Front Cover 1
The Parathyroids: Basic and clinical concepts 4
Copyright 5
Contents 6
Contributors 16
Preface to the Third Edition 20
Preface to the Second Edition 22
Preface to the First Edition 24
Introduction - A History of the Parathyroid Glands and their Secretory Product, Parathyroid Hormone 28
PREHISTORIC DEVELOPMENT 28
DISCOVERY OF THE PARATHYROID GLANDS 29
DISCOVERY OF THE PARATHYROIDS’ ACTIVE PRINCIPLE 32
THE SEARCH FOR MECHANISMS OF PTH ACTION 33
MODERN APPROACHES TO PTH STRUCTURE AND FUNCTION 35
PRIMARY HYPERPARATHYROIDISM—A NEW DISEASE 37
HUMORAL HYPERCALCEMIA OF MALIGNANCY AND THE DISCOVERY OF PARATHYROID HORMONE-RELATED PROTEIN (PTHRP) 40
REDISCOVERY OF THE ANABOLIC EFFECT OF PTH 40
PTH: A TREATMENT FOR OSTEOPOROSIS 41
CONCLUSION 44
References 44
Section I - Molecular, Cellular, and Physiologic Aspects of The Parathyroids 48
Chapter 1 - Parathyroids: Morphology and Pathology 50
Morphology and Pathology 50
INTRODUCTION 50
EMBRYOLOGY 50
ANATOMY AND HISTOLOGY 50
HYPERPARATHYROIDISM 51
FAMILIAL HYPERPARATHYROIDISM 56
UNUSUAL LESIONS OF THE PARATHYROID 56
INTRAOPERATIVE ASSESSMENT OF PARATHYROID—OLD AND NEW 57
SPECIAL STUDIES AND THE PARATHYROID 58
HUMORAL HYPERCALCEMIA OF MALIGNANCY 58
HYPOPARATHYROIDISM 58
References 59
Chapter 2 - Parathyroid Hormone Gene: Structure, Evolution, and Regulation 64
Structure, Evolution, and Regulation 64
INTRODUCTION 64
PREPROPTH 64
GENE STRUCTURE 65
EVOLUTION 66
REGULATION 67
References 69
Chapter 3 - Parathyroid Hormone-related Protein: Gene Structure, Biosynthesis, Metabolism and Regulation 72
Gene Structure, Biosynthesis, Metabolism and Regulation 72
INTRODUCTION 72
ISOLATION AND CLONING OF PTHRP 72
GENE STRUCTURE 74
TRANSCRIPTIONAL REGULATION AND MRNA SPLICING 76
PROTEIN STRUCTURE AND POSTTRANSLATIONAL PROCESSING 79
NUCLEAR IMPORT AND INTRACRINE FUNCTION OF PTHRP 81
TISSUE DISTRIBUTION AND PARACRINE FUNCTION 82
CONCLUSION 85
References 85
Chapter 4 - Interactions of PTH with Receptors and Signaling 92
INTRODUCTION 92
PARATHYROID HORMONE—LIGAND DETERMINANTS OF BIOLOGICAL ACTIVITY 93
THE PTHR1 CLONING, GENE CHARACTERIZATION, AND EVOLUTION 95
STRUCTURAL FEATURES OF THE PTHR1 AND MODE OF LIGAND BINDING 97
LIGAND INTERACTIONS TO THE RECEPTOR’S N-TERMINAL EXTRACELLULAR DOMAIN (ECD) 98
THE PTHR1 TRANSMEMBRANE DOMAIN (TMD) REGION, STRUCTURE, AND MODE OF ACTION 99
MECHANISMS OF SIGNALING TRANSDUCTION AND SIGNAL REGULATION 100
MECHANISM OF CONFORMATIONAL CHANGE AND PROLONGED SIGNALING AT THE PTHR1 101
SMALL MOLECULE LIGANDS FOR THE PTHR 102
References 103
Chapter 5 - Interactions of PTHrP with Receptors and Signaling 108
INTRODUCTION 108
STRUCTURES OF THE PTHRP GENE, MRNA, AND PEPTIDES 109
N-TERMINAL PTHRP AND RECEPTORS 112
MID-MOLECULAR PTHRP AND RECEPTORS 114
NUCLEAR/NUCLEOLAR PTHRP AND ITS RECEPTORS 116
C-TERMINAL PTHRP AND ITS RECEPTORS 118
CONCLUSIONS 120
References 122
Chapter 6 - Control of Parathyroid Hormone Secretion by its Key Physiological Regulators 128
INTRODUCTION 128
IMPORTANCE OF PTH IN MAINTAINING MINERAL ION HOMEOSTASIS IN VIVO 128
