A 2-Year Follow-Up After a 2-Year RCT with Vitamin D and Exercise: Effects on Falls, Injurious Falls and Physical Functioning Among Older Women

© The Au ho 2017. Published by Ox o d Uni e si y P ess on behal o The Ge on ological Socie y o Ame ica. 1239 Jou nals o Ge on ology: Medical Sciences ci e as: J Ge on ol A Biol Sci Med Sci, 2017, Vol. 72, No. 9, 1239–1245 doi:10.1093/ge ona/glx044 Ad ance Access publica ion Ma ch 21, 2017 This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h p://c ea i ecommons.o g/licenses/by-nc/4.0/), which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Fo comme cial e-use, please con ac [email p o ec ed] Resea ch A icle A 2-Yea Follow-Up A e a 2-Yea RCT wi h Vi amin D and Exe cise: E ec s on Falls, Inju ious Falls and Physical Func ioning Among Olde Women Ki s i Uusi-Rasi,1 Radhika Pa il,1 Saija Ka inkan a,1 Pekka Kannus,1,2 Ka iTokola,1 Ch is elLambe g-Alla d ,3 and Ha iSie änen1 1The UKK Ins i u e o Heal h P omo ion Resea ch, Tampe e, Finland. 2Depa men o O hopaedics and T auma Su ge y, Tampe e Uni e si y Hospi al, Tampe e Medical School, Uni e si y o Tampe e, Tampe e, Finland. 3Depa men o Food and En i onmen al Sciences, Uni e si y o Helsinki, Helsinki, Finland. Add ess co espondence o Ki s i Uusi-Rasi, PhD, The UKK Ins i u e o Heal h P omo ion Resea ch, P.O. Box 30, FI-33501 Tampe e, Finland. E-mail: [email p o ec ed] Recei ed No embe 9, 2016; Edi o ial Decision Da e Feb ua y 28, 2017 Decision Edi o : S ephen K i che sky, PhD Abs ac Backg ound: Bo h exe cise and i amin D a e ecommended means o p e en alls among olde adul s, bu hei combined e ec s on all- induced inju ies a e sca cely s udied. Me hods: A 2-yea ollow-up o a p e ious 2-yea andomized con olled ial wi h i amin D and exe cise (Ex) o 409 olde home-dwelling women using a ac o ial 2 × 2 design (D−Ex−, D+Ex−, D−Ex+, D+Ex+). Besides mon hly all dia ies, emo al neck bone mine al densi y ( n-BMD), and physical unc ioning we e assessed a 1 and 2 yea s a e he in e en ion. Resul s: A e he in e en ion, S-25OHD concen a ions declined o baseline le els in bo h supplemen g oups. The g oups did no di e o change in n-BMD o physical unc ioning, excep o leg ex enso muscle s eng h, which emained abou 10% g ea e in he exe cise g oups compa ed wi h he e e ence g oup (D−Ex−). The e we e no be ween-g oup di e ences in he a e o all alls, bu medically a ended inju ious alls educed in D+Ex− and D−Ex+ g oups compa ed wi h D−Ex−. Howe e , all o me ea men g oups had less medically a ended inju ed alle s, HRs (95% CI) being 0.62 (0.39–1.00) o D+Ex−, 0.46 (0.28–0.76) o D−Ex+, and 0.55 (0.34–0.88) o D+Ex+, compa ed wi h D−Ex−. Conclusions: Exe cise-induced bene i s in physical unc ioning pa ly emained 2yea s a e cessa ion o supe ised aining. Al hough he e was no di e ence in he a e o all alls, o me exe cise g oups con inued o ha e lowe a e o medically a ended inju ed alle s compa ed wi h e e en s e en 2yea s a e he in e en ion. Vi amin D wi hou exe cise was associa ed wi h less inju ious alls wi h no di e ence in physical unc ioning. Keywo ds: Physical unc ioning—Inju ious alls—Vi amin D—Exe cise In oduc ion The numbe o olde people will inc ease o e he nex decades, accompanied wi h inc eased numbe o alls and all- ela ed inju- ies, and e ec i e means o p e en ing alls and subsequen con- sequences a e needed. Many isk ac o s o alls and