b200eb228bca9728a6f3738ccf407e51 jcm-15-00133-v3.pdf a7dc6d33bf3f22b9c833b504e2a69910248eae94 jcm-15-00133-v3.pdf 634500210cd6097a4098332f383c8ed6a91264947f96cd8064ecdb83f1db4404 jcm-15-00133-v3.pdf Title: PTH Analog Therapy in CKD G4–G5D: Current Evidence and Potential Role of Abaloparatide in Adynamic Bone Disease Subject: Osteoporosis and fragility fractures are among the most prevalent and clinically significant complications in patients with chronic kidney disease (CKD), particularly in stages G4–G5 and in those undergoing dialysis (G5D). These skeletal disorders are associated with markedly increased morbidity and mortality, including a 2- to 9-fold higher risk of hip fractures compared to the general population, prolonged hospitalization, functional decline, and excess postoperative mortality. Despite this substantial burden, CKD-associated osteoporosis remains underrecognized and undertreated. Limited inclusion of CKD patients in pivotal osteoporosis trials and the absence of high-evidence guidance in clinical guidelines have contributed to a persistent therapeutic gap. PTH analog agents such as teriparatide and abaloparatide have demonstrated robust efficacy in increasing bone mass and reducing fracture risk in the general population. However, their use in CKD remains limited. PTH analog are poorly prescribed in patients with CKD stage G3 and remain off-label for stages G4–G5D, despite the high prevalence of adynamic bone disease across all stages of CKD. Abaloparatide, a selective PTH1 receptor agonist, exerts potent anabolic effects with a lower incidence of hypercalcemia than teriparatide and may offer a favourable safety profile in carefully selected patients. Preliminary data suggest preservation of bone microarchitecture and potential benefits in low-turnover bone disease, although evidence in CKD is still limited. This narrative review examines current evidence on abaloparatide’s potential role in CKD, emphasizing its mechanism of action, efficacy, safety, and relevance for patients with low bone turnover and high fracture risk. Keywords: chronic kidney disease; CKD-MBD; adynamic bone disease; osteoporosis; fragility fractures; bone turnover; bone-forming therapies; Abaloparatide Author: Laia Gifre, Maria Fusaro, Maria J. Lloret, Elisabet Massó, Pilar Peris, Xavier Nogués, Rosana Gelpi, Águeda Prior-Español, Jordi Ara, Mario Cozzolino, Pablo A. Ureña-Torres and Jordi Bover Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Fri Dec 26 02:00:58 2025 CET ModDate: Fri Dec 26 02:04:23 2025 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 990557 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VDGCPS+URWPalladioL-Bold Type 1 Custom yes yes yes 100 0 QKZKVH+VnURWPalladioL Type 1 Custom yes yes yes 101 0 BPPWYC+URWPalladioL-Roma Type 1 Custom yes yes yes 102 0 VYHYZU+URWPalladioL-Ital Type 1 Custom yes yes yes 103 0 BRZZLU+CMSY10 Type 1 Builtin yes yes yes 146 0 MYDOFE+EURM10 Type 1 Builtin yes yes yes 237 0 BKFGPP+PalatinoLinotype TrueType WinAnsi yes yes no 268 0 BKFGPP+PalatinoLinotype TrueType WinAnsi yes yes no 414 0 DXONXA+EURM5 Type 1 Builtin yes yes yes 467 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-01-23 03:08:13 CET RepresentationInformation: jcm-15-00133-v3.