Bariatric surgery, bone loss, obesity and possible mechanisms

Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013   Bariatric  surgery,  bone  loss,  obesity  and  possible  mechanisms   M. M. Brzozowska1, A. Sainsbury2,8, J. A. Eisman1,3,4,5,6, P. A. Baldock3,4,7 and J. R. Center1,3,4 Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; 2The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, The University of Sydney, Australia; 3Clinical School, St Vincent’s Hospital, Sydney, Australia; 4Faculty of Medicine, University of New South Wales, Sydney, Australia; 5Clinical Translation and Advanced Education Department, Garvan Institute of Medical Research, Sydney, Australia; 6Faculty of Medicine, University of Notre Dame, Sydney, Australia; 7Neurological Disease Division, Garvan Institute of Medical Research, Sydney, Australia; 8School of Medical Sciences, University of New South Wales, Sydney, Australia 1 Summary     Bariatric  surgery  remains  the  most  effective  treatment  for  severely  obese  patients.  However,  the   potential  long-­‐term  effects  of  bariatric  surgical  procedures  on  health,  including  bone  health,  are   only  partially  understood.  The  goal  of  this  review  was  to  present  data  on  the  impact  of  bariatric   surgery  on  bone  metabolism  and  to  analyse  possible  reasons  for  the  loss  of  bone  mass  that   frequently  occurs  after  bariatric  surgery.  Such  factors  include  nutritional  deficiencies,  rapid   weight  loss  per  se,  effects  of  fat-­‐derived  adipokines  and  gut-­‐derived  appetite-­‐regulatory   hormones.  However,  the  relative  roles  of  these  factors  in  skeletal  regulation  and  the  mechanisms   by  which  they  work  are  not  yet  fully  defined.  Our  review  was  focussed  on  the  complex   relationship  between  body  weight,  fat  mass  and  bone  mass,  as  well  as  peripheral  and  central   mediators  potentially  involved  in  the  dual  regulation  of  both  energy  and  bone  homeostasis.  We   also  review  the  data  on  the  inverse  relationship  between  central  obesity,  bone  marrow  fat  and   osteoporosis.  As  the  number  of  bariatric  operations  increases,  it  is  imperative  to  recognize   mechanisms  responsible  for  bariatric  surgery-­‐induced  bone  loss,  with  careful  monitoring  of  bone   health  including  long-­‐term  fracture  incidence  in  patients  undergoing  these  procedures.     Obesity  and  bone  –  not  as  simple  as  previously  thought     The  prevalence  of  obesity  worldwide  has  increased  significantly  in  recent  decades  because  of  a   complex  range  of  environmental  and  genetic  factors.  Severe  obesity  is  associated  with  a  number   of  comorbid  conditions  and  shortened  life  expectancy  [1].  One  area  of  research  that  is  beginning   to  attract  greater  attention  is  the  effect  of  obesity  on  bone.  The  general  view  among  healthcare   providers  is  that  osteoporosis  is  not  of  concern  for  obese  patients  because  of  the  known  bone-­‐ strengthening  effects  of  long-­‐term  weight  bearing  [2].  Indeed,  epidemiological  evidence  suggests   that  obesity  is  correlated  with  increased  bone  mass,  and  that  increased  body  weight  protects   against  bone  loss  [2,  3].  However,  despite  such  evidence  of  a  protective  effect  of  obesity  on  bone,   more  recent  data  point  to  a  potential  detrimental  effect.  Contrary  to  popular  belief,  osteoporosis   and  obesity  have  been  shown  to  coexist,  as  evident  in  disorders  involving  fat  redistribution  such   as  type  2  diabetes  mellitus,  Cushing's  disease  and  drug-­‐induced  lipodystrophies  [4].  Indeed,  in   some  cohorts,  the  percent  of  total  fat  mass  is  strongly  and  inversely  associated  with  bone  mineral   density  (BMD)  [5].  Obese  women  have  lower  rates  of  bone  formation,  as  indicated  by  circulating   type  I  collagen  levels,  suggesting  that  increased  body  fat  suppresses  new  collagen  formation  [6].     Besides  effects  on  osteoporosis,  BMD  or  bone  formation  rates,  obesity  is  also  associated   with  fractures,  not  only  in  older  people.  Human  data  show  increased  prevalence  of  forearm   fractures  among  obese  young  adults  as  well  as  reduced  bone  mass  in  obese  children  [7,  8].   Postmenopausal  obesity  appears  to  be  a  risk  factor  for  fracture  at  selected  sites  such  as  the  tibia   and  ankle  [9].  Moreover,  there  is  increasing  evidence  to  suggest  that  visceral  obesity  and  the   metabolic  syndrome  have  potential  detrimental  effects  on  bone  health,  with  a  higher  incidence  of   osteoporotic  fractures  and  impaired  bone  structure  and  strength  observed  among  younger  and   older  adults  with  increased  visceral  adiposity  [10,  11].     While  not  the  focus  of  this  review,  potential  mechanisms  for  any  harmful  effects  of   obesity  on  bone  include  the  metabolic  syndrome  and  its  causes  or  consequences,  as  well  as  via   effects  on  bone  marrow  fat.  Increased  fat  in  the  bone  marrow  compartment  is  linked  with   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013     endplate  depression  and  compression  fractures  in  subjects  with  morphologic  evidence  of  bone   weakness  [12,  13].  Recent  literature  points  to  a  positive  correlation  between  bone  marrow  fat   and  visceral  fat  –  women  with  high  visceral  fat  were  found  to  have  higher  bone  marrow  fat  than   women  with  low  visceral  fat  [14]  –  as  well  as  to  an  inverse  association  between  vertebral  bone   marrow  fat  and  trabecular  BMD  in  premenopausal  obese  women.  These  findings  suggest  that  the   detrimental  effects  of  visceral  fat  on  bone  health  may  be  mediated  in  part  by  accumulation  of   bone  marrow  fat,  providing  further  evidence  of  the  link  between  central  obesity  and  the  risk  for   osteoporosis.     As  well  as  effects  of  obesity  on  bone  health,  new  evidence  suggests  that  weight  loss   interventions  may  also  induce  detrimental  effects  on  bone.  While  the  treatment  of  obesity  is   associated  with  improved  health  outcomes  and  a  better  quality  of  life,  potential  effects  on  bone   have  received  little  attention.  Bone  loss  is  a  part  of  ageing  and  occurs  in  both  genders  after  peak   bone  mass  has  been  attained  [15].  Starting  from  the  middle  of  the  third  decade,  women  lose  35%   of  their  cortical  bone  and  50%  of  their  trabecular  bone  [16],  whereas  men  lose  approximately   two-­‐thirds  of  this  amount  over  their  lifetimes  [17].  Studies  show  that  a  10%  weight  loss  is   associated  with  a  measured  1–2%  bone  loss  at  the  various  bone  sites  [18-­‐22].  In  addition,  the   bone  response  to  weight  reduction  also  varies  among  different  populations.  Studies  reported   with  mixed  populations  including  pre-­‐,  peri-­‐  and  postmenopausal  women,  and/or  men  showed  a   loss  of  total  body  BMD  (0–2.5%)  and  bone  mineral  content  (BMC;  3–4%)  with  weight  loss,  as   well  as  variable  losses  at  peripheral  bone  sites  (1–13%)  [21,  23,  24].  There  is  a  positive   relationship  between  BMI  and  age-­‐adjusted  BMC  [25]  with  a  trend  to  normative  reduction  in   total  BMC  with  a  significant  fall  in  BMI.     At  present,  the  most  effective,  long-­‐term  treatment  for  obesity  remains  bariatric  surgery,   with  Roux-­‐en-­‐Y  gastric  bypass  (RYGB),  laparoscopic  adjustable  gastric  banding  (LAGB  or  gastric   banding)  and  increasingly  sleeve  gastrectomy  being  the  most  commonly  performed  surgical   procedures.  One  of  the  reported  consequences  of  bariatric  surgery,  particularly  following  RYGB,   is  bone  loss,  yet  this  issue  receives  minimal  attention.  The  trend  towards  surgical  treatment   options  not  only  for  very  obese  adults,  but  also  for  younger  and  less  obese  patients,  makes  a   comprehensive  understanding  of  any  adverse  consequences  of  bariatric  surgery  vitally   important.     