbe s unde es ima e he c ude a es published by he
In e na ional Os eopo osis Founda ion o Spain as well as o o he EU coun ies [
28
]. This
disc epancy may be pa ly explained by he exclusion o non-clinical e eb al ac u es
and o he ac u e si es less commonly associa ed wi h os eopo osis. O e all, he mos
equen index ac u e ype was w is . Howe e , he a e o hip ac u es exceeds ha o
w is in olde aged g oups. Simila age- ela ed ends in he equency o agili y ac u es
we e epo ed p e iously [29].
Es ima ed incidence a e o subsequen ac u es was 318.2/10,000 pe son-yea s in all
subjec s du ing he h ee yea s ha ollowed index ac u e (i.e., 3.2% o pa ien s wi h a
p e ious ac u e expe ienced a new ac u e e e y yea ). To da e, no o he s udies ha e
been published ha measu e he isk o imminen ac u es a e a sen inel ac u e in
Spain. Only Azag a e al. ha e published 10-yea ac u e da a in a popula ion coho
in Ca alonia ha p esen ed clinical isk ac o s o os eopo o ic ac u es, wi h he aim o
alida ing he F ax ool in he Spanish popula ion [30].
O e all, he incidence o ac u e was highe o subjec s wi h a p e ious index agili y
ac u e a any si e, compa ed wi h he equency in he gene al popula ion aged 50 o
olde (RR, 1.80). Acco ding o ou indings, Kanis e al. [
17
] obse ed ha , o any ype o
p e ious ac u e, he RR o any u he ac u e anged om 1.83 o 2.03 depending upon
age. The e ec o gende as a p edic o o he isk was only signi ican when he analysis
conside ed dea h as a compe ing isk. P e ious epo s obse ed simila isks in men and
women, excep among subjec s o e 85 yea s o age [
31
]. Ou da a also, howe e , p o ed
he well-known independen e ec o aging on he isk o u he ac u e e en s, [
11
,
14
],
wi h signi ican di e ences in he HR among olde age (
≥
70 yea s). They also ound a
ma ked age- ela ed inc ease in he isk bu did no obse e any di e ences in he isk
among women and men.
No iceable di e ences in he equency o subsequen ac u es we e ound depending
upon si e, wi h highes a es ound in subjec s wi h a p e ious pel is o hip ac u e. Ou
indings, howe e , could no con i m he e ec o he skele al si e on he isk o u he
ac u es. P e ious epo s on he associa ions be ween p io and subsequen ac u es a e
no consis en [
7
]. The ime ha ollows ini ial ac u e is key wi h ega d o he isk and
p e en ion o subsequen ac u e e en s. Se e al p e ious s udies epo ha he highes
isk o u he ac u e e en s occu s wi hin he i s yea a e he index ac u e [
8
–
11
]
and ha he incidence dec eases he ea e . In he cu en s udy, howe e , he incidence o
subsequen ac u e e en s du ing he i s yea a e he index ac u e was no highe han
he a es obse ed du ing he ollowing second and hi d yea s o ollow-up, ega dless o
sex and age. Despi e his, a sligh end was obse ed o w is index ac u es. Au ho s
epo ing highe le els o isk du ing he i s yea a e he index ac u e ha e assessed
longe imescales han ou s udy [9]. Like in ou s udy, Bane el e al. [11] ocused only in
he ea ly yea s ollowing he index ac u e and ound he highes incidence du ing he
second yea (12%), a he han he i s (7.1%).
O e all mo ali y a e eached 37.20/1000 pe son-yea s, which showed an up- o-2-
old excess mo ali y due o os eopo o ic ac u es among he younge -aged g oups [
32
].
The isk o dea h was signi ican ly highe in pa ien s wi h a p e ious hip index ac u e
J. Clin. Med. 2021,10, 1082 9 o 11
(HR, 2.48; p< 0.01), wi h an es ima ed a e o 73.50/1000 pe son-yea s. No signi ican
excess mo ali y was ound o index ac u es in o he skele al loca ions o o he e en o
subsequen ac u es (p= 0.06). As expec ed, ou da a also con i med a highe age-speci ic
dea h isk (p< 0.01, in subjec s aged
≥
80 yea s) as well as lowe dea h isk in women
(p< 0.01)
. In ac , 58.3% o all dea hs occu ed in pa ien s wi h a p e ious hip index ac u e
and a mean age o 83.3 yea s. The obse ed dea h a e a e a hip ac u e was sensi i ely
lowe han p e iously epo ed [
33
,
34
], which could be explained by he longe obse a ion
pe iod o his s udy, as mo ali y is highes du ing he six mon hs ha ollow he e en [
35
].