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-01-22 13:06:37 CET Size: 990557 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 660 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: CKD Associated Osteoporosis and Fracture Risk Item: Title: Renal Osteodystrophy (ROD) Item: Title: Bone Quality in Patients with CKD Item: Title: Abaloparatide: Mechanism of Action and Pharmacokinetic Profile Item: Title: Real-World Evidence on PTH Analogs in Osteoporotic Populations Item: Title: Histomorphometric Analysis in Patients Treated with Abaloparatide Item: Title: PTH Analogs in CKD Item: Title: PTH Analogs and Hyperparathyroidism Item: Title: PTH Analogs in CKD Stages G4–G5D: Safety Considerations Item: Title: Conclusions Item: Title: References Info: Title: PTH Analog Therapy in CKD G4–G5D: Current Evidence and Potential Role of Abaloparatide in Adynamic Bone Disease Author: Laia Gifre, Maria Fusaro, Maria J. Lloret, Elisabet Massó, Pilar Peris, Xavier Nogués, Rosana Gelpi, Águeda Prior-Español, Jordi Ara, Mario Cozzolino, Pablo A. Ureña-Torres and Jordi Bover Subject: Osteoporosis and fragility fractures are among the most prevalent and clinically significant complications in patients with chronic kidney disease (CKD), particularly in stages G4–G5 and in those undergoing dialysis (G5D). These skeletal disorders are associated with markedly increased morbidity and mortality, including a 2- to 9-fold higher risk of hip fractures compared to the general population, prolonged hospitalization, functional decline, and excess postoperative mortality. Despite this substantial burden, CKD-associated osteoporosis remains underrecognized and undertreated. Limited inclusion of CKD patients in pivotal osteoporosis trials and the absence of high-evidence guidance in clinical guidelines have contributed to a persistent therapeutic gap. PTH analog agents such as teriparatide and abaloparatide have demonstrated robust efficacy in increasing bone mass and reducing fracture risk in the general population. However, their use in CKD remains limited. PTH analog are poorly prescribed in patients with CKD stage G3 and remain off-label for stages G4–G5D, despite the high prevalence of adynamic bone disease across all stages of CKD. Abaloparatide, a selective PTH1 receptor agonist, exerts potent anabolic effects with a lower incidence of hypercalcemia than teriparatide and may offer a favourable safety profile in carefully selected patients. Preliminary data suggest preservation of bone microarchitecture and potential benefits in low-turnover bone disease, although evidence in CKD is still limited. This narrative review examines current evidence on abaloparatide’s potential role in CKD, emphasizing its mechanism of action, efficacy, safety, and relevance for patients with low bone turnover and high fracture risk. Keywords: chronic kidney disease; CKD-MBD; adynamic bone disease; osteoporosis; fragility fractures; bone turnover; bone-forming therapies; Abaloparatide Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Fri Dec 26 02:00:58 CET 2025 ModDate: Fri Dec 26 02:04:23 CET 2025 ID: 0xb384bf28ae7eef125f42633dd7d2fd54, 0x5156b4e058e32f0722844e04ac1177a9 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: BRZZLU+CMSY10 FontSubset: true FirstChar: 0 LastChar: 35 FontDescriptor: FontName: BRZZLU+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true ToUnicode: true Font: BaseFont: DXONXA+EURM5 FontSubset: true FirstChar: 22 LastChar: 22 FontDescriptor: FontName: DXONXA+EURM5 Flags: Symbolic FontBBox: 59, -243, 1369, 720 FontFile: true ToUnicode: true Font: BaseFont: VDGCPS+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 243 FontDescriptor: FontName: VDGCPS+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: QKZKVH+VnURWPalladioL FontSubset: true FirstChar: 177 LastChar: 225 FontDescriptor: FontName: QKZKVH+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: BPPWYC+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: BPPWYC+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: VYHYZU+URWPalladioL-Ital FontSubset: true FirstChar: 46 LastChar: 121 FontDescriptor: FontName: VYHYZU+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: MYDOFE+EURM10 FontSubset: true FirstChar: 12 LastChar: 20 FontDescriptor: FontName: MYDOFE+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true ToUnicode: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 34, 204, 124, 223 Annotation: Subtype: Link Rect: 88, 77, 152, 84 Annotation: Subtype: Link Rect: 34, 64, 119, 72 Annotation: Subtype: Link Rect: 34, 773, 179, 809 Annotation: Subtype: Link Rect: 515, 773, 560, 809 Annotation: Subtype: Link Rect: 94, 663, 105, 677 Annotation: Subtype: Link Rect: 182, 663, 193, 677 Annotation: Subtype: Link Rect: 348, 663, 359, 677 Annotation: Subtype: Link Rect: 416, 663, 427, 677 Annotation: Subtype: Link Rect: 503, 663, 514, 677 Annotation: Subtype: Link Rect: 103, 650, 114, 663 Annotation: Subtype: Link Rect: 224, 650, 235, 663 Annotation: Subtype: Link Rect: 286, 650, 297, 663 Annotation: Subtype: Link Rect: 384, 650, 395, 663 Annotation: Subtype: Link Rect: 516, 650, 527, 663 Annotation: Subtype: Link Rect: 115, 636, 126, 649 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 315, 680, 322, 689 ActionDest: 55 Annotation: Subtype: Link Rect: 484, 652, 491, 661 ActionDest: 55 Annotation: Subtype: Link Rect: 426, 624, 433, 633 ActionDest: 55 Annotation: Subtype: Link Rect: 434, 624, 441, 633 ActionDest: 156 Annotation: Subtype: Link Rect: 461, 608, 468, 620 ActionDest: 6 Annotation: Subtype: Link Rect: 390, 586, 397, 594 ActionDest: 156 Annotation: Subtype: Link Rect: 198, 376, 205, 385 ActionDest: 156 Annotation: Subtype: Link Rect: 206, 376, 213, 385 ActionDest: 156 Annotation: Subtype: Link Rect: 522, 335, 529, 343 ActionDest: 156 Annotation: Subtype: Link Rect: 529, 334, 536, 343 ActionDest: 156 Annotation: Subtype: Link Rect: 473, 293, 480, 302 ActionDest: 156 Annotation: Subtype: Link Rect: 213, 251, 225, 260 ActionDest: 156 Annotation: Subtype: Link Rect: 225, 251, 237, 260 ActionDest: 156 Annotation: Subtype: Link Rect: 506, 209, 518, 218 ActionDest: 156 Annotation: Subtype: Link Rect: 464, 153, 476, 162 ActionDest: 156 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 273, 717, 280, 726 ActionDest: 55 Annotation: Subtype: Link Rect: 256, 647, 268, 656 ActionDest: 156 Annotation: Subtype: Link Rect: 233, 605, 245, 614 ActionDest: 156 Annotation: Subtype: Link Rect: 234, 577, 246, 586 ActionDest: 156 Annotation: Subtype: Link Rect: 443, 564, 455, 572 ActionDest: 156 Annotation: Subtype: Link Rect: 249, 367, 256, 376 ActionDest: 156 Annotation: Subtype: Link Rect: 257, 367, 264, 376 ActionDest: 156 Annotation: Subtype: Link Rect: 379, 340, 390, 349 ActionDest: 156 Annotation: Subtype: Link Rect: 503, 298, 510, 307 ActionDest: 156 Annotation: Subtype: Link Rect: 191, 284, 198, 293 