Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents Summary The effect of equivalent oral doses of vitamin D3 600 IU/day , 4200 IU/week and 18,000 IU/month on vitamin D status was compared in a randomized clinical trial in nursing home residents . A daily dose was more effective than a weekly dose , and a monthly dose was the least effective . Introduction Vitamin D deficiency is common in older persons , in particular in residents of homes for the elderly and nursing homes and in patients with hip fracture -LSB- 1 -- 3 -RSB- . In these groups the prevalence of vitamin D deficiency , defined at that time as serum 25 -LRB- OH -RRB- D < 30 nmol/L based on values in healthy blood donors , was reported to be 75 % -LSB- 3 -RSB- . This is mainly explained by the fact that older persons do not often go outside in the sunshine and dietary vitamin D intake is low . Vitamin D deficiency causes secondary hyperparathyroidism , which leads to cortical bone loss , osteoporosis and fractures -LSB- 4 -RSB- . It may also cause fatigue , muscle weakness , increased body sway and falls -LSB- 5 , 6 -RSB- . Vitamin D supplementation in vitamin D deficient elderly increases the serum concentration of 25-hydroxyvitamin D -LRB- 25 -LRB- OH -RRB- D -RRB- and decreases the serum concentration of parathyroid hormone -LRB- PTH -RRB- -LSB- 3 -RSB- . It also decreases wintertime bone loss from the lumbar spine -LSB- 7 -RSB- and increases bone mineral density of the femoral neck -LSB- 8 -RSB- . Vitamin D supplementation combined with calcium decreased body sway and falls in a German study -LSB- 5 -RSB- and decreased hip as well as other non-vertebral fractures in French nursing home residents -LSB- 9 -RSB- , whereas the results in more healthy elderly , living independently in the community were equivocal -LSB- 10 -- 14 -RSB- . Vitamin D status in the elderly may be improved by ultraviolet irradiation -LSB- 15 -RSB- or by vitamin D supplementation -LSB- 3 , 7 , 8 -- 14 -RSB- . Some controversy exists on the required serum 25 -LRB- OH -RRB- D level , but most investigators agree that the level should be at least 50 or even 75 nmol/l -LSB- 16 , 17 -RSB- . The Dutch Health Council advises vitamin D 600 IU daily for elderly of 70 years and older who do not come outside in the sunshine -LSB- 18 -RSB- . Oral vitamin D3 can be taken once a day but also with longer intervals because of its long half life , being around 25 days . It is not known whether equivalent doses once a week or once a month are equally effective . A low calcium intake aggravates vitamin D deficiency by increasing the turnover of vitamin D metabolites by secondary hyperparathyroidism -LSB- 4 -RSB- . On the other side , a high calcium intake does not completely protect against secondary hyperparathyroidism , and thus can not compensate for vitamin D insufficiency -LSB- 19 -RSB- . The calcium requirement for skeletal maintenance is raising with age whereas the capacity for compensating a low calcium intake declines with age -LSB- 20 -RSB- . In the Netherlands the mean daily calcium intake of independently living elderly in homes and apartments of the elderly is about 900 mg -LSB- 2 -RSB- . In the guidelines of the Dutch Health Council , the advised daily amount of calcium for elderly 70 years and older is 1200 mg -LSB- 18 -RSB- . The aim of the present study was to investigate , in a Dutch nursing home population , whether there is a difference in efficacy of different doses and intervals of oral vitamin D3 supplementation with the same total dose . A second aim was to assess the additional effect of calcium supplementation following vitamin D supplementation on serum PTH and markers of bone turnover . Subjects and methods Subjects Ten somatic and psychogeriatric nursing homes participated and 1,006 subjects were invited . Of these , 146 did not respond , 386 refused to participate and 136 did not meet inclusion criteria . Participants were 338 -LRB- 76 male and 262 female -RRB- patients of 70 years or older with a mean age of 84 years -LRB- SD 6.2 -RRB- . Exclusion criteria were going outside in the sunshine more than once a week , the use of vitamin D or calcium supplementation , the use of more than one vitamin D-fortified food or drink per day , complete immobilisation and a very poor life expectancy . Poor cognition was not an exclusion criterion . This did not affect adherence . Nursing homes were enrolled in the study throughout the year . Participants living together in the same nursing home started the study during the same season . The dietary vitamin D intake was estimated at about 100 IU/day , based on fish and margarine consumption . In the Netherlands only margarine is fortified with vitamin D3 -LRB- 3 IU/g -RRB- and the diet does not contain vitamin D2 . Written informed consent was obtained from participants or their proxies . The protocol as well as the patient information letters were approved by the Ethical Review Board of the VU University medical centre . Randomisation Participants were randomised in blocks of six , to receive , during the study period of four and a half months , either oral vitamin D3 600 IU/day -LRB- one tablet -RRB- or placebo , 4200 IU/week -LRB- seven tablets once a week -RRB- or placebo or 18,000 IU/month -LRB- one powder once a month -RRB- or placebo . -LRB- Solvay Pharmaceuticals , Weesp , Netherlands -RRB- . After four months , participants in every group were randomised again to receive during 14 days either calcium carbonate or placebo . The first 156 participants who were randomised received 800 mg calcium carbonate -LRB- 320 mg Ca2 + -RRB- or placebo , the subsequent 120 participants received 1,600 mg calcium carbonate -LRB- 640 mg Ca2 + -RRB- or placebo . The study medication was centrally distributed to ensure compliance . The study was completed by 269 patients . Measurements At baseline co-medication was registered and a questionnaire for dietary calcium intake was used to calculate the mean daily calcium intake from dairy products , underestimating calcium intake by 200 -- 300 mg/day -LSB- 2 , 21 -RSB- . The ability of standing and walking was assessed by a standing score , ranging from 1 -LRB- can not stand alone -RRB- to 5 -LRB- can easily get up and remain standing without help -RRB- and a walking score ranging from 1 -LRB- can not do one active step -RRB- to 5 -LRB- completely independent walking -RRB- . Both scores have previously been described -LSB- 22 -RSB- . During the study all falls and fractures were registered by the nursing staff on special forms and checked with the routine incident registration . At the end of each study period in a nursing home , every ward was asked to complete a questionnaire on the opinion of the nursing staff about the suitability of each distribution form , compliance , the risk of making mistakes , time investment and preferences . Random samples of the returned medication were counted in order to verify compliance . Adequate compliance was defined to exist when more than 80 % of the study medication was ingested . Twice a quality check was made on the research medication by taking random samples for determining the vitamin D3 content of tablets and powders . Fasting blood samples were obtained at baseline , at two and four months . Serum 25 -LRB- OH -RRB- D was measured by radioimmunoassay -LRB- Diasorin , Stillwater , MN -RRB- with an inter-assay coefficient of variation -LRB- CV -RRB- of 10 % at 30 nmol/L . Serum PTH was measured by radioimmunoassay -LRB- Incstar , San Juan Capistrano , CA -RRB- with an inter-assay CV of 10 % at 3.5 pmol/L . Serum carboxy-terminal collagen crosslinks or CTX , a marker for bone resorption , was measured by immuno-assay -LRB- CrossLaps , -LRB- Roche -RRB- with an interassay CV of 5 % . For these parameters the sera of a single participant were all measured within the same run to decrease variation . Serum calcium , phosphate , albumin , creatinine and alkaline phosphatase -LRB- APh -RRB- were measured using standard laboratory procedures , immediately after obtaining the blood samples . Serum calcium was corrected for serum albumin using the formula : Statistical analysis Statistical analysis was