Bone health in pregnant women Essay


One of the of import issues for all adult females is bone wellness, peculiarly during gestation. Pregnancy is associated with chief alterations in Ca metamorphosis, because the developing babe demands plentifulness of Ca for developing a skeleton which contains about 20-30 gms of Ca and chiefly deposited in the latest trimester ( 1-2 ) . Adaptive mechanisms in pregnant female involved to protect a Ca beginning to the foetus include:1 ) increased maternal skeleton reabsorption of Ca and 2 ) greater than before enteric soaking up of Ca ( 3 ) . Enhanced maternal serum free and entire 1, 25 hydroxivitamin D ( 4 ) sound to be responsible for the better enteric Ca soaking up through gestation ( 5 ) . However, big figure of probe show that increased dietetic consumption and enteric soaking up are non equal to supply the Ca required by the foetus ( 6-8 ) . Therefore the maternal skeleton is possible beginning of Ca for the foetus ( 9 ) . The big figure of paperss suggests that bone turnover in pregnant female additions ( 4-5 ) and bone mineral denseness ( BMD ) decreases during gestational period ( 4-11 ) . The OPG/RANKL/RANK system was discovered late and seems to play a cardinal function in bone homeostasis ( 12 ) . RANKL is a cytokine belongs to TNF superfamily that regulates the formation and activation of osteoclasts and bone reabsorption ( 13 ) . OPG is another cytokine was discovered in 1997 and capable of protecting bone mass by suppressing osteoclast distinction and activation ( 14 ) .The OPG/RANKL ratio is considered to be better unmasking of bone reconstructing environment marks. A high ratio indicates bone formation but a low ratio favours bone reabsorption ( 15 ) .Changes in the OPG/RANKL ratio have been concerned in the pathogenesis of bone diseases characterized by bone reabsorption, such as post-menopausal osteoporosis ( 16 ) , and glucocorticoid-induced osteoporosis ( 17 ) . Documents indicate that maternal plasma OPG concentrations increased in the 3rd trimester of gestation, a clip when the demand for Ca for foetal bone mineralization is at its maximal degree and stating that OPG may protect the maternal skeleton from utmost katabolism ( 14, 18-20 ) .The consequence of folic acid on bone turnover and bone metamorphosis has been evaluated in old surveies ( 21-22 ) . Furthermore, there is grounds that folic acid supplementation has benei¬?cial effects on bone position ( 23,24 ) . TNF-? is among the most potent of the osteoclastogenic cytokines that stimulates bone reabsorption both in vitro and in vivo by increasing the proliferation and distinction of osteoclast precursors ( 25 ) .There is no papers about TNF- ? and gestation until now.

Based on the fact that, the maximal rate of bone turnover occurs in the last trimester of the gestation, and folic acerb supplementation during gestation could stand for low bone reabsorption rates, The present survey was carried out to compare the effects of high dosage ( 5mg/day ) and low dosage ( 0.5mg/day ) folic acid on the RANKL/OPG ratio and TNF-? concentration during the gestation.

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Materials and Methods:

