UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Regulation of plasma calcium in man McPherson, George Duncan 1959

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata


831-UBC_1959_A6_7 M187 R3.pdf [ 3.09MB ]
JSON: 831-1.0106104.json
JSON-LD: 831-1.0106104-ld.json
RDF/XML (Pretty): 831-1.0106104-rdf.xml
RDF/JSON: 831-1.0106104-rdf.json
Turtle: 831-1.0106104-turtle.txt
N-Triples: 831-1.0106104-rdf-ntriples.txt
Original Record: 831-1.0106104-source.json
Full Text

Full Text

REGULATION  OP P L A S M A  CALCIUM IN  MAN  BY  GEORGE M.D.,  A  DUNCAN  University  THESIS THE  McPHERSON  o f Western  Ontario,  SUBMITTED I N PARTIAL REQUIREMENTS  MASTER  in  FOR  OF  1956  F U L F I L M E N T OF  THE DEGREE  OF  SCIENCE  t h e Department of PHYSIOLOGY  We  accept  required  THE  this  thesis  as conforming  to the  standard.  UNIVERSITY  OF B R I T I S H  October,  1959  COLUMBIA  ABSTRACT  The  kinetics  o f plasma  studied  by noting  calcium  as gluconate  Twenty-nine subjects.  the response  infusion  osteoporosis.  study. and of  at the rate  tests  were  were  calcium,  comprised  o f 10  carried  A l l were  normals,  followed  phosphorus  by frequent  and c i t r a t e  male  Disease,  a t the time calcium,  blood  of  of  Paget's  of plasma  were  mg/kg/hr.  cases  hospitalized  i n levels  injection  o u t on 20 a d u l t  hyperparathyroidism,  The changes  citrate  r e g u l a t i o n i n man  to intravenous  given  The s e r i e s  hypoparathyroidism, and  calcium  of the  phosphorus  sampling.  by the kidney  Excretion  was  also  determined.  In the to  a l l cases,  infusion normal  also and  rose  plasma  and d e c l i n e d  several hours slightly,  remained  calcium  slowly  later.  b u t more  elevated  as l o n g  levels  after Plasma  slowly  i n response t o  i t had ended,  returning  phosphate  citrate  than  as plasma  rose  and  the plasma calcium  was  calcium, above  normal.  The  increase  proportional  t o the plasma  hypercalcemia. to  estimate  by  the renal  this  series  5.60  -  i n the calcium  From  a tubular  this  linear  maximum  tubules. o f 8 normal  5-80).  calcium  excretion rate during  was  directly  the period of  relationship  i t was  (Tm) f o r r e a b s o r p t i o n  possible of  The v a l u e  obtained  f o rcalcium  subjects  w a s 4.97  - 0.27  calcium  Tm i n  mg/min  (range  In to  be  t h e one  increased  case  of  following  osteoporosis  studied,  correction of a  t h e Tm  appeared  hyperchloremic  acidosis.  The is  a most  plasma  increased important  level  The soft in the  to  calcium  the cases high  rate  excretion during  homeostatic  hypercalcemia  f a c t o r i n r e s t o r i n g the  normal.  rapidity  tissue  calcium  of the  exchange  compartments  of Paget's o f bone  disease,  blood  flow  between  the bone  appeared  t o be  as might  be  much  and  greater  predicted  characteristic  of  the  this  from disease.  In the  presenting  requirements  this  British  it  freely available  for  that  Columbia,  Department  copying  gain  shall  f o r reference  purposes  may  n o t be a l l o w e d  of  I  my  PHYSIOLOGY  September  24. 1959  University  and study.  of this  without  at the  shall  copying  be g r a n t e d  or publication  fulfilment of  the Library  f o r extensive  The University of British V a n c o u v e r 8, C a n a d a . Date  that  degree  o r by h i s r e p r e s e n t a t i v e s .  that  Department  I agree  permission  scholarly  i n partial  f o r an advanced  of  agree  thesis  Columbia,  make  further  of this  by t h e Head  thesis  o f my  I t i s understood  thesis  forfinancial  written  permission.  TABLE OF CONTENTS CHAPTER  PAGE  I  INTRODUCTION  II  METHODS  III  V  11  Subjects  11  Administration of Calcium  12  Diet  12  C o l l e c t i o n of Samples  13  Observation of Patients  13  A n a l y t i c a l Methods  14  RESULTS  15  Observation of the Subjects  15  Plasma Calcium  15  Urine Calcium  16  Phosphorus  17  Citrate  18  Treatment of Data  18  Plasma Calcium Curves IV  1  . . .  20  DISCUSSION  21  APPENDIX  28  CASE HISTORIES  28  SAMPLE CALCULATIONS  30  VI  TABLES .  