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, an estrogenic lack determines a condition characterized by the prevalence of bone reabsorption phase over the bone formation phase .
osteoporosis in postmenopause recognizes also low serum 1,25(oh)2d levels and a reduced intestinal transport of calcium , always due to the estrogenic lack .
the reabsorption markers increase up to two times the values seen in premenopause , while values of bone formation markers increase only by 50% .
the biochemical indicators of increased osteoblastic activity are represented by the serum levels of osteocalcin and of alkaline phosphatase , while the urinary levels of hydroxyproline are expression of an increased osteoclastic activity . in presence of an accelerated bone replacement , osteocalcin and alkaline phosphatase serum levels and urinary hydroxyproline excretion
there is a wide debate concerning the effects of the treatment with l - thyroxin ( lt4 ) on bmd .
thyroid hormones certainly determine an increase of both osteoblastic and osteoclastic activities over both cortical and trabecular bones [ 2 , 3 ] .
however , the data about the real impact that lt4 therapy exerts on bmd of women subjected to prolonged periods of treatment appear contrasting .
in particular , an approach built on the preventive determination of the anamnestic profile considered at risk for bone demineralization in women undergoing lt4 use is lacking .
studies in vitro suggest that thyroid hormones increase more the re - absorption than bone formation , hence determining a loss of bone mass [ 8 , 9 ] .
it has also been reported how thyrotoxicosis increases the fracture risk in post - menopause women and in patients with low bone mass peak .
fractures are more frequent in those parts of the skeleton in which predominates the cortical bone , such as the hip and the distal part of the arm .
a recent study has also shown that endogenous subclinical hyperthyroidism might be considered an additional risk factor for osteoporosis in postmenopausal women , especially for cortical bone , whereas exogenous subclinical hyperthyroidism has no effect on bmd .
post - menopausal women with nodular thyroid disease often undergo continuative and prolonged treatment with lt4 administered at suppressive dosages .
nodular thyroid disease and osteoporosis share common factors : ( a ) both are present with an elevated frequency in the general population ; ( b ) they are more prevalent in the female sex ; ( c ) the incidence increases with age . since increased levels of thyroid hormones may contribute to bone demineralization .
the aim of this study was to evaluate the effects of treatment with a fixed dose of lt4 on bmd in physiological post - menopausal women with normofunctioning nodular thyroid disease , compared to women , the same average age , who did not receive lt4 .
to examine the effects of the treatment with lt4 on the bmd , 110 ( range 5055 years , average age 53 ) , natural post - menopausal patients with normo - functioning uninodular or multinodular benign thyroid disease were enrolled , after informed consent , if they : had last regular menstruation less than 5 years before;had a normal t - score ( 1  sd);did not have secondary causes of bone demineralization ( genetic , endocrine - metabolic , osteoarticular , hematologic , neoplastic , gastrointestinal , drug administration , and/or prolonged immobilization);did not receive lt4 treatment in the previous two years;did not have a history positive for vertebral fracture . had last regular menstruation less than 5 years before ; had a normal t - score ( 1  sd ) ; did not have secondary causes of bone demineralization ( genetic , endocrine - metabolic , osteoarticular , hematologic , neoplastic , gastrointestinal , drug administration , and/or prolonged immobilization ) ; did not receive lt4 treatment in the previous two years ; did not have a history positive for vertebral fracture .
following preliminary evaluation , all patients were prescribed lt4 at the fixed dose of 1.6  g / kg / die . 

exclusion criteria surgical menopause , hormone replacement therapy in the last two years and autoimmune thyroid disorders . 
  
surgical menopause , hormone replacement therapy in the last two years and autoimmune thyroid disorders .
fifty women of the same average age ( range 5055 yrs , average age 53.5 ) , having their last menstruation less than 5 years before ( last referred menstruation ) , with normal t - score ( 1  sd ) and not receiving lt4 .
all patients underwent evaluation of bmd by dual x - ray absorptiometry of the lumbar vertebrae ( bone densitomiters gammadensit x - ray , l'acn scientific laboratories ; cerro maggiore ( mi ) italy ) before lt4 treatment was begun ( t0 ) and 2 years after treatment ( group a ) and/or followup ( group b ) ( t2 ) .
the serum levels of tsh ( eclia , roche diagnostics , monza ( mi ) , italy ) , ft4 , ft3 ( eclia , roche diagnostics , monza ( mi ) , italy ) , abtg and abtpo ( eclia , roche diagnostics , monza ( mi ) , italy ) , were evaluated at t0 and at t2 .
all the patients enrolled underwent measurements of calcium serum levels ( colorimetric method ; roche diagnostics , monza ( mi ) , italy ) , 24 h urinary calcium concentration ( colorimetric method , roche diagnostics , monza ( mi ) , italy ) , serum alkaline phosphatase ( ap ) bone isoenzyme levels ( enzymatic method ; metra tm bap eia ) and 24 h urinary hydroxyproline concentration ( colorimetric method ; lta ; bussero ( mi ) , italy ) at t0 and t2 .
the results are reported as mean  sem throughout the study . according to lt4 therapy ,
patients were divided into 2 groups : a group which received lt4 therapy ( group a ) and group which did not receive any treatment ( group b ) .
the statistical analysis was performed using the student t - test for paired or unpaired data , as suitable .
the odd 's ratios of the risk factors in relationship to bone mineralization loss were determined .
the patients enrolled had a mean age of 53.4 years ( range 5055 yrs ) . as expected
, the treatment with lt4 caused a significant reduction of tsh serum levels ( p < 0.0001 ) at t2 .
at t0 , the group a patients had a mean t - score of 0.22  0.07 which decreased significantly to 1.02  0.10 at t2 ( p < 0.001 ) .
