osteoporosis is defined as a skeletal disorder characterized by compromised bone strength which is an integration of bone density and bone quality , predisposing to an increased risk of fractures associated with chronic pain , disability , and mortality 1 .
estrogen has a key role of maintaining a balance between osteoblastic and osteoclastic activity , and bone remodeling increases when estrogen levels decline 2 .
hormone levels are the main determinants of bone density , but other factors including the presence of other medical conditions also increase the risk of osteoporosis 3 - 5 .
many cancer patients were confronted to cancer - related bone loss and development of osteoporosis in their lives , and these results are mainly caused by ; 1 ) osteolytic factors by cancer cell lines themselves 6 ; and 2 ) bone loss induced by anti - cancer treatment which is called cancer treatment - induced bone loss ( ctibl ) 7 . a variety of neoplasms without bone metastasis
are also known to be related to osteoporosis by producing circulating bone resorption stimulatory factors leading to bone destruction and hypercalcemia 6 , 8 - 12 . in patients with gynecologic cancers ,
reduced spinal bone mineral density ( bmd ) has been reported in patients with cervical cancer 13 , 14 , but no significant differences were observed in lumbar or femoral bmd between patients with endometrial cancer and controls 15 .
ctibl may cause bone fragility and an increased susceptibility to fractures , and bone loss occurs more rapidly and tends to be more severe in patients with ctibl than in those with normal age - related bone loss ; therefore , prevention , early diagnosis , and treatment of ctibl are essential to decrease the risk of fracture 7 , 16 , 17 .
as estrogens act through direct and indirect mechanisms to restrain bone resorption , all oncology therapies that induce hypogonadism cause osteoporosis in a large percentage of patients 17 .
ctibl is most common in patients with breast or prostate cancer who receive chemotherapy , hormone therapy , or surgical castration , as these can cause hypogonadism and induce bone loss 7 , 17 .
there have been a few studies reported about the association between gynecologic cancer treatment and bone loss 18 , 19 .
the aim of the present study was to evaluate the impact of cancer treatment on bmd in the lumbar spine ( ls ) and femur in the postmenopausal women with cervical or endometrial cancer without bone metastasis compared to normal postmenopausal women .
postmenopausal women aged 45 - 57 years who first visited kosin university gospel hospital and were diagnosed with cervical or endometrial cancer without bone metastasis between january 2005 and december 2010 were included in the study .
this study was approved by the institutional review board of kosin university gospel hospital , and all subjects provided their informed consent . all those with cervical or endometrial cancer who had not reached menopause or who received menopausal hormone therapy were excluded in this study .
study subjects who had used drugs known to alter bone or calcium metabolism were also excluded in this study .
all patients who were diagnosed with cervical cancer underwent type ii or iii hysterectomy , bilateral salpingo - oophorectomy ( bso ) , and pelvic lymphadenectomy , and dissections of suspicious para - aortic lymph nodes by intraoperative examination were also made .
most of patients received adjuvant concurrent chemoradiation therapy ( ccrt ) using platinum - based chemotherapy after surgery .
technetium-99m - labeled diphosphonate bone scans or 18f - fluorodeoxyglucose positron emission tomography / computed tomography ( pet / ct ) were performed on all cancer patients for confirmation of bone metastasis .
all patients who were diagnosed with endometrial cancer underwent type i or ii hysterectomy with bilateral salpingo - oophorectomy , washing cytology , and pelvic and/or para - aortic lymph node dissection , followed by internal or external radiation therapy to the pelvis .
finally , 130 patients with cervical cancer and 68 patients with endometrial cancer were enrolled in this study .
