a positive balance of calcium is required for skeletal development and 
 bone mineral accrual . in japan , daily calcium intake tends to be lower than the recommended 
 amount , 600 mg for adults ( 2 ) . vitamin d is also 
 indispensable to achieve normal skeletal development mainly due to its facilitation of 
 calcium absorption in the intestine , and vitamin d deficiency leads to secondary 
 hyperparathyroidism and rickets or osteomalacia . vitamin d deficiency is quite common in 
 developing countries and has reemerged in developed countries ( 3 , 4 ) . we have previously reported 
 seven japanese infant and early childhood cases of vitamin d deficiency ( 5 ) . furosemide belongs to a type of loop diuretics and is often used to increase urine output 
 in the treatment of heart failure and renal failure ( 6 , 7 ) . increased urine output is associated 
 with increased loss of calcium . as a result of hypercalciuria , calcification of the kidney 
 and urinary tract stones many reports have described decreased bone mineral 
 density ( bmd ) in patients treated with furosemide for a long time ( 8 , 9 ) . thiazide is 
 calcium - retention - type diuretic , but it is weaker than furosemide in urinary effect . in 
 addition , diabetes mellitus may be caused by treatment with thiazide ( 10 ) . thus , furosemide is more often used and it is sometimes difficult to 
 substitute thiazide for furosemide . bisphosphonate is now considered the first line treatment for primary and secondary 
 osteoporosis ( 11,12,13,14 ) . bisphosphonate is administered to patients with osteoporosis secondary to 
 glucocorticoid , rheumatoid arthritis , and osteogenesis imperfecta etc . bisphosphonate containing nitrogen functions directly in osteoclasts and significantly 
 suppresses bone resorption ( 17 ) . in this report , we 
 describe two patients with heart failure who received long - term furosemide therapy . both 
 patients showed elevated levels of parathyroid hormone ( pth ) and low bmd . treatment with 
 bisphosphonate successfully increased bmd without obvious side effects , although 
 hypercalciuria and secondary hyperparathyroidism continued . she underwent a curative operation for pulmonary 
 stenosis at the age of 5 and took furosemide for more than 10 yr . she has walked for 20 min every 
 day , although she suffers from mild heart failure . she has a regular menstruation cycle 
 and has reached adult height . at the start of treatment , her height and weight were 149.8 
 cm and 51.6 kg , respectively ( bmi was 23.0 ) . she had a systolic heart murmur and pretibial 
 edema , and her liver was enlarged 1 cm below the right costal margin in the midclavicular 
 line . laboratory data showed that human 
 atrial natriuretic hormone ( hanp ) and b - type natriuretic hormone ( bnp ) levels were 
 elevated as a heart failure marker ( table 
 1table 1 patient data ) . serum levels of calcium , phosphate and alkaline phosphatase ( alp ) were 
 within the normal range , 8.8 mg / dl , 3.4 mg / dl and 181 u / l , respectively urinary calcium was increased judging from 
 0.71 of urinary calcium / creatinine ( ca / cr ) . the ratio of maximal renal tubular 
 reabsorption to the glomerular filtration rate ( tmp / gfr ) was not reduced . dual - energy 
 x - ray absorptiometry ( dxa ) with lunar dpx - l densitometer model detected low bmd of the 
 lumbar spine ( l2-l4 ) , 0.795 g / cm . since the bmd was 71% of the young adult 
 mean ( yam ) and no fragility fracture was found , a diagnosis of decreased bone mass was 
 made , and the oral administration of 5 mg of alendronate daily was started . the serum level of calcium , 8.8 mg / dl , in the 
 eleven months from the start of treatment with alendronate , did not fall below the normal 
 range ( 8.410.0 mg / dl ) . with regard to other laboratory data , which were obtained eleven months after treatment 
 with alendronate , the serum level of intact parathyroid hormone ( pth ) was elevated to 
 180.0 pg / ml ; the 25-hydroxyvitamin d ( 25ohd ) level was relatively low , 15.8 ng / ml ; and the 
 1,25-dihydroxyvitamin d ( 1,25(oh)2d ) level was elevated , 120 pg / ml ( table 1 ) . the urinary excretion of calcium per day 
 increased to 6.2 mg / kg / day . on the other hand , calcium intake was calculated as 390 mg per 