This was a randomised, double-blind survey. Ninety Nulliparous adult females who were visited the AL-Zahra Hospital and one subsidiary clinic, Specialized and Sub-specialized Sheykholrais Clinic of Tabriz University, Tabriz, Iran for antenatal trial and planning gestation, were enrolled in this follow-up survey. Our study’s protocol was approved by Ethical Committee of Tabriz University of Medical Sciences ( Ethics code:9149 ) and registered in the Persian Registry of Clinical Trials ( IRCT ) and given the ID, IRCT201206234105N9. All the perceivers completed the informed consent signifier. The inclusion standards included singleton gestation, no history of any disease or medicine identified to impact bone metamorphosis, chronic high blood pressure, diabetes mellitus, chronic nephritic disease, coffin nail smoke or intoxicant Consumption, early abortion, assisted construct, and age between 20-30 old ages old. Sixty adult females accordingly became pregnant. Baseline venous blood samples were collected at 3-month intervals before construct. After roll uping baseline sample, perceivers having different dosage of folic acid ( 5 mg/day and 0.5 mg/day ) until 36 hebdomad of gestation. The participants contacted every hebdomad and were asked during each visit to declare whether they took folic acerb supplementation or non. Second sampling was done in the 36 hebdomad of gestation. The perceivers that have abortion, multiple gestation, and use of Ca and ferric sulphate during gestation and didn’t complete follow up were excluded from survey. Serum was collected after centrifugation ( at 3000 RPM ) of the sample for 20 proceedingss, so stored at?70°C till analysis. We used the day of the month of mother’s last catamenial period ( LMP ) for ciphering Gestation age. Serum Osteoprotegerin ( OPG ) and Receptor Activator of Nuclear Factor-? B Ligand ( sRANKL ) concentrations were measured by commercially Enzyme-Linked Immunosorbent Assay ( ELISA ) kits available ( Bioassay Technology Laboratory, Cat No: E1558HU and Cat.No: CK-E90425, with intra- and inter- check CV of & A ; lt ; 10 % and & A ; lt ; 12 % severally ) .TNF-? was analyzed in serum by ELISA utilizing Immunodiagnostic kit ( DIAsource Immuno Assay S.A, Cat.No: KAP1751 with intra- and inter- check CV of 6.6 % and 4.5 % ) . All of the statistical analyses were performed utilizing SPSS version 18 package ( SPSS Ins, Chicago, IL ) . Median ( minimum-maximum values ) , or mean±SD were used to show consequences. For odd informations, The Mann–Whitney U-test and Independent Sample t-test were used, and the Wilcoxon trial and a mated Student t-test were used for mated informations. Evaluation of Correlation was done by Spearman ‘s trial. In all investigated instances ? 0.05, was considered statistically important.


At the terminal of survey, 45 pregnant adult females completed follow up: 23 treated with 5 milligrams of folic acid per twenty-four hours in group 1 and 22 treated with 0.5 mg folic acid per twenty-four hours in group 2 ( 15 patients did non finish the survey process: 8 instances because of abortion and 2 instances because of multiple gestation and 5 instances because of discontinuing intercession ) .The demographic informations and baseline features of the two groups are presented in Table1.No signii¬?cant difference was present between two groups at the beginning of the survey ( except LDH ) .

The maternal serum degrees of OPG, sRANKL and TNF? at the baseline and at the 36Thursdayof gestation in high dosage and low dosage group of folic acid have been shown in Table 2.

Maternal serum rating demonstrated that the degrees of OPG in both group was increased but there was statically important difference in group 1 at the 36Thursdayhebdomad of gestation comparison to baseline ( p=0.008 ) .The concentration of sRANKL ( p & A ; lt ; 0.001 ) and TNF? ( p=0.005 ) signii¬?cantly decreased at the 36Thursdayhebdomad of gestation comparison to baseline in group 1. As shown in table 2 sRANKL/OPG ratio was decreased in both group but it was statically important merely in group 1.


Group1 ( mean±SD )

Group2 ( mean±SD )


Maternal age ( Old ages )




Pre gestation Weight ( Kg )




Height ( centimeter )




Pre gestation BMI ( kg/m2)




Diastolic BP ( mmHg )




Systolic BP ( mmHg )




Platelets ( x 1,000 millimeter3)




LDH ( IU/L )




Ca ( mg/dl )




P ( mg/dl )




ALP ( IU/L )








Serum creatinine ( mg/dl )




Urea ( mg/dl )




Urine protein ( mg/24h )




Urine creatinine ( mg/dl )





Under sheepskin

High instruction

13 ( 56 % )

10 ( 43 % )

11 ( 50 % )

11 ( 50 % )



Group1 ( n=23 )

Group2 ( n=22 )


Serum OPG ( pg/ml )



340 ( 120-1200 )

710 ( 120-1500 )

( p=.008 )B

375 ( 160-1310 )

470 ( 130-1400 )

( p=.592 )B


Serum sRANKL ( pg/ml )



91.6 ( 33.40-198.60 )

40 ( 20.10-100.20 )

( P & A ; lt ; .001 )B

86.10 ( 39.70-198.60 )

76.50 ( 43.70-188.5 )

