Osteoporosis in treated adult coeliac disease

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1 71 Osteoporosis in treted dult coelic disese Gut 1995; 36: X A McFrlne, A K Bhll, D E Reeves, L M Morgn, D A F Robertson Deprtent of Gstroenterology nd Wolfson Centre Clinicl Reserch Unit, Royl United Hospitl, Bth X A McFrlne D A F Robertson D E Reeves L M Morgn Royl Ntionl Hospitl for Rheutic Diseses, Bth A K Bhll Correspondence to: Dr D A F Robertson, Deprtent of Gstroenterology, Royl United Hospitl, Bth BA1 3NG. Accepted for publiction 9 Septeber 1994 Abstrct Forty five woen nd 1 en with coelic disese dignosed in dult life, who were lredy on gluten free diet, hd seril bone inerl density esureents t the lubr spine nd feorl neck over 12 onths. Osteoporosis, defined s bone inerl density (BMD) ',2 SD below the norl pek bone ss ws found in 5 / of le nd 47/ of fele coelic ptients. Ptients with BMD -2 SD below ge nd sex tched norl subjects, hd significntly lower body ss index (21.3 kg.-2 copred with 25'2 kg.-2, p<2 Wilcoxon rnk su test) nd lower verge dily clciu intke (86 g/dy copred with 154 g/dy, p<5 Wilcoxon rnk su test) thn ptients with norl bone inerl density. In postenopusl woen with coelic disese there ws strong correltion between the ge t enopuse nd BMD t both the lubr spine (r=.681, p<-1, Spern's rnk correltion) nd feorl neck (r=.632, p<.1). No overll loss of bone ws shown over the 12 onths of follow up, nd reltive to the reference popultion there ws significnt iproveent in BMD t the lubr spine in woen (p<.25, pired t test) nd t the feorl neck in en (p<o5, pired t test). There ws significnt negtive correltion between the nnul percentge chnge in BMD t the lubr spine nd the durtion of gluten free diet (r= -.429, p<-1, Spern's rnk correltion), with the lrgest gin in BMD in ptients with ost recently dignosed coelic disese. Osteoporosis ws shown in 47%/o of ptients with treted dult coelic disese. Recognised risk fctors for osteoporosis in the generl popultion including low body ss index, dietry clciu intke, nd erly enopuse re prticulrly iportnt in coelic disese. Tretent of coelic disese with gluten free diet probbly protects ginst further bone loss, nd in the erly stges is ssocited with gin in bone inerl density. (Gut 1995; 36: ) Keywords: coelic disese, osteoporosis, gluten free diet. Osteolci, bone pin, pthologicl frctures, nd osteoporosis cn occur s presenting fetures of coelic disese,'-6 prticulrly where there is florid lbsorption leding to vitin D deficiency. Ptients with coelic disese now present ore often in dult life with ild nutritionl deficiencies such s iron or folic cid deficiency,7 8 nd recent reports suggest tht reduced bone inerl density is coon t presenttion.9 1 We therefore studied the prevlence of osteoporosis in syptotic dults with treted coelic disese, nd utilised seril bone inerl density esureents to detect ny chnge in bone inerl density over 12 onths. Subjects Fifty five ptients (45 woen nd 1 en) with coelic disese dignosed in dult life (- 18 yers old t the tie of dignosis) nd lredy estblished on gluten free diet were recruited to the study fro the gstroenterology outptients deprtent t the Royl United Hospitl, Bth between 24 Septeber 1991 nd 21 October Coelic disese ws defined s sll intestinl lbsorption ssocited with the chrcteristic sll intestinl ucosl lesion together with clinicl nd histologicl iproveent on gluten free diet. 1 ' The verge ge of the en ws 5.2 yers (rnge yers) nd tht of the woen ws 51-3 yers (rnge yers). With regrd to the woen, the verge ge t enrche ws 14 yers (rnge 1-2 yers; five ptients hd enrche t ge 16 yers or older). Five woen (no overlp with the delyed enrche group) hd history of n episode of preenopusl enorrhoe of t lest six onths. Sixteen woen were preenopusl, 11 were perienopusl, nd 18 were postenopusl (verge ge t enopuse ws 46.3 yers, rnge 34 to 57 yers, eight ptients hd hd the enopuse t ge less thn 45 yers). Seven ptients hd been previously treted with orl vitin D preprtions, six hd been on glucocorticoids in the pst, nd five of the woen were either on, or hd previously been on, horone replceent therpy for ore thn 12 onths. Fourteen ptients (two en) hd history of serious frcture (rib, clvicle, nkle, forer, sternu, scphoid). The verge weight of the woen ws 61-7 kg (rnge kg) nd tht of the en ws 74.5 kg (rnge kg). The verge height of the woen ws 1.62 (rnge 1A ) nd tht of the en ws 1.74 (rnge ). The en ties spent on gluten free diet were 4.25 yers (rnge -4-1 yers) in en nd 9.2 yers (rnge.3-4 yers) in woen. Methods A dietry ssessent ws perfored, bsed on 1 dy weighed record'2 of ll food consued, nd the dietry intkes of clciu, Gut: first published s /gut on 1 My Downloded fro on 15 My 218 by guest. Protected by copyright.