In  this  review,  we  will  highlight  studies  showing  the  impact  of  obesity  surgery  on  bone   metabolism,  focussing  on  the  three  most  commonly  performed  procedures:  RYGB,  gastric   banding  and  sleeve  gastrectomy.  We  will  then  examine  potential  underlying  mechanisms  for   these  observations  of  heightened  bone  turnover  or  bone  loss  after  bariatric  surgery.  While   reductions  in  weight  bearing  [26]  and  delivery  of  vital  nutrients  such  as  vitamin  D  and  calcium   [27,  28]  are  likely  important  contributors  to  bariatric  surgery-­‐induced  bone  loss,  in  this  review,   we  focus  on  novel  potential  mechanisms  emanating  from  the  adipose  tissue–gut–brain  axis.   These  include  adipose  tissue-­‐derived  adipokines  such  as  leptin  and  adiponectin,  the  gut-­‐derived   appetite-­‐regulatory  hormones,  namely  peptide  YY  (PYY),  glucagon-­‐like  peptide  1  (GLP-­‐1)  and   ghrelin,  all  of  which  are  known  to  be  influenced  by  bariatric  surgery,  and  all  of  which  have  been   shown  to  have  significant  effects  on  bone  homeostasis,  and  hypothalamic  regulators  of  energy   balance,  namely  neuropeptide  Y  (NPY).  Finally,  we  call  for  consideration  of  long-­‐term  bone   health  in  further  studies  and  registries  examining  the  benefit,  risk  and  cost  profile  of  obesity   surgery.     Literature  cited  in  this  review  was  published  until  March  2012  and  was  located  via  Pub   Med  using  the  search  terms  ‘bariatric  surgery’,  ‘weight  loss’,  ‘bone  loss’,  ‘bone  metabolism’,  ‘gut   hormones’,  ‘adipokines’,  ‘neuropeptides’  and  ‘bone  markers’.     Overview  of  the  effects  of  bariatric  surgery  on  body  weight  and  bone     Weight  loss  (bariatric)  surgery  provides  the  best  long-­‐term  results  for  patients  with  moderate   obesity  (BMI  between  35  and  39.9 kg/m2)  or  severe  obesity  (BMI  of  at  least  40 kg/m2)  and  who   have  not  responded  to  more  conservative  approaches  to  weight  management.  Bariatric  surgery   is  generally  reserved  for  patients  with  a  BMI  greater  than  40 kg/m2,  or  for  those  with  a  BMI   greater  than  35 kg/m2  whose  obesity  is  complicated  by  one  or  more  major  diseases  such  as  type   2  diabetes  mellitus  or  sleep  apnoea.  There  are  two  major  surgical  categories:  gastrointestinal   diversionary  procedures  such  as  RYGB  and  biliopancreatic  diversion,  as  well  as  gastric   interventions  including  laparoscopic  adjustable  gastric  banding  (LAGB  or  gastric  banding),   vertical  gastroplasty  and  sleeve  gastrectomy.   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013     Bariatric  surgical  procedures  induce  much  more  substantial  weight  loss  than  can  be   produced  by  conventional  medical  and  lifestyle  management  of  obesity.  The  efficacy  of  different   types  of  bariatric  surgery  varies  in  terms  of  weight  loss  achieved  and  improvement  in  obesity   comorbidities.  Weight  loss  post  bariatric  surgery  is  frequently  expressed  as  percent  loss  of   excess  body  weight,  defined  as  the  difference  between  the  preoperative  weight  and  the  ideal   body  weight  (i.e.  BMI  25).  After  RYGB,  patients  lose  up  to  approximately  35%  of  their  initial   weight,  equivalent  to  a  loss  of  62–75%  of  excess  body  weight,  with  this  loss  being  maintained  at   10–14  years  following  surgery  [29-­‐32].  Gastric  banding  results  in  an  average  loss  of  20–30%  of   an  initial  body  weight  [33],  equivalent  to  a  loss  of  41–54%  of  excess  body  weight  loss  [29].   Sleeve  gastrectomy  causes  an  average  body  weight  loss  of  20–30%,  equivalent  to  a  loss  of  45– 64%  of  excess  body  weight  [33,  34].     As  well  as  effects  on  weight  loss,  and  in  some  cases  even  before  significant  loss  of  excess   body  weight,  bariatric  surgical  procedures  have  been  shown  to  resolve  or  ameliorate  type  2   diabetes  mellitus  in  57–86%  of  cases,  hyperlipidaemia  in  approximately  71%  of  cases,   hypertension  in  68%  of  cases,  and  sleep  apnoea  in  80–85%  of  cases,  with  RYGB  having  a  greater   beneficial  effect  on  these  comorbidities  than  other  bariatric  procedures  [29,  35].     As  the  use  of  bariatric  surgery  for  the  treatment  of  morbid  obesity  steadily  increases,   there  is  growing  evidence  that  these  procedures  result  in  changes  in  bone  and  mineral   metabolism,  and  in  some  studies,  a  decline  in  BMD  has  been  observed.  This  evidence  will  be   detailed  for  RYGB,  gastric  banding  and  sleeve  gastrectomy,  below.  It  is  important  to  point  out   that  interpretation  of  the  data  is  limited  at  this  stage  because  of  small  sample  sizes,  inconsistent   study  measures,  varying  degrees  of  bone  loss  as  well  as  potential  difficulties  in  the  accuracy  of   measurement  of  BMD  in  morbid  obesity  and  during  weight  loss.     For  instance,  the  majority  of  studies  have  used  areal  BMD  as  the  primary  outcome  for   bone  health  in  post-­‐bariatric  patients,  as  determined  using  dual-­‐energy  X-­‐ray  absorptiometry   (DXA).  Major  changes  in  fat  mass  and  its  distribution  induced  by  significant  weight  loss  may   affect  the  precision  of  BMD  measurement  in  this  group  of  patients,  especially  when  assessing   bone  area  and  thus  when  estimating  areal  BMD  [36-­‐38].  Variability  in  areal  BMD  increases   significantly  with  tissue  depths  greater  than  25 cm  [39],  and  excess  fat  around  bone  can  result  in   overestimation  of  areal  BMD  in  obese  subjects  [40].  Additionally,  spuriously  increased  bone  area   compared  with  measures  of  BMC  that  are  unaffected  by  obesity,  results  in  a  potential  spurious   decrease  of  BMD  in  obese  subjects  [41,  42].  Thus  measurement  of  BMC,  which  is  more  closely   related  to  fat-­‐free  mass  than  to  fat  mass  [43],  could  increase  an  accuracy  of  addressing  changes   in  bone  mass  by  DXA  in  obese  subjects  undergoing  weight  loss  interventions.     In  addition  to  these  technical  limitations  in  obesity,  effects  of  obesity  on  DXA-­‐based   measurements  of  BMD  also  vary  according  to  the  measurement  technique,  including  the  type  of   DXA  system  used,  the  distribution  of  body  fat,  the  software  used,  and  scan  mode  [44].   Nonetheless,  the  emerging  data  are  generally  consistent  with  accelerated  bone  loss  in  response   to  bariatric  surgery,  and  –  as  outlined  in  subsequent  sections  of  this  review  –  are  backed  by   plausible  hypotheses  that  could  potentially  explain  such  bone  loss.     Effects  of  Roux-­‐en-­‐Y  gastric  bypass  on  bone     Several  studies  [45-­‐57]  have  examined  the  effects  of  RYGB  for  morbid  obesity  on  BMD  and/or   bone  turnover.  In  brief,  these  studies  show  evidence  of  an  early  increase  in  bone  remodelling,  as   indicated  by  an  increase  over  baseline  values  of  circulating  or  urinary  concentrations  of  bone   turnover  markers  such  as  breakdown  products  of  type  I  collagen  (a  major  organic  component  of   bone  matrix  that  is  synthesized  primarily  in  bone)  as  well  as  osteocalcin,  a  non-­‐collagenous   protein  secreted  specifically  by  osteoblasts.  These  changes  have  been  noted  as  early  as  3  months   post  surgery  [45,  50,  51],  and  occurred  in  spite  of  patients  taking  routinely  recommended   calcium  and  vitamin  D  supplements  [45-­‐47,  49,  54,  55,  57].     Indices  of  increased  bone  resorption  have  been  demonstrated  to  persist  long  after  the   RYGB  procedure.  A  recent  study  documented  elevated  serum  osteocalcin  and  serum  N-­‐terminal   telopeptide  (NTX)  concentrations  relative  to  baseline  values  at  18  months  post  RYGB  surgery   [54],  indicating  a  prolonged  increase  in  bone  turnover.  