225 postmenopausal women aged 48 - 59 years who visited the university hospital annually as part of a group check - up for work and lacked specific health problems served as normal controls .
all control women underwent a careful physical examination and a thorough review of medical history at first visit , and the subjects who had history of current treatment with drugs known to alter bone or calcium metabolism were excluded .
all of study participants received dual - energy x - ray absorptiometry ( dexa ) on ls and femur and blood test for bone turnover markers at the time of diagnosis before any cancer treatment , and all of them received follow - up dexa and laboratory tests of bone turnover markers 1 year later , which is the time after completion of cancer treatment .
bmd data of the ls and femur , and laboratory data of bone turnover markers at initial check - up and those in one year were collected for all participants .
bmd in grams per square centimeter and t - scores in the ls ( l1-l4 ) and the left femur neck ( fn ) and femur trochanter ( ft ) were determined using a dual - energy x - ray absorptiometer ( lunar radiation corp , madison , wi , usa ) .
bmd values were categorized into three groups according to the criteria of the world health organization 20 as normal , osteopenic , or osteoporotic relative to the mean and standard error ( se ) of young adult korean women . the in vivo coefficients of variations were all below 2.0% .
blood samples were collected from an antecubital vein in all the subjects in tubes without anticoagulants , in accordance with the declaration of helsinki guidelines , and sera were obtained by centrifugation for determination of bone turnover markers .
calcium ( ca ) and phosphorus ( p ) were measured by atomic extinction photometry .
serum osteocalcin ( ost ) was measured using a novocalcin kit ( metra biosystems inc .
urine deoxypyridinoline ( dpl ) was measured using a pyrilink - d kit ( metra biosystems inc .
all data were expressed as mean  standard deviation ( sd ) . for comparisons of demographic and anthropometric characteristics , serum and urine biochemical markers , and t - scores of basal bmd between patients with gynecologic cancers and controls , one - way analysis of variance ( anova ) and unpaired t - test were performed .
for comparison of these parameters in cancer patients categorized according to cancer stage , unpaired t - test and kruskal - wallis test were used .
the frequencies of osteoporosis , osteopenia , and normal bmd according to basal bone mass were compared between patients with gynecologic cancer and controls using the chi - square test .
postmenopausal women aged 45 - 57 years who first visited kosin university gospel hospital and were diagnosed with cervical or endometrial cancer without bone metastasis between january 2005 and december 2010 were included in the study .
this study was approved by the institutional review board of kosin university gospel hospital , and all subjects provided their informed consent . all those with cervical or endometrial cancer who had not reached menopause or who received menopausal hormone therapy were excluded in this study .
study subjects who had used drugs known to alter bone or calcium metabolism were also excluded in this study .
all patients who were diagnosed with cervical cancer underwent type ii or iii hysterectomy , bilateral salpingo - oophorectomy ( bso ) , and pelvic lymphadenectomy , and dissections of suspicious para - aortic lymph nodes by intraoperative examination were also made .
most of patients received adjuvant concurrent chemoradiation therapy ( ccrt ) using platinum - based chemotherapy after surgery .
technetium-99m - labeled diphosphonate bone scans or 18f - fluorodeoxyglucose positron emission tomography / computed tomography ( pet / ct ) were performed on all cancer patients for confirmation of bone metastasis .
all patients who were diagnosed with endometrial cancer underwent type i or ii hysterectomy with bilateral salpingo - oophorectomy , washing cytology , and pelvic and/or para - aortic lymph node dissection , followed by internal or external radiation therapy to the pelvis .
finally , 130 patients with cervical cancer and 68 patients with endometrial cancer were enrolled in this study .