2 Osteoporosis in treted dult coelic disese E I Figure 1: Rnked T scores (nuber of SDs by which individul ptients bone inerl density differs fro pek bone ss of norl sex tched dults) in 55 ptients with dult coelic disese. protein, nd energy were clculted fro stndrd food coposition tbles. 3 The body ss index (BMI) ws clculted (BMI=weight/(height2)). The presence or bsence of other recognised risk fctors for osteoporosis14'6 (soking, level of physicl ctivity, iobilistion, presence of dibetes ellitus or thyroid disese, nd drugs ingested) ws deterined using stndrd questionnire. On entry to the study ll ptients hd pls clciu, phosphte, totl lkline phosphtse, 25 hydroxyvitin D, nd intct prthyroid horone (zpth) s well s red cell folte nd 24 hour urinry clciu esured. Bone inerl density (BMD) ws esured on entry to the study, nd gin t six nd 12 onths fter entry to the study, t the lubr spine (L1-4) nd t the feorl neck using n Hologic QDR 1 dul energy x ry bone densitoeter. The precision of the densitoeter, expressed s the longitudinl coefficient of vrition of dily lubr spine 'phnto' esureents, ws 5% over the period of the study. BMD ws expressed in bsolute ters (g.c-2) nd the bsolute BMD for ech ptient ws then expressed s Z score nd T score (defined below) when copred respectively with the en BMD of n ge nd sex tched norl popultion nd with the pek BMD (BMD t ge 3 yers) of sex tched norl popultion. For both the T score nd the Z score the reference popultion dt used were those provided by the Aericn nufcturer nd hve been vlidted within our clinicl esureent lbortory ginst the locl popultion. T score= Z score= ptient BMD-en pek BMD of sex tched norls SD of pek BMD of sex tched norls ptient BMD-en BMD of ge nd sex tched norls SD of BMD of ge nd sex tched norls There is close reltionship between low BMD nd frcture risk.16 Soe uthors consider T score <-2 s sufficient to dignosis osteoporosis, wheres others define n isolted reduction of T score s osteopeni, nd require in ddition, the presence of frgility frcture to dignose osteoporosis The Z score provides n index of the reltive risk of frcture copred with tht of n individul with Z score of. A bone inerl density Z score of -1 t the feorl neck suggests 2.6 fold incresed risk of frcture over the ptient's lifetie, nd Z score of -2 iplies 5.2 fold incresed risk of frcture.19 The Z score is used in this study for the purpose of nlysis of risk fctors for reduced bone ss, s the Z score eliintes the effects of ge nd sex by considering ech ptient's BMD in reltion to the ge nd sex tched norl popultion. The chnge in BMD (g.c-2.y 1) is expressed s the bsolute chnge per yer (bsolute BMD fter 12 onths-bsolute BMD on entry) nd s n nnul percentge chnge: Annul % chnge= 711 1x (BMD fter 12 onths-bmd on entry) BMD on entry Any chnge in BMD in reltion to the ge nd sex tched norl popultion is detected s chnge in the Z score: Chnge=Z score fter 12 onths-z score on entry to the study. All 55 ptients were followed for the full 12 onths of the study. Two of the ptients with the lowest initil Z scores underwent ilic crest bone biopsy fter tetrcycline double lbelling technique.2 The sttisticl significnce of differences between unpired dt ws clculted using the Wilcoxon rnk su test. The correltion coefficient ws clculted using Spern's rnk correltion. Ninety five per cent confidence intervls (95% CI) for the difference between pired dt were clculted using Student's t distribution nd significnce ws deterined by pired t test. Results Twenty one woen (47 /O) nd five (5 /o) en hd T score <-2 t either the lubr spine or feorl neck, or t both sites (nine woen nd two en hd T scores <-2 t both the lubr spine nd