‘apa ontrr” a Caicium-enriched Foods and Bone Mass Growth in Prepubertal Girls: A Randomized, Double-blind, Placebo-controlled Trial pont Jean-Philippe Bonjour," Anne-Lise Carrie,’ Serge Ferrari," Helene Ciavien,* Danie! Slosman,* Gerald Twoirtt/»" ‘and Rene Rizzoli" “Division of Bone Diseases, formerly Divison af Clinical Pathophysiology, WHO Collaborating Center for Onteoporotis and Bone Disease, Department of Inernal Medicine, ‘Division of Nuclear Medicine, Department of Radiology, !Divsion of Biology of Growth and Reproduction, Department of Pediatris, University Hospi, Geneva; and Neste Research Coner, Vaud, Switzerand. Abstract ‘igh calclum intake during childhood has been suggested to increase bone mass accrual, potentially resulting in a seater peak bone mass. Whether the effects of calcium sup- plementation on bone mass accrual vary from one skeletal region to another, and to what extent the level of spontaneous calcium intake may affect the magnitude of the respon hhas, however, not yet been clearly established. In a double- blind, placebo-controlled study, 149 healthy prepubertal girls aged 7.90.1 yr (mean=SEM) were either allocated {0 food products containing 850 mg of calcium (Ca-suppl.) oF not (placebo) on a daily basis for 1 yx. Areal bone miner density (BMD), bone mineral content (BMC), and bone size were determined at six sites by dual-energy x-ray absorpti- ometry. The difference in BMD gain between calcium-sup- plemented (Ca-suppl.) and placebo was greater at radial (metaphysis and diaphysis) and femoral (neck, trochanter and diaphyses) sites (7-12 mgjem* per yr) than in the lum- bar spine (2 mglem? per yr). The difference in BMD gains between Ca-suppl. and placebo was greatest in girls with a spontaneous calcium intake below the median of 880 mg/d. ‘The increase in mean BMD of the 6 sites in the low-calcinm consumers was accompanied by increased gains in mean BMC, bone size, and statural height. These results suggest a posse positive effect of calcium supplementation on skel- tal growth at that age. In conclusion, calcium-enriched {foods significantly increased bone mass accrual in prepu- bertal girs, with a preferential effect in the appendicular skeleton, and greater benefit at lower spontaneous calciu intake. (J. Clin, Invest. 1997. 99:1287~1294,) Key words. bone growth « calcium-enriched foods + calcium intake « ‘bone mineral density » statural height Introduction The bone mass accrual occurring during childhood and adoles cence is a major determinant of peak bone mass, and thereby Of the risk of osteoporotic fractures occurring in advanced age ‘Adres corespondence to Pro, Jean-Philippe Bonjour, M.D, Divi- sion of Bone Diseases, formeriy Division of Cincal Pathophysiology. Department of intemal Medicine, University Hospital CHV, Geneva 14, Switzerland. Phone: 41 22 729880: FAX 4-22-3299, Received for publication 23 July 1996 and accepted in revised form Pansany 1997 J.Cin avert ‘© The American Soiey for Cinta vestigation, ne n2i-97389708/128708 $2.00 Volume 99, Number 6, Marsh 1997, s1-% Calum Envohed Foods and Bone Mace Grom n Prepubertal ies (1-3). At the end of the growth period, a large variance in bone mineral density (BMD) and content (BMC), in either the axial or the appendicular skeleton, is observed both in healthy females and males (4-8). Many genetic and environ- mental factors have been suggested to influence bone mast a6 cumolation during this period (9-15). Its usually accepted that increasing calcium intake during ctldnood and adolescence can promote a greater inerease in bone mass, and thereby a higher peak bone mass (16-21). An- alyzing the relationship between hone mass and spontaneous calcium intake, however, indicates that not all studies (22-27) have found a positive correlation between these two variables. ‘On a few prospective randomized double-blind interven tion trials have examined the effects of calcium supplements in children and adolescents (12. 