all-induced inju ies a e ela ed o physical inac i i y and low unc ional abili y (e.g. mobili y limi a ions, educed lowe limb muscle s eng h, and balance de ici ), and also o bone agili y in case o ac u es. Also slow p ocessing speed in he abili y o eac o pe u ba ion may explain inc eased isk o inju ious alls (1). All hese can be modi ied by exe cise (2,3). The e is e idence om andomized con olled i- als and sys ema ic e iews and me a-analyses ha egula s eng h and balance aining can educe he isk o alling in communi y- dwelling olde adul s by 15–50% (4–6). Vi amin D de iciency has also been shown o be associa ed wi h lowe physical unc ioning and g ea e isk o alls and ac u es in olde people (7–9). Howe e , ecen andomized con olled ial (RCTs) wi h high i amin D doses ha e shown ei he no bene i (10) o e en ha m ul e ec s on lowe ex emi y physical unc ioning, alls and ac u es (11,12). No did a ecen RCT o exe cise and i amin D show any syne gic e ec on alls in olde women (13). Cu en ly, bo h exe cise and i amin D supplemen a ion a e ec- ommended o p e en ion o alls among olde adul s. In pa icula , exe cise including s eng h and balance aining has been shown o educe alls and inju ious alls, bu he esul s a e ye inconsis - en (14–16). The e is also some e idence ha bene i s may las , a leas o some ex en , a e cessa ion o he in e en ion as long as he aining induced physical pe o mance is main ained (17). So a , only ew s udies ha e e alua ed a e o alls o inju ious alls once he exe cise aining is s opped (17–20), bu i seems ha he isk o inju ious alls emains educed e en a e cessa ion o he supe ised exe cise aining (19). To ou knowledge, he e a e no ollow-ups a e ceasing i amin D supplemen a ion. P e iously, we showed ha supe ised exe cise aining educed medically a ended inju ious alls among home-dwelling olde women, while he a e o all alls was a ec ed by nei he exe cise no i amin D in e en ion. Exe cise also imp o ed physical unc- ioning, while i amin D did no (13). The aim o his p e-planned 2-yea ollow-up o he DEX ial was o assess whe he he ben- e i s o mul imodal supe ised exe cise aining in educing alls and medically a ended inju ious alls pe sis a e ceasing he aining. In pa icula , we examined he esidual e ec s o he in e en ion on alls, all-induced inju ies and physical unc ioning o up o 2-yea a e comple ion o he in e en ion. Me hods T ialDesign This s udy is a 2-yea ollow-up o he 2-yea double-blind, placebo- con olled i amin D and open exe cise DEX ial (NCT00986466). The pe iod o supe ised exe cise and i amin D/placebo supplemen- a ion deno es he in e en ion pe iod (0–24mon hs) (21). The sub- sequen 2-yea pe iod a e he in e en ion (24–48mon hs) deno es he ollow-up pe iod, which is epo ed he e. Pa icipan s Ini ially, 409 home-dwelling 70-80-yea -old women we e andomly assigned o one o ou g oups: (a) i amin D 20µg/day (800 IU) and exe cise (D+Ex+) (b) placebo and exe cise (D−Ex+) (c) i amin D 20µg/day wi hou exe cise (D+Ex−), and (d) placebo wi hou exe - cise (D−Ex−). The in e en ion esul s ha e been epo ed p e iously (13,22). O he 370 women who comple ed he in e en ion, 15 we e unable o unwilling o con inue wi h he ollow-up. Fi e mo e women wi hd ew du ing he ollow-up pe iod (Figu e1). The s udy p o ocol was app o ed by he E hics Commi ee o he Pi kanmaa Hospi al Dis ic , Finland (R09090). Each pa ici- pan p o ided