ActionDest: 156 Annotation: Subtype: Link Rect: 204, 186, 216, 195 ActionDest: 156 Annotation: Subtype: Link Rect: 275, 186, 287, 195 ActionDest: 156 Annotation: Subtype: Link Rect: 249, 117, 261, 126 ActionDest: 156 Annotation: Subtype: Link Rect: 263, 117, 275, 126 ActionDest: 201 Annotation: Subtype: Link Rect: 252, 103, 264, 112 ActionDest: 201 Annotation: Subtype: Link Rect: 264, 103, 276, 112 ActionDest: 201 Annotation: Subtype: Link Rect: 261, 75, 268, 84 ActionDest: 156 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 198, 730, 210, 740 ActionDest: 156 Annotation: Subtype: Link Rect: 333, 703, 345, 712 ActionDest: 201 Annotation: Subtype: Link Rect: 254, 675, 266, 684 ActionDest: 201 Annotation: Subtype: Link Rect: 231, 633, 243, 642 ActionDest: 201 Annotation: Subtype: Link Rect: 511, 605, 523, 614 ActionDest: 201 Annotation: Subtype: Link Rect: 549, 535, 556, 544 ActionDest: 55 Annotation: Subtype: Link Rect: 536, 479, 543, 488 ActionDest: 55 Annotation: Subtype: Link Rect: 293, 434, 299, 446 ActionDest: 120 Annotation: Subtype: Link Rect: 459, 379, 466, 391 ActionDest: 120 Annotation: Subtype: Link Rect: 479, 200, 491, 209 ActionDest: 201 Annotation: Subtype: Link Rect: 494, 200, 506, 209 ActionDest: 201 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 277, 747, 288, 755 ActionDest: 201 Annotation: Subtype: Link Rect: 544, 555, 556, 564 ActionDest: 201 Annotation: Subtype: Link Rect: 531, 402, 543, 411 ActionDest: 201 Annotation: Subtype: Link Rect: 544, 402, 556, 411 ActionDest: 201 Annotation: Subtype: Link Rect: 375, 346, 387, 355 ActionDest: 156 Annotation: Subtype: Link Rect: 511, 318, 523, 327 ActionDest: 201 Annotation: Subtype: Link Rect: 419, 262, 431, 271 ActionDest: 201 Annotation: Subtype: Link Rect: 432, 262, 444, 271 ActionDest: 201 Annotation: Subtype: Link Rect: 398, 221, 410, 230 ActionDest: 201 Annotation: Subtype: Link Rect: 193, 179, 205, 188 ActionDest: 201 Annotation: Subtype: Link Rect: 438, 179, 450, 188 ActionDest: 201 Annotation: Subtype: Link Rect: 396, 151, 408, 160 ActionDest: 201 Annotation: Subtype: Link Rect: 374, 81, 386, 90 ActionDest: 201 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 182, 744, 194, 754 ActionDest: 201 Annotation: Subtype: Link Rect: 273, 730, 285, 740 ActionDest: 201 Annotation: Subtype: Link Rect: 411, 618, 417, 627 ActionDest: 156 Annotation: Subtype: Link Rect: 311, 562, 323, 571 ActionDest: 201 Annotation: Subtype: Link Rect: 323, 562, 335, 571 ActionDest: 201 Annotation: Subtype: Link Rect: 284, 534, 291, 544 ActionDest: 156 Annotation: Subtype: Link Rect: 325, 493, 337, 502 ActionDest: 201 Annotation: Subtype: Link Rect: 337, 493, 349, 502 ActionDest: 201 Annotation: Subtype: Link Rect: 416, 437, 428, 446 ActionDest: 201 Annotation: Subtype: Link Rect: 429, 437, 441, 446 ActionDest: 201 Annotation: Subtype: Link Rect: 221, 354, 233, 363 ActionDest: 305 Annotation: Subtype: Link Rect: 233, 353, 245, 363 ActionDest: 305 Annotation: Subtype: Link Rect: 207, 326, 219, 335 ActionDest: 305 Annotation: Subtype: Link Rect: 191, 185, 203, 194 ActionDest: 305 Annotation: Subtype: Link Rect: 207, 102, 218, 111 ActionDest: 305 Annotation: Subtype: Link Rect: 238, 85, 245, 97 ActionDest: 310 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 432, 336, 443, 344 ActionDest: 305 Annotation: Subtype: Link Rect: 504, 336, 515, 344 ActionDest: 305 Annotation: Subtype: Link Rect: 497, 312, 504, 321 ActionDest: 55 Annotation: Subtype: Link Rect: 507, 312, 519, 321 ActionDest: 201 Annotation: Subtype: Link Rect: 253, 214, 265, 224 ActionDest: 305 Annotation: Subtype: Link Rect: 268, 214, 280, 224 ActionDest: 305 Annotation: Subtype: Link Rect: 299, 159, 311, 168 ActionDest: 305 Annotation: Subtype: Link Rect: 247, 145, 259, 154 ActionDest: 305 Annotation: Subtype: Link Rect: 299, 75, 311, 84 ActionDest: 305 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 252, 560, 264, 569 ActionDest: 305 Annotation: Subtype: Link Rect: 267, 560, 279, 569 ActionDest: 305 Annotation: Subtype: Link Rect: 544, 505, 556, 514 ActionDest: 305 Annotation: Subtype: Link Rect: 416, 463, 428, 472 ActionDest: 305 Annotation: Subtype: Link Rect: 485, 421, 497, 430 ActionDest: 305 Annotation: Subtype: Link Rect: 348, 379, 360, 388 ActionDest: 305 Annotation: Subtype: Link Rect: 290, 296, 302, 305 ActionDest: 305 Annotation: Subtype: Link Rect: 544, 254, 556, 263 ActionDest: 305 Annotation: Subtype: Link Rect: 368, 100, 380, 109 ActionDest: 305 Annotation: Subtype: Link Rect: 335, 86, 347, 95 ActionDest: 305 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 268, 703, 280, 712 ActionDest: 305 Annotation: Subtype: Link Rect: 232, 605, 244, 614 ActionDest: 201 Annotation: Subtype: Link Rect: 244, 605, 256, 614 ActionDest: 305 Annotation: Subtype: Link Rect: 496, 577, 508, 586 ActionDest: 305 Annotation: Subtype: Link Rect: 290, 451, 302, 460 ActionDest: 201 Annotation: Subtype: Link Rect: 219, 395, 231, 404 ActionDest: 156 Annotation: Subtype: Link Rect: 231, 395, 243, 404 ActionDest: 305 Annotation: Subtype: Link Rect: 239, 312, 251, 321 ActionDest: 426 Annotation: Subtype: Link Rect: 379, 284, 391, 293 ActionDest: 426 Annotation: Subtype: Link Rect: 391, 284, 403, 293 ActionDest: 426 Annotation: Subtype: Link Rect: 548, 225, 555, 237 ActionDest: 323 Annotation: Subtype: Link Rect: 490, 200, 502, 209 ActionDest: 426 Annotation: Subtype: Link Rect: 503, 200, 515, 209 ActionDest: 426 Annotation: Subtype: Link Rect: 497, 131, 509, 140 ActionDest: 156 Annotation: Subtype: Link Rect: 346, 75, 358, 84 ActionDest: 426 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 544, 176, 551, 184 ActionDest: 156 Annotation: Subtype: Link Rect: 285, 149, 292, 161 ActionDest: 46 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 53, 697, 60, 702 ActionDest: 426 Annotation: Subtype: Link Rect: 53, 677, 60, 682 ActionDest: 426 Annotation: Subtype: Link Rect: 66, 660, 73, 666 ActionDest: 426 Annotation: Subtype: Link Rect: 53, 640, 60, 646 ActionDest: 426 Annotation: Subtype: Link Rect: 53, 621, 60, 626 ActionDest: 305 Annotation: Subtype: Link Rect: 53, 586, 60, 592 ActionDest: 305 Annotation: Subtype: Link Rect: 243, 438, 255, 447 ActionDest: 426 Annotation: Subtype: Link Rect: 196, 382, 208, 391 ActionDest: 156 Annotation: Subtype: Link Rect: 209, 382, 220, 391 ActionDest: 426 Annotation: Subtype: Link Rect: 221, 382, 233, 391 ActionDest: 426 Annotation: Subtype: Link Rect: 531, 354, 543, 363 ActionDest: 156 Annotation: Subtype: Link Rect: 544, 354, 556, 363 ActionDest: 426 Annotation: Subtype: Link Rect: 462, 313, 474, 321 ActionDest: 426 Annotation: Subtype: Link Rect: 425, 298, 437, 308 ActionDest: 305 Annotation: Subtype: Link Rect: 188, 172, 200, 181 ActionDest: 305 Annotation: Subtype: Link Rect: 308, 89, 