 day , suggesting a negative balance of calcium because the calcium absorption rate is 
 usually less than 50% . vitamin d intake was calculated as 136 iu per day . in the analyses 
 of biochemical markers of bone turnover , urinary deoxypyridinoline ( dpd ) level was 
 elevated , 10.1 nmol / mmolcr , while urinary ntx and serum osteocalcin levels were normal , 
 46.7 nmolbce / mmolcr and 10.9 ng / ml , respectively . 1 changes in bmd ( l2-l4 ) , urinary ca / cr , and pth during treatment with 
 bisphosphonates . in patient 1 ( a ) , alendronate and subsequent risedronate increased 
 the bmd of l2-l4 . however , decreased urinary calcium was not observed and increased 
 levels of pth were maintained during bisphosphonate therapy , although urinary ca / cr 
 showed significant variance . the replacement of furosemide with thiazide was tried , 
 but was discontinued because of increased complaints of fatigue . in patient ( b ) , bmd 
 of l2-l4 was increased after treatment with alendronate and alfacalcidol , although 
 its slightly increased urinary ca / cr and elevated levels of pth were maintained 
 during therapy . * * percentage of the mean 
 in same - age healthy girls ( 19 ) . ) . however , urinary ca / cr showed significant variance from 0.03 to 1.19 , and no 
 persistent decrease in urinary calcium was observed during bisphosphonate therapy for two 
 years . increased levels of pth were maintained between 135 and 244.9 pg / ml during the 
 therapy . we tried to replace furosemide with thiazide , but this was discontinued because 
 of increased complaints of fatigue . changes in bmd ( l2-l4 ) , urinary ca / cr , and pth during treatment with 
 bisphosphonates . in patient 1 ( however , decreased urinary calcium was not observed and increased 
 levels of pth were maintained during bisphosphonate therapy , although urinary ca / cr 
 showed significant variance . the replacement of furosemide with thiazide was tried , 
 but was discontinued because of increased complaints of fatigue . in patient ( b ) , bmd 
 of l2-l4 was increased after treatment with alendronate and alfacalcidol , although 
 its slightly increased urinary ca / cr and elevated levels of pth were maintained 
 during therapy . * * * percentage of the mean 
 in same - age healthy girls ( 19 ) . patient 2 was a 17-yr - old girl with restrictive cardiomyopathy and pulmonary 
 hypertension . she was also referred to pediatric 
 endocrinologists with lumbago at the age of 17 . she went out for an hour every three days , 
 although she suffers from mild heart failure , and her menstruation is regular . at the 
 first consultation , her height and weight were 152.5 cm and 45.1 kg , respectively ( bmi was 
 19.4 ) . laboratory tests showed elevated levels of hanp and bnp ( table 1 ) . before treatment with alendronate , serum levels of 
 calcium , phosphate and alp were within the normal range , 9.4 mg / dl , 4.4 mg / dl and 125 u / l , 
 respectively . the 25ohd level was relatively low , 16.0 ng / ml , 
 while the 1,25(oh)2d level was slightly elevated , 65 pg / ml . urinary calcium was 
 slightly elevated judging from 0.31 of urinary ca / cr , although the urinary excretion of 
 calcium per day was not increased , 1.5 mg / kg / day . calcium intake was calculated as 300 mg 
 per day , suggesting a negative balance of calcium because the calcium absorption rate is 
 usually less than 50% . urinary dpd and 
 ntx levels , markers of bone resorption , were elevated , 10.1 nmol / mmolcr and 87.0 
 nmolbce / mmolcr , respectively . serum bone - specific alp ( bap ) and osteocalcin , markers of 
 bone formation , were also elevated , 56.9 u / l and 16.8 ng / ml , respectively . since her bmd 
 was 80% of the mean in same - aged healthy girls and she suffered from lumbago , oral 
 alendronate , 5 mg daily , and alfacalcidol , 2.5 g daily , were started ( 18 ) . lumbago disappeared two months after the treatment 
 and the bmd of l2-l4 was increased . however , elevated levels of pth were maintained 
 between 84.2 and 194.8 pg / ml during therapy . the serum level of calcium , 8.8 mg / dl , in the 
 two months from the start of treatment with alendronate did not fall below the normal 
 range . she underwent a curative operation for pulmonary 