he w i en in o med consen p io o andomiza ion. The exe cise aining p og am has been desc ibed p e iously (21). B ie ly, exe cise consis ed o supe ised g oup aining classes wo imes a week o he i s yea , and once a week o he second yea o he in e en ion. The aining p og am was p og essi e and consis ed o s eng h, balance, agili y, and mobili y aining, bo h in he exe cise hall and gymnasium. Pa icipan s in he non-exe cising g oup we e asked o main ain hei p e-s udy le el o physical ac i - i y du ing he in e en ion. All pa icipan s ecei ed a bookle o home exe cise aining a e he in e en ion. Da a Collec ion The numbe o alls was ob ained om p ospec i e all dia ies e u ned mon hly ia mail, and de ails o each egis e ed all we e asce ained o e elephone h oughou he 48-mon h s udy pe iod. A all was de ined “an unexpec ed e en in which he pa icipan comes o es on he g ound, loo o lowe le el.” (23) Inju ious alls we e classi ied as mino inju ious alls and medically a ended inju i- ous alls, he la e being hose o which pa icipan s sough medi- cal ca e (nu se, physician, o hospi al) and included inju ies such as b uises, ab asions, con usions, sp ains, ac u es, and head inju ies. This classi ica ion con o ms wi h ha p oposed by Schwenk e al. (24). The Pegasos pa ien medical eco ds o he Ci y o Tampe e we e sea ched o all pa icipan s’ u iliza ion o heal hca e se ices due o inciden alls du ing he ollow-up pe iod, o ind possibly un epo ed all inju ies o which medical a en ion was sough . Du ing ollow-up, all measu emen s we e done yea ly (a 36 and 48mon hs om baseline). Die a y in ake o calcium and i amin D we e assessed wi h a alida ed ood equency ques ionnai e (25). In addi ion o heigh and weigh , body composi ion and a eal bone mine al densi y ( n-BMD) o he le emo al neck was assessed using dual-ene gy X- ay abso p iome y (DXA, Luna P odigy Ad ance, GE Luna , Madison. WI) (26). Physical unc ioning was assessed by he Sho Physical Pe o mance Ba e y (SPPB) (27), which comp ised s a ic balance, 4 m no mal walking speed and i e- ime chai s and es s, and by he Timed up and go (TUG) es (28). Dynamic balance was assessed using backwa ds walking (29). Maximal isome ic leg-ex enso s eng h a a knee angle 110° was measu ed by a s ain gauge dynamome e (Tam on, Tampe e, Finland). The Communi y Heal hy Ac i i ies Model P og am o Senio s (CHAMPS) physical ac i i y ques ion- nai e o olde adul s was used o moni o changes in physical ac i i y. In addi ion, each pa icipan eco ded he daily s eps wi h a pedom- e e (Om on HJ-112-E) o e he en i e 48-mon h pe iod. Analysis o 25-Hyd oxy-Vi aminD Fas ing se um 25-hyd oxy- i amin D (S-25OHD) was measu ed ial wi h a manual OCTEIA immunoenzymome ic assay (IDS, Boldon, UK) du ing he in e en ion, and wi h an au oma ed IDS-iSYS analyze (IDS) du ing he ollow-up. Rep oducibili y was ensu ed by adhe - ing o he Vi amin D Ex e nal Quali y Assessmen Scheme, DEQAS (deqas.kmpd.co.uk). In e assay a ia ion was a oided by measu ing all samples om he same pa icipan s in he same se ies. Acco ding o he manu ac u e he esul s om he wo assays co ela e e y well ( =0.99). The eg ession equa ion be ween he wo me hods ende ed a posi i e o nega i e bias o 1–3nmol/L be ween 50–80nmol/L. S a is ical Analysis All da a we e analyzed on an in en ion- o- ea basis (ITT). Changes om baseline o he end o he in e en ion (0–24mon hs) ha e