225 postmenopausal women aged 48 - 59 years who visited the university hospital annually as part of a group check - up for work and lacked specific health problems served as normal controls .
all control women underwent a careful physical examination and a thorough review of medical history at first visit , and the subjects who had history of current treatment with drugs known to alter bone or calcium metabolism were excluded .
all of study participants received dual - energy x - ray absorptiometry ( dexa ) on ls and femur and blood test for bone turnover markers at the time of diagnosis before any cancer treatment , and all of them received follow - up dexa and laboratory tests of bone turnover markers 1 year later , which is the time after completion of cancer treatment .
bmd data of the ls and femur , and laboratory data of bone turnover markers at initial check - up and those in one year were collected for all participants .
bmd in grams per square centimeter and t - scores in the ls ( l1-l4 ) and the left femur neck ( fn ) and femur trochanter ( ft ) were determined using a dual - energy x - ray absorptiometer ( lunar radiation corp , madison , wi , usa ) .
bmd values were categorized into three groups according to the criteria of the world health organization 20 as normal , osteopenic , or osteoporotic relative to the mean and standard error ( se ) of young adult korean women .
blood samples were collected from an antecubital vein in all the subjects in tubes without anticoagulants , in accordance with the declaration of helsinki guidelines , and sera were obtained by centrifugation for determination of bone turnover markers .
calcium ( ca ) and phosphorus ( p ) were measured by atomic extinction photometry .
serum osteocalcin ( ost ) was measured using a novocalcin kit ( metra biosystems inc .
urine deoxypyridinoline ( dpl ) was measured using a pyrilink - d kit ( metra biosystems inc .
the statistical software package spss 18.0 ( spss inc . , chicago , il , usa ) was used for all data analyses .
all data were expressed as mean  standard deviation ( sd ) . for comparisons of demographic and anthropometric characteristics , serum and urine biochemical markers , and t - scores of basal bmd between patients with gynecologic cancers and controls , one - way analysis of variance ( anova ) and unpaired t - test were performed .
for comparison of these parameters in cancer patients categorized according to cancer stage , unpaired t - test and kruskal - wallis test were used .
the frequencies of osteoporosis , osteopenia , and normal bmd according to basal bone mass were compared between patients with gynecologic cancer and controls using the chi - square test .
in 130 patients with cervical cancer , the distribution of the international federation of gynecology and obstetrics ( figo ) stage was ib , 73 ( 56.2% ) and iia , 57 ( 43.8% ) . of these patients , 103 had squamous cell carcinoma , 18 had adenocarcinoma , 6 had adenosquamous carcinoma , and 3 had other types of cancer . in 68 patients with endometrial cancer ,
the distribution of surgical figo stage was ia , 54 ( 79.4% ) ; ib , 7 ( 10.3% ) ; iia , 6 ( 8.8% ) ; and iib , 1 ( 1.5% ) .
of these patients , 53 had endometrioid adenocarcinoma , 10 had squamous cell carcinoma , and 5 had papillary serous adenocarcinoma .
age , body mass index ( bmi ) , parity , and time since menopause did not differ significantly between the three groups .
only the t - score of basal bmd at l4 was significantly lower in patients with cervical cancer compared to controls ( table 2 ) , and significant difference in the proportion of osteoporosis according to basal bmd was also observed only at l4 between patients with cervical cancer and normal controls ( table 3 ) . at 1 year , with completion of cancer treatment , t - scores of bmd at all skeletal sites examined except ft were significantly lower in patients with cervical cancer compared to controls , and the proportions of normal bmd at l1 , l4 , and fn in patients with cervical were significantly lower than those of controls .
table 4 and table 5 show no significant differences in the t - scores of basal bmd and the proportion of osteoporosis in the lumbar spine and femur between patients with endometrial cancer and normal controls .
however , after cancer treatment , t - scores of bmd at l3 , l4 , fn , and ft of patients with endometrial cancer were significantly lower than those of controls , and the proportions of normal bmd at all skeletal sites except l2 in patients with endometrial cancer were significantly lower compared to controls . among the biochemical markers measured ,
serum calcium and urine dpl levels were significantly higher in patients with cervical cancer compared to controls at baseline ( table 2 ) .
after cancer treatment , serum osc and urine dpl levels are significantly higher than those of controls .
no statistically significant differences in any of serum markers were detected between patients with endometrial cancer and controls at baseline , however , serum alp levels in patients with endometrial cancer were different from those in controls after 1 year ( table 4 ) .
