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[(h)27.4 (ypoc)-5.8 (alc)12.3 (emi)21.6 (a)-7.9 (.)]TJ
/Span<>> BDC
-0.656 -1.412 Td
( )Tj
EMC
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(\225)Tj
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0 Tw 0 -1.412 Td
[(of t)0.5 (he ja)28.8 (w)45 (.)]TJ
/Span<>> BDC
-0.656 -1.412 Td
( )Tj
EMC
-0.344 0 Td
(\225)Tj
0.002 Tw 1 0 Td
[(In v)-9.7 (ie)19.8 (w )0.5 (of )0.5 (the )0.5 (incr)9.9 (e)10.3 (ased r)-15.8 (is)25.8 (k of )0.5 (fr)5.7 (ac)-13.3 (t)-14.6 (ur)9.5 (e)12.8 (s )0.6 (af)-15.7 (t)13.6 (er denosumab )]TJ
0.135 Tw 0 -1.412 Td
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0 Tw 0 -1.412 Td
[(t)-10.8 (r)9.6 (e)10.4 (a)20 (t)-10.8 (ment should be c)14.2 (onsider)10.1 (ed)-1.1 (.)]TJ
/TT2 1 Tf
0.02 Tc -0.02 Tw 11 0 0 11 51.0236 499.7025 Tm
[(Int)5.7 (r)-1.3 (oduc)-15.2 (t)5.7 (ion)]TJ
/TT1 1 Tf
0 Tc 0.348 Tw 8.5 0 0 8.5 51.0236 481.7025 Tm
[(A)18.4 (c)13.2 (c)13.6 (or)11.2 (din)14.7 (g t)15.5 (o )0.5 (the )0.5 (GL)-7.9 (OB)6 (OC)-13.5 (AN 2018 d)9.6 (a)19.9 (t)-6.9 (a)-5.4 (, )0.5 (pr)8.4 (os)9.1 (t)-6.9 (a)20 (t)13.6 (e )0.5 (c)-5.9 (anc)12.2 (er )]TJ
0.17 Tw 0 -1.412 Td
[(\(1,276,106 ne)19.7 (w c)-5.9 (ase)13 (s)4.1 (; 7.1% of all )0.6 (c)-5.8 (anc)12.2 (er c)-5.9 (ase)13 (s\) is )0.7 (the sec)]TJ
0 Tw (-)Tj
0.04 Tw 0 -1.412 Td
[(ond c)13.7 (ommone)13.2 (s)8.9 (t c)-5.8 (anc)12.1 (er in men )0.6 (g)-1.5 (loball)14.1 (y and has t)0.5 (he se)18.3 (v)26.4 (ent)0.6 (h )]TJ
0.041 Tw 0 -1.412 Td
[(hi)22.2 (g)-1.4 (he)12.8 (s)9 (t c)-5.9 (anc)12.2 (er-r)9.4 (e)30.4 (la)20.1 (t)13.7 (ed mor)-22.8 (t)-6.9 (alit)-27.6 (y \(358,989 )-0.9 (de)10.1 (a)20 (ths)-4.6 (, 3.8% of all )]TJ
0 Tw 0 -1.412 Td
[(c)-5.9 (ase)13 (s\).)]TJ
4.913 0 0 4.913 76.6232 436.6775 Tm
(1)Tj
0.071 Tw 8.5 0 0 8.5 79.4683 433.7025 Tm
[( T)-17.6 (he )0.5 (mana)20.1 (g)14.2 (ement )0.8 (of )0.5 (pr)8.4 (os)9.1 (t)-6.8 (a)19.9 (t)13.6 (e )0.5 (c)-5.9 (anc)12.2 (er has )0.5 (been )0.6 (t)-10.8 (r)5.7 (adi)]TJ