performed using SPSS 12.0.1 . Data are presented as means -LRB- and standard deviation -LSB- SD -RSB- -RRB- or -- in case of skewed distributions -- as medians -LRB- and interquartile range -LSB- IQR -RSB- -RRB- . Associations between baseline serum 25 -LRB- OH -RRB- D and PTH , PTH and AF , and AF and CTX were examined by means of the Pearson correlation coefficient or -- when one or both outcome variables had a skewed distribution -- the Spearman rank order correlation coefficient . Baseline characteristics of dropouts and completers were compared by logistic regression analysis . Linear multilevel analysis with SPSS Mixed Models was used to investigate : -LRB- 1 -RRB- the effect of vitamin D supplementation on change -LRB- from baseline -LRB- t0 -RRB- to 4 months -LRB- t2 -RRB- -RRB- in biochemical outcome variables -LRB- serum 25 -LRB- OH -RRB- D , serum PTH , bone turnover markers -RRB- and -LRB- 2 -RRB- the effect of additional calcium supplementation on change -LRB- from 4 months -LRB- t2 -RRB- to 4.5 months -LRB- t3 -RRB- -RRB- in biochemical outcome variables , adjusting for possible clustering of observations . The included levels were repeated measures -LRB- i.e. , time -RRB- , respondent , and nursing home . Nursing home was included in the final analyses only in case of a change of the effect size of more than 10 % . Separate models were created with 25 -LRB- OH -RRB- D , phosphate , corrected calcium , CTX , PTH , and APh as the respective dependent variables . We examined the potential confounding effect of season , age , sex , mean daily calcium intake , creatinine , standing and walking score at t0 . For PTH and APh , logarithmic transformations were performed to normalize variance to allow parametric tests . For these log-transformed outcome variables , the estimated mean difference between two intervention groups was transformed back using an antilog transformation . The resulting estimate is the ratio of the geometric means of the outcome variable in both intervention groups . The geometric mean resembles the median . The level of significance was set at P < 0.05 . Results Baseline characteristics Table 1 shows the baseline characteristics of the 338 participants enrolled in the study . These were very similar for the different intervention groups . In the total group , baseline mean serum 25 -LRB- OH -RRB- D was 25.0 nmol/L -LRB- SD 10.9 -RRB- . In 55 % of the participants , serum 25 -LRB- OH -RRB- D was lower than 25 nmol/L while 77 % had levels below 30 nmol/L and 98 % below 50 nmol/L -LRB- data not shown -RRB- . Baseline median serum PTH was 7.2 pmol/L -LRB- IQR 5.1 -- 10.5 -RRB- -LRB- ref . values : 1 -- 11 pmol/L -RRB- . There were statistically significant correlations at baseline between serum 25 -LRB- OH -RRB- D and serum PTH values -LRB- r = − 0.25 ; P < 0.001 -RRB- , serum PTH and serum APh values -LRB- r = 0.16 ; P < 0.01 -RRB- , and serum APh and serum CTX values -LRB- r = 0.23 ; P < 0.001 -RRB- -LRB- data not shown -RRB- . The median daily calcium intake from dairy products was 750 mg -LRB- IQR 560 -- 1035 -RRB- . Table 1Characteristics of 338 participants at baseline -LRB- t0 -RRB- by intervention group at t0 -LRB- Pl D = placebo vitamine D , D = vitamin D -RRB- and t2 -LRB- Pl Ca = placebo calcium , Ca = calcium -RRB- TotalD totalD dailyD weekyD monthlyPl D totalCabPl Cab -LRB- = 338 -RRB- -LRB- = 166 -RRB- -LRB- = 55 -RRB- -LRB- = 54 -RRB- -LRB- = 57 -RRB- -LRB- = 172 -RRB- -LRB- = 68 -RRB- -LRB- = 71 -RRB- % female77 .576.583.672.273.778.576.578.9 VariableMean -LRB- SD -RRB- Mean -LRB- SD -RRB- Mean -LRB- SD -RRB- Mean -LRB- SD -RRB- Mean -LRB- SD -RRB- Mean -LRB- SD -RRB- Mean -LRB- SD -RRB- Mean -LRB- SD -RRB- Age -LRB- yr -RRB- 84.2 -LRB- 6.2 -RRB- 84.2 -LRB- 6.5 -RRB- 84.3 -LRB- 6.3 -RRB- 84.3 -LRB- 6.4 -RRB- 83.9 -LRB- 6.9 -RRB- 84.2 -LRB- 5.9 -RRB- 83.3 -LRB- 6.2 -RRB- 84.5 -LRB- 6.8 -RRB- 25 -LRB- OH -RRB- D -LRB- nmol/L -RRB- 25.0 -LRB- 10.9 -RRB- 24.9 -LRB- 10.1 -RRB- 24.0 -LRB- 8.6 -RRB- 26.7 -LRB- 12.6 -RRB- 24.1 -LRB- 8.8 -RRB- 25.0 -LRB- 11.7 -RRB- 25.3 -LRB- 10.6 -RRB- 24.1 -LRB- 9.6 -RRB- Calcium corrected -LRB- mmol/L -RRB- 2.42 -LRB- 0.10 -RRB- 2.42 -LRB- 0.09 -RRB- 2.42 -LRB- 0.09 -RRB- 2.41 -LRB- 0.08 -RRB- 2.42 -LRB- 0.10 -RRB- 2.43 -LRB- 0.10 -RRB- 2.41 -LRB- 0.08 -RRB- 2.42 -LRB- 0.10 -RRB- Phosphate -LRB- mmol/L -RRB- 1.03 -LRB- 0.14 -RRB- 1.02 -LRB- 0.14 -RRB- 1.02 -LRB- 0.13 -RRB- 1.02 -LRB- 0.16 -RRB- 1.02 -LRB- 0.13 -RRB- 1.04 -LRB- 0.14 -RRB- 1.01 -LRB- 0.14 -RRB- 1.03 -LRB- 0.13 -RRB- CTX -LRB- ng/L -RRB- 592 -LRB- 277 -RRB- 571 -LRB- 274 -RRB- 594 -LRB- 274 -RRB- 626 -LRB- 311 -RRB- 496 -LRB- 218 -RRB- 613 -LRB- 280 -RRB- 552 -LRB- 288 -RRB- 565 -LRB- 255 -RRB- Albumin -LRB- g/L -RRB- 33.4 -LRB- 3.3 -RRB- 33.4 -LRB- 3.3 -RRB- 33.0 -LRB- 3.5 -RRB- 33.1 -LRB- 3.4 -RRB- 34.2 -LRB- 2.8 -RRB- 33.4 -LRB- 3.2 -RRB- 34.0 -LRB- 3.2 -RRB- 33.0 -LRB- 3.4 -RRB- Standing score -LRB- 1 -- 5 -RRB- 3.3 -LRB- 1.6 -RRB- 3.3 -LRB- 1.6 -RRB- 3.5 -LRB- 1.6 -RRB- 3.1 -LRB- 1.7 -RRB- 3.5 -LRB- 1.6 -RRB- 3.3 -LRB- 1.6 -RRB- 3.2 -LRB- 1.7 -RRB- 3.5 -LRB- 1.6 -RRB- Walking score -LRB- 1 -- 5 -RRB- 3.0 -LRB- 1.4 -RRB- 3.0 -LRB- 1.4 -RRB- 3.0 -LRB- 1.4 -RRB- 3.0 -LRB- 1.6 -RRB- 3.0 -LRB- 1.3 -RRB- 3.0 -LRB- 1.4 -RRB- 2.9 -LRB- 1.4 -RRB- 3.1 -LRB- 1.4 -RRB- Skewed variableMedian -LRB- IQR -RRB- Median -LRB- IQR -RRB- Median -LRB- IQR -RRB- Median -LRB- IQR -RRB- Median -LRB- IQR -RRB- Median -LRB- IQR -RRB- Median -LRB- IQR -RRB- Median -LRB- IQR -RRB- Calcium intake -LRB- mg/day -RRB- b750 -LRB- 560 -- 1035 -RRB- 750 -LRB- 594 -- 1015 -RRB- 725 -LRB- 623 -- 1039 -RRB- 755 -LRB- 550 -- 1028 -RRB- 788 -LRB- 583 -- 955 -RRB- 750 -LRB- 550 -- 1053 -RRB- 773 -LRB- 614 -- 1024 -RRB- 730 -LRB- 565 -- 1003 -RRB- PTH -LRB- pmol/L -RRB- 7.2 -LRB- 5.1 -- 10.5 -RRB- 7.2 -LRB- 5.2 -- 10.4 -RRB- 7.4 -LRB- 5.2 -- 10.4 -RRB- 6.7 -LRB- 5.3 -- 9.9 -RRB- 7.2 -LRB- 5.1 -- 10.5 -RRB- 7.1 -LRB- 5.1 -- 11.1 -RRB- 6.5 -LRB- 5.2 -- 9.4 -RRB- 7.3 -LRB- 5.1 -- 10.9 -RRB- AF -LRB- U/L -RRB- 85 -LRB- 69 -- 102 -RRB- 86 -LRB- 71 -- 104 -RRB- 82 -LRB- 73 -- 100 -RRB- 90 -LRB- 68 -- 106 -RRB- 87 -LRB- 67 -- 105 -RRB- 85 -LRB- 69 -- 99 -RRB- 89 -LRB- 68 -- 105 -RRB- 82 -LRB- 67 -- 98 -RRB- Creatinine -LRB- μmol/L -RRB- 93 -LRB- 81 -- 103 -RRB- 92 -LRB- 81 -- 103 -RRB- 87 -LRB- 80 -- 95 -RRB- 96 -LRB- 85 -- 104 -RRB- 94 -LRB- 81 -- 105 -RRB- 93 -LRB- 82 -- 105 -RRB- 91 -LRB- 80 -- 102 -RRB- 92 -LRB- 81 -- 102 -RRB- IQR = interquartile rangeaFrom dairy productsbWithin participants completing the vitamin D intervention -LRB- = 276 -RRB- treated with vitamin D -LRB- = 139 -RRB- Trial schedule Figure 1 shows the trial schedule as well as the results of the randomisation procedure of both the vitamin D and the calcium intervention . Of the 341 participants originally enrolled , three were enrolled incorrectly because of hypercalcemia -LRB- corrected serum calcium : 2.69 ; 2.83 ; and 2.85 -RRB- , leaving 338 participants eligible for the study . Fig. 1Flow diagram of progress through the randomized clinical trial of vitamin D supplementation followed by the randomized clinical trial of calcium supplementation Vitamin D intervention The 338 enrolled participants were randomised to treatment with vitamin D3 one tablet of 600 IU each day -LRB- n = 55 -RRB- , a placebo in the form of one tablet each day -LRB- n = 57 -RRB- , vitamin D3 in the form of seven tablets -LRB- 4200 IU -RRB- once a week -LRB- n = 54 -RRB- , a placebo in the form of seven tablets once a week -LRB- n = 58 -RRB- , vitamin D3 in the form of one powder once a month -LRB- n = 57 -RRB- , or a placebo in the form of one powder of 1,800 IU once a month -LRB- n = 57 -RRB- . The treatment period of four months was completed by 276 participants . Of the 62 drop-outs , 41 died during the study period and there were 21 withdrawals : nine participants became terminally ill ; five participants became uncooperative to donate a blood sample ; one participant showed signs of discomfort during blood sampling ; one participant became immobile ; 3 participants were moved elsewhere ; and one participant dropped out for unknown reasons . Finally , one participant was excluded from the analyses due to extremely high levels