been epo ed p e iously (13). He e we epo changes du ing he ollow-up pe iod (24–48mon hs). Incidence a es o alls we e calcula ed as he o al numbe o alls di ided by he ime o e which alls we e moni- o ed (100 pe son-yea s) in each g oup. Nega i e binomial eg ession was used o es ima e incidence a e a ios (IRR) o alls and inju ious alls, and Cox- eg ession models o calcula ing haza d a ios (HR) o alle s and inju ed alle s in each g oup, wi h he D−Ex− g oup as e e ence. Only HR was analyzed o he en i e 48-mon h pe iod, modeling he ime o i s all (i.e. becoming a alle ). Fo physical unc ioning and BMD, be ween-g oup di e ences (24–48mon hs) we e es ima ed by linea mixed models o no mally 1240 Jou nals o Ge on ology: MEDICAL SCIENCES, 2017, Vol. 72, No. 9 dis ibu ed ou comes ( n-BMD, walking speed and isome ic mus- cle s eng h), and gene alized linea mixed models (GLMM) o non-no mally dis ibu ed ou comes (TUG, backwa ds walking and chai s and) using possible con ounding ac o s (e.g. age, heigh and weigh ) as co a ia es. These me hods allowed he inco po a ion o incomple e longi udinal da a in o he analysis. Resul s Follow-up measu emen s a 48mon hs we e done o 350 pa icipan s (85.6% o he o iginal sample; he main eason o discon inua ion was poo heal h). Desc ip i e cha ac e is ics a baseline (0mon hs) a e gi en in Table1, he e we e no be ween-g oup di e ences in n-BMD o physical unc ioning. Die a y in ake o calcium and i amin D we e adequa ely main ained h oughou he s udy, he mean (SD) daily cal- cium in ake was 1098 (378) mg and i amin D in ake 10.4 (3.9) µg a baseline, and 1182 (387) mg and 11.6 (4.9) µg a he end o he ollow- up (48mon hs), espec i ely. A e he in e en ion, S-25OHD concen- a ions s a ed o decline owa ds baseline le els in bo h supplemen g oups; mean S-25OHD being 72.5 (18.5) nmol/L a 48mon hs (see Supplemen a y Figu e1) showing no di e ence be ween he o me i amin D supplemen ed g oups and he placebo g oups (p=.15). Falls and Inju iousFalls O 635 alls in 226 alle s, 356 alls (56%) esul ed in inju ies. O hese 356 inju ious alls, 116 (33%) we e a ended medically. The e was no signi ican di e ence be ween g oups o he a e o all alls o mino inju ious alls, bu less medically a ended inju ious alls occu ed in he D+Ex− and D−Ex+ g oups compa ed wi h he e e - ence g oup (D−Ex−) (Table2). All o me ea men g oups had less medically a ended inju ed alle s HR (95% CI) being 0.62 (0.39– 1.00) o D+Ex−, 0.46 (0.28–0.76) o D−Ex+, and 0.55 (0.34–0.88) o D+Ex+, when compa ed wi h D−Ex− (see Supplemen a y Figu e2). Femo al Neck BMD and Physical Func ioning Absolu e baseline alues a he end o he in e en ion (24mon hs) and pe cen age changes du ing ollow-up (36 and 48mon hs) a e gi en in Table3. Femo al neck BMD declined sligh ly in all g oups du ing he ollow-up pe iod (Table3). A e he end o he in e en ion, physical unc ioning showed gene al decline du ing he 2-yea ollow-up wi h no be ween-g oup di e ences in changes indica ing ha he achie ed mean ea men e ec s compa ed wi h he e e ence g oup we e la gely main ained (Table 3). The e we e no signi ican changes in no mal walking speed o chai s and ime, no did any o he in e en ion g oups di e om D−Ex−. The TUG es ime inc eased indica ing educed pe o mance in all g oups excep o D−Ex+, in which i emained unchanged. Isome ic leg ex enso muscle s eng h declined signi i- can ly in