0 Tw 23.989 0 Td
(-)Tj
0.106 Tw -27.335 -1.412 Td
[(t)-10.8 (ionall)14.3 (y w)-7.7 (it)0.6 (h andr)8.6 (o)9.9 (g)14.1 (en)-2.7 (-depr)-16.2 (i)14.4 (v)23.9 (a)20 (t)-10.8 (ion t)0.5 (her)5.9 (ap)22.7 (y \()61.9 (AD)2 (T)63.3 (, inc)15.9 (ludin)14.7 (g )]TJ
0.145 Tw 0 -1.412 Td
[(bila)20.2 (t)13.6 (er)5.9 (al or)13.6 (c)15.6 (hiec)-12.8 (t)15.6 (om)28.6 (y )0.5 (or medic)-5.5 (al c)-5.9 (as)9 (t)-10.8 (r)5.7 (a)19.9 (t)-10.8 (ion\) )0.5 (usin)15 (g g)13.1 (onado)]TJ
0 Tw 27.335 0 Td
(-)Tj
0.347 Tw -27.335 -1.412 Td
[(t)-10.8 (r)8.6 (opin)-2.7 (-r)9.5 (e)30.4 (le)10.5 (asin)15.1 (g hor)-15.6 (mone )0.9 (\(GnR)-23.8 (H\) a)20 (g)14.1 (ent)-7.2 (s)-4.7 (.)]TJ
0 Tw 4.913 0 0 4.913 221.4667 400.6775 Tm
(2)Tj
0.347 Tw 8.5 0 0 8.5 224.3118 397.7025 Tm
[( Appr)8.2 (o)29.8 (xima)20.2 (t)13.7 (e)30.4 (l)13.8 (y )]TJ
-0.039 Tw -20.387 -1.412 Td
[(half of the pr)8.5 (os)9.1 (t)-6.9 (a)20 (t)13.6 (e c)-5.9 (anc)12.2 (er pa)19.8 (t)-10.8 (ient)-7 (s r)9.6 (ec)12.3 (ei)14.5 (v)26.4 (e AD)2 (T a)19.9 (t some )0.7 (point )]TJ
0.26 Tw 0 -1.412 Td
[(af)-15.7 (t)13.6 (er di)21 (a)20 (gnosis)-4.2 (.)]TJ
0 Tw 4.913 0 0 4.913 112.1431 376.6775 Tm
(3)Tj
(,)Tj
(4)Tj
0.26 Tw 8.5 0 0 8.5 118.9823 373.7025 Tm
[( C)-10.4 (anc)12.2 (er t)0.5 (her)5.9 (ap)22.7 (y le)10.5 (ads t)15.6 (o os)9.1 (t)13.6 (eopeni)21.5 (a and )]TJ
0.005 Tw -7.995 -1.412 Td
[(os)9.1 (t)13.6 (eopor)8.8 (osis )0.8 (whic)16 (h ar)9.5 (e t)13.7 (er)-15.7 (med as c)-5.9 (anc)12.2 (er t)-10.8 (r)9.6 (e)10.4 (a)19.9 (t)-10.7 (ment)47.7 (\226)11.6 (induc)12.1 (ed )]TJ
-0.007 Tw 0 -1.412 Td
[(bone los)11.7 (s \(C)-28.5 (T)-18.6 (IBL)66.3 (\). W)46.9 (e r)9.6 (e)18.2 (v)-9.7 (ie)19.8 (w the im)20.9 (pac)-13.4 (t of C)-28.3 (T)-18.7 (IBL in nonme)16.2 (t)]TJ
0 Tw (-)Tj
-0.022 Tw 0 -1.412 Td
[(as)8.9 (t)-6.9 (a)20 (t)-10.8 (ic )0.7 (pr)8.5 (os)9.1 (t)-6.9 (a)20 (t)13.6 (e )0.6 (c)-5.9 (anc)12.2 (er )0.5 (pa)19.8 (t)-10.8 (ient)-7 (s )0.7 (and the )0.7 (r)8.6 (ole )0.9 (of )0.6 (denosumab )0.8 (in )]TJ