of alkaline phosphatase -LRB- 278 , 1025 , 2661 U/L at , respectively , t0 , t1 , t2 -RRB- for unknown reasons -LRB- further analysis was refused by the patient -RRB- . The number of drop-outs did not differ significantly between the placebo -LRB- n = 35 -RRB- and the vitamin D group -LRB- n = 27 -RRB- . Dropouts were similar to completers with respect to most baseline characteristics -LRB- sex , age , 25 -LRB- OH -RRB- D , corrected calcium , phosphate , albumin , standing score , walking score , mean daily calcium intake , and creatinine -RRB- , but had higher serum levels of CTX , and APh -LRB- P < 0.05 -RRB- -LRB- data not shown -RRB- . Calcium intervention The 276 participants who completed the vitamin D intervention study were randomised to treatment with calcium one tablet each day -LRB- n = 138 -RRB- , or placebo one tablet each day -LRB- n = 138 -RRB- . The treatment period of 14 days was completed by 269 participants . Of the seven drop-outs , three died , three became terminally ill and one participant dropped out for unknown reasons . Only those treated with vitamin D were included in the analysis of the calcium intervention -LRB- n = 68 for calcium ; n = 71 for placebo -RRB- ; there was only one drop-out in each group . Effectiveness of Vitamin D supplementation Nursing home and potential confounding variables at baseline were not included in the final models since the effect sizes were hardly influenced by adding these variables . Serum 25-hydroxyvitamin D Effects of vitamin D supplementation on serum 25 -LRB- OH -RRB- D in the various treatment groups are shown in Table 2 and Fig. 2 . The mean difference in increase of serum 25 -LRB- OH -RRB- D was 38.5 nmol/L -LRB- 95 % confidence interval -LRB- CI -RRB- 25.6 -- 41.5 -RRB- in favour of vitamin D when compared to placebo . Daily , weekly and monthly administration of vitamin D resulted in increase of serum 25 -LRB- OH -RRB- D when compared to placebo -LRB- P < 0.001 -RRB- . The mean difference in increase of serum 25 -LRB- OH -RRB- D was highest after 4 months with daily administration of vitamin D -LRB- mean 47.2 nmol/l -RRB- when compared to weekly -LRB- mean 40.7 nmol/l , P < 0.01 -RRB- and monthly -LRB- mean 27.6 nmol/l , P < 0.001 -RRB- administration . Weekly administration of vitamin D resulted in a greater increase of serum 25 -LRB- OH -RRB- D than monthly administration -LRB- P < 0.001 -RRB- . The percentage of patients with serum 25 -LRB- OH -RRB- D below cut offs of 25 nmol/l , 50 nmol/l and 75 nmol/l is shown in Table 3 . At 4 months , the percentage of patients with serum 25 -LRB- OH -RRB- D < 50 nmol/l was 10.9 , 10.6 and 36.4 % in the daily , weekly and monthly groups of vitamin D supplementation respectively . Table 2Mean and standard deviation -LRB- SD -RRB- or median and interquartile range -LRB- IQR -RRB- for biochemical measurements at baseline -LRB- t0 -RRB- , after 2 months -LRB- t1 -RRB- and after 4 months intervention -LRB- t2 -RRB- with placebo -LRB- Pl -RRB- or vitamin D -LRB- D -RRB- daily , weekly , or monthly in 276 participants Mean -LRB- SD -RRB- or median -LRB- IQR -RRB- GroupsaMean differenceb or ratio geometric meansc -LRB- 95 % CI -RRB- P valuebGroupsaMean differenceb or ratio geometric meansc -LRB- 95 % CI -RRB- P valuebt0t1t2t0 → t2t0 → t2t0 → t2t0 → t2Serum concentration25 -LRB- OH -RRB- D -LRB- nmol/L -RRB- Pl25 .2 -LRB- 12.1 -RRB- 24.3 -LRB- 11.2 -RRB- 25.5 -LRB- 12.0 -RRB- D/Pl38 .5 -LRB- 35.7 -- 41.3 -RRB- 0.000 D daily23 .0 -LRB- 8.3 -RRB- 59.9 -LRB- 16.5 -RRB- 69.9 -LRB- 17.8 -RRB- Dd/Pld47 .2 -LRB- 42.3 -- 52.1 -RRB- 0.000 Dd/Dw6 .6 -LRB- 1.7 -- 11.4 -RRB- 0.009 D weekly27 .3 -LRB- 12.7 -RRB- 58.8 -LRB- 12.8 -RRB- 67.2 -LRB- 14.0 -RRB- Dw/Plw40 .7 -LRB- 35.8 -- 45.6 -RRB- 0.000 Dw/Dm11 .2 -LRB- 6.3 -- 16.1 -RRB- 0.000 D monthly23 .8 -LRB- 8.0 -RRB- 44.8 -LRB- 14.1 -RRB- 53.1 -LRB- 15.9 -RRB- Dm/Plm27 .6 -LRB- 22.8 -- 32.5 -RRB- 0.000 Dm/Dd − 17.8 -LRB- − 22.7 -- − 12.8 -RRB- 0.000 Phosphate -LRB- mmol/L -RRB- Pl1 .04 -LRB- 0.12 -RRB- 1.05 -LRB- 0.14 -RRB- 1.01 -LRB- 0.14 -RRB- D/Pl0 .057 -LRB- 0.025 -- 0.088 -RRB- 0.001 D daily1 .01 -LRB- 0.14 -RRB- 1.07 -LRB- 0.12 -RRB- 1.05 -LRB- 0.11 -RRB- Dd/Pld0 .088 -LRB- 0.033 -- 0.143 -RRB- 0.002 Dd/Dw0 .022 -LRB- − 0.033 -- 0.076 -RRB- 0.434 D weekly1 .03 -LRB- 0.15 -RRB- 1.06 -LRB- 0.13 -RRB- 1.04 -LRB- 0.14 -RRB- Dw/Plw0 .065 -LRB- 0.01 -- 0.12 -RRB- 0.022 Dw/Dm − 0.001 -LRB- − 0.055 -- 0.054 -RRB- 0.981 D monthly1 .02 -LRB- 0.13 -RRB- 1.07 -LRB- 0.16 -RRB- 1.04 -LRB- 0.12 -RRB- Dm/Plm0 .017 -LRB- − 0.037 -- 0.072 -RRB- 0.533 Dm/Dd − 0.021 -LRB- − 0.076 -- 0.034 -RRB- 0.454 Calcium corrected -LRB- mmol/L -RRB- Pl2 .42 -LRB- 0.10 -RRB- 2.40 -LRB- 0.09 -RRB- 2.42 -LRB- 0.09 -RRB- D/Pl0 .029 -LRB- 0.008 -- 0.05 -RRB- 0.007 D daily2 .42 -LRB- 0.10 -RRB- 2.42 -LRB- 0.10 -RRB- 2.45 -LRB- 0.10 -RRB- Dd/Pld0 .036 -LRB- 0 -- 0.071 -RRB- 0.050 Dd/Dw0 .006 -LRB- − 0.03 -- 0.042 -RRB- 0.736 D weekly2 .41 -LRB- 0.08 -RRB- 2.41 -LRB- 0.10 -RRB- 2.43 -LRB- 0.10 -RRB- Dw/Plw0 .019 -LRB- − 0.018 -- 0.055 -RRB- 0.307 Dw/Dm − 0.001 -LRB- − 0.036 -- 0.035 -RRB- 0.974 D monthly2 .42 -LRB- 0.09 -RRB- 2.42 -LRB- 0.09 -RRB- 2.44 -LRB- 0.10 -RRB- Dm/Plm0 .033 -LRB- − 0.003 -- 0.068 -RRB- 0.072 Dm/Dd − 0.005 -LRB- − 0.041 -- 0.03 -RRB- 0.762 PTH -LRB- pmol/L -RRB- cPl7 .2 -LRB- 5.0 -- 11.8 -RRB- 7.8 -LRB- 5.6 -- 10.8 -RRB- 7.5 -LRB- 5.1 -- 11.0 -RRB- D/Pl0 .77 -LRB- 0.7 -- 0.85 -RRB- 0.000 D daily7 .3 -LRB- 5.0 -- 10.3 -RRB- 5.7 -LRB- 4.3 -- 7.45.1 -LRB- 3.7 -- 7.7 -RRB- Dd/Pld0 .66 -LRB- 0.56 -- 0.78 -RRB- 0.000 Dd/Dw0 .83 -LRB- 0.7 -- 0.99 -RRB- 0.037 D weekly6 .5 -LRB- 5.3 -- 9.5 -RRB- 6.5 -LRB- 4.6 -- 8.7 -RRB- 5.9 -LRB- 5.2 -- 7.6 -RRB- Dw/Plw0 .85 -LRB- 0.72 -- 1.01 -RRB- 0.067 Dw/Dm1 .02 -LRB- 0.86 -- 1.22 -RRB- 0.773 D monthly7 .2 -LRB- 5.1 -- 10.9 -RRB- 6.6 -LRB- 4.4 -- 9.3 -RRB- 5.6 -LRB- 4.3 -- 8.9 -RRB- Dm/Plm0 .81 -LRB- 0.68 -- 0.96 -RRB- 0.019 Dm/Dd1 .17 -LRB- 0.99 -- 1.39 -RRB- 0.061 CTX -LRB- ng/L -RRB- Pl598 -LRB- 270 -RRB- 612 -LRB- 274 -RRB- 624 -LRB- 256 -RRB- D/Pl − 14 -LRB- − 57 -- 29 -RRB- 0.491 D daily578 -LRB- 267 -RRB- 574 -LRB- 265 -RRB- 579 -LRB- 279 -RRB- Dd/Pld − 34 -LRB- − 109 -- 41 -RRB- 0.341 Dd/Dw1 -LRB- − 73 -- 75 -RRB- 0.976 D weekly606 -LRB- 316 -RRB- 599 -LRB- 314 -RRB- 595 -LRB- 304 -RRB- Dw/Plw − 27 -LRB- − 102 -- 48 -RRB- 0.445 Dw/Dm − 36 -LRB- − 111 -- 39 -RRB- 0.314 D monthly490 -LRB- 207 -RRB- 528 -LRB- 229 -RRB- 523 -LRB- 230 -RRB- Dm/Plm19 -LRB- − 56 -- 93 -RRB- 0.589 Dm/Dd35 -LRB- − 40 -- 110 -RRB- 0.329 AF -LRB- U/L -RRB- cPl84 -LRB- 67 -- 99 -RRB- 82 -LRB- 69 -- 99 -RRB- 82 -LRB- 67 -- 101 -RRB- D/Pl0 .97 -LRB- 0.92 -- 1.03 -RRB- 0.363 D daily82 -LRB- 72 -- 99 -RRB- 88 -LRB- 69 -- 101 -RRB- 82 -LRB- 67 -- 97 -RRB- Dd/Pld0 .96 -LRB- 0.87 -- 1.06 -RRB- 0.412 Dd/Dw0 .96 -LRB- 0.87 -- 1.06 -RRB- 0.394 D weekly88 -LRB- 66 -- 107 -RRB- 81 -LRB- 64 -- 105 -RRB- 80 -LRB- 69 -- 104 -RRB- Dw/Plw1 .03 -LRB- 0.93 -- 1.14 -RRB- 0.553 Dw/Dm1 .1 -LRB- 1 -- 1.21 -RRB- 0.057 D monthly86 -LRB- 67 -- 103 -RRB- 80 -LRB- 64 -- 96 -RRB- 74 -LRB- 63 -- 100 -RRB- Dm/Plm0 .94 -LRB- 0.85 -- 1.03 -RRB- 0.180 Dm/Dd0 .95 -LRB- 0.86 -- 1.05 -RRB- 0.270 aDifferences in mean change between following groups : D/Pl = vitamin D versus placebo ; Dd/Pld = vitamin D daily versus placebo daily ; Dw/Plw = vitamin D weekly versus placebo weekly ; Dm/Plm = vitamin D monthly versus placebo monthly ; Dd/Dw = vitamin D daily versus weekly ; Dw/Dm = vitamin D weekly versus monthly ; Dm/Dd = vitamin D monthly versus dailybMean difference of for example 38.5 for 25 -LRB- OH -RRB- D -LRB- D/Pl -RRB- means that the mean increase of 25 -LRB- OH -RRB- D over 4 months was 38.5 in the vitamin D group compared to zero -LRB- set as a reference -RRB- in the placebo groupcFor PTH and AF the ratio of geometric means -LRB- resembling the ratio of medians -RRB- is presented in stead of the mean difference . Ratio of geometric means of 0.77 for PTH -LRB- D/Pl -RRB- means that the median PTH decreases with a ratio of 0.77 over 4 months in the vitamin D group compared to a ratio of 1.00 -LRB- set as a reference -RRB- in the placebo groupFig . 