This  observation  is  consistent  with  a   previous  report  describing  raised  serum  osteocalcin  levels  in  patients  examined  10  years  after   RYGB  [49].  It  remains  unclear  whether  the  reported  long-­‐term  increase  in  bone  turnover   markers  represents  an  adverse  effect  of  surgery  with  the  development  of  metabolic  bone  disease,   or  if  it  reflects  a  physiological  adjustment  by  the  skeleton  to  large  changes  in  body  weight  and   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013     thus  skeletal  loading.  In  either  case,  an  increase  in  bone  turnover  is  known  to  have  a  catabolic   effect  on  bone,  with  resorption  exceeding  formation  [58].  Moreover,  accelerated  rates  of  bone   remodelling  increase  bone  fragility  by  creation  of  a  greater  number  of  unfilled  resorptive   excavation  sites  and  impaired  cross-­‐linking  between  collagen  fibres  [59].  Surgery-­‐induced  bone   remodelling  that  continues  despite  achievement  of  normal  weight  could  lead  to  long-­‐term  bone   disease  as  suggested  by  some  case  studies  [60].     However  a  strong  association  between  bariatric  surgery  and  osteoporosis  is  not   supported  by  the  literature  [61].  As  both  bone  mass  and  bone  turnover  rate  predict  fracture  risk   [62],  changes  in  these  parameters  during  weight  maintenance  are  key  to  determining  the  future   fracture  risk  associated  with  weight  reduction.  A  recent  retrospective  study  found  no   significantly  increased  risk  of  fracture  in  patients  a  mean  of  2.2  years  after  bariatric  surgery,   compared  with  controls.  However,  it  did  show  a  trend  towards  an  increased  fracture  risk  3–5   years  post  bariatric  surgery  and  in  patients  who  had  a  greater  decrease  in  body  mass  index  [63].     Despite  these  demonstrations  of  increased  bone  turnover,  there  are  inconsistent   findings  of  changes  in  bone  mass  in  subjects  post  RYGB  surgery  [45,  46].  Most  [45,  50-­‐52]  but   not  all  [46,  49]  reports  suggest  a  decline  in  BMD  and  BMC  during  the  first  year  post  surgery,   predominantly  at  the  hip.  Decreases  in  whole-­‐body  BMC  have  been  reported  to  vary  from  3  to   12%  at  9–24  months  after  RYGB  surgery  [45-­‐52,  55].  The  magnitude  of  bone  lost  in  adults  after   RYGB  is  associated  with  the  amount  of  weight  lost  in  several  studies  [50-­‐52,  56].  Some  of  these   studies  will  now  be  outlined  in  greater  detail.     A  prospective  study  [45]  compared  bone  turnover  in  25  patients  post  RYGB  with  that  of   30  obese  control  participants.  Compared  with  controls,  significant  elevations  in  bone  turnover   markers  such  as  serum  osteocalcin  and  urinary  NTX  were  observed  at  3  and  9  months  post-­‐ operatively,  in  association  with  prominent  and  significant  decreases  in  BMD  of  the  total  hip   (7.8 ± 4.8%,  P < 0.001),  trochanter  (9.3 ± 5.7%,  P < 0.001),  and  total  body  (1.6 ± 2.0%,  P < 0.05),  as   well  as  significantly  reduced  BMC  at  all  of  these  sites  by  9  months  post  surgery.  Other   assessments  of  bone  and  mineral  metabolism  (i.e.  serum  concentrations  of  parathyroid  hormone   and  calcium  as  well  as  24-­‐h  urinary  calcium  excretion)  were  not  different  between  controls  and   post-­‐surgical  patients.  The  post-­‐surgical  group  self-­‐reported  significantly  higher  dietary  vitamin   D  and  calcium  intakes,  suggesting  that  vitamin  and  mineral  supplementation  may  protect  against   secondary  hyperparathyroidism  after  RYGB  surgery.     In  a  recent  prospective  analysis  comparing  pre-­‐  and  post-­‐surgery  values,  a  similar  BMD   loss  of  8%  was  reported  in  the  hip  of  23  patients  investigated  at  12  months  post  RYGB  [51].  In   this  study,  a  linear  relationship  was  observed  between  weight  loss  and  the  decline  in  BMD,  which   was  associated  with  raised  bone  turnover  markers  relative  to  baseline  (P < 0.01)  for  both  urinary   NTX  and  serum  osteocalcin).  There  was  evidence  of  calcium  and  vitamin  D  malabsorption  with   reduced  urinary  calcium  excretion  after  RYGB,  as  well  as  raised  serum  concentrations  of   parathyroid  hormone  and  unchanged  serum  25-­‐hydroxyvitamin  D  concentrations.  Self-­‐reported   oral  vitamin  D  intake  increased  by  260%  by  12  months  post  surgery.  The  results  from  this  study   inferred  that  RYGB  related  bone  loss  is  associated  with  alterations  in  the  calcium-­‐vitamin  D-­‐ parathyroid  hormone  axis,  through  calcium  and  vitamin  D  malabsorption  and  secondary   hyperparathyroidism.     Perhaps  more  troubling  than  the  above  reports  of  RYGB-­‐induced  bone  loss  in  adults  are   reports  on  the  potential  effect  of  bariatric  surgery  on  BMD  in  younger  subjects.  RYGB  remains  the   most  commonly  performed  bariatric  surgical  procedure  for  morbidly  obese  teens  in  most  US   centres.  A  retrospective  study  [53]  of  61  adolescents  reported  significant  post-­‐operative  bone   loss,  with  a  7.4%  decrease  in  BMC  and  a  decline  in  the  Z-­‐score  for  BMD  from  1.5  to  0.1,  remaining   within  expected  value  for  gender  and  age,  likely  due  to  the  high  BMC  and  density  before  surgery   in  this  extremely  obese  population.  Longer  follow-­‐up  is  required  to  determine  whether  bone  loss   in  this  group  of  young  patients  continues,  stabilizes  or  reverses.     Contrary  to  the  above  findings  of  surgery-­‐induced  bone  loss,  a  study  [46]  in  44  pre-­‐  and   postmenopausal  women  reported  unchanged  bone  mass  after  RYGB  in  premenopausal  patients   compared  with  un-­‐operated  age-­‐  and  weight-­‐matched  control  women.  By  contrast,   postmenopausal  women  had  significantly  higher  lumbar  spine  BMD  (P < 0.05)  and  BMC  (P < 0.05)   and  significantly  lower  femoral  neck  BMC  (P < 0.001)  at  up  to  3  years  after  RYGB  surgery,   compared  with  corresponding  values  in  control  postmenopausal  women.  In  addition,   postmenopausal  women  showed  evidence  of  secondary  hyperparathyroidism  and  elevated  bone   resorption  markers  after  RYGB  surgery  in  spite  of  dietary  calcium  and  vitamin  D   supplementation.  This  pattern  of  bone  loss  may  relate  to  elevated  levels  of  serum  parathyroid   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013   hormone  in  postmenopausal  women  which  cause  cortical  (i.e.  femoral  neck  or  33%  radius)  but   not  trabecular  bone  loss  (i.e.  lumbar  spine)  [64-­‐66].  This  study  inferred  that  postmenopausal   status  is  associated  with  accelerated  patterns  of  bone  loss  after  RYGB  as  compared  with   premenopausal  status  and  non-­‐surgical  control  participants.  This  link  between  hypoestrogenism   and  post-­‐surgical  loss  of  BMD  in  postmenopausal  females  has  not  been  clearly  explored  in  the   literature.     Taken  together,  these  studies  show  that  RYGB  surgery  induces  changes  in  bone   remodelling  as  indicated  by  consistent  increase  in  bone  turnover  markers.  Nutritional   deficiencies  that  accompany  RYGB  surgery  may  result  in  metabolic  bone  disease,  with  associated   secondary  hyperparathyroidism  and  rapid  loss  in  BMD.  The  clinical  significance  of  the  observed   biological  and  radiological  changes  is  unclear.  More  studies  are  needed  to  assess  the  impact  of   RYGB  surgery  on  skeletal  health,  notably  to  determine  the  degree  of  post-­‐operative  bone  loss  and   the  clinical  consequences  of  these  changes.     Effects  of  laparoscopic  adjustable  gastric  banding  (gastric  banding)  on  bone     With  a  paucity  of  available  data,  it  is  currently  uncertain  whether  bone  loss  is  a  consequence  of   gastric  banding,  and  whether  or  not  any  such  effects  are  greater  or  lesser  than  those  induced  by   RYGB.  