hematopoietic stem cell transplant ( hsct ) is the treatment of choice for many hematological diseases , and the number of long - term survivors has increased remarkably over recent decades .
hsct is frequently complicated by endocrine abnormalities ; and loss of bone mass is well documented as a sequel to hsct .
previous studies have reported a 515% loss in the bone mineral density ( bmd ) at the lumbar spine ( ls ) and the femoral neck within 1-year after hsct .
the pathogenesis of transplantation - related bone loss is multifactorial and is not completely understood .
the underlying disease itself , primary hypogonadism , irradiation , steroids and posttransplant immunosuppressant may all contribute to bone loss . with this in hindsight , we conducted this study to evaluate the bone loss in patients undergoing hsct and various factors affecting it .
we hypothesize that patients undergoing hsct will have significant loss of bmd due to increase in bone resorption and decrease in bone formation . to the best of our knowledge
, there is no data available on bone loss post - hsct in the indian population .
all patients irrespective of the etiology were enrolled in the study prior to transplant . among these 50 patients 10 died before hsct , 7 patients were not transplanted ( reasons : relapse or patient choice ) , 3 patients lost to follow - up , 3 patients still waiting for hsct and 2 patients were recently transplanted ( posttransplant duration < 1-month ) hence , were not included in analysis .
indication for hsct was aplastic anemia ( 5 ) , multiple myeloma ( 5 ) , thalassemia major ( 4 ) , acute lymphoblastic leukemia ( all ) ( 4 ) , myelodysplastic syndrome ( 3 ) , chronic myeloid leukemia ( 2 ) , acute myeloid leukemia ( 1 ) , and progressive systemic sclerosis ( 1 ) .
preparative regimen consisted of myeloablative regimen using  bucy  protocol ( busulfan  16 mg / kg , cyclophosphamide  120 mg / kg ) .
post - hsct cyclosporine - a ( 5 mg / kg / day ) was used for primary graft versus host disease ( gvhd ) prophylaxis .
all patients were planned for evaluation before hsct , at 36 months and at the end of 1-year .
all 25 patients were available for evaluation at 6 months . at 1-year , only 20 patients could be evaluated because during 612 months 3 patients died , one had a relapse of all and planned for re - hsct and one lost to follow - up .
blood samples were collected in fasting state at 0800 h for biochemical tests ( fasting and postprandial blood glucose , lipid profile , renal and liver function tests ) .
serum osteocalcin was measured by elisa kit ( cat no . 8002 , quidal , usa ) to assess bone formation .
504836 , wampole , teco ) was used as a marker of bone resorption ( sensitivity 3.2 nmol / l , range 540 nmol / l ) .
these were measured at baseline , at 36 months and at the end of 12 months .
dxa scans were performed on hologic qdr-4500 densitometer ( hologic , bedford , ma , usa ) machine ( fan array beam ) .
daily quality control was performed on the phantom spine with coefficient of variation of 1.08% for hip and 1.2% for the ls .
the bmd were performed by the same technician and was repeated on the same machine .
informed consent was taken in all patients or parents if the patient was < 18 years .
chicago , usa ) data were presented as mean  standard deviation , or number ( % ) unless specified .
effects of various nonparametric parameters on change of bmd were compared using independent student 's t - test . a p < 0.05 was considered as statistically significant .
serum calcium and phosphates were normal in all cases , and 25ohd levels were 27.9  14.5 ng / ml . aplastic anemia ( 20% ) , multiple myeloma ( 20% ) , thalassemia major ( 16% ) , and all ( 16% ) were the most common hematopoietic disorders in the study group . all patients received cyclosporine as part of gvhd prophylaxis .
out of these 6 patients , 2 patients had acute gvhd and died , remaining patients had chronic gvhd .
basic characteristics bone mineral density declined significantly at all sites ( total , femur neck ( fn ) , trochanter and ward 's triangle ) of the hip at 6 months when compared to baseline .
there was 59.9% decline in bmd at hip at different sites at 6 months from baseline .
there was no significant change in bmd at lumber spine and whole body at 6 or 12 months [ table 2 and figure 1 ] .
younger patients ( < 18 years ) had significant higher bone loss at neck femur as compared to older patients at 6 months .
similarly , patients who had allogenic graft or were on steroid had significantly more decrease in percent bmd at hip .
bmd changes with immunosuppressive drugs were similar to those between autologous versus allogenic transplant as patients who received autologous graft were not on immunosuppressive therapy .
patients with gvhd received steroid , whereas those without gvhd and autologous transplant did not receive steroid therapy , hence , bmd changes among them were similar to changes with steroid therapy .