GENERAL MECHANISMS DETERMINING THE OVERALL RATE OF PTH SECRETION 131
CELLULAR AND MOLECULAR MECHANISMS BY WHICH REGULATES THE VARIOUS ASPECTS OF PARATHYROID FUNCTION DETERMINING THE OVERALL RATE OF... 132
REGULATION OF OVERALL PARATHYROID FUNCTION BY 1,25(OH)2D3 138
REGULATION OF OVERALL PARATHYROID SECRETORY FUNCTION BY PHOSPHATE 139
EFFECTS OF FGF23 ON OVERALL PARATHYROID FUNCTION 140
CONCLUSIONS 141
References 141
Chapter 7 - Molecular Actions of Parathyroid Hormone 146
INTRODUCTION 146
PTH SIGNAL TRANSDUCTION 146
PTH REGULATION OF GENE TRANSCRIPTION 148
CONTROL OF CELL PROLIFERATION AND SURVIVAL BY PTH 149
REGULATION OF ION TRANSPORT BY PTH 150
References 150
Chapter 8 - Cellular Actions of PTH: Osteoblasts, Osteoclasts, and Osteocytes 154
Osteoblasts, Osteoclasts, and Osteocytes 154
INTRODUCTION 154
CELLULAR ACTIONS OF PTH ON BONE 154
CONCLUSION 160
References 160
Chapter 9 - Physiologic Actions of PTH I: PTH Action on the Skeleton 166
PTH Action on the Skeleton 166
INTRODUCTION 166
PHYSIOLOGIC, PHARMACOLOGIC, AND PATHOLOGIC INTERACTIONS OF PTH WITH THE SKELETON 167
MOLECULAR AND CELLULAR MECHANISMS OF ACTION 169
CONTRIBUTIONS TO MODELING AND REMODELING OF THE SKELETON 172
SUMMARY 174
References 174
Chapter 10 - Physiological Actions of PTH II: Renal Actions 180
Renal Actions 180
INTRODUCTION 180
NEPHRON SITES OF PTH ACTION 180
PTH ACTIONS ON ION TRANSPORT 183
PTH EFFECTS ON METABOLISM 186
PTH METABOLISM BY THE KIDNEY 187
Acknowledgments 188
References 188
Chapter 11 - Physiological Actions of PTH and PTHrP III: Endochondral Bone Formation 192
Endochondral Bone Formation 192
Endochondral Bone Formation 192
THE PTHRP—INDIAN HEDGEHOG PATHWAY IN THE GROWTH PLATE 195
ACTIONS OF PTHRP DURING BONE DEVELOPMENT 198
ACTIONS OF INDIAN HEDGEHOG DURING BONE DEVELOPMENT 202
ROLES OF IHH, PTHRP, AND PTHR1 IN THE POSTNATAL SKELETON 205
CONCLUSION 208
References 208
Chapter 12 - Physiological Actions of PTH and PTHrP IV: Vascular, Cardiovascular, and CNS Biology 214
Vascular, Cardiovascular, and CNS Biology 214
INTRODUCTION 214
PTH/PTHRP BIOLOGY IN CARDIOVASCULAR DEVELOPMENT 214
PTHR SIGNALING IN ARTERIAL BIOLOGY: VASCULAR SMOOTH MUSCLE CELL AND ENDOTHELIAL RESPONSES TO PTH AND PTHRP 215
TIP39 IN VASCULAR PHARMACOLOGY AND POTENTIAL CONTRIBUTIONS OF CNS TIP39 AND PTHRP TO CARDIOVASCULAR MEDICINE 217
IMPACT OF HYPERPARATHYROIDISM ON CARDIOVASCULAR MORTALITY, CORONARY FLOW RESERVE, AND VASCULAR STIFFNESS: AN EMERGING CONCERN IN... 218
SECONDARY HYPERPARATHYROIDISM OF CHRONIC KIDNEY DISEASE (CKD) THE METABOLIC “PERFECT STORM” OF CARDIOVASCULAR RISK
IMPACT OF PTH AND HYPERPARATHYROIDISM ON CALCIFIC AORTIC VALVE DISEASE (CAVD): A SCLEROTIC CONUNDRUM 221
CHRONIC PTH1R ACTIVATION AND THE RENIN–ANGIOTENSIN–ALDOSTERONE (RAA) AXIS IN CARDIOVASCULAR DISEASE: A FEED-FORWARD VICIOUS CYCL... 221
PTH/PTHRP SIGNALING AND THE BONE–VASCULAR AXIS 221
CONCLUSIONS AND FUTURE DIRECTIONS 223
Acknowledgments 223
References 223
Chapter 13 - Physiological Actions of Parathyroid Hormone (PTH) and PTH-related Protein: Epidermal, Mammary, Reproductive, and Pancreatic Tissues 230