0 Tw 0 -1.412 Td
[(im)21 (pr)8.4 (o)25.5 (v)-9.7 (in)14.9 (g bone mas)11.7 (s in suc)16.2 (h pa)19.9 (t)-10.8 (ient)-7 (s)-4.7 (.)]TJ
/TT2 1 Tf
0.02 Tc 11 0 0 11 51.0236 295.7025 Tm
[(Bone L)5.7 (os)4.4 (s in Pr)-1.4 (os)1.5 (t)-5.5 (a)4.6 (t)7.2 (e C)-5.1 (anc)9.6 (er)]TJ
/TT1 1 Tf
-0.005 Tc 0.186 Tw 8.5 0 0 8.5 51.0236 277.7025 Tm
[(Ma)30.2 (jor)-15.8 (it)-27.9 (y of the pr)8.6 (os)9 (t)-6.9 (a)20 (t)13.6 (e c)-5.9 (anc)12.2 (er pa)19.9 (t)-10.8 (ient)-7.4 (s \(>70%\) ar)9.6 (e e)30.4 (lder)11.1 (l)13.8 (y)-4.8 ( )]TJ
/C2_0 1 Tf
0.005 Tw 0 -1.412 Td
[<000B0095001900180003>-143.5 <005C>25.5 <0048>10.4 <004400550056000C0003>-143.5 <005A004B00520003>-143.5 <00440055>9.6 <00480003>-143.5 <0044004F0055>9.6 <0048>10.4 <00440047>13 <005C0003>-143.5 <00440056>11.4 <005600520046004C>21.2 <0044>20 <0057>13.6 <004800470003>-143.5 <005A>-7.7 <004C0057>0.5 <004B0003>-143.5 <00440003>-143.5 <004B004C>22.1 <004A>-1.4 <004B0003>-143.5 <0055>-15.8 <004C0056>25.6 <004E0003>-143.5 <0049>24.4 <00520055>-5.2 <0003>]TJ
/TT1 1 Tf
0 -1.412 Td
[(os)9 (t)13.6 (eopor)8.6 (osis)-4.7 (.)]TJ
0 Tc 0 Tw 4.913 0 0 4.913 101.6454 256.6775 Tm
(5)Tj
-0.005 Tc 0.396 Tw 8.5 0 0 8.5 104.466 253.7025 Tm
[( F)18.7 (ur)-23.1 (ther)-15.7 (mor)9.6 (e)10.9 (, c)-5.9 (anc)12.2 (er ther)5.7 (ap)22.8 (y also le)10.4 (ads t)15.5 (o)-4.9 ( )]TJ
0.047 Tw -6.287 -1.412 Td
[(os)9 (t)13.6 (eopeni)21.2 (a and os)8.9 (t)13.7 (eopor)8.7 (osis whic)15.6 (h ar)9.6 (e t)13.7 (er)-15.8 (med as C)-28.4 (T)-18.6 (IBL.)]TJ
0 Tc 0 Tw 4.913 0 0 4.913 269.8757 244.6775 Tm
(6)Tj
0.574 0 Td
(,)Tj
0.229 0 Td
(7)Tj
-0.005 Tc 0.047 Tw 8.5 0 0 8.5 276.6414 241.7025 Tm
[( In)-4.9 ( )]TJ
0.066 Tw -26.543 -1.412 Td
[(pr)8.6 (os)9 (t)-6.9 (a)19.9 (t)13.7 (e c)-5.9 (anc)12.2 (er pa)20 (t)-10.8 (ient)-7.4 (s)-4.7 (, t)13.6 (e)12.8 (s)9 (t)15.6 (os)9 (t)13.6 (er)8.6 (one de)23 (f)-32.7 (icienc)-17.5 (y is seen sec)]TJ
0 Tc 0 Tw (-)Tj
-0.005 Tc 0.182 Tw 0 -1.412 Td
