Osteoporosis Disorders of Mineral Metabolism and Bone

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]

7.7.3 Hip Fractures

Smoking฀ has฀ been฀ reported฀ to฀ increase฀ the฀ likelihood฀ of฀ osteoporotic฀ hip฀ fractures฀ [467,฀481] ;฀while฀some฀investigators฀have฀afirmed฀this฀association฀ [482–488] ,฀others฀ have฀ argued฀ against฀ it฀ [489,฀ 490] .฀ A฀ dose-dependent฀ effect฀ number฀ of฀ cigarettes฀ smoked฀has฀so฀far฀proved฀dificult฀to฀verify.฀In฀particular,฀the฀increasing฀cigarette฀con- sumption฀among฀younger฀women฀is฀problematic฀ [491] . In฀a฀cohort฀study฀conducted฀in฀116,229฀female฀nurses฀aged฀34–59฀years฀at฀baseline,฀ information฀on฀smoking฀habits,฀postmenopausal฀oestrogen฀consumption฀and฀diseases฀was฀ collected฀on฀biennial฀questionnaires฀over฀a฀total฀period฀of฀12฀years฀ [478] .฀Current฀smokers฀ and฀ex-smokers฀accounted฀respectively฀for฀31฀and฀26฀of฀the฀survey฀sample.฀A฀total฀of฀377฀ incident฀hip฀fractures฀were฀recorded฀in฀women฀with฀a฀mean฀age฀of฀60฀years.฀The฀relative฀ risks฀for฀hip฀fracture฀were฀1.3฀CI:฀1.0–1.7฀for฀all฀current฀smokers฀and฀1.6฀CI:฀1.1–2.3฀for฀ current฀smokers฀of฀25฀or฀more฀cigarettesday.฀After฀adjustment฀for฀menopausal฀status,฀the฀ relative฀risks฀in฀the฀two฀groups฀fell฀to฀1.2฀and฀1.4,฀respectively.฀The฀risk฀in฀ex-smokers฀was฀ not฀higher฀than฀that฀in฀non-smokers,฀but฀the฀beneit฀was฀not฀observed฀until฀10฀years฀after฀ cessation.฀Both฀the฀increased฀risk฀among฀current฀smokers฀and฀the฀decline฀in฀risk฀after฀smok- ing฀cessation฀are฀in฀part฀accounted฀for฀by฀the฀differences฀in฀body฀weight฀ [478] . According฀to฀a฀study฀from฀Denmark฀in฀13,393฀women฀and฀17,379฀men,฀the฀risk฀of฀hip฀ fracture฀in฀smokers฀compared฀with฀non-smokers฀is฀increased฀1.36-fold฀CI:฀1.12–1.65฀in฀ women฀and฀1.59-fold฀CI:฀1.04–2.43฀in฀men.฀There฀appears฀to฀be฀no฀gender฀difference฀is฀ smoking-related฀risk.฀After฀5฀years฀of฀smoking฀cessation,฀the฀fracture฀risk฀was฀already฀found฀ to฀be฀clearly฀reduced฀in฀men฀but฀not฀in฀women฀ [492,฀493] .฀Similar฀results฀have฀been฀reported฀ in฀a฀study฀from฀Lebanon฀indicating฀that฀postmenopausal฀women฀who฀smoke฀are฀particularly฀ at฀risk฀ [494] .฀Differences฀in฀risk฀factor฀patterns฀have฀been฀reported฀between฀cervical฀and฀ trochanteric฀hip฀fractures:฀compared฀with฀never-smokers,฀current฀smokers฀have฀a฀higher฀risk฀ for฀trochanteric฀fractures฀OR฀=฀1.48;฀CI:฀1.12–1.95฀than฀for฀cervical฀fractures฀OR฀=฀1.22;฀ CI:฀0.98–1.52.฀In฀women,฀HRT฀reduced฀the฀risk฀for฀trochanteric฀fractures฀OR฀=฀0.55;฀CI:฀ 0.33–0.92฀more฀than฀for฀cervical฀fractures฀OR฀=฀1.00;฀CI:฀0.71–1.39฀ [495] . Associations฀between฀low฀body฀weight฀and฀smoking฀have฀been฀repeatedly฀reported฀ [471,฀483,฀496] ,฀and฀this฀was฀also฀the฀case฀in฀the฀Danish฀study฀cited฀above฀ [478] .฀Since฀ women,฀in฀particular,฀are฀taking฀up฀smoking฀at฀an฀ever฀younger฀age,฀the฀problem฀of฀osteo- porotic฀fractures฀demands฀increasingly฀serious฀attention฀ [497] .