 stenosis at the age of 5 and took furosemide for more than 10 yr . she has walked for 20 min every 
 day , although she suffers from mild heart failure . she has a regular menstruation cycle 
 and has reached adult height . at the start of treatment , her height and weight were 149.8 
 cm and 51.6 kg , respectively ( bmi was 23.0 ) . she had a systolic heart murmur and pretibial 
 edema , and her liver was enlarged 1 cm below the right costal margin in the midclavicular 
 line . laboratory data showed that human 
 atrial natriuretic hormone ( hanp ) and b - type natriuretic hormone ( bnp ) levels were 
 elevated as a heart failure marker ( table 
 1table 1 patient data ) . serum levels of calcium , phosphate and alkaline phosphatase ( alp ) were 
 within the normal range , 8.8 mg / dl , 3.4 mg / dl and 181 u / l , respectively urinary calcium was increased judging from 
 0.71 of urinary calcium / creatinine ( ca / cr ) . the ratio of maximal renal tubular 
 reabsorption to the glomerular filtration rate ( tmp / gfr ) was not reduced . dual - energy 
 x - ray absorptiometry ( dxa ) with lunar dpx - l densitometer model detected low bmd of the 
 lumbar spine ( l2-l4 ) , 0.795 g / cm . since the bmd was 71% of the young adult 
 mean ( yam ) and no fragility fracture was found , a diagnosis of decreased bone mass was 
 made , and the oral administration of 5 mg of alendronate daily was started . the serum level of calcium , 8.8 mg / dl , in the 
 eleven months from the start of treatment with alendronate , did not fall below the normal 
 range ( 8.410.0 mg / dl ) . with regard to other laboratory data , which were obtained eleven months after treatment 
 with alendronate , the serum level of intact parathyroid hormone ( pth ) was elevated to 
 180.0 pg / ml ; the 25-hydroxyvitamin d ( 25ohd ) level was relatively low , 15.8 ng / ml ; and the 
 1,25-dihydroxyvitamin d ( 1,25(oh)2d ) level was elevated , 120 pg / ml ( table 1 ) . the urinary excretion of calcium per day 
 increased to 6.2 mg / kg / day . on the other hand , calcium intake was calculated as 390 mg per 
 day , suggesting a negative balance of calcium because the calcium absorption rate is 
 usually less than 50% . vitamin d intake was calculated as 136 iu per day . in the analyses 
 of biochemical markers of bone turnover , urinary deoxypyridinoline ( dpd ) level was 
 elevated , 10.1 nmol / mmolcr , while urinary ntx and serum osteocalcin levels were normal , 
 46.7 nmolbce / mmolcr and 10.9 ng / ml , respectively . 1 changes in bmd ( l2-l4 ) , urinary ca / cr , and pth during treatment with 
 bisphosphonates . in patient 1 ( a ) , alendronate and subsequent risedronate increased 
 the bmd of l2-l4 . however , decreased urinary calcium was not observed and increased 
 levels of pth were maintained during bisphosphonate therapy , although urinary ca / cr 
 showed significant variance . the replacement of furosemide with thiazide was tried , 
 but was discontinued because of increased complaints of fatigue . in patient ( b ) , bmd 
 of l2-l4 was increased after treatment with alendronate and alfacalcidol , although 
 its slightly increased urinary ca / cr and elevated levels of pth were maintained 
 during therapy . * * percentage of the mean 
 in same - age healthy girls ( 19 ) . ) . however , urinary ca / cr showed significant variance from 0.03 to 1.19 , and no 
 persistent decrease in urinary calcium was observed during bisphosphonate therapy for two 
 years . increased levels of pth were maintained between 135 and 244.9 pg / ml during the 
 therapy . we tried to replace furosemide with thiazide , but this was discontinued because 
 of increased complaints of fatigue . changes in bmd ( l2-l4 ) , urinary ca / cr , and pth during treatment with 
 bisphosphonates . in patient 1 ( however , decreased urinary calcium was not observed and increased 
 levels of pth were maintained during bisphosphonate therapy , although urinary ca / cr 
 showed significant variance . the replacement of furosemide with thiazide was tried , 
 but was discontinued because of increased complaints of fatigue . in patient ( b ) , bmd 
 of l2-l4 was increased after treatment with alendronate and alfacalcidol , although 
 its slightly increased urinary ca / cr and elevated levels of pth were maintained 