Epidermal, Mammary, Reproductive, and Pancreatic Tissues 230
INTRODUCTION 230
SKIN 230
MAMMARY GLAND 232
REPRODUCTIVE TISSUES 237
ENDOCRINE PANCREAS 241
CONCLUSION 243
Acknowledgments 243
References 243
Chapter 14 - PTH and T-cell Biology 250
EFFECTS OF PTH IN BONE 250
T-CELL SUBSETS AND THEIR ROLE IN BONE HOMEOSTASIS 251
T CELLS AND PTH-INDUCED BONE LOSS 252
ROLE OF T CELLS IN THE ANABOLIC ACTIVITY OF INTERMITTENT PTH TREATMENT 253
ROLE OF T CELLS ON THE EXPANSION OF HSCS INDUCED BY PTH 255
CONCLUSIONS 256
References 256
Chapter 15 - Anabolic and Catabolic Pathways of Parathyroid Hormone on the Skeleton 260
INTRODUCTION 260
PTH SIGNALING 260
ACTIONS OF PTH THAT CONTRIBUTE TO INCREASED BONE RESORPTION: CATABOLIC 261
ACTIONS OF PTH CONTRIBUTING TO INCREASED BONE FORMATION: ANABOLIC 262
GENE PROFILE IN CATABOLIC AND ANABOLIC PTH REGIMES 265
THE ROLE OF T CELLS ON THE ANABOLIC AND CATABOLIC ACTIONS OF PTH 265
THE INFLUENCE OF BONE RESORPTION ON PTH-INDUCED BONE ANABOLISM 267
SUMMARY 267
References 268
Chapter 16 - Metabolism and Measurement of Parathyroid Hormone 272
THE CIRCULATING PARATHYROID HORMONE (PTH) PARADOX 272
FIRST-GENERATION PTH ASSAYS: CIRCULATING PTH IMMUNOHETEROGENEITY 272
SECOND-GENERATION PTH ASSAYS: IMMUNORADIOMETRIC (IRMA) ASSAYS 272
THIRD-GENERATION PTH ASSAY: IMPROVED IRMA 273
ORIGIN OF CIRCULATING PTH MOLECULAR FORMS 273
REGULATION OF CIRCULATING PTH MOLECULAR FORMS 273
MOLECULAR FORMS OF PTH ASSOCIATED WITH SPECIFIC CLINICAL CONDITIONS 274
CONCLUSION 276
References 277
Section II - Clinical Aspects of Primary Hyperparathyroidism 280
Chapter 17 - Parathyroid Growth: Normal and Abnormal 282
Normal and Abnormal 282
INTRODUCTION AND BACKGROUND 282
ABNORMAL PARATHYROID GROWTH 286
INTEGRATION OF PARATHYROID GROWTH AND HORMONE SECRETION 298
Acknowledgments 299
References 299
Chapter 18 - Molecular Basis of Primary Hyperparathyroidism 306
INTRODUCTION 306
CLONALITY OF PARATHYROID TUMORS 307
SPECIFIC GENETIC ABNORMALITIES IN BENIGN PARATHYROID TUMORS 308
OTHER GENETIC ABNORMALITIES IN SPORADIC PARATHYROID TUMORS 314
MOLECULAR PATHOGENESIS OF PARATHYROID CARCINOMA 314
EPIGENETICS AND GENE EXPRESSION ALTERATIONS IN SPORADIC PARATHYROID ADENOMAS 316
ECTOPIC SECRETION OF PTH 317
SUMMARY 318
References 318
Chapter 19 - Epidemiology of Primary Hyperparathyroidism 324
INTRODUCTION 324
INCIDENCE AND PREVALENCE 324
SPECIAL POPULATION CONSIDERATIONS IN SPORADIC PRIMARY HYPERPARATHYROIDISM 326
CLINICAL FEATURES 327
MORTALITY 328
COST OF PRIMARY HYPERPARATHYROIDISM 329
SUMMARY AND CONCLUSION 331
Acknowledgment 331
References 331
Chapter 20 - Clinical Presentation of Primary Hyperparathyroidism: A Global Perspective 336
A Global Perspective 336
INTRODUCTION 336
PRESENTATION IN THE UNITED STATES 336
PRESENTATION IN EUROPE 337
PRESENTATION IN LATIN AMERICA 337
PRESENTATION IN ASIA 338
BONE DISEASE IN PRIMARY HYPERPARATHYROIDISM 338
NEPHROLITHIASIS IN PRIMARY HYPERPARATHYROIDISM 339
NON-CLASSICAL MANIFESTATIONS OF PRIMARY HYPERPARATHYROIDISM 339
DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM 340