31  VII  FIGURES  41  VIII  BIBLIOGRAPHY  50  ACKNOWLEDGEMENTS  The  author  the  Department  and  sponsorship  counsel; Mr. of  the staffs  the of  this  of this  D r . H.  f o rher expert  Mcintosh  technical  o f the graphs;  o f the Department cooperation  Research Council  Copp,  Head  f o rh i s encouragement,  research;  f o rpreparation  f o rtheir  National  t o t h a n k D r . D.H.  of Physiology,  M r s . N. W i l s o n  K. H e n z e  Hospital  wishes  and h e l p f u l o f Canada  project.  i i i  direction,  f o r h i s assistance;  t h e many  of Physiology  of  others  and Shaughnessy  suggestions;  f o rfinancial  and support  1 INTRODUCTION  The of  acute  purpose  of this  intravenous  frequent  sampling  study  was  calcium loading  o f plasma  kinetics  of calcium regulation,  and  i n those  with  The  latter  and  post-surgical  consisted  plasma body  preserved  normal  bone  diverse  hand,  aspects  despite  of calcium  o r an e f f e c t ,  with makes  calcium important.  c o n d i t i o n s as primary advanced  of fractures.  i s associated  gland  the primary,  cause  tetany with  with  and t h e k i d n e y .  post-surgical  to a f a l l  cause  idiopathic and  of  after  bone  closely this  metabolism. many a  disease  study  of plasma  and  secondary and of the  Hypocalcemia,  d e f e c t s i n two  organs  Hypoparathyroidism,  clinical  may  be  signs.  by an excessive l o s s  sufficient Renal  on  - the  whether  or of the idiopathic  calcium which  i t s striking  hypocalcemia  type,  of the  Hypercalcemia  nephritis  (29).  constancy  intensive  d i s e a s e , and i m m o b i l i z a t i o n o f p a r t s  leads  may  disease  or hypocalcemia  of plasma  as i n the treatment  parathyroid of  t h e many  hyperparathyroidism,  Paget's  other  of both  i s one o f t h e most  poorly understood  as a cause  such  tumours,  body  into  metabolism.  The mechanisms whereby  of hyper-  regulation  uremia,  the  into  whether  accompanies  calcium level  constants.  association  states,  that  subjects,  hyperparathyroidism before Paget's  hoped  insight  i n normal  of hypoparathyroidism  of widespread  remain  investigation The  give  effects  deformans).  The regulated  both  the  I t was  disturbances of mineral  types,  and cases  (osteitis  is  known  i n man,  and u r i n e would  the  surgery,  to investigate  type, to  defects  of calcium as i n  2 renal a c i d o s i s , renal r i c k e t s , and the Fanconi syndrome. (30,59,62). In the normal adult man, the concentration of calcium i n the plasma i s between 9 and 11 mg%.  A 70 kilogram man has about  280 mg. of calcium i n the c i r c u l a t i n g plasma, of which 140 mg. i s i n the form of calcium ions.  This i o n i z e d p o r t i o n i s i n free  and rapid exchange with the estimated 500 mg. of i o n i z e d calcium i n the 10 l i t r e s of i n t e r s t i t i a l f l u i d .  (45).  Isotopic studies  show that as much as 52% to 80% of the plasma calcium exchanges with calcium of the i n t e r s t i t i a l f l u i d each minute. (3,64). McLean c a l l s the e x t r a c e l l u l a r f l u i d calcium, the "calcium compartment", and states that i t amounts to 20% of the body weight, containing 700 mg. of calcium ions i n a 70 kilogram man.(45). The soft t i s s u e s contain considerable calcium.  Muscle  contains as much as 8-10 mg./lOO gms. wet weight.(21,28). However, much of t h i s i s believed to be r e l a t e d to membranes, and McLean states that the contents of c e l l s are v i r t u a l l y free of calcium and do not p a r t i c i p a t e i n the rapid exchange between the "calcium compartment" and bone. The calcium of body f l u i d s i s d i v i d e d into three chief forms:  the f r e e l y i o n i z e d , the protein-bound,  diffusible fraction.  and the complexed,  McLean and Hastings, i n 1935, (44) r e l a t e d  the t o t a l calcium to the t o t a l p r o t e i n and formulated a nomogram which r e l a t e s the percentage of protein-bound to t o t a l plasma p r o t e i n l e v e l s .  