no significant differences in clinical , laboratory , or bmd data were observed among patients with cervical cancer divided according to cancer stage before and after cancer treatment , and no differences in these parameters were found among patients with endometrial cancer divided according to stage before and after cancer treatment ( data not shown ) .
many treatments used in gynecologic oncology have the potential to damage bone , and osteoporosis is therefore one of the long - term complications of successful tumor treatment .
best results for osteoporosis treatment can be achieved in the early stages of osteoporosis , and the key to reducing the fracture rate in patients with therapy - induced osteoporosis lies in the early recognition of such complications 17 , 21 , 22 .
there are no evidence - based guidelines for diagnostic evaluation of patients at risk for ctibl , but bmd by dexa is considered the best predictor of fracture risk in general 21 . in the present study ,
t - scores of bmd of the ls and femur in the patients with cervical and endometrial cancer were significantly lower compared to controls after cancer treatment .
anti - cancer treatments for gynecologic cancers are mainly composed of castrating surgery , radiation , and chemotherapy , all of which could cause hypogonadism and induce ctibl 7 , 17
. other mechanisms of ctibl include direct or indirect effects of cancer therapies or malignancy on bone metabolism , inactivity , and inadequate intake of calcium and vitamin d 7 .
several chemotherapy agents may have direct effects on bone metabolism independent of their effects on gonadal hormones , and high - dose chemotherapy regimens , such as regimens used with hematopoietic stem - cell transplantation ( hsct ) , are toxic to osteoprogenitor cells in a dose dependent manner .
radiation therapy can lead to atrophic changes of bone which may be complicated by fracture 23 .
in addition , other drugs commonly used in cancer patients , such as glucocorticoids , cyclosporins , and l - thyroxine , are also associated with bone loss 7 , 17 .
main anti - cancer treatment in the present study comprises ( radical ) hysterectomy with bso and rt ( ccrt for cervical cancer , and radiotherapy for endometrial cancer ) .
we suggest that rt not surgery plays a decisive role in bone loss developed in patients with gynecologic cancer because the impact of surgery , especially bso , on endogenous estrogen may be insignificant , for all of the participants in this study are postmenopausal women at baseline .
high dose local radiation therapy was known to be associated with atrophy of the trabeculae of bone which may be complicated by fracture , and in addition , it has an indirect effect on bone associated with vascular changes 23 .
radiation field includes the bony structures of the pelvis in the in women treated for cervical and endometrial cancer , and pelvic irradiation can contribute to the development of pelvic insufficiency fracture 24 .
previous studies have noted that ccrt reduces bmd on women with cervical cancer 18 , 19 .
18 reported that patients with cervical cancer who were treated with ccrt after surgical treatment showed a significant decrease in the lumbar spine bmd to 91.95.9% , and hwang et al .
19 reported that bmds at l4 and greater trochanter of the femur in women with cervical cancer treated with ccrt were significantly lower than those of the controls . on the contrary , adjuvant chemotherapy in postmenopausal women with endometrial cancer
nine patients with endometrial cancer who received a total of three courses of paclitaxel plus carboplatin chemotherapy following surgery showed no significant decrease of spinal bmd compared to basal value 18 . in the present study ,
t - scores of basal bmd only in l4 were significantly lower in patients with cervical cancer compared to those in controls .
one possibility is that l4 is the most vulnerable segment of the lumbar spine to bone loss related to cervical cancer , which is partially in agreement with the result of hwang et al 19 .
the association between cervical cancer and decreased basal bmd of the lumbar spine before anti - cancer treatment has been noted in few studies .
two studies reported that patients with cervical cancer without bone metastases had significantly lower bmd in the ls compared to controls 13 , 14 . on the contrary , lee et al .