bmd ( g / cm ) at various sites and bone markers pre and post - hsct change in bone mineral density pre - hematopoietic stem cell transplant ( hsct ) , 3 - 6 months and 12 months after hsct among 20 patients who completed 12 months of follow - up factor affecting change in bmd ( % ) at 6 months post - hsct bone formation marker ( serum osteocalcin ) decreased , and bone resorption marker ( n - terminal telopeptide ) increased significantly at 6 months among all patients from baseline .
these changes reverted back at 1-year and became similar to baseline [ table 2 and figure 2 ] .
change in bone markers pre - hematopoietic stem cell transplant ( hsct ) , 3 - 6 months and 12 months after hsct among 20 patients who completed 12 months of follow - up
transplantation of hematopoietic stem cells ( either from a peripheral or bone marrow source ) is being performed in steadily increasing numbers and is now an accepted treatment modality for many hematological and nonhematological diseases .
young patients who survive long - term after hsct , they are confronted with new life long problems if they develop osteoporosis related problems . all the data in the literature
are of the western population , and there are well - known ethnic differences in bone mass . in this prospective study , we have evaluated effect of hsct on bone mass and bone markers at various sites in indian patients . in present study , there was significant bone loss at 6 months at hip region including total femur , fn , femur trochanter and ward 's triangle .
this is similar to the finding by kashyap et al . where the decline in the bmd was prominent at the total hip ( approximately 11% ) and was the sharpest at 6 months posttransplant ( 9.3% in the first 6 months and 3.6% in the second 6 months ) .
studied the effect of pamidronate to prevent bone loss in post - hsct patients . in the group of patients that did not receive pamidronate post - hsct , reported a maximal bone loss in the total hip ( 7.6% ) 6 months posttransplant .
however , they did not find any recovery of bmd at 12 months posttransplant and they reported a bone loss of 7.8% at 12 months posttransplant compared to baseline at hip .
similar to our study , kananen et al . reported a recovery of total hip bmd from baseline at follow - up at median of 75 months posttransplant .
maximal bone loss at 6 months at fn without recovery were also demonstrated by other studies ranging from 5% to 15% .
the nonrecovery of fn bmd from baseline seen in the above studies is in contrast to the present study .
the mean loss in fn bmd was 11.7% with a nonsignificant decrease in postauto hsct patients . in another study by lee
. found that fn bmd remained significantly lower than baseline at the femoral neck , with no trend toward recovery at 24 months .
however , they reported that maximal bone loss takes place in the first 6 months with no further significant loss occurring in the later months .
schulte et al . demonstrated significant bone loss with nadir fn bmd at 24 months with no recovery to baseline even after 48 months .
in contrast , kananen et al . demonstrated recovery of bone mass in fn bmd by + 4.1% at 75 months post - hsct .
a similar trend was observed at femur trochanter and ward 's triangle by various studies . in the follow - up of studies conducted by vlimki et al . , and kananen et al .
, they showed an increase in the trochanter bmd after a median of 75 months post - hsct , but other has seen no recovery at ward 's triangle .
the most interesting observation made in the present study was almost complete recovery at 12 months posttransplant , whereas others have reported partial recovery ranging from 24 to 75 months as discussed above .
tbi is associated with hypogonadism , hypopituitarism that further exacerbates the bone loss . also , irradiation directly damages bone cells and enlarges resorption lacunae and to increase osteoclast number and activity without an increase in bone formation , leading to increased bone resorption and bone porosity .
thirdly , steroid free preparatory regimen was used , and steroid was given only in about half of patients .
lastly , gvhd occurred only in 24% patients compared to a higher prevalence in other studies . in this study ,
where they found total body bmd of patients in the pediatric age group was significantly decreased compared to the adult population .
the bone loss in the younger population is probably multifactorial where growth hormone deficiency , low body mass index , hypogonadism , direct effect of chemotherapy on bone , or effect of disease per se on bone may play significant role .
comparing the effects of hsct on ls and the proximal femur , the bone loss at the ls and whole body was less dramatic .
the baseline total body and ls bmd declined nonsignificantly at 6 months post - hsct with a trend toward recovery of bmd at 1-year , which is similar to other studies .
in contrast , others have reported significant decrease in the ls bmd at 12 months post - bmt .
complete recovery at ls bmd was observed by schulte et al . at 48 months posttransplant .
similar findings were reported by kananen et al . at median of 75 months post - hsct .
the site specific bone loss is seen across all studies and also in this study that is more pronounced at proximal femur than at ls .