 during therapy . * * * percentage of the mean 
 in same - age healthy girls ( 19 ) . patient 2 was a 17-yr - old girl with restrictive cardiomyopathy and pulmonary 
 hypertension . she was also referred to pediatric 
 endocrinologists with lumbago at the age of 17 . she went out for an hour every three days , 
 although she suffers from mild heart failure , and her menstruation is regular . at the 
 first consultation , her height and weight were 152.5 cm and 45.1 kg , respectively ( bmi was 
 19.4 ) . laboratory tests showed elevated levels of hanp and bnp ( table 1 ) . before treatment with alendronate , serum levels of 
 calcium , phosphate and alp were within the normal range , 9.4 mg / dl , 4.4 mg / dl and 125 u / l , 
 respectively . the 25ohd level was relatively low , 16.0 ng / ml , 
 while the 1,25(oh)2d level was slightly elevated , 65 pg / ml . urinary calcium was 
 slightly elevated judging from 0.31 of urinary ca / cr , although the urinary excretion of 
 calcium per day was not increased , 1.5 mg / kg / day . calcium intake was calculated as 300 mg 
 per day , suggesting a negative balance of calcium because the calcium absorption rate is 
 usually less than 50% . urinary dpd and 
 ntx levels , markers of bone resorption , were elevated , 10.1 nmol / mmolcr and 87.0 
 nmolbce / mmolcr , respectively . serum bone - specific alp ( bap ) and osteocalcin , markers of 
 bone formation , were also elevated , 56.9 u / l and 16.8 ng / ml , respectively . since her bmd 
 was 80% of the mean in same - aged healthy girls and she suffered from lumbago , oral 
 alendronate , 5 mg daily , and alfacalcidol , 2.5 g daily , were started ( 18 ) . lumbago disappeared two months after the treatment 
 and the bmd of l2-l4 was increased . however , elevated levels of pth were maintained 
 between 84.2 and 194.8 pg / ml during therapy . the serum level of calcium , 8.8 mg / dl , in the 
 two months from the start of treatment with alendronate did not fall below the normal 
 range . treatment with furosemide is recognized as a risk factor of osteoporosis due to increased 
 excretion of calcium ( 7 ) . patient 2 showed an increased level of urinary 
 ca / cr , but the total amount of daily calcium excretion was not remarkable . this was probably 
 because of incomplete collection of urine judging from the falsely low levels of creatinine 
 clearance when cr excretion levels were considered . thus , these cases support the previous 
 observation that a long - term negative balance of calcium associated with furosemide 
 treatment may lead to secondary hyperparathyroidism and low levels of bmd . thus , the replacement of furosemide with thiazide 
 is an alternative to avoid a negative balance of calcium . however , it is sometimes 
 impossible to change furosemide to thiazide , partly because furosemide has a stronger effect 
 as a diuretic . the diagnostic criteria of decreased bone mass in adolescence have not been defined at 
 present . we judged that it was appropriate for the diagnostic criteria of decreased bone 
 mass in adult to be applied to patient 2 in adolescence ( 18 ) . bmd was measured by dxa with a lunar dpx - l densitometer model in both 
 patients , and therefore standard reference values of lumbar spine in normal adolescents , 
 measured by the same densitometer , were adopted in patient 2 , although the described 
 subjects were white mediterranean spanish adolescents ( 19 ) . since bmd of lumbar spine in patients 1 and 2 were 71% and 80% of the mean in 
 healthy women , respectively , and they had no fragility fracture in spite of lumbago , a 
 diagnosis of decreased bone mass was made . a low intake of 
 calcium was a factor in the deterioration of hyperparathyroidism and low bmd of these 
 patients ( 21 ) . as it is another deterioration factor 
 in hyperparathyroidism and low bmd , we should be aware of the vitamin d status of these 
 patients . these levels do not 
 indicate a vitamin d - deficient status , but a vitamin d - insufficient status , which may cause 
 hyperparathyroidism and rickets in infancy and early childhood as we and others have 
 reported ( 5 , 22 ) . however , our patients were older and vitamin d insufficiency at these levels 
