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Oguz Soydinc, D. Duranyildiz, H. Camlica, F. Tas, V. Yasasever Istanbul University Oncology Institute Istanbul - Turkey$~PC;                    Introduction   Bone metastases are common in many cancers, particularly in advanced stage, including breast, prostate and lung cancer and are associated with significant skeletal morbidity. (9 s The primary malignant neoplasm promotes new blood vessel formation, and these blood vessels carry cancer cells to capillary beds in the bone. Aggregates of tumor cells and other blood cells form embolisms that lodge in distant capillaries in bone. Cancer cells can adhere to vascular epithelial cells to escape the blood vessels. As cancer cells enter the bone, they contact factors in the microenvironment of the bone that support the growth of metastases. @PP?PP&          The prognosis in bone metastases!!(:   vBone tissue is such a dynamic and complex tissue that formation and resorption events are cycling consecutively each other where numerous elements and factors are involved. To monitor this active turnover of bone tissue effectively, measurements of some protein products and enzymes formed and released during this turnover so called biochemical markers can be performed .,wD         $OSTEOCALCIN (bone Gla protein (BGP)<% (($< Osteocalcin, or bone Gla protein (BGP), is the major noncollagenous protein of bone matrix. Molecular weight of 5.8 kD, consists of 49 amino acids, including three residues of gamma-carboxyglutamic acid. Synthesized in bone by osteoblasts and thought to play a role in mineralization and calcium ion homeostasis.X^ZZpZZm0Z<          %" OSTEOCALCIN , ((Osteocalcin is incorporated into the bone matrix and delivered to the circulatory system. Osteocalcin may also function as a negative regulator of bone formation. As osteocalcin is manufactured by osteoblasts, it is often used as a biochemical marker for the bone formation process. ^ZI  y              #!OSTEOPROTEGERIN (OPG)(<    OPG is also known as osteoclast inhibitory factor (OCIT) and is a tumor necrosis factor (TNF) receptor family member. It has a molecular weight of 120 kD, consists of 401 amino acids. FxPPCPPL   )#OSTEOPROTEGERIN((  OPG inhibits the recruitment, proliferation and activation of osteoclasts. It acts as a soluble factor in the regulation of bone mass.       "0f0  *$DOSTEOMARK NTx (cross-linked N-telopeptides of bone type I collagen)<E ((6t   CNTx is a specific biochemical indicator of bone resorption that is generated as the result of osteoclast activity on bone. NTx is specific to bone due to the unique amino acid sequence. It is generated from bone by osteoclasts as a degradation product of type I collagen, and it can easily be measured in urine or serum.L|ZZ?ZZZDd         ZOLEDRONIC ACID "U Bisphosphonates are potent inhibitors of osteoclast activity that are widely used for the palliation and prevention of bone metastases. Zoledronic acid injection is an infused therapy and a member of the class of medicines called bisphosphonates. Zoledronic acid is a treatment for patients with cancer that has spread to the bones. hPPPPPPT    T       X 0 ZOLEDRONIC ACID5 It may reduce or delay bone fractures or pressure on the spinal cord that can result from bone damage from advanced cancer. It can also help patients who already have experienced bone complications. Clinical and experimental evidences indicate that bisphosphonates suppress progression of bone metastases. ZP|PPKPPlP6   2  )  MATERIAL & METHOD( Totally 27 consecutive patients who had histologically confirmed breast and lung cancer associated with scintigraphic evidence and radiographic confirmation (plain X-ray and/or magnetic resonance) of bone metastases were included in the study. Serum was available from 10 healthy volunteers who did not have any serious diseases and were not on drugs known to affect bone and calcium metabolism.Bx   2       Patients eligibility &((N  3- Normal levels of bone marrow activity, - Normal hepatic and renal function, - No acute and chronic infections, - Not received radiotherapy, chemotherapy and hormonal therapy during the last four weeks before study accrual, - Not received steroids within last week before zoledronic acid administration. 