the total calcium concentration in serum and 24 h urine after treatment with lt4 did not change significantly in comparison to the pretreatment values ( tables 1 and 2 ) .
the serum levels of ap and the amount of hydroxyproline excreted with the 24 h urine increased significantly ( p < 0.0001 ) during treatment with lt4 ( tables 1 and 2 ) .
the impact of some risk factors for osteoporosis was evaluated on the bmd of the patients treated with lt4 .
the results of this analysis are shown in table 3 . a positive history for osteoporosis , smoking habit , and length of menopause did not give a significant odd ratio .
in contrast , the following risk factors turned out to influence in a statistically significant manner the bmd : bmi < 19 
kg / m , the onset of menarche after the age of 15 years , a positive history for periods of prolonged amenorrhea , nulliparity .
the results of this study showed that patients with nodular thyroid disease treated with a fixed dose of lt4 have a slight , but highly significant reduction of the bmd after two years of treatment .
forty - one out of 110 women ( 37.3% ) had osteopenia at t2 ( tra 1  e t - score 2.5 
sd ) ; in the control group osteopenia at t2 occurred in 6% of patients .
the loss of bmd appeared mainly related to the following factors : ( 1 ) bmi < 19  kg / m ; ( 2 ) menarche onset after the 15th year of age ; ( 3 ) a clinical history positive for periods of secondary amenorrhea ; ( 4 ) nulliparity . in parallel with the modifications of the bmd after two years of lt4 treatment , it was also observed an increase in 24 h urinary hydroxyproline concentration , suggestive of increased osteoclastic activity , and increased serum ap levels , an index of increased osteoblastic activity .
altogether therefore these data suggest that lt4 treatment increases bone metabolic turnover , with prevalence of the re - absorption phase .
the results of this study , therefore , favor the hypothesis that the treatment with suppressive dosages of lt4 , frequent in the clinical practice of women in menopause with nodular thyroid disease , is a risk factor for the progression of bone demineralization .
in particular , women with the following predisposing risk factors : thinness , delayed menarche , periods of secondary amenorrhea during the reproductive age , nulliparity , are likely to undergo a more profound negative impact of lt4 treatment on bmd .
contrasting results have been published about the role played by lt4 treatment on the bmd .
the discrepancies between the various studies are determined by methodological bias , such as ( a ) progressive reduction of the lt4 dosage prescribed to women which by itself may justify a reduced risk for bone loss ; ( b ) inclusion of patients with a clinical history positive for hypo- or hyper - thyroidism which has been reported to impair bmd ; ( c ) differences in the duration of the treatment ; ( d ) heterogeneous methods and site of bmd evaluation ; ( e ) lack of data collection relative to the role of other possible interfering factors ; ( f ) inclusion of pre - menopausal women ; ( g ) unmatched controls ( for body weight , age at menarche and at menopause , calcium dietary intake , smoking habits , alcohol intake , exercise , etc . ) . a meta - analysis study , published in 1996 , reviewed 41 controlled cross - sectional studies , including about 1250 patients , concerning the impact of thyroid hormone therapy on bmd .
suppressive lt4 therapy was associated with significant bone loss in postmenopausal women ( but not in premenopausal women ) , whereas , conversely , replacement therapy was associated with bone loss in premenopausal women ( spine and hip ) , but not in postmenopausal women .
the detrimental effect of thyroid hormones appeared more marked on cortical bone than on trabecular bone .
we will briefly review the major studies appeared in literature afterwards which can be divided into those showing a detrimental effect of lt4 on bmd and those showing no such an effect [ 1224 ] .
a careful selection of a group of post - menopausal women with thyroid nodular disease under treatment with a fixed doses of lt4 allowed us to show that this treatment causes a slight but significant reduction of bmd .
in addition , bmd reduction was associated with the following osteoporosis risk factors : bmi < 19  kg / m , the onset of menarche after the age of 15 years , history positive for period of amenorrhea , and nulliparity . in consideration
that lt4 treatment is effective in a low percentage of patients with benign thyroid nodules , estimated to be 1020% , a careful benefit / risk evaluation has to be taken into account before lt4 treatment is prescribed , particularly when other risk factors for bone demineralization are present .
the present study confirms comments from our previous article , conducted on 99 post - menopausal women , all of them receiving lt4 , prospectively evaluated after one - year treatment .
in addition , to previous data , the present study consider an homogeneous control group , for average age and clinical features , including only physiological menopause limited to 5-year history ( last menstruation ) .
it also increase to two - year observation length of women receiving therapy , allowing a better understanding of the phenomenon .
moreover , this study excludes conditioning anamnestic factors such as : surgical menopause , hrt , andautoimmune thyroid disorders .
this study evaluated the effects of lt4 administration on the bone mineral density ( bmd ) in physiological postmenopausal women after two years of continuative treatment . 
 110 postmenopausal women with nodular goiter aged between 50 and 55 years were examined before and after 2 years of therapy with a fixed dose of lt4 ( 1.6  mcg / kg / die ) for the treatment of nodular thyroid disease . 
 the results showed that the patients on treatment with lt4 have a slight , but significant reduction of the bmd after 2 years of treatment , associated with increased serum levels of alkaline phosphatase and urinary excretion of hydroxyproline , confirming our data conducted on the same group after one year of therapy . 
 comparison between patients receiving lt4 ( group a ) or not ( group b ) showed that group a patients had significantly lower bmd . 
 we demonstrated the statistically significant influence of the following risk factors on bmd : ( 1 ) body mass index < 19  kg / m2 ; ( 2 ) the onset of menarche after the age of 15 years ; ( 3 ) positive history for period of amenorrhoea ; ( 4 ) nulliparity .