calcium d i r e c t l y  I t has been accepted generally,  3 until  recently, that  constant such  at a l llevels  a s pH,  ultrafiltration  the  protein-bound with  difficulty depend  total  total  accepted  as  tissues,  about  1%  of  in  one  half gram  between  of need. body  extensively presence  by  of an  equilibrium  The  isotope  with  size,  200-300  ratio  i s between  the long  of  bone.  by  axis  The  Of  this,  drawn The  1.3  of the  small  size  of  that  fraction  the  workers had  grams and  fluid.  mechanism  bone  i n body  to  of  less  and  been soft and than  soft  only  as  part  f u n c t i o n i n g as calcium  has been  w h i c h have  (54-),  Thus,  fluid not  has  are i n the  of calcium  reserve  levels  exchange investigated  confirmed  t h e bone  a  the  mineral  i n  f l u i d s . (5»4-2,25,60,11).  i s laid  2.0.(50).  down  The  collagen fibres of the  also  adult  tendons  to preserve  A°, i n which the  and  ionized  kilogram  11  but  upon  techniques  o f bone  20-50  most  important  o f bone  this  calcium  the  i s i n the body  exchangeable f r a c t i o n  calcium  in  and  70  of a  a reserve,  (8,26).  fluids  However,  (40) Suggest  Because  extracellular  calcium  c a n be  that  i n ligaments  structure  that  Rose  fractions,  content  i n the  forms  conditions  are constant. and  remain  determinations.  of this  body  fractions  i f other  of calcium.  these  calcium  the rest  bank  times  level  calcium  the supporting  mineral  of Lloyd  1200-1400 grams.  of the t o t a l  tissues;  calcium,  form i s s t a b l e , and  the t o t a l  upon  than  studies  i n separating  The  less  of t o t a l  o f t h e two  and plasma p r o t e i n l e v e l ,  the  varies  the proportions  crystals  i n crystals calcium crystals  of  to phosphorus are  oriented  of the organic results  colloidal  i n a  matrix tremendous  4 surface area, estimated (8,48,18).  The  at 100 M2/gm of inorganic material  exchangeable or l a b i l e form of calcium i s held  on the surface of the bone c r y s t a l s i n the hydration l a y e r proposed by Neuman ( 5 0 ) .  This f r a c t i o n , estimated  at 1-4%  of  the t o t a l bone calcium, i s r e a d i l y a v a i l a b l e to b u f f e r any sudden change of plasma calcium (10) by i t s contact with the plasma flowing through bone.  Blood to bone exchange of mineral  appears to be governed l a r g e l y by a physico-chemical on t h i s surface (43).  exchange  In a d d i t i o n , there are deeper reactions  between the hydration l a y e r and the c r y s t a l , and a r e c r y s t a l l i z a t i o n within the l a t t i c e i t s e l f . resorption processes  A c c r e t i o n and  also modify the exchange, e s p e c i a l l y i n  the period of active growth of bone (4,50,5 4-9). 5  Parathyroid hormone i s believed to maintain the  constant  calcium l e v e l i n plasma by exerting some control over the bloodbone equilibrium of calcium.  The means whereby t h i s c o n t r o l i s  exerted has not yet been established.  McLean postulated that  chemical dynamics of the l a b i l e f r a c t i o n maintain blood up to 7 mg%,  levels  but that the f i n a l r e g u l a t i o n i s due to a feedback  mechanism of parathyroid stimulation i n response to hypocalcemia, serving to mobilize more calcium from bone (43).  Patt  and  Luckhardt (53) showed that the parathyroid gland responded to changing calcium l e v e l s , so a feedback appears p o s s i b l e . Howard (34) supported t h i s view, s t a t i n g that a gradient e x i s t s at the blood-bone i n t e r f a c e to preserve  a high blood  l e v e l , under the influence of the parathyroids.  calcium  5 Neuman (19)  has postulated that the mechanism of the i o n -  gradient on the bone surface i s the production of c i t r a t e byc e l l s l o c a l l y under the influence of parathyroid hormone. C i t r a t e i s present i n bone i n large amounts - 1% of the f r e s h weight of bone (15).  C i t r i c acid i s capable of c h e l a t i n g  calcium; i t i s r e a d i l y produced at the bone surface, and i s metabolized  elsewhere, c h i e f l y i n the kidney, so i t may  well (37)'  be the mechanism f o r maintaining the bone-blood gradient  The other proposed s i t e of a c t i o n of parathyroid hormone i s the kidney.  