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2/17/2009Endocrine Physiology ofBone and Calcium DisordersJohn P. Bilezikian, M.D.Professor of Medicine and PharmacologyChief, Division of EndocrinologyTuesday, February 17, 2009Outline of Lecture Normal calcium homeostasisUseful indices of calcium metabolismHypercalcemiaHypocalcemiaOsteoporosis1

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2/17/2009Two Major Calcium-Regulating Hormones Parathyroid hormone 1,25-dihydroxyvitamin D3

2/17/2009Regulation of Parathyroid Hormone Ionized calcium 1,251,25--dihydroxyvitamin DThe Calcium-Sensing ReceptorSPNH2 Type I ligands:Direct receptor bindingHSoutside123P45P67inside Type II ligands:allostericmodulationPPPHOOC4

2/17/2009Ca2 Regulation of Parathyroid Hormone Ionized calcium 1,25-dihydroxyvitamin D5

2/17/2009Major Functions of Parathyroid Hormone Regulation of serum calcium and phosphate Bone remodeling Regulation of 1,25-dihydroxyvitamin D levels6

2/17/2009Two Major Calcium-Regulating Hormones Parathyroid hormone 1,25-dihydroxyvitamin D7

2/17/2009Major Functions of 1,25-dihydroxyvitamin D GI absorption of calcium and phosphate Bone remodeling Regulation of parathyroid hormoneRelationship between 2525-hydroxyvitamin D and PTHThomas MK et al. N Eng J Med 1998;338:7781998;338:778-7838

2/17/2009HOW PTH AND 1,25(OH)2D WORK TOGETHERTO CONTROL THE SERUM CALCIUM CONCENTRATION9

2/17/2009Other Circulating Hormones that InfluenceBone Metabolism Parathyroid hormone1,25 (OH)2 vitamin DGonadal steroids (estrogens and androgens)CorticosteroidsThyroid hormoneGrowth hormoneLocal Regulators of Bone Metabolism IGFs and IGF binding proteinsTGF-βBone morphogenic proteinPlatelet-derived growth factor, fibroblastgrowth factorg Prostaglandins Interleukins (IL-1, IL-6) RANKL/osteoprotegerinRaisz LG. Clin Chem 1999;45:1353-8.10

2/17/2009Outline of Lecture Normal calcium homeostasisUseful indices of calcium ful indices of calcium metabolismas gleaned from the multichannel autoanalyzer“THE HOLY TRINITY”CalciumPhosphorousAlkaline phosphatase11

2/17/20094.0Useful Indices of calcium metabolism Calcium, phosphorus Dynamic markers of bone metabolismBone formationBone resorption12

2/17/2009Bone turnover in the adult ng phaseFROM: Primer on the Metabolic Bone Diseasesand Disorders of Mineral Metabolism; 2nd Ed.13

2/17/2009Useful indices of calcium metabolism:biochemical markers of bone turnoverBone resorption N-telopeptide (NTx) C-telopeptide (CTx) Deoxypyridinolinedl(f(free,total)Bone formation Bone-specific alkalinephosphatase OsteocalcinOl i Propeptides type I collagen(P1NP)1.Sornay-Rendu E. J Bone Miner Res. 2005;20:1813-19.Useful Indices of calcium metabolism Calcium, phosphorus Dynamic markers of bone metabolism Calciotropic hormones– Parathyroid hormone– Vitamin D 25-hydroxyvitamin D 1,25-dihyhydroxyvitamin D14

2/17/2009Storage form: index of vitamin Dsufficiency or insufficiencyVITAMIN D DEFICIENCY IN MEDICAL INPATIENTSNormal laboratory reference rangeNormal physiologic rangeThomas MK et al. N Eng J Med 1998;338:778-78315

2/17/2009Useful Indices of calcium metabolism Calcium, phosphorus Dynamic markers of bonemetabolism Calciotropic hormones Measurement of bone massREDUCED BONE MASS IS A KEYRISK FACTOR FOR FRACTURE16

2/17/2009Relationship Between BMD andFracture Risk in Untreated PatientsReduced bone mass is a key35risk factor for the fragility -4-3-2-10Bone density (SD units)Dual Energy X-Ray Absorptiometry (DXA)Hologic DelphiGE Lunar Prodigy17

2/17/2009Features of bone densitometry by DXA(dual energy X-ray absorptiometry) SafeAccuratePreciseNormative population databasesCCorrelatesl t withith fracturef triski kA diagnostic standard forosteoporosisBone loss as a function of age1PA spine0-1T-score-2-3T -2.5-4-5-6202530354045Faulkner KG, et al. J Clin Densitom 1999;2:343-50.50556065707580859095Age18