2Mean -LRB- ± 1.96 × SD -RRB- serum 25 -LRB- OH -RRB- D concentrations at baseline , 2 and 4 months during treatment with vitamin D daily , weekly , or monthly , or placeboTable 3Percentage of participants with 25 -LRB- OH -RRB- D levels below a certain cut-off point at baseline and after vitamin D or placebo supplementationGroup : TotalPlaceboVitamin D totalVitamin D dailyVitamin D weeklyVitamin D monthly25 -LRB- OH -RRB- D < 25 nmol/LBaseline -LRB- t0 -RRB- 55.356.953.660.948.951.12 months -LRB- t1 -RRB- 30.157.82.92.20.06.84 months -LRB- t2 -RRB- 27.452.62.22.20.04.525 -LRB- OH -RRB- D < 50 nmol/LBaseline -LRB- t0 -RRB- 97.596.498.6100.095.7100.02 months -LRB- t1 -RRB- 65.494.836.526.119.165.94 months -LRB- t2 -RRB- 58.097.119.010.910.636.425 -LRB- OH -RRB- D < 75 nmol/LBaseline -LRB- t0 -RRB- 99.699.3100.0100.0100.0100.02 months -LRB- t1 -RRB- 95.299.391.287.089.497.74 months -LRB- t2 -RRB- 88.3100.076.663.072.395.5 Secondary outcome measures : serum phosphate and corrected calcium Serum phosphate and corrected serum calcium values increased significantly more in the vitamin D group than in the placebo group . However , no differences between daily , weekly , or monthly administration were found -LRB- Table 2 -RRB- . Serum parathyroid hormone and bone turnover markers Effects of vitamin D supplementation on serum PTH , serum APh and CTX in the various treatment groups are shown in Table 2 . Serum PTH -LRB- P < 0.000 -RRB- decreased in the vitamin D group from 7.2 to 5.5 pmol/l when compared to placebo , which is a decrease of 23 % -LRB- ratio 0.77 , 95 % CI 0.70 -- 0.85 , < 0.001 -RRB- . The decrease of serum PTH was greater with daily administration of vitamin D when compared to weekly -LRB- P < 0.05 -RRB- and monthly -LRB- P < 0.10 -RRB- administration . The difference between weekly and monthly administration of vitamin D was not significant . The serum concentrations of alkaline phosphatase and CTX did not change following vitamin D supplementation . Effectiveness of calcium supplementation There was no effect of calcium supplementation on any of the six biochemical outcome variables when compared to placebo . Also after stratification by administration of vitamin D -LRB- daily , weekly or monthly -RRB- , an effect of calcium supplementation was not observed except for corrected calcium levels which increased more in the calcium group than in the placebo group in the daily dose vitamin D group only -LRB- P < 0.05 -RRB- . No effect was found of calcium doses -LRB- 800 mg vs 1,600 mg calcium carbonate -RRB- . Adding nursing home and other potential confounding variables at baseline did not influence the results . Fractures The number of falls and fractures did not differ between the intervention groups and the control groups , which was expected given the short study period of four and a half months . Compliance The compliance assessed within 96 random samples of the returned medication was good . In the daily administration group , all 33 participants were compliant -- i.e. , used at least 80 % of the tablets -- -LRB- median = 97.0 ; IQR 94.5 -- 100 -RRB- . For weekly administration , 80 % of the 35 participants were compliant -- i.e. , used at least 80 % of the tablets -LRB- median = 98.5 ; IQR 84.0 -- 100 -RRB- . For monthly administration , 93 % of the 28 participants were compliant -- i.e. , used at least four out of five powders -LRB- median = 100 ; IQR 85.0 -- 100 -RRB- . Survey nursing staff A survey among the nursing staffs of the participating nursing home wards showed a distinct preference -LRB- 72 % -RRB- for daily administration compared to weekly and monthly . Thirty-ning percent of the nursing staffs reported the impression that fewer mistakes were made using daily administration instead of weekly or monthly administration . Discussion The results of this study confirm the poor vitamin D status often observed in institutionalised elderly . In this study , baseline serum 25 -LRB- OH -RRB- D levels in these nursing home residents was comparable to those observed in other studies in institutionalized elderly in the Netherlands -LSB- 2 , 3 -RSB- , resulting in median serum PTH levels in the upper normal range . A negative correlation between serum PTH and serum 25 -LRB- OH -RRB- D was observed , confirming other studies -LSB- 4 -RSB- . In all treatment groups oral vitamin D supplementation appeared to be effective , resulting in increasing serum 25 -LRB- OH -RRB- D levels and decreasing serum PTH levels as observed in other studies -LSB- 3 , 4 , 23 -RSB- . However , no effect was seen on serum alkaline phosphatase and CTX levels . Daily administration of vitamin D3 was significantly more effective than weekly and monthly administration . This could be due to more regular absorption in the gut or better compliance . The percentage of participants with serum 25 -LRB- OH -RRB- D < 50 nmol/l after four months of supplementation was about 10 % in the daily and weekly groups , but was more than 35 % in the monthly group . An option would be to increase the dose when vitamin D is supplemented only once per month . The dose of 600 IU/day was chosen according to the Dutch and US recommendations -LSB- 4 , 18 -RSB- . In order to attain a higher percentage of people with serum 25 -LRB- OH -RRB- D > 50 nmol/l , the dose of vitamin D should be 700 -- 800 IU/day as was recommended for patients with osteoporosis in a recent review -LSB- 24 -RSB- . The overall decrease of serum PTH was 23 % with vitamin D supplementation , which corresponds to our previous vitamin D supplementation study in a nursing home -LSB- 15 -RSB- and which is a larger decrease than that observed in healthy independently living elderly women where the decrease of serum PTH was 15 % -LSB- 8 -RSB- . This is consistent with the more severe vitamin D deficiency and the greater degree of secondary hyperparathyroidism observed in these , mainly psychogeriatric , nursing home residents . Improvement of vitamin D status and suppression of PTH secretion may reduce bone turnover and bone loss , increase bone mineralization and thereby reducing fracture risk , although this was not the subject of this study . For calcium supplementation , calcium citrate , lactate or carbonate can be used . In this study , calcium carbonate was used based upon bioavailability , cost and clinical efficacy -LSB- 25 -RSB- . The absorption of calcium from dairy products is about similar to that from calcium carbonate -LSB- 26 , 27 -RSB- . Because of the side effects of calcium carbonate -LRB- gastrointestinal irritation , constipation , belches -RRB- , possibly more pronounced in a population of frail elderly with substantial comorbidity and comedication , one should not choose a too high supplementation dose . Given the expected dietary calcium intake of about 900 mg per day , two supplementation doses 800 mg calcium carbonate -LRB- 320 mg Ca2 + -RRB- and 1,600 mg calcium carbonate -LRB- 640 mg Ca2 + -RRB- , respectively -RRB- were used . The median calcium intake in these Dutch nursing home residents -LRB- 750 mg per day from dairy products , total estimated dietary intake 950 -- 1,000 mg per day -RRB- was slightly lower than the guidelines recommend and relatively high compared to institutionalised elderly in other countries , probably due to a higher dairy intake . This was expected since every Dutch nursing home has its own dietician . Calcium supplementation combined with vitamin D in the last part of the study did not lead to a decrease of biochemical markers of bone turnover . An explanation might be that immobility is a cause of high bone turnover , which is not suppressed by calcium supplementation . The nursing staff 's preference for daily supplementation of vitamin D is probably due to the fact that it fits better in a regular distribution routine , is less time consuming and less susceptible for making mistakes . In conclusion , 98 % of the participants had a baseline serum 25 -LRB- OH -RRB- D lower than 50 nmol/L . Oral vitamin D3 supplementation , administered daily was more effective than weekly doses in nursing home residents , while monthly administration was the least effective , 35 % still having a serum 25 -LRB- OH -RRB- D < 50 nmol/l after 4 months treatment in this group . Calcium supplementation did not augment the effect of vitamin D supplementation .