[(ond)9.6 (ar)-31.9 (y t)15.5 (o andr)8.6 (o)9.9 (g)14.2 (en depr)-15.8 (i)14.4 (v)23.9 (a)19.9 (t)-10.7 (ion fr)8.6 (om AD)2.2 (T inc)15.6 (ludin)14.7 (g GnR)-23.6 (H)-5.1 ( )]TJ
0.05 Tw 0 -1.412 Td
[(a)20 (g)14.1 (ent)-7.4 (s or sur)1.3 (gic)-5.9 (al c)-5.9 (as)9 (t)-10.8 (r)5.6 (a)20 (t)-10.8 (ion.)]TJ
0 Tc 0 Tw 4.913 0 0 4.913 162.6099 208.6775 Tm
(7)Tj
0.574 0 Td
(,)Tj
0.229 0 Td
(8)Tj
-0.005 Tc 0.05 Tw 8.5 0 0 8.5 169.3755 205.7025 Tm
[( AD)2.2 (T is k)-12.8 (no)25.5 (wn t)15.6 (o induc)12.2 (e bone)-4.9 ( )]TJ
-0.046 Tw -13.924 -1.412 Td
[(los)11.4 (s)-4.7 (, ther)9.6 (e)22 (b)20.5 (y incr)9.6 (e)10.3 (asin)14.6 (g the r)-15.8 (is)25.6 (k of os)9 (t)13.6 (eopor)8.7 (osis and bone fr)5.7 (ac)]TJ
0 Tc 0 Tw (-)Tj
-0.005 Tc -0.039 Tw 0 -1.412 Td
[(t)-14.7 (ur)9.6 (e)12.8 (s)-4.6 (, ult)-10.8 (ima)19.9 (t)13.7 (e)30.4 (l)13.8 (y af)-14.2 (f)24.4 (ec)-13.2 (t)-10.8 (in)14.7 (g t)0.5 (he q)22.1 (ualit)-27.9 (y of lif)24.4 (e \(QOL)66.3 (\) of pa)20 (t)-10.8 (ient)-7.3 (s)-4.7 (.)]TJ
0 Tc 0 Tw 4.913 0 0 4.913 284.021 184.6775 Tm
(6)Tj
/TT2 1 Tf
0.02 Tc -0.02 Tw 9 0 0 9 51.0236 156.0016 Tm
[(P)12 (a)4.6 (t)5.8 (hoph)15.8 (y)5.6 (siolog)1.3 (y)]TJ
/C2_0 1 Tf
0 Tc 0 Tw 8.5 0 0 8.5 51.0236 144.0016 Tm
[<0037>-17.7 <004B00480003>-47.8 <0045004C00510047004C0051>14.9 <004A0003>-48 <005200490003>-47.9 <004F004C>22.4 <004A>9.8 <0044005100470003>-48.3 <0055>9.6 <00480046>12.4 <00480053>14.1 <0057>15.6 <005200550003>-48 <00440046>-13.3 <0057>-10.8 <004C>14.4 <0059>23.9 <0044>19.9 <0057>15.6 <005200550003>-48 <005200490003>-47.9 <005100580046>15.6 <004F0048>10.5 <004400550003>-48.2 <0049>16.1 <00440046>-13.2 <0057>15.6 <00520055001001FD00250003>]TJ
/TT1 1 Tf
0.194 Tw 0 -1.412 Td
[(\(R)-46.7 (ANK)17.2 (\) t)15.6 (o it)-7.2 (s li)22.4 (g)9.7 (and R)-46.5 (ANK)-16.1 (L t)-10.8 (r)-15.7 (i)22.1 (g)-11.2 (g)14.2 (ers a si)22.4 (gnal t)-10.7 (r)5.7 (ansduc)-13.3 (t)-10.8 (ion )]TJ
0.375 Tw 0 -1.412 Td