28-30). Although the results of these studies suggest that calcium supplementation can pos tively influence bone mass gain inthis population, the magni ude of the effects appears to be ul ferent it the axial and 3p pendicular skeleton a8 wel as at the metaphyseal or ciapiyseal levels (12, 28-30), Significantly, the mean bone mass gain in re sponse {© caleium supplements has been found 10 be only modest at the lumbar spine and proximal femur, 0 major sites of subsequent oeteoporotic fracture (12,28, 30). The dif culty of consistently demonstrating a significant effect of cal ium in the various parts of the skeleton may be related to dif: ferences in the osteodensitometric method used (for example, {dual photon absorptiometry [DPA] [12, 28] versus the mot precise dusleenergy xray absorptiometry [DXA] {20}, to di ferences in the stage of pubertal maturation atthe time of ca cium supplementation (28, 29), or oeilferences in the level of spontaneous calcum intake, as observed in adult subjects (31) ‘We conducted a randomized, double-blind, placebo-con: trolled study in 2 homogenous cohort of prepubertal girls 0 assess the effects of calcium supplementation on bose mass gain at various sites of the skeleton. Inthe context ofa large scale program for nutritional prevention curing culdhood of ‘osteoporosis, as well as to anticipate the risk of low fong-term compliance to pharmaceutical caleum supplements a a popu: Jation level, ve administered palatable calcium-enriched foods commonly taken at breakfast of as snacks to children living it an affluent western society Methods ‘Subjects an study design. Tae protocol was approved by the Ethical |. Abbreviaions wed in dhs paper: BMAD, bone mineral apparent density, BMC, bone mineral sonent; BML, Done mineral Cesiy (Ca-suppl. calcium supplemented; DXA, dual energy ray absorp cometey: ROL region of interest 1 GOERS, cant?tao Geneva formed content wat oie rom he pens thd chien, Mealy pepeberal cscs gl ih mead ae (ty at rans yg Boca) were ted te tbe ac Hath Yous Sarvs othe nea cones m0 pero fom Apt Noes, 98 Te towing excuse. “i'wete apie no pre spprova ato mente es na the el or rate tan the 7 pore according to Geneva fer oes, pretence of pial sigs of puber, croc diese, fprreincial dane opebeo hen saabagton ong tor soqured bone dete or ope ne of meron 19 ib ject earned nino gaps el esr othe {De Gfeponanena aio ake ovoid an even dbon {ie lowe ohghcacum conser. © at f 90 gl instal ptt for ec rp For eaknown reason rp. rat aur 40 of corolineat eager (3 m8) et he tov eprinel pty Sef scl toes podacien of At spl propre lode ald ne be pred bajo 9 gen Enc i0 on of te 19 one pcs wre dle ed Terie of earument peed to ie group faving ow he trate ropes te ange fi pase ft ay, Th pains Se deren oe aunber of gece eno ewe te troupe tation tet cabo oe el). Atte ofthe iereaton perio, apenng of he nl code reveal hatte ier dropout me in th fin ew the clin sta Denied erp Clon oplnen (Copp. Cai to lk xt was sd nity ct el prs nn), Does at Ses powdered dang chose, hole bara opus The ‘Siocon (mpting) of ctcrenhed paso fod frodura aso fll chose S16 3 are! eben, Size isbscus i Souja 36: woe Se ing cove 50 vt choclate bar, 29. yor 78 we oe cep oon con (ageing wee oe Slt cate 28 5c ay TM Sap trues 73 21 powdered ning ccs, 27 we 26 cor tte br 9 yogurt 106 The conejo ser Content Leen) wet: hosts aes T8519 cara fakes, 86 18 bau, 17 et le, 120 119 pn Sere ding sie tv Hy choclate a 290 2 9 fr 18 160 Ths fs ad prenly beset pa Sb ad longer tlre i's por nly lang 4 al nom of alse gi On avrige the intake fo elu caved prod pr dy povided lean suplenrta tout mg. un cna (ioe) grup me gran sly to one prods intr fener, roti id a mite ote, bt ‘riot alde else The mica eens between he clin Shed ana pes toch wa noe serge Pen Oz gp 03g exoehyts (sync), 09 Over the nue imran pti wh cach bjt eee Eset of 36 fied proaca (1st every mx Paeats woe sted oe comumpton ofthe wo food prods every yt lar fsa foes for batt or sanche.Compnce was fected Yt porns and vers eagh epi prone asd mere Oy ined detan Gt laven) Ca cuaminatns mere omdaed by pecan (6 Tat othe Sexinny athe tf th ‘howenton por wth eng of svopomete rae nd ‘sme fuera sate Catia nts onerment. An stints oh pontoons ct ciumistat rig trenton prod vs cba by eg theres of hes eabency qucstonmaes made st 2 sass Hearrnentof ons wna Bo mre once OM) an areal bone mera deat (BMD. pr) a estas of fone tas wre determined he hoping ade endo te ody ut cvey ny sian (OH) wins owe {QbK Zo inten Wate, Ma. Sa hele sts were sessed: dal meaphysohe aos daphy ofthe ais ei ste expen) theta pon td oss oe dE ion of the radial shale according 1 the manufacturer's software), femoral neck, femoral trochanter, femoral diaphysis, and L2-L4 ver tba ateroryonteriv view aa previously reported (8,32). The co ‘ficient of variation of repeated measurements a hese sits (as de termined in young healthy adults) varied between 0 and 1.6% fom MD, and U3 to 50% for HMC and bone area, The