O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O B I O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I I O

calcium supplementation
secondary hyperparathyroidism
vitamin d deficiency
vitamin d supplementation


Congenital anomalies of the male urethra The spectrum of congenital anomalies of the male urethra is presented . The embryologic basis of each anomaly , when known , is discussed . Clinical and imaging features of each entity are presented . Introduction The development of the male genitourinary system is complex . Numerous anomalies of the male urethra exist , either as isolated anomalies or in combination with other disorders . The current understanding of the embryology and anatomy of normal male urethral development might help explain the causes of the various anomalies as well as their relationships . Embryology of the male urethra Between weeks four and five of fetal life , the cloaca is separated from the amniotic cavity by the cloacal membrane -LSB- 1 -RSB- . The cloaca is divided into the urogenital sinus and the hindgut by the urorectal septum , which descends in a rostral-to-caudal fashion -LRB- Fig. 1 -RRB- . The urogenital sinus is the precursor of the bladder and posterior urethra . The urorectal septum is formed by proliferation , migration and fusion of mesodermal folds that arise from the lateral walls of the cloaca . When the urorectal septum reaches the caudal aspect of the cloaca , the cloacal folds , which lie on the dorsal portion of the cloacal membrane , fuse to form the rudimentary perineum . The cloacal membrane subsequently undergoes disruption such that the hindgut and phallic cloaca open separately to the exterior , divided by the urorectal septum -LRB- Fig. 2 -RRB- . Fig. 1Embryologic development of the male genitourinary tract . The cloaca is divided into the urogenital sinus -LRB- precursor of the bladder and posterior urethra -RRB- and the hindgut by the urorectal septum -LRB- adapted from reference 2 -RRB- Fig. 2Embryologic development of the male genitourinary tract . The urorectal septum continues to descend and the cloacal membrane undergoes disruption . The hindgut and phallic cloaca now open separately to the exterior -LRB- adapted from reference 4 -RRB- The most caudal aspect of the cloaca -LRB- phallic cloaca -RRB- extends distally through the developing genital tubercle . Proliferation of rostral mesoderm of the genital tubercle displaces the cloaca so that it lies on the caudal aspect of the developing glans -LRB- Fig. 3 -RRB- . Failure of this step results in epispadias . The endodermal lining of the phallic cloaca appose to form the urethral plate . Portions of the cloacal membrane also contribute to the urethral plate -LRB- Fig. 4 -RRB- . The urethral plate undergoes median cleavage . Following mesodermal proliferation and fold fusion extending proximally to distally , the shaft urethra and proximal two-thirds of the glandular urethra are formed . This is lined by endoderm . The distal urethra at the glans penis is formed from fusion of distal folds that arise from the apical part of the glans distal to the cloaca and subsequent urethral plate -LRB- Fig. 4 -RRB- . It is lined by ectoderm -LSB- 2 -- 4 -RSB- . Discontinuity in the urethral plate or abnormality of fusion of the urethral folds can lead to hypospadias . Fig. 3Embryologic development of the male genitourinary tract . The phallic cloaca extends distally through the developing genital tubercle . Proliferation of rostral mesoderm of the genital tubercle displaces the cloaca so that it lies on the caudal aspect of the developing glans -LRB- adapted from reference 2 -RRB- Fig. 4Embryologic development of the male genitourinary tract . Median cleavage of the urethral plate occurs . The urethral plate forms the deep and lateral walls of the proximal urethra . The phallic cloaca opens to the exterior at the base of the glans -LRB- adapted from reference 4 -RRB- Normal anatomy of the male urethra The male urethra is divided into the prostatic , membranous and penile -LRB- cavernous -RRB- urethra -LRB- Figs. 5 and 6 -RRB- . The prostatic urethra courses through the prostate and is the widest part of the urethra . On the posterior wall of the prostatic urethra lies the urethral crest , an elevated longitudinal ridge of tissue . The verumontanum -LRB- seminal colliculus -RRB- is located at the midportion of the urethral crest and is the site of the ejaculatory duct orifices . Additionally , the orifice of the prostatic utricle , a glandular grouping , is located at the summit of the verumontanum . The utricle , a derivative of the Mullerian duct and urogenital sinus , and the male homologue of the uterus and vagina , is a blind indentation that extends dorsally into the prostate and can measure up to 6 mm . The prostatic ducts drain into the prostatic sinus , the fossa on either side of the elevated urethral crest . The intermuscular incisura produces an indentation on the anterior aspect of the prostatic urethra , at the level of the verumontanum , and results from prominent collagenous tissue . Fig. 5Normal male urethral anatomyFig . 6Voiding cystogram in a 3-year-old with prior urinary tract infection . Normal urethral anatomy is shown -LRB- P prostatic urethra , short arrow incisura , long arrow verumontanum -RRB- The membranous urethra is the shortest , least distensible portion of the urethra . It is surrounded by the sphincter urethrae membranaceae -LRB- external sphincter -RRB- , which in addition to vessels , nerves and deep transverse perineal muscle represents the urogenital diaphragm . The internal sphincter is located at the bladder neck . The penile urethra is the longest portion of the urethra . The proximal portion of the penile urethra , the bulbar urethra , is dilated and is the site of drainage of Cowper 's ducts . The penile urethra is also dilated distally at the glans penis , where it forms the fossa navicularis . The midportion of the penile urethra is tethered superiorly by the suspensory ligament -LSB- 5 -RSB- . Congenital anomalies of the urethra Posterior urethral valves Posterior urethral valves -LRB- PUV -RRB- , first described in 1717 by Morgagni , occur in one of every 5,000 -- 8,000 male infants -LSB- 6 -RSB- . PUV can lead to bilateral renal obstruction , bladder dysfunction , vesicoureteral reflux , hydronephrosis and renal damage . In 1919 , Young proposed a classification system consisting of three types of valves . Type I valves -LRB- the most common -RRB- arise from the verumontanum and extend distally to attach to the lateral walls of the urethra as two leaflets -LRB- type Ia -RRB- or as a unicuspid leaflet -LRB- type Ib -RRB- . Type II valves extend proximally from the verumontanum to the bladder neck , and type III valves represent a diaphragm attached to the circumference of the urethra with a central hole , distal -LRB- type IIIa -RRB- or proximal -LRB- type IIIb -RRB- to the verumontanum -LSB- 1 , 8 -RSB- . The existence of Young 's type II valves is debated -LSB- 7 -RSB- . Type III valves are considered by many to be the same entity as Cobb 's collar and are discussed in the section on congenital urethral strictures -LSB- 1 , 7 -RSB- . The valves are composed of connective tissue interspersed with smooth muscle , similar to the tissue encasing the ejaculatory ducts , and are lined by stratified squamous epithelium rather than the transitional epithelium that lines the posterior urethra -LSB- 1 -RSB- . The embryologic defect leading to the development of PUV is not known . Many authors believe the anomaly is caused by abnormal integration of the Wolffian ducts into the urethra , while others consider it a result of persistence of the cloacal membrane -LSB- 1 , 7 -RSB- . Autopsy studies have shown that the valves represent a single obliquely oriented diaphragm rather than a bicuspid structure as originally believed -LSB- 7 , 9 -RSB- . The term congenital obstructive posterior urethral membrane -LRB- COPUM -RRB- has , therefore , been introduced -LSB- 10 -RSB- . Many cases of PUV are detected by prenatal sonography . Normal fetal renal parenchyma and amniotic volume