he o me exe cise g oups bu was main ained in he non- exe cise s. S ill, a he end o he ollow-up he maximal isome ic leg ex enso s eng h was signi ican ly g ea e in he o me exe cise g oups, mean di e ence being 10% o D+Ex+ and 8% o D−Ex+ compa ed wi h D−Ex−. Change in p opo ion o he women able o do backwa ds walking es was simila in all g oups, indica ing ha Figu e1. T ial p o ile. Jou nals o Ge on ology: MEDICAL SCIENCES, 2017, Vol. 72, No. 9 1241 he o me exe cise g oups had main ained he bene i compa ed wi h D−Ex− (Table3, and Supplemen a y Figu e3). Habi ual physical ac i i y declined sligh ly. The equency o mode a e-in ensi y physical ac i i y (CHAMPS) declined in all ou g oups om he baseline mean o 6.7 (5.0) o 5.2 (4.3) h/week being simila in all g oups a he end o he ollow-up (p=.79). Mean num- be o daily s eps also educed by abou 400 s eps om he baseline mean o abou 6,000 wi h no be ween-g oup di e ences (p=.77). Discussion This 2-yea ollow-up o he 2-yea DEX ial showed no be ween- g oup di e ences in alls o alle s in gene al, bu esul s we e di - e en o medically a ended inju ious alls. Du ing he ollow-up, bo h D+Ex− and D−Ex+ had signi ican ly less medically a ended inju ious alls compa ed wi h D−Ex−. Howe e , in all in e en ion g oups, including D+Ex−, he e we e less medically a ended inju ed alle s compa ed wi h D−Ex−, in spi e o he inding ha D+Ex− did no di e om D−Ex− in physical unc ioning ei he du ing he in e en ion o ollow-up and physical unc ioning declined also in he exe cise g oups a e ceasing he supe ised aining. Wi hou i amin D supplemen a ion, also S-25OHD concen a ions declined owa ds baseline le els in bo h supplemen ed g oups, while he e was no signi ican change in mean concen a ions in he o me pla- cebo g oups. Femo al neck BMD declined h oughou he 4-yea s udy pe iod in all g oups. Nei he i amin D no exe cise could p e en bone loss, al hough i s a e educed sligh ly du ing he 2-yea in e en ion. The amoun o bone loss was simila o p e ious s udies showing less han 1% annual bone loss among olde women (30). Hansen e al. showed ha e en high dose cholecalci e ol did no meaning ully a ec BMD sugges ing ha la ge inc eases in calcium abso p ion a e needed o inc ease BMD (10). Also he in ensi y o mechanical load- ing which may esul in inc eased BMD needs likely o be g ea e han he aining gi en in his s udy (17,18). A he end o he 2-yea ollow-up, some o he exe cise-induced gain in physical unc ioning was main ained; he o me exe cise s con inued o ha e be e balance han he e e ence g oup. Also, abou a hal o aining-induced gains in isome ic muscle s eng h emained ill he end o he ollow-up. O he es s o physical unc- ioning showed sligh decline in all g oups and be ween-g oup di - e ences achie ed du ing he in e en ion we e mos ly main ained. Howe e , be e physical unc ioning canno explain he ewe medi- cally a ended inju ious alls seen in D+Ex−, because his g oup did no di e om he e e ence g oup ei he du ing he in e en ion o ollow-up. Table2. Ra e o Falls pe 100 Pe son-Yea s in Each S udy G oup Du ing he 2-Yea Follow-Up (24–48mon hs), and Incidence Ra e Ra ios (IRR) (95% CI) o Falls and Inju ious Falls and Haza d Ra io (HR) (95% CI) Fo Falle s and Inju ed Falle s Ou come D−Ex−D+Ex−D−Ex+D+Ex+ Falls, all 103.0 81.5 84.2 97.1 Mino inju ious alls 29.4 20.1 20.0 24.3 Medically a ended inju ious alls 23.8 10.6 