2/17/2009Referents for comparisonsof bone mass measurements Z-score:: a measure of bone density instandard deviations fromfnormal age- andsex-matched cohorts T-score:: a measure of bone density instandard deviations from cohorts at peakpbone mass (25-30 years old)Spine: L1-L4BMD gm/cm2T-Score1.32 11.200T1.08-1Z0.96-20.84-3T - 2 Z - 0.50 720.72-4420406080100Age19

2/17/2009Diagnostic StandardT-SCOREInterpreting T-scores (World Health Organization)Correlates with life time fracture risk for Caucasian Women-4.0-3.5-3.0NormalBone MassLowBone Mass(Osteopenia)Osteoporosis-2.5-2.0-1.5-1.0-0.50 0.5 1.0T-score20

2/17/2009Outline of Lecture Normal calcium homeostasisUseful indices of calcium SES OF HYPERCALCEMIA PrimaryHyperparathyroidism MalignancyM li Other endocrinopathy HyperthyroidismPheochromocytomaVIPomaAdrenal insufficiencyMedications lithiumthiazide diureticsththyroidid hormonehVitamin AVitamin D Vitamin D Toxicityy Granulomatous disease– Tuberculosis– Sarcoidosis– Any otherLymphomaFHHImmobilizationAcute or chronic renaldisease21

2/17/2009MAJOR CAUSES OF HYPERCALCEMIA(From Mundy and Martin)# OF PATIENTSPrimaryHyperparathyroidism% OF TOTAL11154Malignancy7235Others (sarcoid,ththyroid,id vitit D,D etct126Unknown126PRIMARY HYPERPARATHYROIDISM A common endocrine disorder characterizedb iincompletelybyl t l regulated,l t d excessiveisecretion of parathyroid hormone from one ormore parathyroid glands. Primary Hyperparathyroidism is associatedwithith hhypercalcemiali andd elevatedlt d llevelsl offparathyroid hormone.22

2/17/2009Human Parathyroid 0ArgGluMetSerAsnLeuHisArgLysLysLeuGlnAspValHisAsn PheLeuGlyLysTrpLeu30- COOHHypoparathyroidism23

2/17/2009PRIMARY HYPERPARATHYROIDISMBefore 1970: A disease of bone, stones,and groans24

2/17/2009Emergence of the Modern Clinical Profileof Primary HyperparathyroidismCope et al. Heath et al.1930--1965 1965-19741930Mallette etal.1965-1974Silverberg,Bilezikian et riaNotreported36%40%39%Overt SkeletalDisease23%10%14%1 4%1.4%Asymptomatic0.6%18%22%80%25

2/17/2009Biochemical and hormonal profilein Primary Hyperparathyroidism IndexPatientsnl rangeCalcium (mg/dl)Phosphorus (mg/dl)Alk Phos (IU/l)PTH (pg/ml)25--OH Vit D (ng/ml)251,25--OH2 Vit D (pg/ml)1,25Urinary calcium (mg)DPD (nmol/mmol Cr)10.710.7 0.12.9 2.9 0.1114 114 4121 121 721 21 159 2248 1217 68.48.4--10.22.5--4.52.5 10010--65109-5215-60250-3004-21PRIMARY HYPERPARATHYROIDISMBefore 1970: A disease of bone, stones, andgroansSince 1970: A disease of asymptomatichypercalcemia26

2/17/2009BONE MASS MEASUREMENTS INPRIMARY HYPERPARATHYROIDISMBone and stone disease in primaryhyperparathyroidism: 1965-2007Mallette, BilezikianHeath & Aurbach1965-1972Silverberg,Bilezikian et al.1984-2007n 57n 121Nephrolithiasis37%17%Bone disease(Radiological)14%1.4%27

2/17/2009BMD in Postmenopausal Women WithPrimary HyperparathyroidismBone Mineral Density:B% of Expected100*** DiffersDiff fromfradius,dip .05Femoral NeckRadius908070Lumbar SpineSilverberg, Bilezikian et al.JBMR, 1989Normal BoneSkeletal Site Cancellous CorticalLumbar spine****Total HipFemoral neck****Radius (1/3 site)****CorticalCancellous28

2/17/2009Densitometric and HistomorphometicCharacteristics of Bone in PrimaryHyperparathyroidism Cancellous bone (lumbar spine):relatively well preserved Cortical bone ((distal radius):)preferentially affected (i.e. reduced)TO CUT IT OUT ORTO LEAVE IT IN A KEY CLINICAL DILEMMA INPRIMARY HYPERPARATHYROIDISM29