feorl neck). Eight of the ptients (six woen) with T score <-2 hd pst history of iportnt bone frcture. Rnked T scores t lubr spine nd feorl neck re shown in Figure 1. Eleven (2%) ptients (nine woen, two en) hd Z score <-2 t either the lubr spine or feorl neck, or both, four of who (ll fele) hd Z score <-2 t both the lubr spine nd feorl neck. Thirteen (24%) ptients (1 woen, three en) hd -2-Z score <-1. Thirty one (56%) ptients (26 woen, five en) hd Z score - -1 t both the lubr spine nd feorl neck. Coprisons between these three groups of ptients re shown in the Tble. All ptients with Z score <-2 lso hd T score <-2. There ws close correltion between the BMD (g.c-2) t the lubr spine nd feorl neck (en: r=+.782, p< 2, Gut: first published s /gut on 1 My Downloded fro on 15 My 218 by guest. Protected by copyright.

3 712 McFrlne, Bhll, Reeves, Morgn, Robertson Men vlues of biocheicl, dietry, nd nthropoetric results. Z score rnge Z<-2-2sZ<- I (n= 1 1) (n= 13) Woen/en 9/2 1/3 Age (y) Yers on gluten free diet % chnge in lubr spine BMD/y * % chnge in feorl neck BMD/y + 2-8** ** Body ss index (kg.-2) 21-3** 23-1 Intke of clciu (g/d) (% RNI) 86 (123)* 115 (158) ] Intke of energy (kj/d) (%RNI) 7879 (94) 912 (112) EB i15 (98) Intke of protein (g/d) (% RNI) 7 (147) 79 (169) Seru clciu (ol/l) ( ) Seru phosphte (oli) (-8-1-5) Alkline phosphtse (IU/1) (21-92) Red cell folte (g.ol/) ( ) PTH (pol/l) (<4.3)* hydroxyvitin D (nolal) (1-1) h urine clciu (ol/24 h) ( ) Heoglobin (g/l) Men corpusculr volue (fl) (75-95) Significnt difference between ptients with reduced bone inerl density (BMD) (Z -2cZ<- 1) nd ptients with norl bone inerl density (Z-- 1) is denoted by n (*=p<.5, **=p<-2, ***=p<1, Wilcoxon rnk su test). RNI=reference nutrient intke; PTH=prthyroid horone. c;- E )._ C. EWJ 1.4 r _- 1. F_ t both lubr spine nd feorl neck (Tble), ptients with Z score <-2 t one or woen: r=+.74, p< 1). The lbmd t both sites hd significntly lower verge dily the lubr spine (L1-4) in woen is shown in clciu intke (86 g/d copred with 154 Figure 2. g/d, p< 5) nd lower BMI (21.3 kg.-2 Seril BMD esureents showed n ver- copred with 25.2 kg.-2, p<.2). There ge nnul chnge t the lubr spine in en ws no significnt difference (p> 1) of +.21 g.c-2.y-1 (95% CI= -.9, between these groups in the length of tie on +.55 g.c-2.y- 1) equivlent to % gluten free diet, ge t dignosis of coelic dischnge, nd in woen of +O2 3 (95O/% ese, ny of the blood or urine biocheicl CI=--4, + 1 g.c-2.y- 1) equivlent indices, or of other risk fctors for osteoporosis to +.25% chnge. The verge nnul (soking, level of physicl ctivity, use of chnge t the feorl neck in en ws +.16 glucocorticoids, ge t enrche in woen). g.c 2*y 1 (95% CI=-7, +-39 There ws no significnt difference in Z g.c-2.y-1) equivlent to 2.41% chnge, scores in preenopusl, perienopusl, or -- - intke for nutrient tht would be dequte for 5% of the norl popultion). The United Kingdo reference nutrient intke (RNI) for.4 2X Pek bone ss nd the subsequent decline in Age (y) bone ss re both deterined by genetic nd Figure 2: Lubr spine bone inerl density (BMD) in 45 woen with coelic disese. cquired fctors. Acquired or environentl Men (2 SD) re derivedfro the ge nd sex tched norl popultion. fctors tht y contribute to low bone ss (n=31) clciu is 7 g/dy for dults.21 The en pls concentrtions of cl- 26/5 ciu, phosphte, totl lkline phosphtse, hydroxyvitin D, red cell folte, nd hour urine clciu were in the norl rnge (Tble), however, soe ptients hd inor 154 (151) reduction of clciu or phosphte, or slight 75 (158) increse in totl lkline phosphtse or ipth No ptient hd subnorl 25 hydroxyvit in D vlue, but levels ner the lower liit of.96 the