10.6 21.4 Falls wi h ac u es 4.0 3.0 2.9 5.1 IRR All alls 1 0.78 (0.53–1.14) 0.80 (0.55–1.18) 0.88 (0.60–1.28) Mino inju ious alls 1 0.66 (0.38–1.13) 0.68 (0.39–1.16) 0.79 (0.47–1.33) Medically a ended inju ious alls 1 0.45 (0.23–0.87) 0.44 (0.23–0.86) 0.84 (0.48–1.50) HR All alle s 1 0.86 (0.63–1.19) 1.01 (0.74–1.39) 0.99 (0.72–1.38) Medically a ended inju ed alle s 1 0.62 (0.39–1.00) 0.46 (0.28–0.76) 0.55 (0.34–0.88) No e: D−Ex−=placebo; D+Ex−=20µg i amin D daily; D−Ex+=placebo + exe cise; D+Ex+=20µg i amin D daily + exe cise. Table1. Desc ip i e G oup Cha ac e is ics (mean, SD) a he Baseline o he 2-Yea In e en ion (0mon hs) Cha ac e is ic D−Ex− N=102 D+Ex− N=102 D−Ex+ N=103 D+Ex+ N=102 Age, yea s 73.8 (3.1) 74.1 (3.0) 74.8 (2.9) 74.1 (2.9) Heigh , cm 160.7 (5.4) 159.2 (5.8) 159.4 (6.1) 159.7 (5.9) Weigh , kg 72.0 (12.4) 73.0 (13.1) 70·9 (10·6) 73·2 (10·5) Fa , % 41.1 (6.7) 42.0 (7.2) 41.3 (6.4) 42.8 (5.3) Calcium in ake, mg/day 1,040 (345) 1,125 (420) 1,119 (346) 1,109 (385) Vi amin D in ake, µg/day 10.2 (4.1) 10.9 (4.2) 10.3 (3.6) 10.4 (3.9) S-25(OH)D, nmol/L 67.6 (18.8) 65.8 (17.1) 69.5 (18.0) 65.5 (17.5) Cogni i e s a us, MMSE sco e (0–30)* 28.5 (1.7) 28.3 (1.4) 28.2 (1.4) 28.3 (1.5) SPPB, ange 10.6 (3–12) 10.7 (1–12) 10.9 (7–12) 10.8 (5–12) ADL sco e (6–36)†6.7 (1.6) 7.0 (2.2) 6.8 (1.9) 6.9 (1.8) IADL sco e (8–48)†9.8 (2.7) 10.7 (4.9) 9.9 (3.8) 10.3 (4.0) Di icul ies ou doo mobili y, n (%) 18 (17.6) 19 (18.6) 17 (16.5) 17 (16.7) No es: ADL=Ac i i ies o daily li ing; D−Ex−=placebo; D+Ex− =20µg i amin D daily; D−Ex+=placebo + exe cise; D−Ex+=20µg i amin D daily + exe cise; MMSE=Mini Men al S a e Examina ion; IADL=Ins umen al ac i i ies o daily li ing; SPPB=Sho physical pe o mance ba e y. *Highe sco e indica es be e unc ioning. †Lowe sco e indica es be e unc ioning. 1242 Jou nals o Ge on ology: MEDICAL SCIENCES, 2017, Vol. 72, No. 9 Exe cise-induced imp o emen s in lowe ex emi y unc ion, mobil- i y, and balance can educe he se e i y o alls (5,14), bu no consis - en ly (16,31). Ne e heless, o main ained bene i s i is c ucial ha he imp o emen s a e no los . P e iously i has been shown ha gains in balance induced s eng h and balance aining can be pa ly main ained by weekly low-in ensi y Tai Chi aining (32), and e en ligh in ensi y home-based weigh -bea ing exe cise aining may educe alls and inju- ious alls compa ed wi h con ols (17,33). In ou p e ious ollow-up o an exe cise in e en ion ial, physical pe o mance was pa ly main- ained in a combina ion aining g oup, while mos o he bene i s dis- appea ed in he pu e esis ance o balance aining g oups (18). E en 5yea s la e he combina ion aining g oup had signi ican ly less medi- cally a ended inju ious alls. Howe e , physical pe o mance was no measu ed, and i is no known whe he di e ences in muscle s eng h o balance s ill exis ed and accoun ed o he obse ed e ec (19). In his s udy, habi ual physical ac i i y es ima ed as daily s eps, o ime spen in mode a e physical ac i i y was consis en wi h he gene al olde Finnish popula ion (34). Habi ual physical ac i i y es ima ed by pedome e s and ques ionnai es (CHAMPS) declined o e ime in all g oups. Du ing he in e en ion, he exe cise s we e mo e physically ac i e (by abou he amoun o supe ised aining; 1–2h pe week) han he non-exe cise s, bu a e cessa ion o he aining, he exe cise s’ physical ac i i y e u ned o he le el o