the bulk of this loss occurs in the first 6 months that corresponds with high dosage of cyclosporine and glucocorticoids given in the first 6 months for gvhd prophylaxis .
the defective osteoblast function in the proximal femur may contribute to the dramatic bone loss at proximal femur .
differences in the tissue expression of several proteins related in bone metabolism such as bone morphogenetic protein-2 , several growth factors , and their receptors may also contribute to it .
post - hsct , these patients are bed bound for 24 weeks that could have further contributed to the bone loss at the proximal femur .
it is clear that the exact mechanism still needs to be elucidated with further studies . in the present study ,
the bone formation marker serum osteocalcin declined significantly at around 36 months from the baseline and returned to baseline at 12 months posttransplantation .
the bone resorption marker serum n - telopeptide reached its peak at 36 months posttransplantation and subsequently returning to almost baseline at 12 months posttransplant .
in which they used serum osteocalcin and c - telopeptide as bone formation and bone resorption markers respectively .
however , vlimki et al . reported that though the bone formation marker ( bone alkaline phosphatase ) returned to baseline by 6 months , the bone resorption marker ( serum c - telopeptide ) remained elevated throughout the study duration with a peak at 6 weeks duration .
other studies have reported nadir osteocalcin levels in the immediate posttransplant period at 3 weeks posttransplantation with recovery to baseline by 3 months and peak c - telopeptide levels at 4 weeks with recovery to baseline at 1-year .
this also commensurate with current knowledge that bone markers usually precedes the bone changes . in the present study ,
also the bone markers may have reached peak earlier , which could have missed as we have measured these markers at 36 months .
however , still we could show that changes in bone mass during posttransplant period is reflective of both - decreased bone formation and increased bone resorption , and recovery of bone mass is also associated with reversal of changes in bone markers . the main limitation of the study was heterogeneity with respect to age , gender , pubertal status , diagnosis , and type of transplantation ; and sample size was small .
however , rarity of the disease and infrequent hsct did not allow us to select large group . in indian conditions , long follow - up is also a problem , but we could do 1-year follow - up , and further continuation of the study will help to narrow down the wide dispersion in the results .
a significant bone loss is observed at 6 months in patients with post - hsct .
it is the highest at ward 's triangle followed by femoral trochanter , femoral neck , total hip , ls and whole body .
there is recovery of bone mass at femoral neck , total hip , ls and whole body with a trend toward recovery at femoral trochanter at 12 months posttransplant except ward 's triangle .
younger age , allogenic transplant , immunosuppressive therapy posttransplant , and steroid use are all related to bone loss in patients undergoing hsct .
bmd should be performed in all patients undergoing hsct at 1-year posttransplantation to assess the bone health .
those patients with persistent low bmd may require long - term follow - up and antiresorptive therapy .
 introduction : hematopoietic stem cell transplant ( hsct ) is frequently complicated by endocrine abnormalities and loss of bone mass . this prospective study was conducted to evaluate the bone loss post-hsct.materials and methods : a total of 50 patients was evaluated pretransplantation , and 25 had hsct ( 17 males , 8 females ; 19 allogenic , 6 autologous ) 
 . bone mineral density ( bmd ) and bone markers were measured at baseline , 36 months and 12 months.results:the mean age and body mass index were 25.1  16.3 years and 19.4  4.5 kg / m2 , respectively . there were 15 adults ( 60% ) , and 10 adolescents ( 40% ) . 
 there was a significant decline in bmd from the baseline at total femur ( 8.7% ; p < 0.0001 ) , femoral neck ( 5.0% ; p = 0.003 ) , femoral trochanter ( 6.0% ; p = 0.001 ) , and ward 's triangle ( 9.9% ; p < 0.0001 ) at 6 months posttransplantation . 
 from the 6 months to 12 months , there was a significant improvement in bmd at above sites except at ward 's triangle . 
 the decline in bmd was nonsignificant at the whole body ( 0.3% , p = 0.748 ) and the lumbar spine ( 2.7% , p = 0.130 ) at 6 months posttransplant . 
 younger patients with allogenic graft and steroid use are more likely to have significant loss of bmd at hip posttransplant . 
 serum osteocalcin decreased , and n - telopeptide increased at 36 months , which return to baseline at 1-year posttransplant.conclusions:a significant bone loss is observed at 6 months in patients with post - hsct . 
 the bone loss occurs predominantly at cortical bone . 
 there is recovery of bone mass at 12 months posttransplant except at ward 's triangle . 
 bone loss after hsct is multifactorial . 
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