[(pa)19.8 (t)0.5 (hw)26 (a)27.3 (y whic)16 (h sub)11.7 (seq)22.4 (uentl)13.9 (y s)9 (t)-10.8 (imula)20.5 (t)13.6 (e)12.8 (s os)9.1 (t)13.6 (eoc)15.9 (las)9.1 (t f)-12.2 (unc)]TJ
0 Tw (-)Tj
-0.011 Tw 0 -1.412 Td
[(t)-10.8 (ionin)15.2 (g)1 (, wher)9.9 (e)10.3 (as os)9.1 (t)13.6 (eopr)8.8 (o)14.2 (t)13.7 (e)7.4 (g)14.2 (er)-15.7 (in binds t)15.5 (o R)-46.6 (ANK)-16 (L pr)9.5 (e)18.2 (v)26.3 (ent)-10.6 (in)14.9 (g )]TJ
0.151 Tw 0 -1.412 Td
[(bone r)9.6 (e)12.8 (sor)-16.7 (p)14.1 (t)-10.8 (ion.)]TJ
0 Tw 4.913 0 0 4.913 116.537 98.9766 Tm
(9)Tj
(-)Tj
(11)Tj
0.151 Tw 8.5 0 0 8.5 127.0922 96.0016 Tm
[( T)-17.7 (he bindin)14.8 (g of R)-46.6 (ANK t)15.6 (o R)-46.6 (ANK)-16 (L c)-5.9 (ause)12.9 (s )]TJ
0.193 Tw -8.949 -1.412 Td
[(os)9.1 (t)13.6 (eoc)15.9 (las)9.1 (t dif)-14.2 (f)24.4 (er)9.7 (ent)-10.6 (i)21.2 (a)19.9 (t)-10.7 (ion )0.5 (in the pr)9.5 (e)12.8 (senc)12.5 (e of c)13.7 (olon)29.7 (y s)9 (t)-10.8 (imu)]TJ
0 Tw (-)Tj
0.042 Tw 0 -1.412 Td
[(la)20.1 (t)-10.8 (in)14.9 (g f)16.1 (ac)-13.2 (t)15.5 (or 1 \(C)-10 (SF1\), )0.6 (and bone )0.5 (r)9.6 (e)12.8 (sor)3.1 (bin)14.8 (g ac)-13.3 (t)-10.7 (i)14.3 (v)-9.8 (it)-27.6 (y )0.5 (in )0.6 (ma)20.2 (t)-14.7 (ur)9.6 (e )]TJ
0.041 Tw 0 -1.412 Td
[(os)9.1 (t)13.6 (eoc)15.9 (las)9.1 (t)-7.4 (s)-4.7 (. Os)9.2 (t)13.6 (eopr)8.7 (o)14.3 (t)13.6 (e)7.4 (g)14.2 (er)-15.7 (in af)-15.7 (t)13.7 (er bindin)14.8 (g t)15.6 (o R)-46.6 (ANK)-16 (L inhibit)-6.8 (s )]TJ
0 Tw 0 -1.412 Td
[(os)9.1 (t)13.6 (eoc)15.9 (las)9.1 (t)15.5 (o)9.9 (g)14.2 (ene)13 (sis and os)9.4 (t)13.6 (eoc)15.9 (las)9.1 (t ac)-13.3 (t)-10.8 (i)14.3 (v)24 (a)19.9 (t)-10.8 (ion \()]TJ
/C2_1 1 Tf
0.02 Tc -0.02 Tw 8.1 0 0 8.1 226.4648 48.0016 Tm
[<03150029>16.8 <004C>13.5 <004A>-2.3 <001100030014>]TJ
/TT1 1 Tf
0 Tc 0 Tw 8.5 0 0 8.5 254.7267 48.0016 Tm
(\).)Tj
4.913 0 0 4.913 259.8607 50.9766 Tm
(12)Tj
/TT2 1 Tf
0.02 Tc 9 0 0 9 301.0394 539.4837 Tm
[(C)-5.1 (anc)9.6 (er T)60 (r)-0.9 (e)5.2 (a)4.6 (t)5.8 (ment)37.5 (\226Induc)9.6 (ed Bone L)5.7 (os)4.4 (s)]TJ