hei con ol coun e pa s. Vi amin D has been posi i ely associa ed wi h be e musculo- skele al heal h and physical unc ioning, and ewe ac u es (35,36). Howe e , he e is also e idence ha i amin D has no e ec , o may e en be ha m ul in e ms o alls o ac u es (10–12). Recen ly, Hansen e  al. (10) ound ha compa ed wi h placebo, high-dose cholecalci e ol did no ansla e o be e physical unc ioning o ewe alls. Simila ly, Bischo -Fe a i e al. (11) ound ha mon hly high-dose i amin D ea men did no imp o e physical unc ion- ing and was associa ed wi h inc eased isk o alls compa ed wi h 24,000 IU gi en mon hly (a dose co esponding o 800 IU/day). Only a ew s udies ha e e alua ed e ec s o bo h i amin D and exe cise on physical unc ioning (37), and none o hese s udies had a ollow-up a e he in e en ion, no epo ed alls. These esul s indica ed no e ec o i amin D supplemen a ion on muscle s eng h Table3. Baseline Values (SD) and Mean Changes (95% CI) O e Time in BMD and Physical Func ioning in Each S udy G oup (The Righ mos Column, pb, Shows he Signi icance o Di e ence in Changes Compa ed wi h D−Ex−) Ou come Absolu e Baseline Value, Mean (SD) Change a 24 Mon hs, % pa Compa ed wi h D−Ex− Change a 36 Mon hs, % Change a 48 Mon hs, % pb o he O e all G oup-Wise Di e ence Femo al neck BMD, g/cm2 D−Ex−0.872 (0.141) −1.4 (−2.1 o −0.7) −1.7 (−2.5 o −0.9) −2.6 (−3.5 o −1.8) D+Ex−0.821 (0.107) −0.9 (−1.7 o −0.1) .017 −1.2 (−2.1 o −0.4) −2.7 (−3.6 o −1.8) .34 D−Ex+0.848 (0.115) −1.1 (−1.8 o −0.4) .012 −1.9 (−2.7 o −1.1) −2.1 (−3.1 o −1.3) .93 D+Ex+0.875 (0.134) −1.1 (−1.8 o −0.5) .041 −2.4 (−3.1 o −1.6) −3.2 (−4.1 o −2.4) .35 No mal walking speed, m/s D−Ex−1.04 (0.21) −2.8 (−5.7 o 0.0) −4.2 (−7.3 o −1.1) −5.1 (−8.2 o −2.1) D+Ex−1.00 (0.21) −3.5 (−6.6 o −0.5) .72 −5.0 (−8.2 o −1.7 −4.9 (−8.2 o −1.5) .61 D−Ex+1.01 (0.19) −1.8 (−4.8 o 1.2) .007 −0.7 (−3.9 o 2.6) −0.5 (−3.7 o 2.8) .11 D+Ex+1.03 (0.20) −2.1 (−5.0 o 0.7) .46 −4.7 (−7.9 o −1.7) −3.9 (−7.0 o −0.8) .98 Chai s and ime, s D−Ex−12.6 (2.4) −0.8 (−4.2 o 2.7) −1.7 (−5.3 o 1.9) −0.7 (−4.6 o 3.3) D+Ex−12.6 (3.3) −4.5 (−8.0 o −0.9) .46 −3.3 (−6.9 o 0.4) −3.9 (−8.0 o 0.2) .58 D−Ex+12.5 (2.8) −7.4 (−11.0 o −3.8) .027 −5.9 (−9.6 o −2.3) −6.9 (−10.9 o −2.8) .95 D+Ex+12.4 (2.5) −7.7 (−11.2 o −4.3) .054 −5.5 (−9.1 o −1.9) −5.2 (−9.2 o −1.2) .19 TUG ime, s D−Ex−9.31 (2.07) −0.5 (−3.9 o 2.9) 4.6 (1.2 o 8.0) 8.7 (4.7 o 12.7) D+Ex−9.73 (6.44) 2.5 (−0.9 o 5.8) .011 7.2 (3.9 o 10.5) 7.4 (3.4 o 11.4) .21 D−Ex+8.93 (1.94) 1.9 (−1.7 o 5.5) .19 4.4 (0.8 o 8.0) 1.9 (−2.4 o 6.2) .002 D+Ex+8.89 (1.64) −1.4 (−4.9 o 2.1) .63 4.3 (0.7 o 7.8) 5.0 (0.8 o 9.2) .62 Muscle s eng h, N/kg D−Ex−23.1 (6.1) 1.4 (−3.2 o 6.1) 0.6 (−4.2 o5.5) 2.3 (−2.5 o 7.2) D+Ex−23.4 (7.7) 3.0 (−1.5 o 7.4) .10 3.4 (−1.4 o 8.3) 2.0 (−2.9 o 6.9) .68 D−Ex+23.6 (6.0) 16.7 (12.3 o 21.2) <.001 12.3 (7.7 o 16.9) 10.2 (5.7 o 14.9) .003 D+Ex+22.2 (6.6) 17.3 (12.7 o 21.9) <.001 12.7 (7.9 o 17.5) 12.4 (7.5 o 17.3) .007 Backwa ds walking, p opo ion o hose able o do 6.1 m, % A baseline A 24mon hs A 36mon hs A 48mon hs D−Ex−42.2 50.0 48.3 48.1 D+Ex−30.4 40.5 .68 43.9 45.9 .34 D−Ex+45.1 72.7 .001 65.9 61.7 .32 D+Ex+51.0 78.0 .026 71.6 73.8 .56 No es: D−Ex−=placebo; D+Ex−=20µg i amin D daily; D−Ex+=placebo + exe cise; D+Ex+=20µg i amin D daily + exe cise. aBased on analysis o co a iance (ANCOVA). bp alue o he o e all g oup-wise di e ence om he end o in e