References 341
Chapter 21 - Asymptomatic Primary Hyperparathyroidism 344
INTRODUCTION 344
INCIDENCE AND PATHOGENESIS OF PRIMARY HYPERTHYROIDISM 344
CLINICAL PRESENTATION OF PRIMARY HYPERPARATHYROIDISM: THEN AND NOW 345
DIAGNOSIS AND BIOCHEMICAL CHARACTERIZATION OF ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM 346
CLASSICAL ORGAN INVOLVEMENT IN ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM 348
NON-CLASSICAL ORGAN INVOLVEMENT IN ASYMPTOMATIC PHPT 351
PRIMARY HYPERPARATHYROIDISM: YESTERDAY, TODAY, AND TOMORROW 353
References 354
Chapter 22 - Normocalcemic PHPT 358
INTRODUCTION 358
PATHOPHYSIOLOGY 358
DIAGNOSIS 359
EPIDEMIOLOGY 360
CLINICAL PRESENTATION 361
NATURAL HISTORY 363
MANAGEMENT 364
SUMMARY AND CONCLUSIONS 364
Acknowledgments 364
References 364
Chapter 23 - Familial and Hereditary Forms of Primary Hyperparathyroidism 368
INTRODUCTION 368
SYNDROMIC FORMS OF PHPT 368
NON-SYNDROMIC (ISOLATED) FORMS OF PHPT 381
GENE TESTING IN CLINICAL PRACTICE FOR PHPT PATIENTS 383
CONCLUSIONS 385
Acknowledgments 385
References 385
Chapter 24 - Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism 392
HISTORICAL PERSPECTIVE AND NOMENCLATURE 392
CLINICAL CHARACTERISTICS OF FHH 393
LABORATORY AND DYNAMIC STUDIES IN FHH 394
GENETICS AND MOLECULAR GENETICS OF FHH 399
GENOTYPE–PHENOTYPE ASSOCIATIONS 404
DIAGNOSIS AND MANAGEMENT OF FHH 405
CLINICAL CHARACTERISTICS OF NEONATAL HYPERPARATHYROIDISM 406
GENETICS AND MOLECULAR GENETICS OF NEONATAL HYPERPARATHYROIDISM, INCLUDING NEONATAL SEVERE HYPERPARATHYRODISM 407
DIAGNOSIS AND MANAGEMENT OF NHPT AND NSHPT 408
CONCLUSIONS 409
Acknowledgments 409
References 409
Chapter 25 - Primary Hyperparathyroidism in Children and Adolescents 416
INTRODUCTION 416
ETIOLOGY OF PEDIATRIC PRIMARY HYPERPARATHYROIDISM 419
PATHOLOGY 422
CLINICAL FEATURES AND COMPLICATIONS 422
ASCERTAINMENT AND DIAGNOSIS 422
MANAGEMENT AND OUTCOME 423
OUTCOMES 424
SUMMARY 424
References 424
Chapter 26 - Acute Primary Hyperparathyroidism 428
Acute Primary Hyperparathyroidism 428
RISK OF DEVELOPING ACUTE PRIMARY HYPERPARATHYROIDISM 428
DEMOGRAPHICS 429
LABORATORY EVALUATION 429
TARGET ORGAN MANIFESTATIONS 431
PATHOLOGY 431
PATHOPHYSIOLOGY 432
ACUTE PARATHYROID CRISIS ASSOCIATED WITH PREGNANCY 432
OTHER ASSOCIATIONS WITH ACUTE PRIMARY HYPERPARATHYROIDISM 432
ANIMAL MODELS OF ACUTE PRIMARY HYPERPARATHYROIDISM 432
TREATMENT 433
OUTCOMES 433
SUMMARY 434
References 434
Chapter 27 - Parathyroid Carcinoma 436
INTRODUCTION 436
EPIDEMIOLOGY 436
ETIOLOGY 436
PATHOGENESIS 437
PATHOLOGY 438
CLINICAL FEATURES 440
IMAGING STUDIES 441
NATURAL HISTORY AND SURVEILLANCE 442
MANAGEMENT 442
MANAGEMENT OF HYPERCALCEMIA 444
PROGNOSIS 445
CLOSING REMARKS 445
References 445
Chapter 28 - Bone Turnover Markers in Primary Hyperparathyroidism 450
INTRODUCTION 450
BONE TURNOVER MARKERS 450
MANAGEMENT OF PHPT AND EFFECTS ON BONE TURNOVER MARKERS 451
CONCLUSION 453
References 454
Chapter 29 - Bone Histomorphometry and Bone Quality in Primary Hyperparathyroidism 456
INTRODUCTION 456
BONE HISTOMORPHOMETRY: STATIC AND DYNAMIC INDICES 456