Two  studies  [67,  68]  of  obese  premenopausal  women  reported  an  early  increase  above   baseline  in  markers  of  bone  resorption  (urinary  and  serum  concentrations  of  type  I  collagen   breakdown  products)  and  a  decrease  in  femoral  and  trochanter  BMD  with  no  significant  change   in  total  body  BMD  at  12  (67,68)  and  24  months  after  gastric  banding  [67].  Total  body  BMC   showed  progressive  decreases  relative  to  baseline  in  the  majority  of  patients  at  12  and  24   months  after  gastric  banding  [67],  which  correlated  with  the  changes  in  body  composition  and   the  decrease  in  fat  mass.  In  both  of  these  studies,  there  was  an  absence  of  secondary   hyperparathyroidism,  indicating  that  other  factors  besides  lack  of  calcium  and  vitamin  D  were   involved  in  post-­‐surgical  bone  remodelling.     We  know  of  two  other  gastric  studies  [50,  69]  investigating  effects  of  gastric  banding  or   vertical  banded  gastroplasty  on  bone;  both  of  these  studies  included  an  RYGB  arm  and  both   produced  conflicting  results.  A  small  Swiss  pilot  study  [50]  compared  the  skeletal  effects  of   gastric  banding  (n = 9)  with  those  of  RYGB  (n = 4)  over  24  months,  with  morbidly  obese  men  and   women  in  the  control  arm  (n = 6).  No  significant  changes  from  baseline  in  BMC  were  reported  at   24  months  in  the  gastric  banding  and  control  groups.  However,  there  was  a  significant  decrease   from  baseline  in  BMC  in  the  RYGB  group  (P = 0.005),  accompanied  by  significant  increases  in   bone  turnover  markers  (serum  osteocalcin  and  urinary  deoxypyridinoline).  In  the  other  study   [69],  by  contrast,  men  and  women  who  underwent  RYGB  surgery  (n = 29)  showed  less  loss  of   BMC  and  BMD  in  the  first  year  after  surgery  than  people  who  had  undergone  vertical  banded   gastroplasty  (n = 31),  these  difference  reaching  statistical  significance  in  female,  but  not  in  male   subjects.  These  changes  are  all  the  more  noteworthy  given  that  RYGB  patients  lost  significantly   more  weight  and  total  body  fat  than  those  who  underwent  gastric  procedures,  indicating  that  the   underlying  mechanism  for  any  bone  loss  after  gastric  banding  or  gastroplasty  –  if  confirmed  in   future  studies  –  is  more  involved  than  a  simple  decrease  in  adiposity  or  weight  bearing.     Effects  of  sleeve  gastrectomy  on  bone     There  is  also  little  available  data  on  changes  in  bone  mass  or  metabolism  following  sleeve   gastrectomy,  an  increasingly  popular  form  of  bariatric  surgery.  A  single  prospective,  comparative   study  [70]  that  examined  the  impact  of  sleeve  gastrectomy  and  RYGB  on  bone  mass  and   remodelling  found  significant  loss  of  bone  mass  in  the  lumbar  spine  and  hip  at  12  months  post-­‐ operatively  in  all  surgical  patients,  relative  to  baseline  values.  Bone  loss  was  less  pronounced  in   the  spine  and  femur  after  sleeve  gastrectomy  than  after  RYGB,  albeit  this  difference  among   surgeries  was  not  statistically  significant  and  the  bone  resorption  marker  NTX  was  significantly   elevated  over  baseline  in  both  surgical  groups.  Clearly,  further  work  is  required  to  assess  the   effect  of  sleeve  gastrectomy,  if  any,  on  bone  mass.     Potential  mechanisms  for  bone  loss  after  bariatric  surgery     Several  mechanisms  may  explain  the  changes  in  bone  metabolism  observed  after  bariatric   surgery.  Reduced  delivery  of  essential  nutrients,  including  calcium  and  vitamin  D,  are   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013     consequence  of  diversionary  bariatric  procedures  such  as  RYGB,  as  well  as  of  the  energy   restriction  that  follows  all  successful  bariatric  operations.  On  top  of  this,  pre-­‐existing  alterations   in  calcium  homeostasis  [71]  and  vitamin  D  deficiencies,  which  are  common  in  obese  patients   [28],  may  further  contribute  to  inadequate  delivery  of  these  essential  nutrients,  thereby   contributing  to  secondary  hyperparathyroidism  and  metabolic  and  skeletal  abnormalities.   However,  although  some  studies  implicate  decreased  calcium  and  vitamin  D  intake  or  absorption   [60,  72]  in  bone  loss  after  bariatric  surgery,  several  of  the  studies  reported  in  the  previous   section  [45,  67,  72]  demonstrated  heightened  bone  turnover  or  bone  loss  after  bariatric  surgery   despite  apparently  adequate  calcium  and  vitamin  D  supplementation,  as  indicated  by  reported   intake  and/or  the  absence  of  any  secondary  increase  in  circulating  parathyroid  hormone  levels.     The  direct  impact  of  micronutrients  and  vitamin  deficiencies  on  bone  health  in  post   bariatric  RYGB  patients  has  not  been  well  documented,  partly  because  of  lack  of  standardized   guidelines  for  the  nutritional  care  and  assessment  of  these  individuals.  The  described  studies   relate  to  different  post-­‐operative  calcium  and  vitamin  D  dietary  and  supplementation  protocols.   Prescribed  supplements  have  varied  in  dose,  and  although  sufficient  for  a  general  population,   they  might  not  have  prevented  nutritional  deficiencies  in  bariatric  surgery  patients.  Lack  of   rigorous  post-­‐operative  follow-­‐up,  and  varying  recommended  dosages  of  calcium  and  vitamin  D   supplements  across  studies,  might  also  have  contributed  to  differences  in  estimated  bone  loss   across  studies.  Only  a  single  study  [51],  which  reported  evidence  of  calcium  and  vitamin  D   malabsorption  after  RYGB  surgery,  monitored  vitamin  D  and  calcium  compliance  through   standardized  questionnaires  of  intake  from  food  sources  and  supplements.     Besides  nutritional  deficiencies,  another  major  mechanism  that  is  thought  to  contribute   to  increased  bone  turnover  and  reduced  bone  mass  after  bariatric  surgery  is  weight  loss  per  se,   resulting  in  reduced  mechanic  load  on  the  skeleton.  However,  the  study  reported  earlier  [69],   demonstrating  that  bone  loss  was  less  pronounced  after  RYGB  than  after  gastroplasty  –  despite   significantly  greater  weight  and  fat  loss  –  suggests  that  other  factors  besides  mechanical  loading   are  at  play.  Indeed,  it  has  been  reported  in  adolescents  that  weight  loss  accounted  for  as  little  as   14%  of  the  loss  of  BMC  after  bariatric  surgery,  indicating  a  significant  contribution  by  additional   factors  [73].  While  studies  to  date  have  not  enabled  definitive  dissection  of  the  relative   contribution  of  changes  in  nutrient  status  and/or  weight  loss  to  changes  in  bone  after  bariatric   surgery,  these  studies  point  to  other  mediators  of  change.     Hormonal  responses  to  bariatric  surgery  could  conceivably  contribute  to  the  associated   bone  loss.  Dietary  energy  restriction  (without  bariatric  surgery)  has  been  shown  to  induce   neuroendocrine  changes  that  would  be  expected  to  accelerate  bone  loss  [74].  Such  changes   include  reduced  circulating  concentrations  of  thyroid  hormones,  sex  hormones  and  insulin-­‐like   growth  factor-­‐1,  with  concomitant  increases  in  circulating  cortisol  levels  [74].  However,  it  is  not   known  whether  bariatric  surgery  –  like  weight  loss  elicited  by  dietary  intervention  alone  –  also   induces  such  hormonal  changes  that  could  impair  bone  health.  On  the  other  hand,  there  is  a   growing  body  of  literature  showing  that  bariatric  surgery  alters  the  secretion  of  hormones  from   adipose  tissue  (notably  the  adipokines  leptin  and  adiponectin)  and  the  gastrointestinal  tract   (notably  the  appetite-­‐regulating  gut  hormones  PYY,  GLP-­‐1  and  ghrelin),  all  of  which  have   recently  been  shown  to  have  significant  effects  on  bone  homeostasis.  