2/17/2009Guidelines for Parathyroid Surgery(Bilezikian et al., 3rd International Workshop,J Clin Endocrinol Metab, 2009) Hypercalcemia ( 1 mg/dl abovenormal) Stone or overt bone disease Reduced bone densityy ((T -2.5)) Age ( 50 years old)Hypoparathyroidism30

2/17/2009Humoral Hypercalcemia of MalignancyMalignant tumors synthesize andsecrete humors that stimulateosteoclast--mediated bone resorptionosteoclast31

2/17/2009Parathyroid HormoneHormone-Related Proteinas an Etiology of HHMCriteria Produced by the tumor Blood level correlates with hypercalcemia Mimics the clinical syndrome Reducing the PTHRP “burden” reverses hypercalcemia32

2/17/2009Circulating PTHRP Levels inHypercalcemia of Malignancy MalignancyHTLV--1 THTLVT-cell lymphomaClassical squamous cell carcinomaAdenocarcinomaBreast carcinomaMyeloma and other hematological malignancies% Elevated99%85%58%50%21%Budayr et al. Annals Int Med, 1989Ikeda et al. J Clin Endo & Metlab, 1994Potential Physiological Functions of PTHRP Lactation Placental Calcium Transport Neonatal Calcium Metabolism Proliferation and Differentiation of the Skin Bone Growth Chondrocyte Development Smooth Muscle Function33

2/17/2009CAUSES OF HYPERCALCEMIA Primary Hyperparathyroidismgy Malignancy Other endocrinopathy HyperthyroidismPheochromocytomaVIPomaAdrenal insufficiencyMedications lithiumthiazide diureticsthyroid hormoneVitamin AVitamin D Vitamin D Toxicityy Granulomatous disease– Tuberculosis– Sarcoidosis– Any otherLymphomaFHHImmobilizationAcute or chronic renal diseaseSymptoms, signs, and treatment ofhypercalcemiaTo be discussed tomorrow!34

2/17/2009Outline of Lecture Normal calcium homeostasisUseful indices of calcium ocalcemia Hypoparathyroidism– Deficient secretion of parathyroidhormone Secondary hyperparathyroidism– Appropriate response to hypocalcemicstimulus Other causes35

2/17/2009HypocalcemiaHypoparathyroidism - Deficient secretion of parathyroid hormone Autoimmune hypoparathyroidism– MultipleM lti l end-organdendocrined i glandl d insufficiencyiffi i– Isolated parathyroid gland deficiency Familial hypoparathyroidism– Defective processing of PTH gene product– Defective cellular trafficking of PTH gene product– Developmental agenesis (X(X-linked) Activating mutations of the calcium receptor Congenital (DeGeorge Syndrome) PostPost--surgical hypoparathyroidismHypocalcemiaSecondary Hyperparathyroidism - Appropriate response to hypocalcemic stimulus Vitamin D r diseaseRenal disease Vitamin D resistant states– Vitamin D resistant rickets– Vitamin D dependent rickets Drugs– Foscarnet– Pentamidine– Ketaconazole Pseudohypoparathyroidism36

2/17/2009Symptoms, signs, and treatment ofhypocalcemiaTo be discussed tomorrow!Outline of Lecture Normal calcium homeostasisUseful indices of calcium metabolismHypercalcemiaHypocalcemiaOsteoporosis37

2/17/2009Postmenopausal Osteoporosis Osteoporosis6 to 8 million US women age 50 Low bone mass20 to 24 million Fractures40% will suffer an osteoporotic fracture in theirlifetimeVertebral:Hip:Forearm:15.6%17 5%17.5%16.0% 2.0 million fractures annuallyMelton LJ, et al. J Bone Miner Res 1992;7:1005-10.Looker AC, et al. J Bone Miner Res 1997;12:1761-8.National Osteoporosis Foundation. 1998, 2002.38

2/17/2009Human Costs of Osteoporosis Impaired function, decreased mobility More bone loss due to decreased activity Compressed abdomen,reduced appetite Reduced pulmonaryfunctionp disorders Sleep Shortened survival Poor self esteemRoss PD et al. Ann Intern Med 1991;114-23.Silverman SL. Bone 1992;13 (suppl 2):S27-31.Cooper C, et al. Am J Epidem 1993;137:1001-5.Lyles et al. Am J Med 1993;94:595-601.Schlaich C, et al. Osteoporos Int 1998;8:261-7.Photo courtesy of the National Osteoporosis Foundation39

2/17/2009Incidence of Osteoporosis and al Osteoporosis Foundation, 2002.Osteoporosis: defining the Problem“A skeletaldisordercharacterized bycompromisedbone strengthpredisposing toan increasedrisk of fracture.”Osteoporotic boneHealthy boneNIH Consensus Development Conference on Osteoporosis, 2000.8040