posse i- ence of the caleium-enrched foods on Skeletal size was assessed by "snaiyzing the changes in scanned bone area (mm ofthe ix egions of interest desenbed above. At the level of the femoral neck, the height (1, the cimenson parallel tothe hip as) of the region ois terest (ROD rectangular box was maintained coastant from one ex mination tothe other. Only the width (..,the dimension perpende "alr co the hip ans) was agjsted to the growth of the bone scan 8 Similar proportion af oft tne om cach re ofthe femoral neck. or the trochanter, the ROI box was maintained constant. In aaition, at the level af L2-L4, the heigh (mu) of the region of interest was ce Upper ee of L2 multiplied by a conversion factor (1 line = LOIS rm). Am estimate of the mean vertebral width was derived by divid- ig the area by the eugpt of L2-L At the level of the mustemoral shat the extemal ameter of the diaphysis was estimated by ans tional analysis. A region of interest was dined at baseline a having 2 constant length (lines x 1.003 ~ 45.14 mm) starting fom the ridemoralsbaft (halfway between the greater trochanter and the Upper edge ofthe patella). To assess to what extent calsiam induced increase areal BMD would be de o an effect on bone size 2 om ated to volumetric mineral density, an estimate of hi ater vanable {one mineral spptret density, BMAD) wae clelated a previously eseribed for lumbar spine, midradius, and femoral neck (33-3). Follow-up afer reamment discontinuation. Within the active teat men cohort 00 gil (42 fom he place wa 3 fo he eal supplemented group) underwent a third examination LE ater the nd of the interveation phase, Bone and anthropometc venables ‘were measured and caletum Nake, as aSsesseu OY a fOUFEAequensy |uestionnaire, wa also recorded. ‘Expression of he resus and sisal analyz. Asthough the in- tervention lasted 48 WE, the changes in the various anthvopometic snd osteodensitome:rc variables are exprested in Unity without correction forthe eiference between! yr and 18 wk, The differences In the anthropometric and oneodensitometric variables inthe cl cium enriched and placebo groups were analyoed both in erms of ac Tie-tratment coat, (which incladed the cabject who someumed the stdy Toods during 48 wk) and an intention toiect cohort (a ‘punting forall subjects who entered the study and had measure monte codons at 48k). Done was ins weve dicnined sepa foreach skeletal ste; the average BMD changes atthe st studied sites were alo calculated, Results were exprsted as either absolute (@em’ per yr) or eta terms (yr). Mean change tn the bone rea ofthe six regions of interest was aso computed fo asses potential ‘changes in bone ie. Al els are given as mean:=SEM. The ller- ences beiween the Ca-suppl. and placsbo groupe were evalosted us ing a wovtiled Staden’s best for unpaired values fn adction, for the subjects on whom three measurements (at 0.48 and 96 wk) were avalable, an ANOVA text for repeated measures was tplied (0 evaluate whether any cakeium effect observed at the end ofthe inte tinuaion Finally, 2 comparative analysis Of the effet of Cirsupo. 08 areal (BMD) vs. volumetric bone mineral density (MAD) in ada ‘and femoral diaphyiawas mae by vlan se changes 22 S00 tom the mean values recorded at baseline inthe intetion-to-teat cohort (r= 144), Results Cohorts studied and compliance. OL the 149 prepubertal girls initially enrotled, 144 had their BMD measured at baseline and 448 wk later (intention-to-treat eshor:). Among the ive subjectsTable |, Baseline Characteristics of Pepubertal Girls Assigned t2 Consume Foods Enriched in Calcium (Intentionto-Treat No. ofsubests pers) Height (em) Wereht (kg) agi metapnyis BMD (gem) 25925 Rall diaphysis BMD (gem?) 623 Femoral nck BMD (alo) ones. Femoral trochanter BMD (y/em*) 51026 Femoral diphysis BMD (g/en") w2p=10 1028210 Lanier spine (2-14)DMD Gent) GET TA {All values are given a mean=SEM, Areal BMD valves are in mcm? None ofthe diferenees between means recorded inthe slcium-aupple ‘mented andthe placebo groups were fund oe tasicaly spieast who declined to be examined at the end of the I-yr interval, three belonged tothe Ca-suppl. group, and two tothe placebo group. At baseline no difference between the we groupe was found with respect to age, statural height, body weight, or BMD at any skeletal site (Table 1). From the initial cohort, 108, igrls remained compliant (active-treatment cohort) 10 the study food products over the whole study