do not necessarily predict good postnatal renal function -LSB- 11 -RSB- . Intrauterine intervention , while improving hydronephrosis , does not prevent the development of renal dysplasia -LSB- 12 -RSB- . Newborns might present with pulmonary hypoplasia secondary to oligohydramnios , or an abdominal mass caused by hydronephrosis or bladder distension . In older patients clinical signs include failure to thrive , poor urinary stream , sepsis , poor renal function or salt-losing nephropathy -LSB- 13 -RSB- . Treatment is by fulguration of the valve , although in infants vesicostomy or pyeloureterostomy might be performed prior to valve ablation . Posterior urethral dilatation persists after fulguration in 20 % of patients . Despite therapy , 40 % of patients have poor renal growth and another 40 % develop end-stage renal disease -LSB- 12 , 14 -RSB- . A normal or near normal serum creatinine level or GFR at 1 year of life , following decompression of the urinary tract , are useful positive prognostic indicators -LSB- 12 , 14 -RSB- . In contrast , the development of proteinuria is associated with a poor prognosis -LSB- 14 -RSB- . Ultrasonography is usually the initial imaging modality used to evaluate patients with suspected PUVs . US reveals a thick bladder wall and bilateral but asymmetric hydronephrosis . Transperineal sonography can demonstrate dilatation of the posterior urethra -LRB- the `` keyhole '' sign -RRB- -LRB- Fig. 7 -RRB- -LSB- 15 -RSB- . A perirenal urinoma from forniceal rupture or urinary ascites can also be seen . PUV is the most common cause of urinary ascites in the newborn -LSB- 16 -RSB- . Echogenic kidneys might also be seen and are associated with a poor prognosis -LSB- 14 -RSB- . Fig. 7Posterior urethral valves . Sonography demonstrates a thick-walled bladder and dilatation of the prostatic urethra -LRB- arrow -RRB- , the `` keyhole sign '' Typical findings of PUV on voiding cystourethrography -LRB- VCUG -RRB- include a trabeculated bladder with diverticula , dilatation of the prostatic urethra and a discrepancy between the caliber of the prostatic urethra and the bulbar and penile portions of the urethra -LRB- Fig. 8 -RRB- . During voiding , the contrast stream between the prostatic urethra and bulbous portion of the urethra is more dorsal in position than normal . Vesicoureteral reflux is present in 50 % of cases and is more often unilateral than bilateral . Reflux into the prostate might also be seen . Fig. 8Posterior urethral valves . An image from a VCUG demonstrates a thick-walled trabeculated bladder and dilatation of the posterior urethra -LRB- long arrow -RRB- , and the location of the valve -LRB- small arrow -RRB- Prune-belly syndrome Prune-belly syndrome -LRB- PBS -RRB- was first described in 1950 by Eagle and Barret as a triad of deficient abdominal wall muscles , urinary tract anomalies and cryptorchidism . Associated abnormalities include cardiac , limb and intestinal abnormalities -LRB- 30 % of patients have malrotation -RRB- . Although PBS is primarily seen in males , it has been described in females ; female patients have genital abnormalities including bicornuate uterus and vaginal atresia -LSB- 17 -RSB- . Urinary tract abnormalities , which can be evaluated by sonography and VCUG , include both upper tract disease and lower tract disease . Hydroureter , more pronounced than the coexisting hydronephrosis , is caused by poor ureteral peristalsis and poor bladder emptying rather than true obstruction . Varying degrees of renal dysplasia with or without cystic change might be present . Characteristic findings on VCUG include a large , smooth-walled bladder without trabeculations and marked bilateral vesicoureteral reflux into tortuous and laterally positioned ureters . A urachal diverticulum might be present , resulting in anterior and midline tethering of the bladder dome -LRB- Fig. 9 -RRB- . Calcification is rarely identified within the bladder and urachal diverticulum and is secondary to urinary stasis -LSB- 18 -RSB- . Fig. 9Prune-belly syndrome . a Images from a VCUG show the characteristic smooth-walled bladder that is tethered anteriorly by a urachal remnant -LRB- long arrow -RRB- . Note the utricle -LRB- short arrow -RRB- arising from the dilated prostatic urethra , which is positioned dorsal to the wide bladder neck . b Voiding film shows dilatation of the proximal urethra consistent with megalourethra . Megalourethra can coexist in these patients The prostatic urethra is dilated secondary to or in association with prostatic aplasia or hypoplasia . -LRB- Pathologically , the verumontanum is small and the ejaculatory ducts are normal . -RRB- Unlike PUVs , the prostatic urethra in patients with PBS is high in position and its posterior wall is elongated relative to its anterior wall . A normal utricle might be present . The penile urethra might be normal , or additional urethral anomalies such as megalourethra , urethral atresia or coexisting posterior urethral valves can be present . Patients with urethral obstruction do not survive -LSB- 17 -RSB- . Congenital urethral stricture Although most urethral strictures in males are post-traumatic , there are rare reports of congenital urethral strictures of the bulbous urethra in neonates and older children -LSB- 19 -RSB- . These might be secondary to a failure of canalization of the cloacal membrane during fetal development -LSB- 1 , 20 -RSB- and have also been referred to as Cobb 's collar , Moormann 's ring and Young 's type III valve -LSB- 7 , 19 -RSB- . Patients present with urinary tract infection . Older children might have diurnal enuresis . Diagnosis is by VCUG or retrograde urethrography . VCUG will demonstrate focal narrowing of the bulbous urethra , while retrograde urethrography will confirm a normal penile urethra . The site of urethral narrowing in congenital urethral stricture is distal to the external urethral sphincter , which differentiates this entity from PUV -LRB- Fig. 10 -RRB- . Vesicoureteral reflux can be seen in up to 53 % of patients -LSB- 20 -RSB- . Treatment is by transurethral incision . Other causes of urethral stricture , including trauma , must be excluded . Fig. 10Congenital urethral stricture . A markedly dilated urethra is seen proximal to a congenital stricture in the bulbous urethra . Retrograde urethrography in this patient -LRB- not shown -RRB- demonstrated a focal narrowing at the bulbous urethra with a normal penile urethra . The site of obstruction is more distal than that seen with PUV Congenital urethral polyps Congenital urethral polyps are benign and arise from the prostatic urethra near the verumontanum . They are composed of vascular connective tissue , although glandular and nerve tissue have been described . Because they have a stalk , these polyps are mobile and can move proximally into the bladder or distally into the bulbous urethra . They can be a cause of urethral obstruction or bleeding . VCUG is diagnostic and demonstrates a mobile filling defect in the bladder neck or below the verumontanum -LRB- Fig. 11 -RRB- . Endoscopic resection is the treatment of choice -LSB- 21 , 22 -RSB- . Fig. 11Urethral polyp . a Image from a VCUG demonstrates a polypoid filling defect arising from the prostatic urethra -LRB- arrow -RRB- . b Note change of position of the filling defect -LRB- arrow -RRB- during the examination -LRB- images courtesy of J. Michael Zerin , MD -RRB- Mullerian duct remnants : enlarged prostatic utricle and Mullerian duct cyst The normal prostatic utricle -LRB- Latin for `` pouch of the prostate '' -RRB- is a minute , blind opening located at the verumontanum -LSB- 23 , 24 -RSB- . It is a glandular grouping lined with epithelial cells with differentiation similar to those lining the main prostatic ducts and acini -LSB- 23 -RSB- . It has no function and is the male homologue of the female uterus and vagina -LRB- Fig. 12 -RRB- . Fig. 12Utricle . Voiding cystourethrogram in a child with urinary tract infection demonstrates a normal utricle that was incidentally detected -LRB- arrow -RRB- . The ventral urethra is not filled with contrast material Midline cystic structures arising at the dorsal aspect of the prostatic urethra