Vitamin D and Oestrogen Metabolism

not฀inluenced฀by฀differing฀serum฀levels฀of฀calcium฀or฀phosphorus฀for฀review,฀see฀ [454] .฀ Smokers฀and฀non-smokers฀may฀behave฀very฀differently฀in฀terms฀of฀coffee,฀alcohol฀and฀ vitamin฀D฀intake฀and฀physical฀activity฀ [455] ,฀and฀reduced฀calcium฀intake฀may฀also฀lead฀to฀ an฀ increase฀ in฀ 1,25-OH 2 -D฀ via฀ a฀ reduction฀ in฀ oestrogen฀ levels฀ [453,฀ 456] .฀ Oestrogen฀ metabolism฀ is฀ increased฀ by฀ the฀ induction฀ of฀ 2-hydroxylation฀ of฀ oestradiol฀ in฀ the฀ liver฀ increased฀production฀of฀2-OH-oestrogens฀ [457] ,฀and฀smoking฀has฀a฀more฀pronounced฀ effect฀on฀the฀activity฀of฀orally฀than฀parenterally฀administered฀oestrogens฀ [458] .฀Oestrogens฀ are฀metabolised฀more฀rapidly฀in฀the฀liver฀of฀smokers,฀and฀this฀in฀turn฀may฀lead฀to฀reduced฀ PTH฀levels.฀Similarly,฀the฀raised฀cadmium฀burden฀in฀the฀kidneys฀may฀contribute฀to฀the฀ reduction฀in฀1,25-OH 2 -D฀ [459,฀460] .฀Owing฀to฀this฀reduction฀in฀1,25-OH 2 -D,฀less฀cal- cium฀would฀be฀absorbed฀ [461,฀462] ฀and฀taken฀up฀into฀bone.฀Reduced฀osteocalcin฀levels฀in฀ smokers฀diminish฀osteoblast฀activity,฀as฀has฀also฀been฀demonstrated฀in฀in฀vitro฀experiments฀ [463] .฀Calculated฀in฀terms฀of฀decades,฀bone฀density฀naturally฀declines฀signiicantly,฀even฀ without฀smoking,฀and฀25-OH-D฀levels฀correlate฀with฀bone฀density฀ [464,฀465] .฀According฀to฀ a฀study฀from฀Denmark,฀25-OH-D฀and฀1,25-OH 2 -D฀levels฀in฀smokers฀are฀reduced฀by฀10฀ and฀PTH฀levels฀by฀about฀20฀ [453] .฀These฀reduced฀levels฀were฀detected฀in฀50฀of฀smokers฀ [453] ,฀as฀also฀conirmed฀in฀another฀recently฀published฀study฀ [452] .฀Continued฀smoking฀ does฀not฀alter฀bone฀alkaline฀phosphatase฀and฀urinary฀hydroxyproline฀excretion฀ [452] .