period. Among the 41 subjects 08%) who drepped aut from the sty, Al ee ported lassitude with the consumption of twa imposed food products per day, and one left the Geneva district. Dropout "umes antes tne onset of the intervention phase ranged from 4 to 32 wk (enean, 15.3:°1.6 wk,» = 25) and 4 to 28 wk (mean, 130=21 wk, 16) in the Ca-suppl. and placebo erouns, spectively In the ative treatment cohort, 82.9%" 4% (n= $3) and 90.2=1.4% (n ~ 53) of the study foods were consumed ‘throughout the intervention period in the Ca-suppl. and ple- cebo groups, respectively, as estimated by egular interviews of the subjects mothers. Aftrd& wk, none ofthe examined sub- jeets displayed any sign of puberty. Calum suake. Spoatancous calcium intake, as determined by three tequency quesuonnaires at 16-Wx intervals, were Similar in both groups (916=42, and 87936 mg/d in Ca-supp. dnd placebo groups espeeively). Taking into account the i dividual compliance over the 48-wk intervention period, the ‘mean daily amount of supplemented calcium ingested with the fnriced foods wes 80710 mg. Thus, the calcium inake n> creased from 91642 (0 172324 md inthe Casuppl group. “Anthropomerric and bone mass changes. Table It shows the anthropometic and osteodensitometrc values recorded in the active-treatment groups after a -y interval. At baseline, the imcan values nthe Casuppl. and the placebo groupe did not differ Setween the two groups, and were similar to hose of the inention-o-reat groups presented in Table 1. The in eats in statural height, body weight, and BMD at the var ous skeletal sites in the placebo exoup were within the ex: pected range for prepubertal gira ofthis age, and wore ll Scaisticlly significant (P < 0001 by two-sided paired sample analysis). The coresponding BMD guns calculated in ether absolute (mglom® pet yt) oF relative (ie) terms are pre- Sented im Table and Fig. 1, cespecively. Atal tes, the toean incremant it booe stats war grater im the Ce-eapp than in the placebo group. However, the difference in BMD was smaller in the lumbar spine tha inthe racial and femoral Stes. The magaitad ofthe calium eect, further estimated 3s the ratio ofthe mean bone mass gain in the Ca-suppl. group wer that bserved im the place group (A Casto pl eho) (Table M), ranged fom 1.09 to 1.75 (mean of sx mea sured skeletal sits, 1.52). Interestingly, the 4 Ca-supp. 8 plae edo rato for lumosr spine SMD was gute Simla tO st cakeulated fr eight gain. tn contrast to al osteodenstometsic Variables and to statural height the mean change in ether body weight oF BMI was not greater inthe Ca-supp.BrOup than in the placebo group (Tsble TS) Table 11 Anthropometric and Osteodenstometric Values Determined at Baseline and 48 Wk Later in Prepubertal Girls Consuming Foods Enriched or Not in Calcium (Active: Treatment Cohort) Age (yt) rosso §922007 Height (om) wa=08 Weigh (ka) 259208, BMI ky) 166203 174203 Radiat metaphysis BMD (glen) 2924 Radial diaphyss BMD (glen) sn9e4 Femoral neck BMD (sie) Femoral chante BMD (sem) Femoral daphyse BMD (jlem Camis spine (3-8) BM ico Allvaluec ae given ac mean2SEM. Areal BMD valger ce in mgm All vale recorded a 48 wh were sail 7982007 37202 269306 ass asi ie2e02 952 anes Be2 =H sist ine values at? = 0001 by twosded paired Studens test analysis Casupol/ Pace values corespand to the rato ofthe gin in he alia ‘SPplemeated over that in he placebo group cesta the means othe inva lence feo a A wk nd 3 Paelie,“P = 0.8 © 008,196 042, )~ 01 svannpared te sorexponng change the placebo sy. Caleium-Envched Foods and Bone Mass Growth in Prepubertal inky 1288= icici Figure. BMD gainsin prepubertal girs consuming food products enriched or notin calcium during 48 wk active treatment cohort) oF for various lengths of ime (inteationto-teatcohor) Bar represeat nmeans=SEM. The number of subjects inthe active treatment cobort wae as allows Place (open hart) = 53. CaletimSipplemented (dashed bar) ~ 55. In the inteaton-o-est cohort, numbers Were placebo (open bars) = 67, calcium supplemented (dashed bars) = 77 Fp 008, 8? = 005; 3 = 00387 = 0.0 The mean increment in BMD for the six measured skeletal sites as expressed in both absolute and relative terms, is illus: trated in Fig 2. The difference between the Ca-suppl. and pla =bo groups was highly significant in both the active-treatment ans intention-to-teat cohors. The effeet on mean BMD gain remained highly signiteant (P < U2), even after adjustment forage, height, and weight at