BONE TURNOVER IN PRIMARY HYPERPARATHYROIDISM 457
BONE MASS IN PRIMARY HYPERPARATHYROIDISM 458
BONE STRUCTURE IN PRIMARY HYPERPARATHYROIDISM 460
MECHANISM OF MAINTENANCE OF CANCELLOUS BONE VOLUME AND STRUCTURE AT THE ILIAC CREST 463
EFFECTS OF PARATHYROIDECTOMY ON BONE STRUCTURE AND REMODELING ACTIVITY IN THE ILIAC CREST 466
EFFECTS OF PRIMARY HYPERPARATHYROIDISM ON MATERIAL PROPERTIES OF BONE MATRIX 467
CONCLUSION 470
Acknowledgments 470
References 470
Chapter 30 - Skeletal Imaging in Primary Hyperparathyroidism 474
INTRODUCTION 474
DUAL-ENERGY X-RAY ABSORPTIOMETRY 474
HIGH-RESOLUTION PERIPHERAL QUANTITATIVE COMPUTED TOMOGRAPHY (HRPQCT) 476
TRABECULAR BONE SCORE 478
CONCLUSION 479
References 480
Chapter 31 - Primary Hyperparathyroidism and the Kidney 482
INTRODUCTION 482
CO-EVOLUTION OF THE PARATHYROID GLAND AND KIDNEY: FROM WATER TO LAND 483
RENAL CALCIUM REABSORPTION 483
CLINICAL ASSESSMENT OF CALCIUM PROCESSING BY THE KIDNEY 484
RENAL PHOSPHATE REABSORPTION 486
CLINICAL ASSESSMENT OF PHOSPHATE PROCESSING BY THE KIDNEY 486
RENAL BICARBONATE REABSORPTION 488
RENAL PRODUCTION OF 1,25-DIHYDROXYVITAMIN D 488
ROLE OF KIDNEY IN SETTING THE SERUM LEVEL OF CALCIUM AND PHOSPHATE IN PHPT 489
EFFECT OF RENAL FAILURE AND DRUGS ACTING ON THE KIDNEY 489
EFFECT OF TREATMENT OF PHPT ON THE KIDNEY 490
URINARY STONE DISEASE 490
NEPHROCALCINOSIS 492
References 492
Chapter 32 - Non-traditional Manifestations of Primary Hyperparathyroidism 496
INTRODUCTION 496
PSYCHOLOGICAL AND COGNITIVE SYMPTOMS AND QUALITY OF LIFE 496
CARDIOVASCULAR DISEASE 500
RHEUMATIC DISEASE 503
GASTROINTENSTINAL DISEASE 503
CANCER 504
CONCLUSIONS 504
References 504
Chapter 33 - Vitamin D and Primary Hyperparathyroidism 508
CROSS-SECTIONAL STUDIES 508
WHY ARE PRIMARY HYPERPARATHYROIDISM AND LOW VITAMIN D LEVELS SO CONSISTENTLY ASSOCIATED? 509
VITAMIN D SUPPLEMENTATION STUDIES 510
GENERAL CONCLUSIONS 512
References 513
Chapter 34 - Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism 516
INTRODUCTION 516
METHODS 516
WORKSHOP GROUP #1: DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM 517
CLINICAL PRESENTATIONS OF PRIMARY HYPERPARATHYROIDISM 518
MANAGEMENT 519
BLUEPRINT FOR FUTURE RESEARCH (ADAPTED FROM REFERENCE 1) 522
CONCLUSION 522
Acknowledgments 522
References 523
Chapter 35 - Preoperative Localization of Abnormal Parathyroid Glands 526
INTRODUCTION 526
ULTRASOUND 527
PARATHYROID SCINTIGRAPHY 531
COMPUTED TOMOGRAPHY 535
MAGNETIC RESONANCE IMAGING (MRI) 538
RADIOGUIDED SURGERY 539
CONCLUDING REMARKS 540
References 542
Chapter 36 - Surgical Management of Primary Hyperparathyroidism 546
INTRODUCTION 546
CLINICAL PRESENTATION TO THE SURGEON AND DIAGNOSTIC CONSIDERATIONS 546
INDICATIONS FOR SURGERY 546
PREOPERATIVE PREPARATION 547
OPERATIVE APPROACHES 548
POSTOPERATIVE MANAGEMENT 552
OUTCOMES OF PARATHYROID SURGERY 552
SPECIAL CONSIDERATIONS 553
SUMMARY 557
References 557
Chapter 37 - Medical Management of Primary Hyperparathyroidism 560
INTRODUCTION 560
GENERAL MEASURES 560
PHARMACOLOGIC THERAPY 561
SPECIFIC SITUATIONS 576