represent two distinct categories of Mullerian duct remnants . They are described as enlarged prostatic utricles when they communicate with the urethra and as Mullerian duct cysts when they do not . These terms have been used interchangeably , contributing to confusion in nomenclature . An enlarged prostatic utricle is a congenital abnormality . Although its embryogenesis is not certain , theories include its derivation from the Mullerian duct or urogenital sinus -LSB- 23 -RSB- or secondary to an error in the production or sensitivity to Mullerian regression factor -LSB- 25 -RSB- . Unlike normal prostatic utricles , enlarged prostatic utricles are lined by squamous epithelium . Patients present with urinary tract infection , epididymitis , and postvoid dribbling -LSB- 23 -- 26 -RSB- . Diagnosis is made by VCUG . During voiding , filling of a structure arising from the dorsal aspect of the prostatic urethra is seen -LRB- Fig. 13 -RRB- . Retrograde urethrography is also diagnostic . In some cases , urethroscopy demonstrates absence of the verumontanum -LSB- 23 -RSB- . Fig. 13Enlarged prostatic utricle . There is filling of a large utricle -LRB- arrow -RRB- that arises from and communicates with the posterior urethra in this patient with intersex abnormality . The patient has had penile urethral reconstruction -LRB- asterisk bladder -RRB- Enlarged prostatic utricles are classified according to a grading system . In grade 0 , the opening is located in the prostatic urethra but the utricle does not extend over the verumontanum . In grade I the utricle is larger but does not extend to the bladder neck . In grade II , it extends over the bladder neck , and in grade III , the opening of the utricle opens into the bulbous urethra rather than the prostatic urethra -LSB- 23 -RSB- . Enlarged prostatic utricles are often seen in patients with intersex , hypospadias -LRB- 11 -- 14 % -RRB- , and cryptorchidism . There is a direct relationship between the degree of hypospadias and utricular size -LSB- 25 -RSB- . In contrast to enlarged prostatic utricle , Mullerian duct cysts are acquired abnormalities . They present later in life , are not associated with abnormal genitalia and do not communicate with the urethra . Histologically , they are lined by columnar or cuboidal epithelium identical to that of a normal prostatic utricle . Kato et al. -LSB- 23 , 24 -RSB- have proposed that Mullerian duct cysts develop at a later stage than enlarged prostatic utricles , secondary to narrowing or obstruction of the communication between the normal utricle and the urethra . Patients present with an incidental rectal mass , constipation , urinary retention , hematuria or obstructive azospermia -LSB- 23 -- 26 -RSB- . On US , CT or MRI a cystic mass is identified dorsal to the prostatic urethra -LRB- Fig. 14 -RRB- . This may contain debris . VCUG is not helpful , since these cysts do not communicate with the urethra . Surgical excision is curative . Of note , there is a 3 % incidence of malignancy in Mullerian duct cysts , most commonly occurring in the fourth decade -LSB- 25 -RSB- . Fig. 14Mullerian duct cyst . Transverse sonographic image of the bladder in this 15-year-old boy with recurrent epididymitis demonstrates a cystic mass with internal debris -LRB- arrow -RRB- posterior to the bladder -LRB- asterisk -RRB- Cowper 's syringocele Cowper 's glands are small paired glands located dorsal to and on either side of the membranous urethra . They secrete a mucous substance during ejaculation that acts as a lubricant . The main duct draining Cowper 's glands drain below the urogenital diaphragm into the ventral aspect of the bulbous urethra -LSB- 27 , 28 -RSB- . During VCUG , the main duct and Cowper 's glands can fill with contrast material and appear as a tubular channel paralleling the ventral aspect of the undersurface of the bulbous membranous urethra and ending at the urogenital diaphragm -LRB- Fig. 15 -RRB- -LSB- 29 -RSB- . This finding is usually of no clinical significance . Fig. 15Cowper 's gland . During voiding there is filling of a structure at the ventral aspect of the bulbourethra -LRB- arrow -RRB- Cowper 's syringocele , a rare anomaly , occurs when there is dilatation of the main draining duct . Maizels et al. -LSB- 30 -RSB- described four types of Cowper 's syringocele : simple syringocele , in which there is reflux into a minimally dilated duct ; imperforate syringocele , in which the orifice draining the dilated duct is closed and there is cystic dilatation of the distal duct at the level of the bulbourethra ; perforate syringocele , in which the orifice draining the duct is patulous and there is free reflux into the duct resembling a diverticulum ; and ruptured syringocele , in which the distal portion of the duct is dilated but is not in communication with the more proximal portion of the main duct -LSB- 30 -RSB- . Cowper 's syringocele can also be classified as open or closed , open if it communicates with the urethra and closed if it does not -LSB- 31 -RSB- . Clinically , patients present with frequency , urgency , dysuria , post-void incontinence , hematuria or urinary tract infection . Diagnosis is made by VCUG , retrograde urethrography or urethrocystoscopy . Treatment requires marsupialization of the syringocele . Anterior urethral valves and diverticula Anterior urethral valves and diverticula are rare . Most anterior valves -LRB- 40 % -RRB- are located in the bulbous urethra , but they can also be located at the penoscrotal junction -LRB- 30 % -RRB- and penile urethra -LRB- 30 % -RRB- -LSB- 32 -RSB- . They are composed of folds located on the ventral aspect of the urethra that rise during voiding , resulting in urethral obstruction -LSB- 33 -RSB- . Anterior urethral diverticula communicate with the urethra and are found on the ventral aspect of the urethra between the bulbous and mid-penile urethra -LSB- 32 -RSB- . Although many authors distinguish between anterior urethral valves and diverticula , others consider them the same entity . It has been proposed that valves cause proximal urethral dilatation with the formation of a saccular diverticulum -LSB- 32 -RSB- . Conversely , progressive enlargement of a diverticulum can result in a distal valve-like flap . Embryologic theories of anterior urethral diverticula formation include a developmental defect in the corpus spongiosum leading to formation of a diverticulum , cystic dilatation of urethral glands , and sequestration of an epithelial rest -LSB- 33 -RSB- . McLellan et al. -LSB- 28 -RSB- have demonstrated connections between an anterior urethral diverticula and cowperian ducts , proposing that anterior urethral diverticula and valves arise from the anterior lip of a ruptured cowperian duct syringocele . Clinical presentation depends on the patient 's age and the degree of urethral obstruction and includes difficulty voiding , incontinence and recurrent urinary tract infections . VCUG is diagnostic -LRB- Fig. 16 -RRB- . Some authors describe a difference in appearance between anterior diverticula and valves ; in valves , the urethral dilatation forms an obtuse angle with the ventral floor of the urethra , while in a urethral diverticulum , the angle is acute -LSB- 31 -RSB- . Vesicoureteral reflux can be found in up to one-third of patients with anterior urethral valves and 20 % of patients with diverticula -LSB- 32 -RSB- . Sonography has also been used for diagnosis -LSB- 34 -RSB- . Stone formation within a diverticulum has been reported -LSB- 35 -RSB- . Treatment consists of transurethral valve ablation or , in the case of diverticula , transurethral or open diverticulectomy and urethroplasty -LSB- 32 -RSB- . Fig. 16Anterior urethral diverticulum . Arrow points to a diverticulum arising from and communicating with the ventral aspect of the urethra Anterior urethral valves occurring in the fossa navicularis , the most distal aspect of the urethra , are referred to as valves of Guerin . These are described as a septum partially separating the lacuna magna -LRB- a widening at the dorsal aspect of the distal urethra at the glans penis -RRB- from the urethra . Valves of Guerin might have a different embryologic basis