Current  knowledge  about   the  extent  of  their  involvement  in  any  bariatric  surgery-­‐induced  bone  loss  and  the  mechanisms   underlying  such  effects  is  limited,  but  we  hereby  outline  current  insights  as  a  framework  for   future  research.     Adipokines,  bariatric  surgery  and  bone     Adipose  tissue  releases  a  wide  variety  of  proteins,  called  adipokines,  including  leptin,   adiponectin,  visfatin  and  resistin,  among  others,  which  are  known  to  not  only  regulate  adipose   tissue,  but  to  also  be  involved  in  the  complex  regulation  of  bone  physiology  [75-­‐81].  More   recently,  the  skeleton  has  also  emerged  as  an  endocrine  organ,  with  bone  cells  –  osteoblasts  and   osteoclasts  –  secreting  a  variety  of  proteins,  called  osteokines.  Osteokines  not  only  influence   bone  homeostasis,  they  also  influence  energy  and  glucose  homeostasis  [82-­‐89].  The  cross-­‐talk   between  adipose  tissue  and  the  skeleton  thus  constitutes  a  homeostatic  feedback  system,  with   adipokines  and  osteokines  linking  these  tissues  in  an  active  adipose–bone  axis.  For  the  purposes   of  this  review,  we  will  focus  on  the  possibility  that  bariatric  surgery  can  affect  bone  metabolism   and  bone  mass  via  effects  on  adipokine  secretion.     Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013   Leptin     Leptin  is  a  cytokine-­‐like  hormone  secreted  by  adipocytes  [90].  One  of  the  major  determinants  of   leptin  secretion  is  fat  mass,  with  circulating  leptin  levels  increasing  with  increasing  fat  mass  [91].   Leptin  is  well  known  for  its  role  in  the  regulation  of  food  intake,  energy  expenditure  and  energy   balance  [92],  but  it  has  also  emerged  as  a  regulator  of  bone  mass  via  direct  effects  on  bone  cells   as  well  as  via  indirect  effects  involving  the  hypothalamus  [93],  as  will  be  outlined  later.  However,   before  examining  leptin-­‐induced  regulation  of  bone,  we  will  focus  on  what  is  known  about  the   effects  of  bariatric  surgery  on  leptin.     Several  studies  have  shown  that  serum  leptin  concentration  decreases  after  the  massive   weight  reduction  induced  by  bariatric  surgery.  These  studies  point  to  strong  correlations   between  changes  in  serum  leptin  concentration  with  changes  in  BMI  [94-­‐96]  as  well  as  fat  mass,   serum  insulin  concentration,  and  the  insulin  resistance  index  [96].  Emerging  clinical  evidence  is   consistent  with  the  possibility  that  this  post-­‐surgical  reduction  in  circulating  leptin  levels  could   contribute  to  any  associated  bone  catabolism.  For  instance,  a  prospective  study  of  20  individuals   [54]  examined  serum  concentrations  of  bone  turnover  markers  as  well  as  leptin  at  6  and  18   months  after  RYGB  surgery.  In  this  study,  the  increase  in  serum  NTX  relative  to  baseline  levels   significantly  correlated  with  the  decrease  in  serum  leptin  levels  (r = 0.45;  P = 0.04)  as  well  as  the   reduction  in  BMI  (r = 0.58;  P = 0.009)  and  the  increase  in  serum  25-­‐hydroxy  vitamin  D  (r = 0.43;   P = 0.05).  In  multiple  regression  analysis,  however,  only  the  reduction  in  circulating  leptin  levels   was  a  significant  predictor  of  the  increase  in  NTX  (P = 0.016),  indicating  that  the  RYGB-­‐induced   decrease  in  leptin  may  be  causally  related  to  increased  bone  turnover.     In  keeping  with  the  possibility  of  reduced  circulating  leptin  levels  inducing  bone   catabolism  after  gastric  surgery,  several  reports  have  shown  that  leptin  directly  stimulates  bone   growth  in  vitro  and  increases  bone  density  in  leptin-­‐deficient  animals  [97-­‐99]  likely  via  direct   effects  on  bone.  For  instance,  peripherally  administered  leptin  had  a  stimulatory  effect  on  bone   mass  in  leptin-­‐deficient  ob/ob  mice  [97].  This  effect  was  thought  to  be  due  to  a  direct  anabolic   effect  within  the  bone,  driving  the  differentiation  of  bone  marrow  stem  cells  into  the  osteoblastic   (bone  forming)  cell  lineage,  while  simultaneously  inhibiting  the  differentiation  of  osteoclasts   (bone-­‐resorbing  cells)  [100,  101].     In  contrast  to  the  anabolic  effects  of  leptin  acting  directly  on  bone,  leptin  has  been   reported  to  have  centrally  mediated  antiosteogenic  actions  on  trabecular  (spongy)  bone.  The   central  antiosteogenic  effect  of  leptin  was  first  revealed  as  an  increased  trabecular  bone  mass   observed  in  leptin-­‐deficient  ob/ob  mice  and  leptin  receptor-­‐deficient  db/db  mice,  as  well  as  the   effect  of  hypothalamic  leptin  administration  to  reduce  trabecular  bone  mass  in  leptin-­‐deficient   and  wild-­‐type  mice  [93].  However,  more  recent  work  shows  that  the  antiosteogenic  actions  of   leptin  are  limited  to  trabecular  bone,  with  leptin-­‐deficient  ob/ob  mice  exhibiting  decreases  in   cortical  bone  mass  [102]  in  conjunction  with  consistently  elevated  trabecular  bone  mass  [103].   Given  the  greater  contribution  of  cortical  bone  mass  to  total  BMD  and  content  than  trabecular   bone  [104],  this  differential  effect  of  leptin  on  trabecular  and  cortical  bone  probably  accounts  for   the  observation  of  decreased  weight-­‐corrected  BMC  and  BMD  in  ob/ob  mice  [102],  as  well  as   independent  reports  of  overall  decreases  in  BMD  in  leptin-­‐deficient  animals  [97,  99,  105,  106].   In  light  of  these  findings,  we  hypothesize  that  the  reduction  in  circulating  leptin  levels   consistently  observed  after  bariatric  surgery  would  lead  to  a  reduction  in  the  direct  stimulatory   effects  of  leptin  on  bone  cells.  Reduced  leptin  signalling  in  the  hypothalamus,  would  predict  a   decrease  in  cortical  bone  mass  and  overall  BMD  or  content,  albeit  with  a  potential  increase  in   trabecular  bone  formation.  However,  leptin  insensitivity  is  likely  to  modulate  aspects  of  leptin   signalling  in  the  chronically  obese  subjects  [107].  More  work  would  be  required  to  test  this   working  hypothesis.     Adiponectin     Adiponectin  is  an  adipokine,  the  circulating  concentrations  of  which  correlate  negatively  with   obesity  in  general  and  central  adiposity  in  particular  [108,  109].  Adiponectin  increases  insulin   sensitivity,  and  its  circulating  levels  are  reduced  in  obesity  and  diabetes  [110,  111].  Osteoblasts   express  both  adiponectin  and  its  receptors  [112],  and  show  increased  differentiation  in  response   to  the  peptide  [113].  Oshima  et al.  [113]  also  showed  that  adiponectin  could  conceivably   increase  bone  mass  by  suppressing  osteoclastogenesis  as  well  as  the  bone  resorption  activity  of   osteoclasts  in  vivo  (in  mice)  and  in  vitro.  In  contrast  to  these  stimulatory  effects  on  bone,   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013     circulating  adiponectin  has  been  shown  to  have  a  negative  effect  on  bone  formation  due  to   indirect  induction  of  formation  of  bone-­‐resorbing  osteoclasts  via  stimulation  of  receptor   activator  of  nuclear  factor  kappa-­‐B  ligand  (RANKL)  and  inhibition  of  osteoprotegerin  production   by  osteoblasts  [114].  Further  evidence  for  potential  antiosteogenic  actions  of  adiponectin  comes   from  observations  of  its  ability  to  bind  some  growth  factors  [115]  and  to  reduce  circulating   insulin  concentrations  [116],  which  would  tend  to  oppose  any  anabolic  effects  of  this  cytokine  on   bone  and  other  tissues.     Despite  uncertainty  from  basic  research  as  to  the  role  of  adiponectin  in  the  regulation  of   bone,  with  potential  osteogenic  and  antiosteogenic  actions  reported,  most  of  the  published   clinical  studies  indicate  that  adiponectin  is  a  negative  regulator  of  bone  mass  in  women  and  men   [76,  77,  117-­‐119].  