References 577
Section III - Non-Parathyroid Hypercalcemic States 582
Chapter 38 - Hypercalcemia Due to PTHrP 584
PTHRP DISCOVERY AND MOLECULAR IDENTIFICATION 584
METABOLISM OF PTHRP 587
CIRCULATING FORMS OF PTHRP 587
PTHRP AS A CLINICAL TARGET 595
SUMMARY 596
References 596
Chapter 39 - Hypercalcemia Associated with Local and Ectopic Hormone Production 604
1.-HYDROXYLASE 604
25-HYDROXYVITAMIN D-24-HYDROXYLASE 606
SYSTEMIC ELEVATIONS OF CYTOKINES IN MALIGNANCY-ASSOCIATED HYPERCALCEMIA 607
BREAST CANCER 607
MULTIPLE MYELOMA 608
References 609
Chapter 40 - Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor and Downstream Effector Molecules 614
INTRODUCTION 614
THE PTH/PTHRP RECEPTOR SYSTEM 614
HUMAN DISORDERS CAUSED BY MUTATIONS IN THE PTH/PTHRP SIGNALING PATHWAY 617
MUTATIONS IN GENES DOWNSTREAM OF THE PTH/PTHRP RECEPTOR 625
CONCLUSIONS 628
References 628
Chapter 41 - The Differential Diagnosis of Hypercalcemia 634
INTRODUCTION 634
PARATHYROID HORMONE-MEDIATED HYPERCALCEMIA 634
PARATHYROID HORMONE-RELATED PROTEIN-MEDIATED HYPERCALCEMIA 635
MIXED PTHRP AND CYTOKINE-MEDIATED HYPERCALCEMIA 636
1,25-DIHYDROXYVITAMIN D-INDUCED HYPERCALCEMIA 637
OTHER CAUSES OF EXCESSIVE BONE RESORPTION 638
SUPPLEMENT AND DRUG-INDUCED HYPERCALCEMIA 638
OTHER CAUSES OF HYPERCALCEMIA, MECHANISM UNKNOWN 639
AN APPROACH TO THE PATIENT WITH HYPERCALCEMIA 639
References 641
Chapter 42 - Acute Management of Hypercalcemia 644
INTRODUCTION 644
DIFFERENTAL DIAGNOSIS OF HYPERCALCEMIA 644
PATHOPHYSIOLOGY OF ACUTE HYPERCALCEMIA 645
CLINICAL FEATURES OF HYPERCALCEMIA 647
THERAPY OF ACUTE HYPERCALCEMIA 648
References 653
Section IV - Secondary and Tertiary Hyperparathyroid States 658
Chapter 43 - Vitamin D and Parathyroid Hormone 660
INTRODUCTION 660
THE VITAMIN D–CALCIUM HOMEOSTATIC SYSTEM 660
PTH AND VITAMIN D INTERACTIONS IN CALCIUM BALANCE 662
PTH AND VITAMIN D ADEQUACY 663
PTH AND VITAMIN D—RECIPROCAL INFLUENCES 665
MAGNESIUM, PTH, AND VITAMIN D 666
References 666
Chapter 44 - The Parathyroids in Renal Disease: Pathophysiology and Systemic Consequences 668
Pathophysiology and Systemic Consequences 668
INTRODUCTION 668
PATHOGENESIS OF CKD-MBD 668
SYSTEMIC CONSEQUENCES OF ABNORMAL MINERAL METABOLISM IN CKD 671
SUMMARY 674
References 674
Chapter 45 - Clinical Skeletal Syndromes Associated with Parathyroid Disorders in Chronic Kidney Disease 680
INTRODUCTION AND EVOLUTION OF SECONDARY HYPERPARATHYROIDISM 680
SKELETAL DISEASES ASSOCIATED WITH PARATHYROID HORMONE IN CHRONIC RENAL FAILURE 681
CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD) 684
OSTEOPOROSIS 685
BONE MINERAL DENSITY AND USE OF FRAX AT DIFFERENT STAGES OF CKD 685
BIOCHEMICAL MARKERS OF BONE TURNOVER COMBINED WITH PTH IN THE MANAGEMENT OF SKELETAL ABNORMALITIES IN CKD 687
BONE BIOPSY FOR QUANTITATIVE HISTOMORPHOMETRY IN SKELETAL DISORDERS OF CKD 688
TREATMENT OF SKELETAL FRACTURES IN CHRONIC KIDNEY DISEASE 688
CONCLUSIONS 692
References 692
Chapter 46 - Other Secondary Hyperparathyroid States 698
DISORDERS OF CALCIUM BALANCE 698
PHOSPHATE-WASTING DISORDERS 702