than other types of anterior urethral valves . Some propose a failure of alignment between the glans urethra and penile urethra while others believe they represent an anatomic variant , as many patients are asymptomatic -LSB- 36 -RSB- . Valves of Guerin have been associated with urethral bleeding . VCUG is diagnostic and will demonstrate a small collection of contrast material at the dorsal aspect of the distal urethra -LRB- Fig. 17 -RRB- . Marsupialization of the valve into the urethral lumen is the treatment of choice -LSB- 37 -RSB- . Fig. 17Valves of Guerin . A small contrast-filled diverticulum -LRB- arrow -RRB- is present , arising from the dorsal aspect of the glans urethra . There is no urethral obstruction Megalourethra Megalourethra is caused by defective formation of the corpus spongiosum and corpora cavernosa secondary to a mesodermal defect . There are two types of megalourethra : -LRB- 1 -RRB- scaphoid , in which there is ventral urethral dilatation and hypoplasia of the corpus spongiosum , and -LRB- 2 -RRB- fusiform , in which there is circumferential urethral dilatation and hypoplasia of the corpus spongiosa and corpora cavernosa . Megalourethra is often associated with other congenital abnormalities including cryptorchidism , renal agenesis , hypospadias , primary megaureter , PBS , VACTERL complex -LSB- 38 -RSB- and severe gastrointestinal anomalies -LSB- 39 -RSB- . These patients have a functional rather than anatomic urethral obstruction , causing stasis and back pressure into the upper urinary tracts . Diagnosis is by VCUG -LRB- Fig. 18 -RRB- . Reconstructive surgery is required . Fig. 18Megalourethra . Single view from a VCUG in a boy with partial sacral agenesis demonstrates focal dilatation of the urethra -LRB- arrow -RRB- . Note the wide bladder neck Urethral duplication Urethral duplication is a rare anomaly frequently seen in association with other anomalies including hypospadias , epispadias , cleft lip and palate , congenital heart disease , tracheoesophageal fistula , imperforate anus and musculoskeletal anomalies -LSB- 40 -RSB- . Duplication commonly occurs along the sagittal plane . The ventral urethra is the more functional urethra and contains the verumontanum and sphincters -LSB- 40 -RSB- . When urethral duplication is present along the coronal plane , bladder duplication is always present -LSB- 41 -RSB- . Urethral duplication can be classified into three types using Effmann 's classification -LSB- 42 -RSB- . In type I , there is partial duplication of the urethra . In type II , there is complete duplication of the urethra . Type II urethral duplication can be subclassified as IIA1 if both urethras arise from separate bladder necks , type IIA2 if one channel arises from the other , and type IIB if there is duplication with one meatus . IIA2 Y-duplication occurs when one urethra arising from the bladder neck or posterior urethra opens to the perineum . This type of urethral duplication often coexists with stenosis of the anterior portion of the normally positioned urethra -LSB- 43 -RSB- and other severe congenital anomalies -LSB- 44 -RSB- . Type III urethral duplication consists of complete duplication of the urethra and bladder . Embryologically , urethral duplication can be caused by abnormal Mullerian duct termination and growth arrest of the urogenital sinus -LSB- 40 -RSB- or misalignment of the termination of the cloacal membrane with the genital tubercle -LSB- 41 -RSB- . Depending on the type of duplication , patients might be asymptomatic . Symptoms include urinary tract infection , epididymitis , and incontinence -LSB- 43 -RSB- . Diagnosis can be made by VCUG or retrograde urethrography -LRB- Figs. 19 and 20 -RRB- . Urodynamic studies are helpful to confirm the position of the functional urethra in order to distinguish it from congenital urethroperineal fistula -LRB- see below -RRB- -LSB- 44 -RSB- . One-third of patients have associated vesicoureteral reflux -LSB- 41 -RSB- . Fig. 19Complete urethral duplication -LRB- type II -RRB- . Image from a voiding cystourethrogram demonstrates contrast agent filling a dorsal and ventral urethra -LRB- arrows -RRB- . Vesicoureteral reflux is presentFig . 20Partial urethral duplication -LRB- type I -RRB- . There is partial duplication of the urethra in this patient with a history of hypospadias repair . The two channels -LRB- arrows -RRB- join to a single channel , which is demarcated by the catheter Congenital urethroperineal fistula Although congenital urethroperineal fistula -LRB- CUF -RRB- resembles Y-type urethral duplication , it should be considered a separate entity . In Y-type urethral duplication the ventral urethra opens to the perineum and , as in all urethral duplications , is the functional urethra . In contrast , in CUF , the dorsal urethra is the functional urethra and the ventral urethra -LRB- fistula -RRB- is hypoplastic -LSB- 41 , 45 -RSB- . The differentiation between Y-type duplication and CUF is particularly important in the surgical management of these patients . In Y-duplication the functional ventral channel should not be resected , while in the CUF resection of the ventral channel is curative -LSB- 45 -RSB- . The embryology of CUF is not clear . Diagnosis is made by retrograde urethrography or VCUG to determine the dominant urethra . In the case of congenital urethroperineal fistula , voiding will be predominantly through the dorsal urethra . Urodynamics is important to determine the position of the external urethral sphincter -LSB- 39 -RSB- . Anorectal malformations Congenital anorectal malformation represents a complicated spectrum of anomalies that range from anal stenosis to imperforate anus with communication with the urogenital system -LSB- 46 -RSB- . In males , the anomaly is characterized by gastrointestinal anomalies , imperforate anus and frequently other congenital anomalies including tracheoesophageal fistula , heart disease , limb anomalies and radial and renal abnormalities -LRB- VACTERL complex -RRB- -LSB- 47 -RSB- . The malformation can be classified as low or high/intermediate . Fistulous communications between the blind-ending rectum and the urinary tract are more common in males with high/intermediate anomalies . Rectobulbocutaneous fistulous tracts have also been described in which a fistula arises from the rectum , communicates with the bulbous urethra at its mid-portion and continues ventrally to terminate at the scrotum wall -LSB- 48 , 49 -RSB- . A concurrent rectourethral fistula to the posterior urethra or , less commonly , the bladder , has been described in 28 % of patients of imperforate anus -LSB- 50 -RSB- and there is a high incidence of other urethral anomalies as well -LSB- 39 , 40 -RSB- . Embryologically the normal sequence of cloacal division by the urorectal septum into the urogenital sinus and rectum is disrupted . Preexisting fusion of mesoderm at the dorsal aspect of the cloacal folds might be present , which prevents normal caudal descent of the urogenital septum and results in a urorectal septal defect . Recent reports describe a possible genetic link between abnormalities of the Sonic Hedgehog gene -LRB- Shh -RRB- and midline developmental abnormalities such as those seen with the VATERL association -LSB- 40 , 47 , 51 -RSB- . Diagnosis is made by VCUG or distal loop study following colostomy -LRB- Figs. 21 and 22 -RRB- . Fig. 21Anorectal malformation . Image from a VCUG demonstrates an anourethral fistula -LRB- arrow -RRB- in a newborn . This is also referred to as an H-type fistula because of its configurationFig . 22Anorectal malformation . Distal loop study in an infant with a high imperforate anus demonstrates a fistula extending from the rectum to the posterior urethra Conclusion The development of the male urethra is complex . Although understanding its embryology can help explain certain anomalies , there are others in which the embryologic defect has not been elucidated . Imaging , including VCUG and retrograde urethrography , is helpful in defining the anatomy and identifying associated findings .

B B O O B I O O O B B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

male urethra
anomalies
embryology
congenital