44 !      9 /  #       Zoledronic Acid Treatment6      Zoledronic acid (Zometa, Novartis) 4 mg was administered as a 15-minute infusion in 100 ml normal saline. All patients received zoledronic acid on an outpatient basis.@k>       B      Analysis of parameters &(( R Blood samples were obtained by venipuncture at basal, in 7th and 28th day after the zoledronic acid infusion, clotted , centrifuged and maintained at -20 C. The 24-hour urine samples were collected, daily produced urine volume was 2.75 liters in patients and 3.5 liters in the healthy controls; centrifuged and maintained at -20 C. hwl               9+vThe test levels were measured by enyzme -linked immunosorbent assay. Data analysis was performed by using SPSS 11.("'.wd!       - +%  - Most of the patients were middle-aged, Male predominance in lung cancer patients, Diffuse bone metastases, Most of the patients with other distant metastases beyond bone metastases.+ -   2 & *   ;   ,&3* Serum osteoprotegerin levels in patients were significantly higher than the control group (p<0.001). Serum osteocalcin and urine osteomark levels were not significantly different between patients and control group (p>0.05). @f|[   P        V !Effect of Zoledronic Acid(B      9 No statistically significant change due to infusions of zoledronic acid in patients with bone metastases for both serum osteocalcin and osteopretegerin levels (p>0.05). Significant change was seen following infusion of zoledronic acid in patients with bone metastases is for urine osteomark levels (p=0.035). zZZZZ, 7   6        '   4    4)Correlation of parameters $((     No significant correlation between serum osteocalcin, osteoprotegerin and urine osteomark levels in patients with bone metastases. ( &            Conclusion ( Serum osteoprotegerin in patients with breast and lung cancer with bone metastases could be used as a diagnostic marker. Urine osteomark can be an useful marker for the follow-up of zoledronic acid therapy. 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Development of bone metastasisl  0,5V =  "8XH  0޽h ? 33___PPT10i.GPB+D=' = @B +  0L0 s(    N|51?d   frequency median survival ( %) (month) M.Myeloma 70 - 95 24 Prostate 65 - 75 36 Breast 65 - 75 24 Lung 30 - 40 7 Thyroid 60 48 M. Melanoma 14 - 45 6 Bladder 40 6 - 90@ 20 $,(Q0    "       )                                                       $| hh88~  s *T5H  `  5    3 r5|`f3d1?  ~2NCI, 1997; International Myeloma Foundation, 2001.303 3 H  0޽h ? ̙33y___PPT10Y+D=' = @B +  0 p\0(  \x \ c $(H  `   x \ c $5H'g   H \ 0޽h ? 33___PPT10i.0ID+D=' = @B +  0L0 0<(  ~  s */H<9   ~  s *<5H"9  H  0޽h ? 33___PPT10i.qH0bQ+D=' = @B +  0 `*(  x  c $d8H9B   r  S <9H]'  H  0޽h ? 33___PPT10i. pƸ+D=' = @B +  0 00(  x  c $UH9o   x  c $xVHm9  H  0޽h ? 33___PPT10i.jДPq+D=' = @B +  0 0(  x  c $qH9   x  c $rH h  H  0޽h ? 33___PPT10i. ̅+D=' = @B +  0L0 @0(  ~  s *\xH[      t A      8c8c     ?HA)BCD|E||'    0F T-  ,-9  0V T( Differentiation, activation, and survival of osteoclasts are regulated by the balance between RANKL (RANK ligand) and osteoprotegerin (OPG). ,        <d uOSTEOPROTEGERIN(  H  0޽h ? 33___PPT10i.?Q`S+D=' = @B +  0 *(  x  c $åH  `   r  S åH]'g  H  0޽h ? 33___PPT10i. P۟+D=' = @B +  0 `*(  `x ` c $tѥH<@B   r ` S (zH/q  H ` 0޽h ? 33___PPT10i.`I+D=' = @B +  0  0(   x  c $0H'gB   x  c $H `p  H  0޽h ? 33___PPT10i.`H+D=' = @B +  0 $*(  $x $ c $H9B   r $ S H]9L  H $ 0޽h ? 