POST-RENAL TRANSPLANT 704
ACID–BASE DISORDERS 705
MEDICATIONS 705
References 706
Section V - The Hypoparathyroid States 712
Chapter 47 - Hypoparathyroidism in the Differential Diagnosis of Hypocalcemia 714
DEFINITION OF THE PROBLEM 714
DIFFERENTIAL DIAGNOSIS OF HYPOCALCEMIA 715
CLINICAL EVALUATION 718
LABORATORY EVALUATION 719
GENE AND ANTIBODY TESTING 720
References 721
Chapter 48 - Magnesium Depletion and Parathyroid Function 724
INTRODUCTION 724
THE CALCIUM-SENSING RECEPTOR 724
THE ROLE OF MAGNESIUM IN CASR FUNCTION 725
CLINICAL MANIFESTATIONS OF MAGNESIUM DEFICIENCY 726
CONDITIONS THAT PRODUCE MAGNESIUM DEFICIENCY 728
HOMEOSTASIS AND FUNCTIONS OF MAGNESIUM 728
DIAGNOSIS OF MAGNESIUM DEFICIENCY 728
THE MAGNESIUM TOLERANCE TEST 729
TREATMENT OF MAGNESIUM DEFICIENCY AND ITS EFFECT ON THE PARATHYROID CALCIUM-SENSING RECEPTOR 729
MAGNESIUM DEPLETION AND VITAMIN D STATUS 730
SUMMARY 731
References 731
Chapter 49 - Epidemiology of Hypoparathyroidism 734
INTRODUCTION 734
INCIDENCE AND RISK FACTORS 734
PREVALENCE 738
COST 739
HOSPITALIZATION 739
MORBIDITY 739
MORTALITY 741
CONCLUSION 742
References 742
Chapter 50 - The Molecular Genetics of Hypoparathyroidism 746
INTRODUCTION 746
ISOLATED HYPOPARATHYROIDISM 747
HYPOPARATHYROIDISM ASSOCIATED WITH COMPLEX DISORDERS 751
DIAGNOSTIC WORK-UP IN NON-SURGICAL, IDIOPATHIC HYPOPARATHYROIDISM, PRENATAL DIAGNOSIS, AND GENETIC COUNSELING 756
CONCLUSION 758
References 758
Chapter 51 - Surgical Hypoparathyroidism 764
INTRODUCTION 764
HYPOPARA AFTER THYROID SURGERY 764
HYPOPARA AFTER PARATHYROID SURGERY 765
CLINICAL MANIFESTATIONS 765
PREDICTING AND PREVENTING SURGICAL HYPOPARATHYROIDISM 766
PARATHYROID AUTOTRANSPLANTATION 767
MANAGEMENT OF IMMEDIATE POSTOPERATIVE HYPOCALCEMIA: OUR PROTOCOL 769
SUMMARY 769
References 769
Chapter 52 - Autoimmune Hypoparathyroidism 772
INTRODUCTION 772
HISTORY 772
CLINICAL FEATURES OF APS1 773
PATHOGENESIS 777
ETIOLOGY 780
TREATMENT 780
Acknowledgments 782
References 782
Chapter 53 - Clinical Manifestations of Hypoparathyroidism 788
INTRODUCTION 788
NEUROLOGIC MANIFESTATIONS 788
CARDIAC MANIFESTATIONS 791
OPHTHALMIC MANIFESTATIONS 792
CUTANEOUS MANIFESTATIONS 792
DENTAL MANIFESTIONS 792
HYPOPARATHYROIDISM-ASSOCIATED MYOPATHY 793
GASTROINTESTINAL MANIFESTATIONS 793
SKELETAL MANIFESTATIONS 793
RENAL MANIFESTATIONS 793
LATENT AND SUBCLINICAL HYPOPARATHYROIDISM 794
PRESENTING SIGNS AND SYMPTOMS 794
References 795
CHAPTER 54 - Skeletal Manifestations of Hypoparathyroidism 798
INTRODUCTION 798
SKELETAL MANIFESTATIONS OF HYPOPARATHYROIDISM 798
SKELETAL EFFECTS OF PTH TREATMENT IN HYPOPARATHYROIDISM 801
SUMMARY 804
References 805
Chapter 55 - Molecular and Clinical Aspects of Pseudohypoparathyroidism 808
HISTORY AND NOSOLOGY 808
PTH SIGNAL TRANSDUCTION AND THE ROLE OF G-PROTEINS 810
MOLECULAR BIOLOGY OF THE GNAS GENE 813
TISSUE-SPECIFIC IMPRINTING OF GNAS 814
PATHOPHYSIOLOGY OF PTH RESISTANCE IN PSEUDOHYPOPARATHYROIDISM 815
MOLECULAR CLASSES OF PSEUDOHYPOPARATHYROIDISM 816
MULTIPLE HORMONE RESISTANCE IN PSEUDOHYPOPARATHYROIDISM TYPE 1A 818
CLINICAL FEATURES 819