entry (data not shown). The cor ‘responding mean increases in both BMC and hone area were also greater in the Ca-suppl, group than in the placebo group, but did not reach statistical significance (data not shown). In the Ca-suppl subjects belonging to the Intention-10-reat co- hort, the change in mean BMD ofthe six skeletal sites was pos- BUD mgtemeny) Fiqure2. Mean BMD gains in prepubertal gil consuming food prodvcts enriched or notin calcium during 48 wk (active-reatment ohort of for various eng of tine (tention total cabor) For ‘each subjects the Yearly guns recorded atthe six sties skeet sitet presented in Fie. 1 (relative value, and Table (abso values) Were averaged. Bas represent metnrsSEM. The number of sib in the ative-zeatment cohort was as fellows: placebo (open brs) = 55. caloum-rapplemented (dated bart) = $5. In tha inaction ‘reat cohort. numbers were placebo (open bart) ~ 67, calcu supplemented (dashed bars) = 7. ***P-< 0.00 itvely correlated (r = 024, P = 0.038, n = 77) withthe cumu- lative amount of calcium ingested trom the enriched foods. Effects of calcium supplements in relation to sporiancous calcium intake. To evaluate the effects of calcium-enriched foods on bone mas gaia in relation to spontaneous calcium in take (as assessed by averaging the resuls from the food fre {quency questionnaires made at 0,24, and 48 wk), the Ca-supl and placeho groups were divided in two subgroups according to the median of their spontaneous calcium intake (885 and 880 maid in the intentiono-treat and active-teatment co- hort, respectively). At baseline there was no statistically sig nificant difference between the Ca-suppl. and placebo groups Table Ul. Changes in Anthropometric Variables, BMD, BMC and Bone Size in Response to Calcium-Enriched Foods in d According o their Spontaneous Calcium intak Prepubertal Girls Disrbu _ Peabo Cant Cosuph Pato Cha Poste 7 nam a7 aa ae ee CCalium intake (mpi) eons THE asa ante spat a Regt (ome) 7202 sss02 48502 sasose azn 302. 8 Weight Gwyn) 3350238030? aazos 39:03 a3c03 BMD (owemye) 19 m2 ne2 23 02! ass3 (at) osm) gang GG Stes gates T0536 Aone area amiyr) SA7ER7 —oDBEZH ATE 6932 S44 ASE ATT gag aloo ae give mean-=SEM. “Ine mesian ofthe spontaneous ay cohorts respectively. BMD, BMC, and bone ara valuee leu intake was 355 and 850 in the nention-o tea and aesve-weabnent he meas ofthe i skeletal Stes presented in Tale {V and averaged in cach subset ie total alia intake corresponds to te sum of the dary cleom taken seontaneousy an ef cnciom nthe enriched fod sredoes po "P= 00, 9P-= 0U2.1P = 00 a compared tothe coreesponcing placebo sroup. 1290 Bonjour ora50 e) samo exe) Figure 3. Changes in BMD in cesponse 1 calcium-enriched foods in prepubertal girs isributed according (o their spontaneous calcium the 6 skeletal sites. The coresponding absolute changes a BMD are presented in Table I, The mesian spontaneous calcium intake sin Grsted above the bar. the mean spontaneous cacium inake was {50-16 apd 1142233 malin the intention co-reat cohort and {5/5217 and 1185=39 meld in the ative weatment cohort. °° P= (001 as compared to the corresponding placebo group. in terms of BMD at any site (data not shown); this was ob- served in both the spontaneously low std ii groups, which had mean calcium intakes of 650233 (n = 72) and 1143233 mgld (n = 72), respectively. Both statural height and body weight, however, were sigificanly greater ‘among the spontaneously high- versus low-calcium consumers (129.2027 vo, 126520.7 em, P< 0.001; 275205 ve.25.7405 ke, P < 0001, respectively). The mean BMD gain in response to calcium supplements as expressed in absolute (Table II) or relative (Fig. 3) terms, was more pronounced among the [ow calcium consumers (8 Ca-suppl. iA placebo: 142-18 g/cm", ‘epending on the site examined), Indeed, linear regression analysis showed that the mean BMD gain at the six skeletal sites was significantly correlated to the fotal calcium consuinp- reakiua intake sion in the spontaneously low (7 = 0.32. P < 0.007), but aot in the high-caleum intake subgroups of the intention-to-ceat co- host (7 ~ 0.02, NS). “Effet of calcium on BMC, skeletal size, and statural height. ‘As shown in Table III, there were aso significant increments in both mean BMC (8 Ca-suppl /A placebo ratio, 1.21-1.23) and mean bone area ofthe six investigated skeletal sites (A Ca- fuppl./A placebo ratio, 115-116) in the subgroup of Low. calcium consumers. The change in mean bone size wes