33___PPT10i.@+D=' = @B +  0 (0(  (x ( c $@ H,;   x ( c $ HT   H ( 0޽h ? 33___PPT10i.[Q+D=' = @B +  0 ,0(  ,x , c $H<9   x , c $H `p  H , 0޽h ? 33___PPT10i.r +D=' = @B +  0 80(  8x 8 c $H<    x 8 c $H'g7   H 8 0޽h ? 33___PPT10i.۵r+D=' = @B +$  0 PX$(  Xr X S (+H  `   r X S ,H `p  H X 0޽h ? w3ff80___PPT10. 1_O 0 f^$(  x 'Zg  $ #"*j'g  < =?S g  d -0(cC @`  <TG? S  z 8/7D(ccc @`1  <$S?'  #Serum CA15.3 level Normal/ Elevated@  #cC    @`  <^?Ss g  f 7/50(cC @`  <f? s S  f 8/70(cC @`9  <(s?'s  %Other metastases except bone No/ Yes@  %cC&  @`   <|?Sgs  f 6/60(cC @`   <? Ss  g 2/130(cC @`>   <(?' s  .Extension of bone metastases Limited/ Diffuse0/ .cC2   @`   <T?S(g g 12/00(cC @`   <? (S h 0/ 150(cC @`   <?'(   Gender M/ F@   cC @`  <?S/g( k 54 11.40 ( cC @`  <ű? /S( m 57.5 12.60 ( cC @`  <?'/ ( Age0 cC @`(  <ܱ?SZg/ Lung cancer n=12D (( cC$ @`K  <? ZS/ Breast cancer n=15f(( cccC$ @`  <?'Z / DC @`ZB  s *) ?'ZgZZB  s *) ?' g ZB  s *) ?'Z' ZB  s *) ?gZg ZB  s *1 ?'/g/ZB  s *1 ? Z ZB  s *1 ?SZS ZB  s *1 ?'(g(ZB  s *1 ?'gZB  s *1 ?'s gs ZB  s *1 ?' g H  0޽h ? 33___PPT10i.p(+D=' = @B +  0 @*(  @x @ c $H  `   r @ S X H9  H @ 0޽h ? 33___PPT10i.{+D=' = @B +  0 #(  x  c $H  `     ` # #"&#''g   <? ` b>0.05 *(C @`  <?  X 19 (1-820) (  @`  <?R  s442.5 (29- 8400)0(cC @`R  <84?  R OSTEOMARK (urine) (nM)b  cccC,  @`   <.? `  V<0.001( @`   <|F?   Y 5.1 (4.2-7) (  @`   <\H?R  p11.5 (6.2-18)0(cC @`   <t\?  R  OSTEOPROTEGERIN (U/L)b  cccC @`   <W?`  S>0.05( @`  <n?   ]9.8 (2.7-15.8)( @`  <x?R  r11.3 (3.0-41.0)0(cC @`=  <L? R  OSTEOCALCIN (ng/mL)b    cccC  @`)  <h?R` Median (min-max)4(cc6 @`  <(? R DC @`  <T?` mp(  @`  <?  Control (n=10)(  @`  <඲?R  Patients (n=27)(  @`  <x? R \ C   @`HB  C  `HB  C  `HB  C   HB  C ``ZB  s *1 ?RRZB  s *1 ? `H  0޽h ? 33___PPT10i.  .B+D=' = @B +  0 0^(  ~  s *H  `    0 TA ?H  H  0޽h ? 33___PPT10i.( ~+D=' = @B +  0 <<(  <~ < s *ղH  `   ~ < s *`ֲH9e   H < 0޽h ? 33___PPT10i.VI+D=' = @B + 0 /'`O(  t   O #"&('v - <T??   s707.5 (420-2295)0(cC @` , <t? ?  p780 (88-4000)0(cC @` + <x?W  s442.5 (29- 8400)0(cC @`R * <? W  OSTEOMARK (urine) (nM)b  cccC,  @` ) <??&  p11.1 (7.6-31)0(cC @` ( <? &?  p11.3 (5.9-17)0(cC @` ' <8?W&  p11.5 (6.2-18)0(cC @` & <|4?&W  OSTEOPROTEGERIN (U/L)b  cccC @` % <>??B& r11.6 (2.8-7785)0(cC @` $ <H? B?& r12.7 (2.1-9595)0(cC @` # <R?WB & r11.3 (3.0-41.0)0(cC @`= " <_?BW& OSTEOCALCIN (ng/mL)b    cccC  @`)  <k?WB Median (min-max)4(cc6 @`  <t?WB DC @`   <~?? Day 28th2 (cC"   @`   <舵? ? Day 7th2(cC"   @`  <?W   Basal level2 ( cC   @`  <?W \ C   @`HB . C HB / C   HB 0 C  HB 1 C  ZB 3 s *1 ?WW ZB 4 s *1 ?BBH  0޽h ? 33___PPT10i.\8+D=' = @B +  0 @P0(  Px P c $TH<9   x P c $Anatomik metabolizma Dola_1mdaki tmr hcreleri kanla ilik bo_luuna engelsiz geerler. Metafize ula_an bu tmral agregatlar gllenmeler olu_turur ve proteolitik enzimler salg1lar. Bu maddeler de tmr hcrelerinin damar d1_1na 1kmas1n1 ve kemik dokusuna yerle_mesini kolayla_t1r1r   PZ   |H  0޽h ? 3380___PPT10. u 0 ZR(  X  C    R  S  0   NZOMETA works by: Slowing the bone destroying activity that occurs with bone metastases. Fighting the abnormal cells that cause bone to wear away (osteolytic lesion).    H  0޽h ? 3380___PPT10. P`! 0 @8(  X  C    8  S H  0   BOPG inhibits the binding of RANK to RANKL (osteoprotegerin ligand)t H  0޽h ? 3380___PPT10. `l# 0 A90P(  PX P C    9 P S w5 0   COPG inhibits the binding of RANK to RANKL (osteoprotegerin ligand) t H P 0޽h ? 3380___PPT10.   0 C;@T(  TX T C    ; T S ($ 0   COPG inhibits the binding of RANK to RANKL (osteoprotegerin ligand) v H T 0޽h ? 3380___PPT10. \$bx< pUugOzz>H藂AHLR$[Hi/%v=qO`NI:~&E6&n;uL#'3$x&JNޓXfss{?ɧT:0a:Uyl `өT@&R57tR8$ F< Ki%^|ٴβ^):/6J 1!{/\`bJ\vR +KA? {9_ @!6O`xw/L2+enGk[@9<%Zc Ǭ21ǁ]X4Sjc^y5 k0żs%* 1Wcހy#0o\y3-bކy;wb~k)/ju/ =B^$U:pIB<'2Cx=2Jrh}չn3 Fn;D5gOs_'ӓ i VcI?c4~4jLDzWk>mZB/*i\Aډaa]u ? 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