7.8 Skin and Mucosa

The฀skin฀changes฀produced฀by฀smoking฀are฀many฀and฀varied,฀ranging฀from฀inlammatory,฀ allergic฀reactions฀through฀to฀the฀development฀of฀malignant฀anomalies.฀Of฀particular฀impor- tance฀in฀this฀context฀are฀the฀carcinogenic฀and฀mitogenic฀properties฀of฀tobacco฀smoke฀and฀ its฀capacity฀for฀radical฀formation. Nicotine฀displays฀a฀variety฀of฀reactions฀with฀mucocutaneous฀tissue,฀in฀particular฀because฀ different฀nAChR฀subtypes฀see฀Sect.฀4.1฀in฀Chap.฀4฀located฀there฀are฀formed฀by฀keratinocytes฀ [498–500] ,฀ibroblasts,฀endothelial฀cells฀ [501] ,฀melanocytes฀ [502] ฀and฀lymphocytes฀ [503] .฀ Filaggrin,฀a฀humectant฀which฀improves฀skin฀texture,฀is฀formed฀in฀this฀way฀in฀keratinocytes฀by฀ Ca 2+ -mediated฀secretion฀ [504] .฀Nicotine฀disturbs฀the฀equilibrium฀between฀cell฀proliferation,฀ growth฀arrest฀and฀apoptosis,฀but฀this฀need฀not฀be฀connected฀with฀tumour฀growth-promoting฀ activity฀cf.฀the฀indings฀reported฀by฀Heeschen฀ [505] . A฀suggested฀role฀for฀nicotine฀in฀the฀pathogenesis฀of฀palmoplantar฀pustulosis฀PPP฀was฀ investigated฀but฀the฀observed฀alteration฀in฀the฀nAChR฀subtypes฀a 7 -฀and฀a 3 -subtype฀was฀ not฀clearly฀demonstrated฀because฀ex-smokers฀were฀used฀in฀the฀ex฀vivo฀experiments฀ [506] ฀ and฀differentiation฀between฀the฀causes฀nicotine฀or฀tobacco฀smoke฀was฀impossible.฀The฀ enhanced฀occurrence฀of฀PPP฀in฀smokers฀seems฀to฀be฀conclusive฀ [507] . The฀constituents฀of฀tobacco฀and฀the฀toxic฀substances฀formed฀during฀the฀process฀of฀com- bustion฀see฀Sect.฀3.1฀in฀Chap.฀3฀are฀capable฀primarily฀of฀forming฀haemoglobin฀adducts.฀ Polynuclear฀aromatic฀hydrocarbons฀pose฀a฀particular฀danger฀to฀the฀skin฀and฀mucosa,฀in฀ addition฀to฀the฀lungs.฀The฀most฀noticeable฀indings฀in฀smokers฀are: Yellow฀staining฀of฀the฀fingers •฀ Wrinkling,฀especially฀on฀the฀facial฀skin฀of฀women •฀ Precancerous฀lesions฀and฀squamous฀cell฀carcinomas฀of฀the฀lips฀and฀buccal฀mucosa •฀ Delayed฀wound฀healing฀ •฀ [508] Frequent฀and฀premature฀necrosis฀of฀skin฀grafts฀ •฀ [509–511]

7.8.1 Skin Changes

As฀long฀ago฀as฀the฀1850s,฀during฀the฀assessments฀for฀insurance฀purposes,฀it฀was฀remarked฀ that฀smokers’฀skin฀was฀pale฀yellow฀and฀wrinkled฀ [512] .฀Around฀the฀same฀time,฀in฀contrast฀ with฀non-smokers,฀similar฀symptoms฀were฀noted฀in฀smokers฀among฀British฀army฀oficers฀ who฀had฀served฀in฀colonial฀India฀ [513] .฀Skin฀ageing฀is฀encouraged฀by฀smoking฀and฀expo- sure฀to฀sunlight฀ [514] .฀The฀skin฀of฀cigarette฀smokers฀has฀been฀characterised฀as฀pale฀and฀ thickened,฀with฀a฀greyish฀hue฀but฀without฀any฀change฀in฀pigmentation.฀In฀some฀cases,฀ evidence฀of฀wrinkling฀of฀the฀entire฀skin฀surface฀is฀visible฀in฀the฀cheeks.฀This฀skin฀type฀is฀ encountered฀in฀79฀of฀female฀smokers฀and฀only฀19฀of฀female฀non-smokers฀ [514] .฀In฀this฀ context,฀cigarette฀smoking฀is฀a฀factor฀that฀operates฀independently฀of฀other฀noxious฀agents฀ [515,฀516] .฀Heavy฀smokers฀50฀pack-years฀are฀affected฀more฀than฀less-intensive฀smok- ers.฀The฀increased฀risk฀for฀facial฀wrinkling฀has฀been฀reported฀as฀dose-dependent฀pack- years,฀ but฀ BMI,฀ alcohol฀ consumption฀ and฀ sun฀ exposure฀ total฀ 50,000฀ h฀ are฀ also฀ important,฀as฀well฀as฀age฀and฀gender฀ [515] . The฀development฀of฀these฀changes฀can฀be฀attributed฀to฀the฀effects฀of฀combustion฀products฀ of฀tobacco฀on฀the฀epidermis฀and฀dermis฀via฀the฀blood฀supply.฀In฀the฀facial฀region,฀the฀reduced฀ moisture฀of฀the฀stratum฀corneum฀is฀a฀major฀factor฀ [517] .฀Changes฀involving฀the฀lips฀may฀be฀ related฀to฀mechanical฀factors฀due฀to฀pursing฀of฀the฀lips฀and฀contact฀with฀combustion฀products฀ during฀smoking.฀Smokers฀have฀also฀been฀reported฀to฀exhibit฀elastosis฀independently฀of฀sun฀ exposure,฀as฀demonstrated฀by฀skin฀biopsies฀ [518] .฀Both฀the฀number฀and฀thickness฀of฀the฀