ac- companied by a tend toward greater statural height gain (Q CCasuppl (8 placebo ratio, L113) which nearly achieved Statistical significance, Indeed, the reduced gain in bone area and statural height observed inthe spontaneously low. versus high-calcium consumers appeared to be corrected by the cal ‘ium-entiched foods (Table 11D. ‘A Similar patiern was observed in he projected area ofthe lumbar spine, and further morphometric analysis indicated that in the spontaneously low-caicium intake subgroup, the vertebral height gain at L2-L was significantly greater in the CCa-suppl. than inthe placebo group (Table IV), At the level of the femural midsba,a significant difference in width change ‘was also observed between the Ca-suppl- and the placebo groups in the spontaneously low-caleum intake subgroup (Table 4). ‘To evaluate whether the calcium effect on bone mass was associated with a commensurate increase in volumetric min tral density, gain in Z scores from basolino values was eales Tated for both BMD and BMAD at the level of the radial and femoral diaphyses, two sites where the response was particu larly significant. In the low.calcium consumers of the active treatment cohort presented in Table III, the difference in BMD Z.ccore goin betwoen the two groups was greater (Ca: suppl. (1 = 29] minus placebo [n = 25] = ~ 0.28 and + 0.18, P< O05, in radial and femoral diaphysis, respectively) than that in BMAD Zseore (Ca-suppl. minus placebo = +003 and 0.08, P > 0.1, in radial and femoral diaphysis, respectively) Foilow-up 1 yr after treatment termination 100 irks (C suppl n = 55; placebo, n = 45) out of the 108 in the active treatment cohort were followed up to I yr after they stopped Table IV. Changes atthe Level of the Lumbar Spine and Midfemoral Shaft at the End of the Intervention (&2-1) and I yr Afer Lumbar spine 2 Bune arc (0) ‘8 Wie (mmye) § Height (mmr) BMC imgiyr) BMD (mafemy) 13 Bone area (mn 8. Width amye) BMC (mat) ‘8 BMD (ange pery2) agen sash 5826 Values are meanSEM recorded in gis having ad third Discontinuation of the Treatment (3-3-1) in Girls Having a Spontaneously Low Calcium Intake 1675295, 1929 {yr after uestment dscominution (active treatment cobort). All ais vere statstealy prea by pred est anal. P< 048," P = DGS "Ps 0.2 as compared to the placebo group esng.3n ANOVA tet for re pasted messre, rh in Prepuborat ile 1294the consumption of the study foods. Most of the absolute df ferences in mean bone mast and size gains recorded at the end of the intervention period was stil detectable yr after termi pation ofthe dietary intervention (mean BMD, S83 vs 52+ migfem?, P = 0.05; mean BMC, 1265366 vs. 136256 mg, P (0.101; mean bone area, 43:26 vs, 131=5 mm, P < 008; statue ral height, 11.92:03 vs. 11 290.3 em, # = WY, the Ca-suppl and placebo groups, respectively, ANOVA test for repeated ‘measurement). Among the 100 girs who underwent a third ex- “amination, 49 belonged to the group of spontaneously low-al ‘cum consumers in whom the effects of the caleium-enriched foods on HMI, BMC, scanied Done area and stacura heigint had been particularly significant. At the levels of the lumbar spine and femoral midshaft, the differences in height and ‘width gain, observed at the end of the intervention period ‘were stl statistically significant 1 yr after treatment discontine sasion (Table IV). Discussion ‘A recently held National Institutes of Health Consensus De: ‘elopment Conference concluded that a calcium intale above the Recommended Dietary Allowance (RDA) of 800 mg/d may fead to an increased rate of bone accumulation in children aged 6-10 yr (35). This report underlined the necesiy to con sider the eects of caleum on regional changes in bone mass, and recommended the impeovement of strategies to achieve and maintain optimal dietary intake of calcium by both nutr- tional and supplemental means (35). I is appropriate to dis oss the present study in relation io these considerations Compliance rate. Inthe presen study, the compliance rate was about 75% after I yr. A higher rate could have heen antic ipated, considering that calcium was supplemented using en- riched palatable foods usualy taken at either breakfast or 35 sacks, and Known t0 be weil acepted by children. The psy chologieal constraint on the families involved in concolled t= als, however, a the fact that they were blinded with respect to the study product played an important roe in this phenom: Changes DMD gains, Oveall, us