norl rnge were detected in few. Bone biopsies showed severe osteoporosis, with 39 rked trbeculr thinning, but there ws no 135 9s1 increse in osteoid thickness or ny other histologicl evidence of osteolci in either <-2 or of the ptients who hd this investigtion. sterisk Copred with ptients with Z score -1 nd in woen of +.3 (95% CI= -.5, postenopusl woen t either the lubr +12 g.c-2.y-1) equivlent to % spine or feorl neck. In postenopusl chnge. feles, however, the ge t enopuse ws The chnge in Z score t the lubr spine significntly correlted with the lubr spine ws +-26 (95% CI=- 3, +.56) in en Z score (r=+.681, p< 1) nd with the nd +.7 (95% CI=+.1, +.14, p <.25 feorl neck Z score (r= +.632, p< 1, Fig pired t test) in woen. The chnge iin the Z 3). Ptients with history of bone frcture hd score t the feorl neck ws +25 (95% no significnt difference in Z score when cotest) in pred with ptients with no history of frcture. CI=+4, +A46, p<5 pired t en nd +.8 (95% CI=-.2, +l. 18) in There ws no significnt correltion woen. between the durtion of the GFD nd the The verge intkes of clciu, eneirgy, nd feorl or lubr Z score, but there ws protein were bove the reference nutrient negtive correltion between the nnul per- the centge chnge in the BMD t the lubr intke for ech nutrient (2 SDs bove spine (woen: r=-.45, p< 1, en: r=-.79, p< 5, Fig 4). Mny of the ost recently dignosed ptients showed significnt iproveent in BMD over the 12 onths of the study. The four osteoporotic woen --se. -- who lost bone ore rpidly thn - 2% per *, +2 SD nnu t the lubr spine hd ll undergone the enopuse t ge 4 yers or less. Men Discussion *~-. * Bone ss increses throughout childhood nd dolescence22 23 to the pek bone ss t _ * bout the third decde with slow decline -2SD therefter in en nd preenopusl woen24 nd rpid loss of bone ss in I I I woen in the erly postenopusl yers.25 Gut: first published s /gut on 1 My Downloded fro on 15 My 218 by guest. Protected by copyright.

4 Osteoporosis in treted dult coelic disese 713 ) cn N C.) ) -F E ) U- lb 2-1 _ U_ -2 _ M -1 _---- o--* n -4 I Age t enopuse (y) Figure 3: Feorl neck Z score v ge t enopuse in postenopusl woen. There is significnt correltion between bone inerl density nd ge t enopuse (n= 18, r=-632, p<.1, Spern's rnk correltion). 1 ṃ )c., cn. E ) Cr C-_ 1 P _* : b * _ - nd frcture risk include dietry clciu intke, the level of physicl ctivity, nd in woen, oestrogen deprivtion.25 In coelic disese the villous trophy nd lbsorption re thought to occur t the tie of first exposure to gluten - tht is, t wening. Ptients in this study were ll dignosed in dult life, fter the ge t which the xiu rte of gin of bone ss occurs,22 nd possible explntion for the low BMD seen is tht they filed to rech n optil pek bone ss in erly dult life.9 Forty seven per cent of ptients in this study hd osteoporosis defined s bone inerl density 2 SD or ore below the en sex tched pek bone ss. Reduced bone inerl density occurred in ll ge rnges, in both sexes, nd in ny cses ws quite profound. Twenty four per cent of ptients hd - 2<Z score < - 1, nd therefore t lest twofold increse in lifetie frcture risk, nd 2% of ptients hd Z score <-2, nd therefore t lest fivefold increse in lifetie frcture risk. Postenopusl ptients with coelic disese who hd n erly enopuse were Fo Men (n = 1) * Woen (n = 45) Durtion of gluten free diet (y) Figure 4: There is negtive correltion between the rte of chnge (BMD) (% chnge peryer) in reltion to durtion on gluten free r= , p< 1, Spern's rnk correltion). prticulrly susceptible to low bone density, nd to rpid loss of bone ss (>- 2/o/yer) wheres woen with n onset of enopuse fter the ge of 5 yers seeed to be reltively