DIAGNOSIS OF PSEUDOHYPOPARATHYROIDISM 822
TREATMENT 823
CONCLUSION 825
References 825
Chapter 56 - Treatment of Hypoparathyroidism with Calcium and Vitamin D 834
TREATMENT 835
CONCLUSION 836
References 836
Chapter 57 - Treatment of Hypoparathyroidism with Parathyroid Hormone 838
INTRODUCTION 838
TREATMENT OF HYPOPARATHYROIDISM WITH PTH(1–34) 838
TREATMENT OF HYPOPARATHYROIDISM WITH PTH(1–84) 840
SUMMARY, AREAS OF UNCERTAINTY, AND FUTURE DIRECTIONS 847
References 849
Section VI - The Parathyroids and Osteoporosis 852
Chapter 58 - Parathyroid Hormone in the Pathophysiology of Osteoporosis 854
INTRODUCTION 854
EARLY POSTMENOPAUSAL BONE LOSS 854
AGE-RELATED CHANGES IN PTH SECRETION 855
RELATIONSHIP OF AGE-RELATED INCREASES IN SERUM PTH TO INCREASED BONE TURNOVER AND BONE LOSS 857
ETIOLOGY OF THE SECONDARY HYPERPARATHYROIDISM OF AGING 859
SUMMARY AND CONCLUSIONS 860
References 860
Chapter 59 - Parathyroid Hormone and Glucocorticoid-induced Osteoporosis 864
INTRODUCTION 864
MECHANISM OF GLUCOCORTICOID- INDUCED BONE LOSS 864
MECHANISM OF ANABOLIC ACTION OF PTH ON BONE IN GIOP 864
ROLE OF PTH IN THE PATHOGENESIS OF GIOP 865
TREATMENT OF GIOP WITH PARATHYROID HORMONE 866
CONCLUSION 868
References 868
Chapter 60 - Parathyroid Hormone as Monotherapy for the Treatment of Osteoporosis 870
INTRODUCTION 870
INDICATIONS FOR PTH THERAPY IN OSTEOPOROSIS 870
MODE OF ACTION 871
PERSISTENCE OF EFFECT 875
RECHALLENGE WITH PTH 875
COST EFFECTIVENESS OF TPTD 875
PTH TREATMENT IN GLUCOCORTICOID-TREATED PATIENTS 876
OTHER POTENTIAL APPLICATIONS FOR PTH TREATMENT 877
CONCLUSION REGARDING OSTEOPOROSIS TREATMENT 877
References 877
Chapter 61 - Combination Osteoporosis Therapy with Parathyroid Hormone 880
INTRODUCTION 880
COMBINATION OSTEOPOROSIS THERAPY 880
PARATHYROID HORMONE AND ESTROGEN OR SELECTIVE ESTROGEN-RECEPTOR MODULATOR THERAPY IN POSTMENOPAUSAL OSTEOPOROSIS 881
PARATHYROID HORMONE AND BISPHOSPHONATES IN POSTMENOPAUSAL OSTEOPOROSIS 881
PARATHYROID HORMONE AND DENOSUMAB IN POSTMENOPAUSAL OSTEOPOROSIS 884
COMBINATION THERAPY IN MALE OSTEOPOROSIS 884
PARATHYROID HORMONE AFTER ANTIRESORPTIVE THERAPY 885
ANTIRESORPTIVE THERAPY AFTER PARATHYROID HORMONE 886
HYPERCALCEMIA AND HYPERCALCIURIA WITH COMBINATION THERAPY 887
SUMMARY 887
References 888
Chapter 62 - The Role of Parathyroid Hormone in Fracture Healing 892
THE BIOLOGY OF FRACTURE REPAIR 892
THE ROLE OF PTH IN PRE-CLINICAL MODELS OF FRACTURE HEALING 895
THE ROLE OF PTH IN CLINICAL MODELS OF FRACTURE HEALING 899
THE EFFECT OF PTH WITH ADDITIONAL ADJUVANTS 901
CONCLUSIONS 902
References 902
Chapter 63 - Parathyroid Function and Disease during Pregnancy, Lactation, and Fetal/Neonatal Development 904
INTRODUCTION 904
MINERAL PHYSIOLOGY DURING PREGNANCY 904
MINERAL PHYSIOLOGY DURING FETAL DEVELOPMENT 907
MINERAL PHYSIOLOGY DURING LACTATION 908
MINERAL PHYSIOLOGY IN THE NEONATE 911
PARATHYROID DISORDERS DURING PREGNANCY 912
PARATHYROID DISORDERS DURING LACTATION 917
PARATHYROID DISORDERS DURING FETAL AND NEONATAL DEVELOPMENT 919
CONCLUSIONS 922
References 923
Index 930