( p=.426 )B


Serum TNF? ( pg/ml )



5.30 ( 4.10-10.20 )

4.8 ( 2.5.-9.00 )

( p=.005 )B

5.85 ( 4.20-8.9 )

6.5 ( 5.00-8.8 )

( p=.135 )B






twenty-two ( .09-1.47 )

.07 ( .02-.45 )

( P & A ; lt ; .001 )B

.27 ( .04-.74 )

.24 ( .04-.67 )

( p=.211 )B


Bivariate correlativity analyses confirmed a positive relationship between the decreased soluble receptor activator of atomic factor- kappa B ligand after 9 months handling of high dose folic acid ( Delta sRANKL ) with reduced tumour mortification factor alpha serum degree ( Delta TNF? ) ( r=0.451, p=0.031, Delta sRANKL= ( at the terminal of survey of High dose folic acid intervention ) —sRANKL ( Basal ) , Delta TNF?=TNF? ( at the terminal of survey of High dose folic acid intervention ) —TNF? ( Basal ) ) . But increased OPG degrees did non show an reverse correlativity with reduced sRANKL and TNF? degrees ( r=0.299, p=0.166 and r=351, p=100 severally ) .The average alterations in serum OPG, sRANKL and TNF? at the terminal of survey with high dosage and low doses folic acid are shown in Fig. 1

Fig.1. Effect of folic acerb supplementation on Percentile fluctuations in serum osteoprotegerin ( OPG ) , soluble receptor activator of atomic factor-kappa B ligand ( sRANKL ) and tumor mortification factor alpha ( TNF? ) at the terminal of survey between group 1 ( 5mg/day ) vs. group 2 ( 0.5mg/day ) ( average ) .

Discussion:Osteoporosis is a cosmopolitan job and affects peculiarly adult females ( 26 ) . Pregnancy-associated osteoporosis ( PAO ) seemed to be an uncommon job of gestation but it leads to serious troubles such as breakability breaks and elongated back hurting in affected adult females. Definite prevalence of Pregnancy-associated osteoporosis ( PAO ) is unknown. ( 27, 28 ) but to day of the month about 120 instances have been defined since first study by Nordin and Roper. ( 29 ) Most instances develop PAO throughout the first gestation and Recurrence of ( PAO ) with future gestations is uncommon, but has been informed to happen ( 26, 27, 28 ) . No standard intervention protocol has been established for the intervention of pregnancy-associated osteoporosis, due to the absence of a positive etiology. ( 27 ) Document shows that PAO causes important morbidity in the process of hurting and disablement, the most of patients demoing assorted vertebral breaks in the early puerperium and besides show loss of tallness which can develop at the terminal of gestation, in puerperium, or even subsequently. ( 30, 31, 32, 33, 34 ) .

Osteoprotegerin, named as “bone defender ” and known as a cytokine that increases the denseness and volume of bone tissue by cut downing the sum of active osteoclasts ( 35 ) . RANKL is a member of TNF superfamily ( 15 ) and its Overexpression of soluble RANKL in transgenic mice consequences in a skeletal phenotype with many similarities to postmenopausal osteoporosis, including reduced BMD, increased bone reabsorption cortical porousness and skeletal breakability ( 34 ) . Some probe showed that OPG reserved bone loss in theoretical accounts of sex-steroid inadequacy and glucocorticoid-induced osteoporosis, arthritic arthritis, multiple myeloma, and metastatic bone disease ( 12 ) . Since OPG straight counter all RANKL mediated activities through RANK, RANKL/OPG ratio is an of import determiner of bone mass and skeleton unity. In malignant diseases, such as myeloma, osteolytic bone metastases of prostate and chest malignant neoplastic disease enhance in look of RANKL by tumour cells and tumor-inducted addition of the RANKL/OPG ratio in bone microenvironment can be observed. ( 35 ) .