seals ica that fasing calcium intake from approximately 900 to 1730 mg/d led 10 a substantial increment, 35 %0 50%iyr (Fig. 2), ia the rate of bone mass accumulation in prepubertal girs. The ap- pendiculr sites appeared to be more responsive than the axial skeleton, Indaed, the effect wa found to be minimal in the lumbar spine, as assessed by measuring spinal BMD in the classical anteroposterior view. Among the appendicular re- ons, the most Obvious positive effets were observed at sites essentially consisting of cortical bone (eg, ragial and femoral diaphysis) Nevertheless, BMD gain was ako positively infs- enced by calcium supplementation atthe trochanter and femo- ral neck levels aswell asa the radial metaphysis. So far, only tone placebo controled study has compared the efees of cal one’ ace serUsmolaS aay le enh tes the whet in 22 ant upplemminion ar diferent Ey of the skeleton i 22 bra! female "and male’ children 2B) The abcro spoites atthe levels of himbar sone (< 1.0%6/ye) amd proximal femur. 24th vapion the calcite dil ot achieve stato 2 Figer 91) duane tHe ime fi sdetakesrin’prepibertal Chi pplemcnis were associated wita 8 nigner radial BMD gain (30. Taken together, these resus (os well as ‘other studies in experimental animals [36] aud human subjects [37 38) suggest thatthe appencicular skeleton, (particulary regions precominantly composed of compsct bone) peat :0 bermore sensitive than the val skeleton to the effet ofc ‘um supplementation above RDA. Important, however, ah sium supplement appesy ao to have an elect on BMC and bone size at the level of the lumbar spine. Therefore, the tse of only areal BMD inte clsial DPA/DXA antero-pos- terior vew may well underimate the elect of calm Sup- pMementation onthe ail skeleton daring arowth Speruuneous clu intake and reponse to oalcium up plements A thorough metz-analyis of calcium balance cata Tecealy indicate that there i thesbold level of clcum in- take in humans (3), presiously demonsrated in anal ex periments (40) in cikzen and adolescents, the level above Sich avin clu intake Ihereaeincalcum retention appears tobe et between 200 {0 1500 mld (5). Acrordngy, ur study lary inate that the response to calcium suppiementation in teams of bore tras ain was markedly dependent on the level of spoatane Gur calsum intake, Indoot, the benefit wat 35-18 (2) o ‘syn greater in the spontaneotly low (eg les than 88D tmp) versus highalcium consumers. Our daa suggest that Calcium intake below 800-900 mg/d may not be suticent for optimal bone mase aces in 7-9 yrold prepubertal airs,On The other hae the effet of avium suplementaon appears tobe rather mid at that age when the spontaneossconsumn- tom is larger than 1100-1200 mg. To our knowledge, his i tne tst evidence from 8 placedo-contrlied sty showing that there isa calcium intake threshold below which supple ‘entation can be particuley beneficial fo prepubertal - dren. A review of controled clint trials testing the etfs of calcium supplementation on BMD in postmenepatsal women sso inccnrt a reater Dene fowl constr: Or results suggest thatthe we ofa simple frequeney ques cionaire could be wef for ideniving children who would partcuacy bene fom an increase calcium take Mechanoms of he efecto calcium supplements. The pos tv effect of akan previously seported nhl pli cbo-controles clinical tral cried out in prepubertal hl dren (28 30) have essemialy been assibed toa reduction in bone remodeling (62). favor of hit notion was the fact that the level of serum ostoeacn, a bioeaemical marker of bone remodsing in adult, was sgicanty seduced in the cactus ‘Supplemented prepubertal group (28) Such an explanation f compatible wth the currently favored mechanism roposed to count forthe inhibitory eect of calcium on age-related Bone loss (31,41, 45-46). Tn thet aforementioned stad, the postive Bone macs effet of calcium (given a either citrate malate or carbonate fas) wis not associated with any chonge i either bone area or satura eight (28,30, Our study was sot med at elas Satine mechan of slum etfect on bone mass. Conse Sling the mechani of eat effet on bowe mass C jetty So 0 maine the compliance West ahh pos the the protocol dd Rat inlnde any howto wine sie Neverhlos neil ckimination of the changes In Sanne i height sugges that cleo supple 1 longer associated with an se the gloup of spontaneous lowcaleum com: 2the gain of both me achieved inthe spontaneously high-calcium consumers. Morphometric analysis