Thus,  given  the  negative  correlation  between  body  weight  and  adiponectin   levels,  it  might  be  expected  that  bariatric  surgery-­‐induced  weight  loss  would  result  in  increased   circulating  adiponectin  levels  and,  consequently,  an  increase  in  its  antiosteogenic  actions.   Support  for  this  notion  comes  from  a  prospective  study  of  42  women  who  were  investigated  at   12  months  after  gastric  bypass  surgery  [52].  In  this  study,  circulating  adiponectin  levels  had  a   significant  and  positive  correlation  with  the  reduction  in  BMD  relative  to  baseline,  and  this  effect   was  unrelated  to  baseline  parameters  of  body  weight  or  body  composition,  or  to  the  gastric   bypass-­‐induced  changes  in  these  parameters.     Other  adipokines     Adipokines  such  as  visfatin  and  resistin  have  been  reported  to  have  a  variety  of  effects  on  bone,   predominantly  of  the  type  that  would  be  expected  to  inhibit  bone  mass.  In  keeping  with  a   generally  negative  effect  of  these  adipokines  on  bone,  resistin  may  play  a  role  in  bone   remodelling  as  it  stimulates  osteoclastogenesis  as  well  as  the  proliferation  of  osteoblasts  in  mice   [80],  and  circulating  resistin  was  found  to  be  a  negative  determinant  of  lumbar  BMD  in  middle-­‐ aged  men  [76].  By  contrast  visfatin  is  hypothesized  to  have  an  insulin-­‐like  effect  as  it  stimulates   glucose  uptake  as  well  as  the  proliferation  and  production  of  type  1  collagen  by  human   osteoblasts  [81],  which  may  be  expected  to  contribute  to  increased  bone  mass.  Clearly,  further   research  is  required  to  define  the  precise  role  of  these  adipokines  in  bone  homeostasis,  and   whether  their  expression  and  secretion  are  affected  by  bariatric  surgical  procedures.     Gut  hormones,  bariatric  surgery  and  bone     Besides  effects  on  adipokine  output  from  adipose  tissue,  another  potential  mechanism  by  which   bariatric  surgery  could  influence  bone  homeostasis  is  via  alterations  in  the  secretion  of  gut   hormones,  several  of  which  have  been  shown  to  not  only  influence  appetite  and  thereby  possibly   contribute  to  reduced  hunger  post  bariatric  surgery,  but  to  also  have  significant  effects  on  bone.   There  are  several  appetite-­‐regulating  hormones  secreted  by  the  gut,  the  circulating   concentrations  of  which  have  been  shown  to  be  altered  by  bariatric  surgery.  Examples  include   PYY  [120,  121],  GLP-­‐1  [121],  ghrelin  [122,  123],  oxyntomodulin  [124],  glucose-­‐dependent   insulinotropic  polypeptide  [121],  cholecystokinin  [121]  and  pancreatic  polypeptide  (PP)  [121,   125].  For  the  purposes  of  this  review,  however,  we  will  focus  on  three  particular  gut  peptides:   PYY,  GLP-­‐1  and  ghrelin.  The  reason  for  this  selection  is  that  these  are  the  three  gut  hormones  for   which  the  greatest  body  of  literature  exists  both  on  effects  of  different  forms  of  bariatric  surgery   on  their  circulating  concentrations,  as  well  as  effects  of  these  gut  hormones  on  bone.     Peptide  YY     PYY,  a  36-­‐amino-­‐acid  peptide,  is  a  member  of  the  NPY  family  of  peptides  that  also  includes  NPY   and  PP.  Like  other  members  of  the  NPY  family  of  peptides,  PYY  binds  to  and  induces  effects  via  Y   receptors  (Y1,  Y2,  Y4,  Y5  and  –  in  some  species,  but  not  humans  –  y6).  PYY  is  secreted  primarily   from  L-­‐cells  residing  in  the  intestinal  mucosa  of  the  ileum  and  large  intestine  [126].  It  is  released   into  the  circulation  as  the  full-­‐length  version,  PYY1–36,  as  well  as  the  truncated  version,  PYY3– 36,  the  latter  being  the  major  form  of  PYY  found  in  the  circulation  in  the  postprandial  state  [126].   NPY  and  PYY1–36  have  similar  affinities  for  Y1,  Y2,  and  Y5  receptors,  whereas  PYY3–36  has   selective  affinity  for  Y2  receptors  [126,  127].     PYY  is  recognized  as  a  critical  regulator  of  food  intake  and  energy  homeostasis.   Circulating  PYY  concentrations  are  increased  in  response  to  acute  food  intake  as  well  as  short-­‐ Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013   term  energy  excess  in  lean,  overweight  and  obese  people  [128].  Increased  PYY  output  likely   contributes  to  restoration  of  energy  homeostasis  during  periods  of  energy  excess,  mediated  by   inhibition  of  food  intake  [129],  most  likely  via  activation  of  Y2  receptors  in  the  arcuate  nucleus  of   the  hypothalamus  [130].  Besides  inhibiting  appetite,  PYY  has  also  been  shown  to  increase  energy   expenditure  in  lean  and  obese  men  [131]  and  to  decrease  energy  efficiency  and  increase  core   body  temperature  in  rodents  [132],  thereby  further  contributing  to  restoration  of  energy   balance.     In  light  of  the  above-­‐mentioned  weight-­‐reducing  effects  of  PYY,  as  well  as  observations   of  increased  circulating  PYY  levels  in  response  to  at  least  some  forms  of  bariatric  surgery  [120,   121,  133],  PYY  is  thought  to  contribute  to  the  success  of  surgery-­‐induced  weight  loss.  For   instance,  several  studies  have  shown  an  exaggerated  postprandial  increase  in  plasma  PYY  levels   following  RYGB  surgery,  which  may  contribute  to  the  ability  of  an  individual  to  maintain  weight   loss  after  this  procedure  [121,  134].  Additionally,  two  studies  have  reported  increases  over   baseline  in  fasting  and  postprandial  circulating  PYY  concentrations  at  3,  6  and  12  months  post   sleeve  gastrectomy  [135,  136].  It  remains  unclear  whether  gastric  banding  has  any  stimulatory   effect  on  fasting  or  postprandial  circulating  PYY  levels  [137].  In  contrast  to  effects  of  RYGB,  a   recent  study  reported  that  fasting  PYY  concentrations  in  the  circulation  decreased  in  proportion   to  weight  loss  following  LAGB,  compared  with  BMI-­‐matched  controls  [138].  These  findings   suggest  that  –  in  contrast  to  RYGB,  which  seems  to  have  the  opposite  effect  –  compensatory   changes  in  circulating  mediators  of  appetite  could  encourage  weight  regain  after  LAGB-­‐induced   weight  loss  [138].     While  an  increase  in  circulating  PYY  levels  may  reduce  hunger  and  promote  weight  loss   after  RYGB  or  sleeve  gastrectomy,  it  may  also  promote  bone  loss,  with  human  data  suggesting  a   negative  correlation  between  PYY  levels  and  bone  mass  under  a  variety  of  conditions.  Obese   subjects  have  been  reported  to  have  significantly  reduced  circulating  fasting  and  postprandial   levels  of  PYY  [139]  and  greater  BMD  [140].  Moreover,  in  lean  premenopausal  women,  circulating   PYY  levels  are  significantly  and  negatively  correlated  with  total  body  and  hip  bone  mass,  with   PYY  contributing  to  9%  of  the  variance  in  BMD  of  the  hip  [141].  Circulating  PYY  concentrations   are  markedly  elevated  in  anorexia  nervosa  [142],  and  this  change  is  related  to  the  significant   bone  loss  in  this  illness,  particularly  in  the  spine  [143].  Moreover,  circulating  PYY  levels  were   found  to  be  a  negative  predictor  of  serum  concentrations  of  aminoterminal  propeptide  of  type  1   collagen  (PINP),  a  bone  formation  marker,  and  lumbar  BMD  Z-­‐scores  in  amenorrhoeic  athletes,   albeit  their  PYY  levels  were  comparable  with  that  of  eumenorrheic  athletes  [144].  While  these   significant  associations  are  consistent  with  the  hypothesis  that  enhanced  PYY  action  post  RYGB   or  sleeve  gastrectomy  could  contribute  to  the  associated  alterations  in  bone  homeostasis  and   bone  loss,  whether  these  data  are  due  to  an  effect  of  PYY  on  bone  metabolism  or  are  a  result  of   numerous  effects  of  the  response  to  altered  energy  metabolism,  remains  to  be  determined.   