protected fro low bone density, nd did not suffer rpid bone loss. It is cler tht the protective effect of oestrogens on bone ss reins iportnt in woen with coelic disese. There ws predoinnce of feles in the study (4.5: 1) which is higher thn tht reported for coelic disese in generl (1:1 to 2: 1).27 This bis in the study popultion is probbly explined by the dending nture of the study which discourged en in full tie eployent fro tking prt. However, the gnitude of the bnorlities shown sees to be of the se order in en nd woen. There ws high proportion of perienopusl nd postenopusl woen, but it is unlikely tht ll of the reduction in BMD is due to enopusl loss. Preenopusl woen hd lower (not significnt, p>.1) bsolute BMD thn enopusl woen, nd soe of the ptients with the lowest Z scores were preenopusl. In soe individuls, clciu intke ws rginl. Bred nd cerels contribute pproxitely 25% of dietry clciu,28 nd unless the individul hs n dequte intke of diry products, gluten free diet y not provide dequte dietry clciu. In ddition, the United Kingdo recoended nutrient intkes for clciu y not be dequte for dults with treted coelic disese s there is evidence for continued lbsorption of clciu despite gluten free diet.29 The correltion of bone ss with dietry clciu intke deonstrted in this study provides evidence to support recoendtion to increse clciu intkes in ptients with coelic disese to levels recoended for dults by the Aericn Ntionl Institutes of Helth3 (1 g/d for preenopusl woen nd 15 g/d for post enopusl woen not treted with oestrogen). There were no biocheicl preters which predicted osteoporosis in this study, but the cler ssocition with BMI is helpful, nd is consistent with the recognised ssocition in the generl popultion We hve shown n overll increse in the BMD Z score over the 12 onths of the study t the lubr spine in woen nd feorl neck in en which is surprising nd requires explntion. The lrgest gins in Z scores nd bsolute BMD were detected in the ost recently dignosed ptients suggesting tht * there is reversible coponent to the osteopeni present t the tie of dignosis of =~~~---- coelic disese, nd tht this cn be iproved *~ by tretent with gluten free diet. The rpid loss of bone in woen who hd the enopuse t ge less thn 45 yers ephsises the continuing skeletl deinerlistion nd need for ctive tretent in this group. of bone inerl density diet (n=55, Screening for osteoporosis by esuring bone inerl density in dult coelic disese sees to be worthwhile with high yield, ny ptients hving reduced bone inerl density. Gut: first published s /gut on 1 My Downloded fro on 15 My 218 by guest. Protected by copyright.

5 714 McFrlne, Bhll, Reeves, Morgn, Robertson This hs therpeutic potentil, nd hving identified t risk individuls the need for dherence to gluten free diet cn be ephsised nd dvice regrding tretent cn be offered, which y include incresing dietry clciu intke or considering horone replceent tretent in postenopusl woen, in prticulr those with n erly enopuse. This work ws supported by grnt fro the Coelic Trust. 1 Juergens JL, Scholz DA, Wollger EE. Severe osteolci ssocited with occult stetorrhoe due to non tropicl sprue. Report of 5 cses. Arch Intern Med 1956; 98: Hjjr ET, Vincenti F, Slti CS. Gluten induced enteropthy: osteolci s principl nifesttion. Arch Intern Med 1979; 131: De Boer WA, Tytgt GN. A ptient with osteolci s single presenting sypto of gluten sensitive enteropthy. Jf Intern Med 1992; 232: Melvin K, Hepner G, Bordier P, Nele G, Joplin G. Clciu etbolis nd bone pthology in dult coelic disese. Q Jr Med 197; 39: Bode S, Hssger C, Gudnd-Hoyer E, Christinsen C. 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