Previous probes in worlds have demonstrated that serum OPG degree has progressive addition during human gestation, with a lessening in serum RANKL ( 14, 18, 20 ) . In conformity, in this survey, the pregnant adult females in both group showed higher degrees of OPG in comparing with baseline but it was important merely in high dosage group and important lessening of sRANKL was observed merely in high dosage group.Few surveies evaluated the consequence of folic acid on bone turnover and bone metamorphosis ( 22-23 ) and merely one survey evaluated the consequence of folic acid on bone metamorphosis and turnover during gestation. Bagher Larijani et Als have evaluated the consequence of folic acid on OPG, RANKL concentration during gestation. They showed that adult females who took 1 milligram of folic acerb day-to-day addendum from the beginning of the gestation until the bringing clip had signii¬?cantly higher plasma degrees OPG concentration in comparing with adult females who took until the terminal of the 2nd trimester while sRANKL concentration was signii¬?cantly lower. For the i¬?rst clip, their consequences demonstrated grounds that folic acerb supplementation during gestation could stand for low bone reabsorption rates by higher OPG and lower sRANKL concentrations ( 24 ) . In our survey possible consequence of high dosage and low dosage of folic acerb supplementation on bar of bone reabsorption and PAO during gestation and in future in pregnant adult females is investigated. Our informations for the i¬?rst clip show that high dosage ( 5 mg/day ) of folic acid signii¬?cantly decrease the concentration of the serum sRANKL and increase serum OPG and besides for the first clip we show that sRANKL/ OPG ratio lessening in high dosage group while low dosage of folic acid doesn’t have such effects. Besides Manizheh sayyah M et Al showed that folic acerb addendums during gestation, irrespective dose could diminish Hcy degrees although it was reduced more important in the high dosage group and they show that folic acerb supplementation specially high dosage of it have good consequence on pregnant adult females and can forestall hypertensive upset. ( 36 ) Furthermore Bagher Larijani et al reported low concentration of Hcy in adult females who took 1 milligram of folic acerb day-to-day addendum from the beginning of the gestation until the bringing clip ( 24 ) . This two survey are in understanding with our survey and corroborate good consequence of folic acerb supplementation during gestation. Herrmann et Al. reported that the proliferation of osteoclasts and the programmed cell death of bone-forming cells motivated via HCY and B vitamin dei¬?ciency interact with bone metamorphosis, which consequences in a negative bone turnover ( 37 ) . There is grounds that the look of RANKL and RANK cistrons in peripheral blood mononuclear cells are signii¬?cantly higher in hyperhomocysteinemic persons than in controls. Folic acerb intervention for 6 hebdomads signii¬?cantly reduced cistron look of RANKL/RANK in peripheral blood mononucleate cells from these persons ( 38 ) .How of all time in our survey the fluctuation of serum Hcy degree didn’t step but our consequence besides present important lessening in sRANK degree and conform the capacity of folic acid in diminishing sRANKL degree.

It is now clear that inflammatory cytokines such as IL-1, TNF and M-CSF that have long been associated with osteoclastic bone loss, map by exciting RANKL production by osteoblast precursors and/or developed bone-forming cells [ 39 ] ; and/or by diminishing OPG production and/or by up modulating RANK receptor topographic point on osteoclast precursors, therefore increasing their sensitiveness to normal RANKL concentrations. ( 40 ) Harmonizing to topics were told, in this survey for the first clip we evaluated the consequence of high dosage and low dosage of folic acid in serum TNF? degree. Our informations show that in high dosage group TNF? degree lessening significantly and its lessening has correlativity with lessening sRANKL degree. Besides old surveies have presented that TNF? prompts osteoclastogenesis via the RANKL system, as TNF? up-regulated RANKL messenger RNA look ( 41 ) and our findings are in understanding with this survey.

The complete nature of folic acid’s particular effects on bone metamorphosis has non yet been perfectly understood, hence a series of researches are necessary to uncover unknown characteristics of this procedure and it seems that larger sample size and besides mensurating new markers for bone reabsorption, such as serum C-telopeptide of type 1 collagen, urine N-telopeptide of type 1 collagen and besides bone mineral densitometry will be of great importance to turn out our results. In drumhead, our findings suggest that high dosage of folic acerb supplementation could diminish bone resorptive bio-markers and prevent PAO in pregnant adult females by increasing OPG degree and diminishing sRANKL and TNF? degrees