en ion (24mon hs) o 48mon hs. Based on Gene alized Linea Mixed Models (GLMM) o Linea Mixed Models (LMM). Jou nals o Ge on ology: MEDICAL SCIENCES, 2017, Vol. 72, No. 9 1243 o unc ion ollowing exe cise. This is in acco dance wi h he DEX ial, which showed ha i amin D in e en ion wi h o wi hou exe - cise had no e ec on physical unc ioning o alls compa ed wi h he e e ence g oup du ing he in e en ion. Howe e , du ing ollow-up D+Ex− had 55% less medically a ended inju ious alls and nea ly 40% less medically a ended inju ed alle s han he e e ence g oup. One explana ion could be ha i amin D con e ed a delayed p e- en i e e ec on se e e alls h ough an unknown mechanism. The e was no co esponding e ec on physical unc ioning, which declined simila ly in bo h non-exe cise g oups wi h o wi hou i amin D.Fu he mo e, hough he achie ed bene i in physical unc ioning was pa ly main ained a e cessa ion o aining, i declined in bo h exe cise g oups, and exe cise s wi h i amin D did no di e om exe cise s wi hou i amin D.Also, S-25OHD conce a ions e u ned o baseline le els in bo h supplemen ed g oups wi h no signi ican di e ence compa ed wi h he e e ence g oup. These indings do no suppo he delayed bene i o i amin D concen a ions on alls. A majo s eng h o his s udy is he long 2-yea ollow-up a e he 2-yea in e en ion. The d op-ou a e was low; only 15 women (4%) o he o iginal coho who comple ed he in e en ion we e no willing o con inue in he ollow-up, and i e mo e discon inued a e he i s ollow-up yea mainly due o declined heal h s a us. Physical unc ioning was objec i ely measu ed, and alls we e assessed wi h p ospec i e and con olled mon hly all dia ies, ee o ecall bias, o e he en i e 48mon hs. Medical eco ds we e sc u inized o con- i ming sel - epo ed medically a ended inju ious alls. Vi amin D concen a ions we e also assessed annually du ing he ollow-up in win e when concen a ions a e expec ed o be a hei lowes le els. A limi a ion was ha de ailed in o ma ion on pa icipan s’ physical ac i i y in he ou s udy g oups was no a ailable du ing he ollow- up. Ou s udy did no include olde men o ins i u ionalized pe sons, and he esul s can only be gene alized o olde home-dwelling women. Also, he s udy was powe ed o alls, and esul s ega ding inju ious alls o alle s should be in e p e ed cau iously, hough a e consis - en wi h cu en li e a u e (14,19). Vi amin D supplemen a ion may be mo e e ec i e among people wi h i amin D insu iciency. In his s udy, despi e he decline in i amin D concen a ions a e s opping supplemen a ion, pa icipan s s ill had adequa e i amin D s a us (38). In conclusion, exe cise-induced bene i s in physical unc ioning pa ly emained 2yea s a e cessa ion o supe ised exe cise ain- ing. Al hough he e was no di e ence in he a e o all alls, o me exe cise g oups had less medically a ended inju ed alle s compa ed wi h e e en s e en 2yea s a e he in e en ion. Vi amin D wi hou exe cise was also associa ed wi h less inju ious alls wi h no co e- sponding di e ence in physical unc ioning. In he absence o a s uc u ed exe cise aining p og am, aining e ec s a e likely o educe wi h ime, as do habi ual physical ac i i y. T aining p og ams ocusing on balance and esis ance aining and adequa e i amin D in ake should be an in eg al pa o daily li e in olde adul s o p e en ing inju ious alls. 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