Animal  studies,  however,  support  the  former  scenario.     An  effect  of  PYY  per  se  on  bone  has  been  confirmed  by  a  recent  analysis  of  PYY  knockout   and  PYY  overexpressing  transgenic  mouse  models,  with  male  and  female  knockouts   demonstrating  enhanced  osteoblast  activity  and  greater  trabecular  bone  mass,  and  transgenic   mice  exhibiting  reduced  osteoblast  activity,  reduced  femoral  BMD  as  well  as  increased  bone   resorption  [145].  The  contrasting  effects  of  the  PYY  knockout  and  transgenic  models  on  bone   strongly  indicate  that  PYY  reduces  bone  mass  by  inhibiting  osteoblast  activity  and/or  stimulating   bone  resorption  through  osteoclasts  [145].  While  these  data  fit  the  hypothesis  that  increases  in   circulating  PYY  levels  seen  post  RYGB  or  sleeve  gastrectomy  may  contribute  to  any  associated   increase  in  bone  turnover  or  decrease  in  bone  mass,  it  is  important  to  point  out  that  another   study  of  an  independently-­‐generated  PYY  knockout  mouse  line  reported  an  osteopenic   phenotype,  with  reductions  in  vertebral  cancellous  bone  mass  and  bone  strength  [146].  Further   work  is  required  to  clarify  the  role  of  PYY  in  the  regulation  of  bone  mass  and  metabolism.     Glucagon-­‐like  peptide-­‐1     GLP-­‐1  is  a  key  incretin  which,  along  with  PYY,  is  released  from  the  lower  intestinal  endocrine  L-­‐ cells  in  response  to  ingested  nutrients  [147].  GLP-­‐1  exerts  glucoregulatory  actions  by  stimulating   insulin  secretion,  slowing  gastric  emptying  and  attenuating  glucose-­‐dependent  glucagon   secretion  [148].  GLP-­‐1  promotes  satiety  [149],  and  sustained  GLP-­‐1-­‐receptor  activation  via   treatment  with  agents  such  as  exenatide  (marketed  as  Byetta  or  Bydureon)  is  associated  with   weight  loss  in  both  preclinical  and  clinical  studies  [150].   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013       Relatively  few  studies  have  examined  changes  in  circulating  GLP-­‐1  concentrations  in   obese  patients  after  gastric  bariatric  procedures.  There  have  been  reports  of  either  a  reduction   or  no  change  in  fasting  GLP-­‐1  levels  following  gastric  banding  [137,  151,  152].  Conversely,   increases  in  fasting  and  postprandial  circulating  GLP-­‐1  levels  have  been  reported  in  a  single   study  following  sleeve  gastrectomy  [153].  Similarly,  post-­‐surgical  increases  in  plasma   postprandial  GLP-­‐1  levels  have  been  documented  following  diversionary  operations,  and   augmented  levels  of  circulating  GLP-­‐1  may  account  for  the  antidiabetic  effect  of  the  RYGB   procedure,  evident  before  any  weight  loss  has  occurred  [121].  On  balance,  the  available  studies   to  date  suggest  that  fasting  and/or  postprandial  circulating  GLP-­‐1  levels  are  increased  following   RYGB  and  sleeve  gastrectomy,  with  either  no  change  or  a  decrease  in  fasting  GLP-­‐1  following  the   less  invasive  procedure  of  gastric  banding.     It  is  conceivable  that  any  differences  in  GLP-­‐1  actions  post  bariatric  surgery  could   influence  bone,  because  recent  rodent  studies  have  indicated  that  changes  in  incretins  such  as   GLP-­‐1  may  play  a  role  in  bone  metabolism  [154].  However,  the  directionality  of  any  such  effect  is   not  yet  clear.  GLP-­‐1  receptor  knockout  mice  exhibit  cortical  osteopenia  and  bone  fragility  as   assessed  by  bone  densitometry,  as  well  as  increased  numbers  of  osteoclasts  (bone-­‐resorbing   cells)  and  heightened  bone  resorption  [154].  In  contrast  to  these  indications  of  antiosteogenic   GLP-­‐1  actions  from  knockout  mice,  rats  treated  with  GLP-­‐1  for  3  days  via  a  subcutaneously   implanted  osmotic  pump  displayed  elevated  expression  of  osteoblastic  genes  in  bone  tissue   [155].  This  effect  of  exogenous  GLP-­‐1  administration  on  bone  was  apparent  in  both  normal  rats,   as  well  as  in  glucose  intolerant  rats,  and  it  occurred  without  any  change  in  plasma  glucose  and   insulin  after  treatment  [155].  These  findings  demonstrate  an  insulin-­‐independent  anabolic  effect   of  GLP-­‐1  on  bone,  and  suggest  that  GLP-­‐1  could  be  a  useful  therapeutic  agent  for  improving  the   deficient  bone  formation  and  bone  structure  associated  with  glucose  intolerance  [155].  However,   information  about  the  role  of  GLP-­‐1  in  the  regulation  of  bone  is  scanty  and  –  moreover  –  has  not   been  investigated  in  human  studies.  More  work  will  be  required  to  determine  whether  and  how   potential  changes  in  GLP-­‐1  action  post  bariatric  surgery  contribute  to  any  observed  changes  in   bone  metabolism  and  mass.     Ghrelin     Ghrelin  is  a  potent  appetite-­‐stimulating  hormone,  synthesized  in  the  gastric  antrum  and  fundus   [156].  The  circulating  concentrations  of  ghrelin  increase  under  pre-­‐prandial  and  fasting  [157]   conditions,  and  this  change  likely  contributes  to  the  drive  to  eat  after  periods  without  food  [157].   Ghrelin  is  thought  to  play  a  role  in  long-­‐term  maintenance  of  energy  stores,  because  as  well  as   stimulating  appetite,  it  also  decreases  energy  expenditure  [158].  Ghrelin  is  thought  to  act,  at  least   in  part,  via  increasing  expression  of  the  orexigenic  hypothalamic  NPY  system  [159],  which  also   stimulates  appetite  and  reduces  metabolic  rate  [160].     Reports  of  circulating  ghrelin  levels  after  bariatric  surgery  vary,  with  either  no  change  or   increases  in  fasting  plasma  ghrelin  relative  to  baseline  after  gastric  banding  [152,  161,  162].  By   contrast,  a  reduction  in  fasting  plasma  ghrelin  relative  to  baseline  levels  was  found  when   measured  up  to  5  years  after  sleeve  gastrectomy  [163].  Inconsistent  post-­‐surgical  changes  in   circulating  ghrelin  levels  have  been  found  after  diversionary  bariatric  procedures  such  as  RYGB,   with  studies  demonstrating  a  reduction  [164,  165],  no  change  [122,  166]  or  increased  ghrelin   levels  versus  baseline  [167-­‐169].  However,  most  studies  demonstrate  a  decrease  in  fasting   and/or  postprandial  circulating  ghrelin  levels  in  RYGB  patients  compared  with  control  patients   and  to  baseline  readings,  with  this  change  possibly  contributing  to  the  greater  weight  loss   associated  with  this  procedure  than  with  less  invasive  procedures  such  as  gastric  banding  [120,   123].     In  addition  to  clear  effects  on  energy  homeostasis,  ghrelin  may  play  a  role  in  the   regulation  of  bone  metabolism  through  its  effects  on  growth  hormone  and  –  as  a  consequence  –   insulin-­‐like  growth  factor-­‐1  secretion  via  actions  on  the  growth  hormone  secretagogue  receptor,   which  binds  ghrelin  [170].  The  growth  hormone  secretagogue  receptor  is  also  expressed  by   osteoblastic  cells,  which  have  been  reported  to  secrete  ghrelin  [171].  Ghrelin  stimulates   osteoblast  proliferation  and  differentiation  in  vitro  [171-­‐174],  while  also  promoting   osteoclastogenesis  and  the  bone-­‐resorbing  activity  of  mature  osteoclasts  [175].  At  present,  the   relative  contributions  of  gastric  and  osteoblastic  ghrelin  to  the  control  of  bone  mass  are  yet  to  be   defined.  However,  anabolic  effects  of  ghrelin  appear  to  predominate  in  vivo,  because  it  increases   BMD  when  administered  to  rats  [171].  