7.7.2 Osteoporosis

Osteoporosis฀is฀assessed฀in฀terms฀of฀bone฀mineral฀density,฀and฀the฀common฀occurrence฀of฀ femoral฀neck฀fractures฀is฀important฀in฀this฀context฀ [466] .฀The฀inluence฀of฀smoking฀has฀ been฀a฀topic฀of฀controversial฀discussion฀in฀the฀past฀ [467] ,฀and฀research฀has฀focussed฀par- ticularly฀on฀postmenopausal฀women.฀An฀association฀between฀bone฀mineral฀density฀and฀ smoking฀was฀already฀demonstrated฀in฀the฀1980s฀ [467–470] .฀In฀summary,฀a฀moderate฀effect฀ of฀cigarette฀smoking฀was฀identiied฀on฀the฀reduction฀in฀bone฀mineral฀density฀of฀pre-฀and฀ post-menopausal฀women.฀The฀number฀of฀cigarettes฀smoked฀daily฀correlated฀approximately฀ with฀bone฀mineral฀density฀ [471] .฀This฀correlation฀was฀independent฀of฀body฀weight.฀A฀rela- tively฀large฀study฀in฀544฀men฀and฀822฀women฀detected฀decreases฀in฀hip฀bone฀mineral฀ density฀in฀smokers฀compared฀with฀non-smokers฀ [472] ,฀relecting฀the฀positive฀association฀ between฀smoking฀and฀decreased฀bone฀mineral฀density฀in฀old฀age. The฀anti-osteoporotic฀effect฀of฀hormone฀replacement฀therapy฀HRT฀with฀oestrogens฀ is฀ attenuated฀ by฀ smoking฀ whereas฀ the฀ anti-osteoporotic฀ effect฀ of฀ raloxifene฀ remains฀ unchanged฀ [473] .฀Female฀smokers฀with฀a฀low฀BMI฀have฀an฀increased฀risk฀for฀bone฀loss,฀ even฀during฀HRT฀ [474] .฀The฀ageing-related฀rise฀in฀IL-6฀levels฀is฀important฀for฀the฀patho- genesis,฀and฀IL-6฀is฀further฀increased฀by฀smoking฀ [475] . Men฀and฀women฀aged฀61–73฀years,฀born฀and฀residing฀in฀a฀rural฀area฀of฀England฀and฀at฀ risk฀for฀cardiovascular฀disease฀and฀osteoporosis,฀were฀compared฀with฀a฀control฀group฀in฀ terms฀of฀smoking฀habits฀ [476] .฀The฀data฀revealed฀reduced฀bone฀mineral฀density฀in฀men฀and฀ women฀who฀smoked฀see฀Fig.฀ 7.7 ,฀with฀greater฀decreases฀detected฀in฀the฀spine฀than฀in฀the฀ femoral฀neck.฀The฀subjects’฀build,฀drinking฀habits฀and฀physical฀activity฀were฀not฀associ- ated฀with฀the฀reduction฀in฀bone฀mineral฀density฀Fig.฀ 7.8 ฀ [476] . A฀low฀BMI฀consistent฀with฀extreme฀thinness฀is฀a฀risk฀factor฀for฀reduced฀bone฀mineral฀ density:฀thin฀women฀have฀a฀very฀much฀lower฀bone฀mineral฀density฀than฀women฀who฀are฀ more฀corpulent฀ [477] ,฀and฀this฀adverse฀situation฀is฀further฀compounded฀by฀cigarette฀smok- ing฀ [469,฀478,฀479] .฀A฀recently฀published฀study฀has฀conirmed฀the฀potentiating฀effect฀of฀ thinness฀and฀smoking฀together฀ [480] ,฀but฀these฀factors฀can฀be฀counteracted฀by฀HRT. 1.2 0.8 0.6 0.4 0.2 1.2 1.0 0.8 0.6 0.4 0.2 1.0 Bone Mineral Density [gcm 2 ] Bone Mineral Density [gcm 2 ] Lumbar spine Femoral neck Lumbar spine Femoral neck Men Women NS n = 42 ExS n = 140 S n = 42 NS n = 99 ExS n = 64 S n = 23 Fig. 7.8 ฀฀฀Cigarette฀smoking฀ and฀bone฀mineral฀density฀in฀ men฀and฀women.฀Mean฀ values฀and฀95฀conidence฀ interval,฀halved.฀NS฀ non-smokers;฀ExS฀฀ ex-฀smokers;฀S฀smokers฀ [476] Femoral neck Total body Spine 0.5 0.0 − 0.5 Decrease in Bone Mineral Density [per cent per year] − 1.0 0.5 0.0 − 0.5 − 1.0 0.5 0.0 − 0.5 − 1.0 Fig. 7.7 ฀฀฀Adjusted฀mean฀change฀in฀bone฀mineral฀density฀in฀the฀femoral฀neck,฀whole฀body฀and฀spine฀ in฀smokers฀n฀=฀31;฀hatched฀bars฀and฀non-smokers฀n฀=฀354;฀white฀bars.฀Bone฀mineral฀density฀ was฀corrected฀for฀body฀weight,฀age,฀sex,฀nutritional฀status฀calcium฀+฀vitamin฀D฀or฀placebo฀and฀ for฀calcium฀intake.฀Statistically฀signiicant฀differences฀between฀smokers฀and฀non-smokers฀were฀ detected฀for฀the฀femoral฀neck฀p฀฀0.02฀and฀whole฀body฀p฀฀0.05฀ [461]