25 reported that total femoral bmd , not spinal bmd , was significantly lower in patients with cervical cancer compared to controls , and it is contrary to other studies including ours .
cancer - induced bone loss ( cibl ) may develop by osteolytic factors secreted by human cancer cell lines 6 .
several factors are known to be related to the activation of osteoclasts by tumor cells including parathyroid hormone - like peptide 8 - 10 transforming growth factor 11 , osteoclast activating factor 12 , and prostaglandins 13 . in cancer patients ,
greater osteoclastic activity , markedly reduced osteoblastic surface , osteoid surface , and osteoid volume have been noted by quantitative histochemical studies of the bone 6 , 26 . if the reduced bone mass in patients with cancer was related to the bone - resorbing factors secreted by cancer - cell lines , we would expect to develop hypercalcemia . in our study ,
serum calcium levels were borderline significantly higher in patients with cervical cancer compared to controls ( p = 0.049 ) , but this hypercalcemic condition in cervical cancer group was not observed after cancer treatment .
13 suggested one possible explanation that some cases of malignancy may have been associated with elevated levels of bone - resorbing materials even in the absence of hypercalcemia because of regulatory mechanisms that maintain normocalcemia , as proposed by henderson et al .
, there were no significant differences of basal bmd in the ls and femur between patients with endometrial cancer and controls , and it is similar to the result of lee et al . 15 .
we hypothesized that bmd values at the ls and femur were not different between two groups because bone mass in patients with endometrial cancer may have reached a balance between the negative effect of cibl and the positive effect of high endogenous estrogen levels related to endometrial cancer 28 .
biochemical bone turnover markers are indicators of bone metabolism , both the formation and resorption of bone 29 . in the present study ,
serum osc and urine dpl were lower in patients with cervical cancer than in controls after cancer treatment , and total alp levels were lower in endometrial cancer group after cancer treatment than in controls .
lower level of total alp in in endometrial cancer group is the opposite to hwang et al .
19 who reported significant higher levels of total alp in patients with cervical cancer who received anti - cancer treatment compared to controls .
although our study had a relatively larger sample size compared to that in other studies that examined bmd in patients with gynecologic cancer after cancer treatment 18 , 19 , limitations of this study mainly stem from its retrospective observational study design .
all patients with gynecologic cancer in the present study did not receive the same anti - cancer treatment .
in addition , we did not consider other confounding factors related to bmd which may provide a clearer association between anti - cancer treatment for gynecologic cancer and bone density .
 objective : this study aimed to evaluate the impact of cancer treatment on bone mineral density ( bmd ) in the lumbar spine ( ls ) and femur in the postmenopausal women with cervical or endometrial cancer without bone metastasis compared to normal control postmenopausal women.methods : we retrospectively evaluated the bmd data in the ls , femur neck ( fn ) and trochanter ( ft ) by dual - energy x - ray absorptiometry and laboratory data of bone turnover markers at baseline and after one year in 130 patients with cervical cancer , 68 patients with endometrial cancer , and 225 healthy controls.results : there were no significant differences in the t - scores of basal bmd in ls and femur between patients with endometrial cancer and controls , and only t - score of basal bmd at the fourth lumbar vertebra ( l4 ) was significantly lower in patients with cervical cancer compared to controls . 
 one year later , t - scores of bmd at all ls sites and fn in patients with cervical cancer and t - scores of bmd at l3 , l4 , fn , and ft in those with endometrial cancer after cancer treatment were significantly lower compared to controls . 
 lower proportions of normal bmd at all skeletal sites except l2 in patients with endometrial cancer and those at l1 , l4 , and fn in patients with cervical cancer were observed compared to controls after cancer treatment.conclusions : our results suggest that cancer treatment increase bone loss in postmenopausal women with cervical and endometrial cancer . 
Introduction
Materials and Methods
Subjects
Measurements of BMD
Measurement of serum calcium, phosphorus, osteocalcin, and total alkaline phosphatase, and urine deoxypyridinoline
Statistical analyses
Results
Discussion