of the changes observed in the lumbar spine and in femoral diaphysis suggests that calcium could enhance both the longitudinal and the cross-sectional growth of the bones [Ay teviewed by Nordin (4, the possibility that milk calcium may positively influence longitudinal growth has been sus- pected for several decades. In many studies it was dificult 0 ‘iscriminate between the effects of ealeium from those of milk ‘contained proteins oF energy. In the present study, both ca ‘sium enriched and placobo food products provided identical amounts of proteins and energy. Thus, the possibilty that milk calcium may affect not only the remodeling, but also the mod- ling of the skeleton, deserves to be further investigated. AS previously indicated, the tested foods were enriched with cal Sum from milk extract. With the daily consumption af «wo tested foods, the mean difference ia the phosphorus intake was 386 mg/d as compared to 870 mg/d mean diflerence of calcium. based on previous dietary siary recoraing in prepubertal gris fof that age (47), one can estimate that the enriched foods in- creased the intake of phosphorus by 30-35% as compared toa 100% increase for calcium intake. To what extent tis increase Jnthe phosphorus intake played a contributing role in the stim ‘lation of home miss accrual reported inthis study remains | be determined. ‘An important issue is whether the positive effect on bone ‘mass goin will be sustained after discontinuation of calcium supplementation, and thus be ultimately translated into higher [peak bone mass. As mentioned above, our data suggest that milk caleium supplementation may increase bone mast not only by inhibiting the process of remodeling, but also by stimu: lauing bone modeling. According to this hypothesis one may expect that the contribution of the modeling effect on bone mace will nt completely disappear after diceontinuetion ofthe calcium supplementation. Indeed, our data suggest at part of the gain in bone mass and bone size was not lost| yr after the end of the calcium supplementation. Further prospective long, {erm studies wil eventually provide a definite answer to the ‘question of whether of not transient rie inthe intake of cl cium during growth can permanently increase the amount of| Done tissue through 2 modeling effect in certain parts of the skeleton, {In summary, caleum-enriched food given to prepubertal rls with a spontaneous calcium intake below RDA signif cantly increased bone mass gain at several sites ofthe appen icular skeleton, including the proximal femur. Morphometric analysis provided evidence for acalewm effect on bone model- ing which was associated with an increase in statural growth, ‘Acknowledgments We ate indebted 19 De. P. Hazeghi, M.D, and to the Geneva Public Youth Service for he recruitment othe subjects athe team ofthe bone densitometry unit, and to Mrs. - Gardiol,C. Ang and M-C. Brandt for their help in preparing the manserip, This work wns supported by Nesee Ltd, Lavsanne, Switzerland and by the Swie National Sconce Fandation (grants 32-32415.81 an 31 4095894, Reterences sn agement Rave es Nem York Calcium Enriched Foods and Bone Mass Growth in Prepubertal Gis 2 a CW Senedd Coton. 1 Tc croatia cap Soe Si ta tere i Rene eos ona spt og Pa Se Cie BEE Cad rea area metoln. cx iat up as Cl Lap, me gent Camm nd RB, Mar (985. one msn ermal ae tn 78 dean 0 ein cane mtb a hae cnet nce 7S Bi Att of pk oe ma 1 ik Encrot a ie en! a Thi Bach Sn, nd RR. cia as ry nen pence "Yack NA 7A Eman, 1 Hoppe, MG Yeats, PN. Sambrook, ant’ Cen en Scar a ah. {a Sime Hoppe, A Sah ME Coe Pato Moly ica Ri on ta pte oes ana Ea ea nossa nl a Sl eM SB Tact a cnt CH Cm ‘rss era of raw oom en Cl at CS. a toe 9, Means pepo ee iene Go Kaeo id ro. nse ede 6 es gM nr Me Ra Roe Sl. 3 hr) Sev MG Gx. ut i dete Send. RE Lao A Coe, Mi 17. Chan. ©. 1981. 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Mato VD. Fontaea, C.Tominc, Gael. CH. Chest, 19 airs that fluence ek bane me’ sun se lon an he town evens for threshold behavior m1 Clin Naty S892 Sel roroe is me. Wemgarner EM Parkes, eM Bal dW, Ex nan. 187 Bioaataty tate tne mngestn and ese incase stew of contalled cna iss. Am Cie Nat, S4(euppl 27620. "2 Pari, AMC T9M. ye io fas of promih Benya so bane 45. Kans A196 Cale nti srs pletion for se opooss Pat Mer mepoe Brd ClnBa S1SE tide tens Osteopontin 85-2 “Cnen 1, Theta R- Rizo and JP. Bono, 19%, Pas pu bent ater stay babs ie adolescents ving ns wer sos" ele