The main limi a ion o ou s udy is he lack o da a om o he clinical ac o s ha
could ha e con ibu ed o in-dep h unde s anding o he isk o subsequen ac u es (bone
mass densi y, p e ious eco d o alls, his o y o p io ac u es, use o d ugs a ec ing bone
me abolism). One o he s eng hs o ou s udy is ha , as opposed o da abase s udies,
we manually e iewed clinical eco ds o all 1369 cases o con i m eligibili y as well as
ou comes’ in o ma ion.
5. Conclusions
In summa y, his epo p o ides in o ma ion on he magni ude and consequences o
agili y ac u es in he as-ye unexplo ed Spanish popula ion aged
≥
50 yea s, in ol ing
bo h gende s, as well as majo skele al si es associa ed wi h os eopo osis, no limi ed o
hip. This is he i s s udy o epo on he incidence a e o imminen ac u es a e an
os eopo o ic sen inel ac u e in Spain, wi h age, sex, and skele al loca ion o he index
ac u es as possible isk ac o s. Ou esul s suppo he inc eased isk o imminen
ac u e a e a ecen ac u e and p o ide key elemen s o ea ly iden i ica ion o isk and
he applica ion o a ge ed s a egies aimed a p e en ing u u e ac u es and mo ali y,
such as he in e en ions ecommended by he F ac u e Liaison Se ices [36].
Supplemen a y Ma e ials:
The ollowing a e a ailable online a h ps://www.mdpi.com/2077-038
3/10/5/1082/s1. Table S1: F ac u e codes acco ding o ICD-9, Table S2: Incidence a e o subsequen
ac u e e en s by ype o index ac u e and ollow-up pe iod (yea s), and Table S3: Rela i e Risk o
subsequen ac u e e en s by age, sex and index ac u e si e.
Au ho Con ibu ions:
Concep ualiza ion, M.G. and M.-J.M.-G.; me hodology, M.-J.M.-G. and
M.A.V.-G.; alida ion, F.-J.O.-M., M.-A.C., M.J.M. and B.H.-C.; o mal analysis, M.G. and M.-J.M.-G.;
in es iga ion, all au ho s; esou ces, R.M. and D.G.-R.; w i ing—o iginal d a p epa a ion, M.G. and
M.-J.M.-G.; w i ing— e iew and edi ing, M.-J.M.-G. and M.A.V.-G.; supe ision, M.A.V.-G.; p ojec
adminis a ion, M.-J.M.-G.; unding acquisi ion, M.-J.M.-G. and M.-A.C. All au ho s ha e ead and
ag eed o he published e sion o he manusc ip .
Funding:
This wo k was unded by Conseje ía de Salud de la Jun a de Andalucía, P oyec o de
Inno ación PIN-0092-2016, which had no ole in he design o conduc o he s udy; in he collec ion,
analyses, and in e p e a ion o he da a; o in he p epa a ion, e iew, o app o al o he manusc ip .
Ins i u ional Re iew Boa d S a emen :
The s udy was app o ed by he E hical Re iew Boa d o
Se ille (p o ocol code: CI#2147, 09/02/2013) and was pe o med in acco dance wi h he e hical
s anda ds as laid down in he 1964 Decla a ion o Helsinki and i s la e amendmen s. Fo his ype o
s udy, indi idual o mal consen was no equi ed.
In o med Consen S a emen :
In o med consen was ob ained om all subjec s in ol ed in
he s udy
.
Da a A ailabili y S a emen :
The da a p esen ed in his s udy a e a ailable on eques om he
co esponding au ho . The da a a e no publicly a ailable due o p i acy.
Acknowledgmen s:
We hank he pa icipan s in his s udy o hei aluable con ibu ion. W i ing
assis ance was p o ided by Juliana Ma inez.
Con lic s o In e es : The au ho s decla e no con lic o in e es .