Contrary  to  the  increased  BMD  observed  in  ghrelin-­‐ Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013   infused  rats  [171],  ghrelin  knockout  mice  have  unaltered  BMD  and  BMC  [176],  and  similar   effects  were  observed  in  growth  hormone  secretagogue  receptor  knockout  mice  [177],   suggestive  of  compensatory  pathways  that  counteract  effects  of  ghrelin  deficiency     While  animal  studies  suggest  a  predominantly  anabolic  effect  of  ghrelin  on  bone,  clinical   findings  are  not  yet  clear.  Overnight,  ghrelin  secretion  has  been  found  to  be  positively  and   significantly  related  to  BMD  in  adolescent  women  [178],  but  no  consistent  relationship  was  seen   between  fasting  ghrelin  levels  and  BMD  in  older  men  and  women  [179].     Taken  together,  while  different  forms  of  bariatric  surgery  may  alter  circulating  ghrelin   levels,  and  while  ghrelin  is  emerging  as  a  potentially  positive  regulator  of  bone,  whether  ghrelin   contributes  to  changes  in  bone  metabolism  or  mass  in  response  to  bariatric  surgery  is  yet  to  be   determined.     Central  control  of  bone     In  dissecting  possible  links  between  bariatric  surgical  procedures,  the  changes  in  adipokine  or   gut  hormones  concentrations  they  induce,  as  well  as  the  associated  changes  in  bone  metabolism   and  mass,  it  is  important  to  address  central  mechanisms  controlling  bone,  because  these  central   mechanisms  may  provide  a  link  between  these  associations.  The  fields  of  neuroscience  and  bone   biology  have  recently  converged,  following  the  discovery  that  bone  remodelling  is  directly   regulated  by  the  brain  [93,  180].  Orexigenic  neurons,  which  express  both  NPY  and  agouti-­‐related   peptide  (AgRP),  and  anorectic  neurons  expressing  pro-­‐opiomelanocortin  –  the  precursor  to  the   anorexigenic  alpha  melanocyte-­‐stimulating  hormone  (α-­‐MSH)  –  and  cocaine-­‐  and  amphetamine-­‐ regulated  transcript  (CART),  are  located  in  the  arcuate  nucleus  of  the  hypothalamus,  a  major   brain  centre  involved  in  the  regulation  of  energy  homeostasis  [181].  Activity  of  these  anabolic   and  catabolic  hypothalamic  neurons  is  regulated  by  both  leptin  and  insulin  [182].  Recent  work   has  demonstrated  that  NPY,  AgRP,  α-­‐MSH  and  CART  likely  play  a  role  in  the  regulation  of  bone   [93,  183-­‐185].  Other  pathways  implicated  in  the  central  control  of  bone  include  nitric  oxide   signalling  [186],  neuromedin  U  signalling  [187],  and  the  cannabinoid  system  [188,  189].  For  the   purposes  of  highlighting  potential  mechanisms  by  which  changes  in  adipokine  or  gut  hormone   concentrations  associated  with  bariatric  surgery  may  induce  changes  in  bone  metabolism  or   mass,  however,  in  this  review,  we  will  focus  uniquely  on  the  NPY  system,  with  which  we  have   worked  extensively.  The  reader  is  referred  to  other  reviews  [190-­‐192]  for  a  more  detailed   assessment  of  central  control  of  bone.     Neuropeptide  Y  and  bone     NPY  is  produced  predominantly  by  neurons  in  both  the  central  and  peripheral  nervous  systems   and  is  present  in  both  sympathetic  and  parasympathetic  nerve  fibres,  often  co-­‐secreted  with   noradrenaline  [193].  NPY  is  a  critical  downstream  regulator  of  leptin  signalling,  with   hypothalamic  NPY  expression  inversely  associated  with  serum  leptin  levels  [194].  The  NPY   system  regulates  energy  homeostasis  and  is  one  of  the  most  potent  stimulators  of  appetite  [195].   It  also  has  a  marked  effect  on  bone  mass.     Experimental  increases  in  central  NPY  expression  in  mice  produce  a  marked  (up  to   sevenfold)  decrease  in  bone  formation  and  bone  mass  [103].  Consistent  with  a  negative   relationship  between  NPY  and  bone  mass,  ablation  of  NPY  production  or  signalling  in  mice   induces  a  generalized  increase  in  bone  mass  and  bone  formation  [102,  196].  These  NPY  effects   on  bone  formation  have  been  shown  to  involve  signalling  both  within  the  hypothalamus  [103,   197]  as  well  via  direct  effects  on  osteoblasts,  through  Y1  receptor  pathways  [196,  198].     In  light  of  the  antiosteogenic  effect  of  NPY,  it  has  been  postulated  that  NPY  acts  as  a   critical  integrator  of  body  weight  and  bone  homeostatic  signals;  increasing  bone  mass  during   times  of  energy  excess  (and  consequent  obesity)  when  hypothalamic  NPY  expression  levels  are   low,  and  reducing  bone  formation  to  conserve  energy  under  ‘starving’  conditions,  when   hypothalamic  NPY  expression  levels  are  high  [197,  199].  As  such,  we  postulate  that  negative   energy  balance  after  bariatric  surgery,  which  is  known  to  be  associated  with  a  reduction  in   serum  leptin  [94-­‐96]  may  result  in  increased  hypothalamic  NPY  expression,  which  in  turn  may   contribute  to  associated  increases  in  bone  turnover  or  loss  of  bone  mass  [103].     Sleeve  gastrectomy  and  gastric  bypass  surgery  appear  to  attenuate  the  normal  adaptive   response  to  energy  restriction  and  weight  loss  with  increased  circulating  concentrations  of  the   anorexigenic,  gut-­‐derived  hormone,  PYY  [200].  PYY  inhibits  NPY  secretion  by  binding  to   Brzozowska  et  al.:  Bariatric  surgery  and  bone   Obesity  Reviews,  14(1):  52-­‐67,  2013     hypothalamic  Y2  receptors  [201,  202],  which  are  known  to  regulate  bone  mass  [180].  As  NPY   null  mice  demonstrated  a  generalized  bone  anabolic  phenotype  [197],  down-­‐regulation  of  NPY  in   response  to  PYY  could  not  explain  how  increases  in  PYY  might  lead  to  bone  mass  loss  post   bariatric  surgery.  However,  osteoblasts  express  Y1  receptors,  thus  PYY  could  inhibit  osteoblast   activity  and  reduce  bone  mass  through  a  direct  pathway  [203,  204].  Such  a  direct  PYY  signalling   pathway  in  osteoblasts  has  been  confirmed  by  a  recent  analysis  of  PYY  knockout  and  PYY   transgenic  mouse  models.  The  contrasting  skeletal  phenotypes  of  these  two  models  indicated   that  PYY  has  a  negative  relationship  with  osteoblast  activity  in  cancellous  and  cortical  bone   [145].  Thus,  PYY  may  directly  reduce  bone  mass  in  those  surgical  procedures  that  result  in   increased  PYY  secretion.     Conclusion     Bariatric  surgery  remains  the  most  effective  treatment  for  severely  obese  patients.  However,  the   potential  long-­‐term  effects  of  bariatric  surgical  procedures  on  health,  including  bone  health,  in   this  unique  group  of  people  are  only  partially  understood.  As  outlined  in  this  review,  there  is  a   complex  relationship  between  body  weight,  fat  mass  and  bone  mass,  with  many  peripheral  and   central  mediators  potentially  involved  in  the  dual  regulation  of  both  energy  and  bone   homeostasis.  Increased  body  weight  may  not  be  a  simple  protective  factor  for  bone  as  previously   thought,  and  thus  bariatric  surgical  procedures  that  result  in  bone  loss  need  careful   consideration.  Multiple  factors  are  involved  in  post-­‐surgical  bone  mass  loss  including  nutritional   deficiencies,  rapid  weight  loss,  as  well  as  possible  effects  of  changes  in  circulating  concentrations   of  fat-­‐derived  adipokines  and  gut-­‐derived  appetite-­‐regulatory  hormones.  However,  the  roles  of   adipokines  and  gut  hormones  in  skeletal  regulation,  as  well  as  the  mechanisms  by  which  they   work,  are  not  yet  fully  defined.  As  the  number  of  bariatric  operations  increases,  and  the  age  and   BMI  range  of  patients  on  which  they  are  performed  broadens,  it  is  imperative  to  recognize   mechanisms  responsible  for  bariatric  surgery-­‐induced  bone  loss,  with  careful  monitoring  of  bone   health  and  long-­‐term  fracture  incidence  in  patients  undergoing  these  procedures.     Conflict  of  interest  statement     Authors  declare  no  relevant  conflict  of  interest. 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