319, 98 ActionDest: 305 Annotation: Subtype: Link Rect: 320, 89, 332, 98 ActionDest: 426 Annotation: Subtype: Link Rect: 335, 89, 347, 98 ActionDest: 426 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 334, 758, 346, 767 ActionDest: 426 Annotation: Subtype: Link Rect: 479, 717, 491, 726 ActionDest: 156 Annotation: Subtype: Link Rect: 492, 717, 503, 726 ActionDest: 156 Annotation: Subtype: Link Rect: 370, 647, 382, 656 ActionDest: 305 Annotation: Subtype: Link Rect: 382, 647, 394, 656 ActionDest: 305 Annotation: Subtype: Link Rect: 395, 647, 407, 656 ActionDest: 426 Annotation: Subtype: Link Rect: 348, 536, 360, 545 ActionDest: 426 Annotation: Subtype: Link Rect: 188, 494, 200, 503 ActionDest: 305 Annotation: Subtype: Link Rect: 481, 480, 493, 489 ActionDest: 305 Annotation: Subtype: Link Rect: 515, 466, 527, 475 ActionDest: 426 Annotation: Subtype: Link Rect: 298, 424, 310, 433 ActionDest: 426 Annotation: Subtype: Link Rect: 314, 327, 326, 336 ActionDest: 305 Annotation: Subtype: Link Rect: 434, 299, 446, 308 ActionDest: 426 Annotation: Subtype: Link Rect: 504, 187, 516, 196 ActionDest: 305 Annotation: Subtype: Link Rect: 416, 173, 428, 182 ActionDest: 305 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 395, 742, 402, 754 ActionDest: 323 Annotation: Subtype: Link Rect: 406, 745, 413, 754 ActionDest: 156 Annotation: Subtype: Link Rect: 413, 744, 425, 754 ActionDest: 201 Annotation: Subtype: Link Rect: 426, 744, 438, 754 ActionDest: 201 Annotation: Subtype: Link Rect: 438, 744, 450, 754 ActionDest: 426 Annotation: Subtype: Link Rect: 267, 114, 305, 125 Annotation: Subtype: Link Rect: 104, 77, 141, 87 Annotation: Subtype: Link Rect: 147, 77, 183, 87 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 257, 731, 295, 742 Annotation: Subtype: Link Rect: 417, 705, 455, 716 Annotation: Subtype: Link Rect: 497, 679, 534, 690 Annotation: Subtype: Link Rect: 131, 642, 168, 652 Annotation: Subtype: Link Rect: 482, 616, 520, 627 Annotation: Subtype: Link Rect: 59, 578, 96, 588 Annotation: Subtype: Link Rect: 162, 539, 200, 550 Annotation: Subtype: Link Rect: 276, 501, 314, 512 Annotation: Subtype: Link Rect: 520, 462, 557, 473 Annotation: Subtype: Link Rect: 477, 424, 514, 435 Annotation: Subtype: Link Rect: 360, 399, 397, 410 Annotation: Subtype: Link Rect: 59, 336, 96, 346 Annotation: Subtype: Link Rect: 313, 296, 351, 307 Annotation: Subtype: Link Rect: 271, 271, 309, 282 Annotation: Subtype: Link Rect: 59, 233, 96, 244 Annotation: Subtype: Link Rect: 441, 207, 478, 218 Annotation: Subtype: Link Rect: 308, 169, 345, 180 Annotation: Subtype: Link Rect: 201, 118, 238, 129 Annotation: Subtype: Link Rect: 59, 80, 96, 90 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 202, 743, 240, 754 Annotation: Subtype: Link Rect: 246, 718, 283, 729 Annotation: Subtype: Link Rect: 464, 692, 501, 703 Annotation: Subtype: Link Rect: 508, 692, 544, 703 Annotation: Subtype: Link Rect: 147, 668, 184, 678 Annotation: Subtype: Link Rect: 191, 668, 227, 678 Annotation: Subtype: Link Rect: 95, 629, 133, 639 Annotation: Subtype: Link Rect: 230, 590, 267, 601 Annotation: Subtype: Link Rect: 274, 590, 310, 601 Annotation: Subtype: Link Rect: 292, 565, 330, 576 Annotation: Subtype: Link Rect: 386, 552, 424, 563 Annotation: Subtype: Link Rect: 118, 514, 155, 524 Annotation: Subtype: Link Rect: 179, 462, 217, 473 Annotation: Subtype: Link Rect: 