/TT1 1 Tf
0 Tc 0.556 Tw 8.5 0 0 8.5 301.0394 527.4837 Tm
[(D)3.6 (ecr)9.7 (e)10.4 (ase in e)12.8 (s)8.9 (t)-10.7 (r)8.6 (o)9.9 (g)14.1 (en and t)13.6 (e)12.8 (s)9 (t)15.6 (os)9.1 (t)13.6 (er)8.8 (one oc)13.2 (c)-9.7 (ur)-15.9 (r)-15.8 (in)14.9 (g w)-7.7 (it)0.7 (h )]TJ
0.09 Tw 0 -1.412 Td
[(h)27.4 (ypo)9.9 (g)13.1 (onadism le)10.6 (ads )-0.6 (t)15.6 (o f)16.2 (as)8.9 (t)13.6 (er bone los)11.7 (s)-4.7 (, and )-0.7 (in the ab)11.6 (senc)12.6 (e )]TJ
0.362 Tw 0 -1.412 Td
[(of )0.5 (incr)9.6 (e)10.4 (ased bone )0.5 (f)24.4 (or)-15.7 (ma)20.2 (t)-10.8 (ion, )0.8 (it ma)27.5 (y )0.5 (le)10.5 (ad t)15.6 (o os)9.1 (t)13.6 (eopeni)21.5 (a )]TJ
0.317 Tw 0 -1.412 Td
[(and e)18.2 (v)26.4 (ent)-14.5 (uall)13.8 (y os)9.1 (t)13.6 (eopor)8.9 (osis)-4.2 (.)]TJ
0 Tw 4.913 0 0 4.913 417.2137 494.4587 Tm
(8)Tj
0.317 Tw 8.5 0 0 8.5 420.0588 491.4837 Tm
[( In men )0.5 (w)-7.7 (it)0.6 (h pr)8.5 (os)9.1 (t)-6.9 (a)20 (t)13.6 (e c)-5.9 (an)]TJ
0 Tw 13.333 0 Td
(-)Tj
0.318 Tw -27.335 -1.412 Td
[(c)12.2 (er r)9.6 (ec)12.3 (ei)14.5 (v)-9.8 (in)14.9 (g AD)2 (T)63.4 (, the decr)9.5 (e)10.4 (ased cir)13.7 (c)-9.7 (ula)20 (t)-10.8 (in)14.9 (g t)13.7 (e)12.8 (s)9 (t)15.5 (os)9.1 (t)13.7 (er)8.7 (one )]TJ
0.246 Tw 0 -1.412 Td
[(and e)12.8 (s)9 (t)-10.8 (r)8.6 (o)9.9 (g)14.2 (en, )0.5 (decr)9.5 (e)10.3 (ased os)9.1 (t)13.6 (eoblas)8.9 (t)-10.7 (ic bone f)24.4 (or)-15.7 (ma)20.2 (t)-10.8 (ion, )0.7 (and )]TJ
0.127 Tw 0 -1.412 Td
[(incr)9.8 (e)10.4 (ased os)9.1 (t)13.6 (eoc)15.8 (las)9.1 (t)-10.8 (ic bone r)9.6 (e)12.9 (sor)-16.5 (p)14 (t)-10.8 (ion )0.5 (r)9.6 (e)12.8 (sult in ac)13.1 (c)12.2 (e)30.4 (ler)6 (a)20 (t)13.6 (ed )]TJ
0.05 Tw 0 -1.412 Td
[(bone los)11.7 (s)-4.7 (.)]TJ
0 Tw 4.913 0 0 4.913 339.8336 446.4587 Tm
(13)Tj
(,)Tj
(14)Tj
0.05 Tw 8.5 0 0 8.5 352.3631 443.4837 Tm
[( T)-17.6 (her)9.6 (e c)13.7 (ould be a decr)9.5 (e)10.3 (ase in musc)15.8 (le mas)11.6 (s due )]TJ
0.34 Tw -6.038 -1.412 Td
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