 would have been unlikely to have been the main cause of hyperparathyroidism and low bmd . immobilization is another factor in increased calcium loss and low bmd , but both of our 
 patients walked around every day or every three days , respectively . probably the activities 
 of our patients were not major sources of increased calcium loss and low bmd . congestive 
 heart failure and cyanosis are also harmful to bone health , but our patients did not suffer 
 from severe heart failure or a low saturation level of oxygen ( 23 ) . in addition , hypogonadism in late adolescence is associated with low 
 bmd ( 24 ) . both of our patients had regular 
 menstruation cycles , although their serum levels of e2 , lh and fsh were unclear . large control studies have 
 shown that alendronate and risedronate are effective at preventing bone loss in patients 
 with primary and secondary hyperparathyroidism ( 12 ) . an observational follow - up showed that alendronate was well tolerated over a 10-yr period 
 for osteoporosis in postmenopausal women ( 25 ) . however , it was reported that severe suppression of bone turnover and non - spinal fractures 
 developed during long - term alendronate therapy ( 26 ) . bisphosphonates should be used carefully , with measurement of bmd and biochemical markers of 
 bone turnover . although a consensus on the time to discontinue bisphosphonates has not 
 currently been achieved , we are planning to discontinue them , once bmd reaches 100% of the 
 mean of healthy women or before excessive suppression of bone turnover is observed . besides , intravenous administration of bisphosphonates often leads to a symptomatic or 
 symptomatic hypocalcemia . it was reported that vitamin d deficiency resulted in severe 
 hypocalcemia , coupled with an intravenous bisphosphonate ( 27 ) . however , oral administration of alendronate is seldom related to hypocalcemia 
 ( 28 ) . neither of our patients had developed 
 hypocalcemia at several months after the initiation of oral alendronate , although the levels 
 of 25ohd were vitamin d - insufficient statuses . furosemide inhibits transcellular nacl reabsorption in the thick ascending loop of henle , 
 and then suppresses the transepithelial potential difference and calcium , magnesium and 
 sodium reabsorption . since the target of furosemide in the kidney is not affected by 
 bisphosphonate , it is highly likely that hypercalciuria continues after the administration 
 of bisphosphonate . however , it is necessary to examine whether the long - term of 
 administration of bisphosphonate ameliorates hypercalciuria . although bisphosphonate could 
 not reduce the excretion of calcium in urine , it increased bmd in our patients , probably due 
 to the inhibition of bone resorption . in conclusion , two patients with mild heart failure who had received long - term furosemide 
 therapy developed secondary hyperparathyroidism and low bmd . treatment with bisphosphonate 
 successfully increased bmd without obvious side - effects , although hypercalciuria and 
 secondary hyperparathyroidism remained .
bisphosphonate is widely used to treat patients with primary and secondary osteoporosis . 
 the chronic administration of furosemide is considered a risk factor for osteoporosis 
 mainly due to the increased urinary excretion of calcium , leading to a long - term negative 
 balance of calcium . 
 we describe two patients with mild heart failure who took furosemide 
 for more than 5 yr and developed hyperparathyroidism and lumbago associated with low bone 
 mineral density . 
 their serum levels of intact parathyroid hormone and bone mineral density 
 ( bmd ) of the lumbar spine ( l2-l4 ) were 180.8 and 144.3 pg / ml , and 71% and 80% of the mean 
 of healthy women , respectively . 
 the oral administration of alendronate or risedronate was 
 effective for lumbago and improved bmd , although the urinary excretion of calcium and 
 hyperparathyroidism were not changed . 
 for the medical treatment of lumbago and decreased 
 bone mass secondary to the long - term administration of furosemide , bisphosphonate is 
 proposed when the dose of furosemide can not be reduced . 
 however , it may be important to 
 give sufficient calcium and vitamin d to patients to improve secondary 
 hyperparathyroidism .