278, 424, 316, 435 Annotation: Subtype: Link Rect: 329, 387, 366, 397 Annotation: Subtype: Link Rect: 373, 387, 409, 397 Annotation: Subtype: Link Rect: 263, 322, 300, 333 Annotation: Subtype: Link Rect: 140, 285, 177, 295 Annotation: Subtype: Link Rect: 184, 285, 220, 295 Annotation: Subtype: Link Rect: 365, 258, 402, 269 Annotation: Subtype: Link Rect: 106, 221, 144, 231 Annotation: Subtype: Link Rect: 150, 221, 186, 231 Annotation: Subtype: Link Rect: 411, 182, 448, 193 Annotation: Subtype: Link Rect: 392, 143, 430, 154 Annotation: Subtype: Link Rect: 59, 106, 96, 116 Annotation: Subtype: Link Rect: 59, 67, 96, 78 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 409, 743, 447, 754 Annotation: Subtype: Link Rect: 314, 705, 351, 716 Annotation: Subtype: Link Rect: 357, 705, 393, 716 Annotation: Subtype: Link Rect: 279, 679, 316, 690 Annotation: Subtype: Link Rect: 478, 667, 515, 678 Annotation: Subtype: Link Rect: 521, 667, 557, 678 Annotation: Subtype: Link Rect: 268, 642, 306, 652 Annotation: Subtype: Link Rect: 312, 642, 348, 652 Annotation: Subtype: Link Rect: 430, 616, 468, 627 Annotation: Subtype: Link Rect: 59, 578, 96, 588 Annotation: Subtype: Link Rect: 104, 540, 142, 550 Annotation: Subtype: Link Rect: 123, 526, 560, 537 Annotation: Subtype: Link Rect: 496, 475, 533, 486 Annotation: Subtype: Link Rect: 59, 438, 96, 448 Annotation: Subtype: Link Rect: 454, 399, 492, 410 Annotation: Subtype: Link Rect: 155, 361, 193, 371 Annotation: Subtype: Link Rect: 77, 323, 114, 333 Annotation: Subtype: Link Rect: 396, 296, 434, 307 Annotation: Subtype: Link Rect: 140, 259, 177, 269 Annotation: Subtype: Link Rect: 184, 259, 220, 269 Annotation: Subtype: Link Rect: 471, 220, 508, 231 Annotation: Subtype: Link Rect: 109, 182, 146, 193 Annotation: Subtype: Link Rect: 350, 143, 388, 154 Annotation: Subtype: Link Rect: 179, 106, 216, 116 Annotation: Subtype: Link Rect: 104, 67, 142, 78 Annotation: Subtype: Link Rect: 148, 67, 184, 78 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 59, 731, 96, 742 Annotation: Subtype: Link Rect: 102, 731, 138, 742 Annotation: Subtype: Link Rect: 282, 692, 319, 703 Annotation: Subtype: Link Rect: 59, 655, 96, 665 Annotation: Subtype: Link Rect: 109, 629, 146, 639 Annotation: Subtype: Link Rect: 142, 604, 179, 614 Annotation: Subtype: Link Rect: 288, 577, 326, 588 Annotation: Subtype: Link Rect: 165, 539, 202, 550 Annotation: Subtype: Link Rect: 327, 513, 365, 524 Annotation: Subtype: Link Rect: 284, 475, 322, 486 Annotation: Subtype: Link Rect: 328, 475, 364, 486 Annotation: Subtype: Link Rect: 201, 437, 238, 448 Annotation: Subtype: Link Rect: 245, 437, 281, 448 Annotation: Subtype: Link Rect: 478, 411, 515, 422 Annotation: Subtype: Link Rect: 521, 411, 557, 422 Annotation: Subtype: Link Rect: 184, 386, 221, 397 Annotation: Subtype: Link Rect: 228, 386, 264, 397 Annotation: Subtype: Link Rect: 59, 348, 96, 358 Annotation: Subtype: Link Rect: 391, 309, 429, 320 Annotation: Subtype: Link Rect: 125, 296, 560, 307 Annotation: Subtype: Link Rect: 358, 245, 395, 256 Annotation: Subtype: Link Rect: 294, 220, 331, 231 Annotation: Subtype: Link Rect: 423, 27, 560, 37 Checksum: f232e910 Type: CRC32 Checksum: b200eb228bca9728a6f3738ccf407e51 Type: MD5 Checksum: a7dc6d33bf3f22b9c833b504e2a69910248eae94 Type: SHA-1 Checksum: 634500210cd6097a4098332f383c8ed6a91264947f96cd8064ecdb83f1db4404 Type: SHA-256