In 1929,  A l b r i g h t (2) advanced the theory that  parathyroid hormone caused phosphaturia  and a secondary r i s e i n  blood calcium by lowering the Ca x P product. supported.  Jahan and P i t t s , i n 1948,  This has not been  (36) concluded that the  hypercalcemia and hypercalcuria produced by administration of parathyroid hormone were dependent upon an extrarenal action of the hormone i n mobilizing calcium from the body stores, not upon any s p e c i f i c depression of renal tubular reabsorption of either phosphorus or calcium. that the phosphaturic  Handler and Conn have shown  e f f e c t of parathyroid hormone seemed  to depend upon experimental  conditions and the means by which  the parathyroid hormone was  administered  Calcium loading techniques study calcium regulation.  (24).  have been widely used to  A good deal of the pertinent work  has been d i r e c t e d toward studying the response of blood  and  urine phosphate l e v e l s to calcium loading as an estimation of parathyroid a c t i v i t y , rather than to study calcium k i n e t i c s  6 d i r e c t l y (27,35,38).  While the kidney i s prominent i n the  regulation of other e l e c t r o l y t e s , i t s r o l e regarding has not been emphasized.  calcium  I f the d i f f u s i b l e f r a c t i o n i s 60% of  the t o t a l plasma calcium, then the f i l t e r e d load per day i s 180 l i t r e s x 60 mg. or 10.8 gms.  Since normal excretion i s  l e s s than 300 mg/day, the reabsorptive mechanism must be very efficient  (45).  The presence of a tubular reabsorption maximum (Tm) f o r calcium would help to explain the minute to minute constancy of plasma l e v e l s .  While a high Tm would r a i s e blood l e v e l s , a  lowered Tm might not be r e f l e c t e d i n lower blood l e v e l s as long as m o b i l i z a t i o n of calcium from the bones was e f f i c i e n t . Since there i s a tremendous reserve, t h i s d e f i c i t could be compensated f o r a long time. Investigation into the r e l a t i o n between plasma l e v e l s of calcium and renal excretion rates, which are necessary to calculate the tubular maximum, have been done by several workers (57,52,66,31)•  Their clearance periods have often  been short, or else plasma l e v e l s have not been w e l l defined, so that conclusive r e s u l t s were not obtained. In  19^-9,  Wolff and B a l l (66), working on dogs given an  intravenous calcium load, stated that there was no e f f e c t i v e threshold f o r r e t e n t i o n of calcium, and that the plasma l e v e l of calcium was apparently not regulated appreciably by renal function.  Freedman et a l (20), i n 1958,  stated that only a  small f r a c t i o n of the c a l c u l a t e d increase i n the f i l t e r e d  7 load  of  stated  calcium that  filtered  calcium  rates  i n dogs  levels  as  physiological to  a  that  calcium  On "renal  on  other  threshold"  the  urine.  to  changes  Tm  for  noted  response  and  calcium  i s by  Keuman  given  gave  (12)  were  could  studied the  also  loading  study  and  that, the  three  noted kidney  unable  i n  dogs,  be  and  8.5  a the  mg%  The  in  calcium.  be  i n 1954  (23)  to  above  a  who  hypoparathyroidism  level,  in  sensitive  reference  relationship  plasma  persons  excretion  e x c r e t i o n was  linear  a  to  very  first  a  McCance  calcium  must  patients with of  observed  i t s rapid  Bassett,  threshold to  i n 1929,  intravenous  and  excretion rates  the  and  He  above  intravenous  Goldman  seemed  calcium,  excretion at  levels.  A  with  observed  were  (1),  calcium  of  (55)  calcium  Albright  (4-1)  calcium.  there  and  calcium  stated  i n plasma  intravenous each,  for  directly  calcium.  which  (65)  Freeman  Tm.  hand,  balance  They  calcium the  a  patient  controlled  mg%  for  intravenous  i n 1939  Widdowson, a  Chen  and  intravenous  maximum 37  as  after  hypoparathyroid and  high  exhibited  the  given  varied i n 1957,  Poulos,  tubular  range.  demonstrate,  Williamson  reabsorption  load.  demonstrate  plasma  excreted.  calcium  excretion not  was  noted  to  in  between the  "renal  threshold".  Any consider The most  loading  the  kidney  possible  i s known  evidence  technique  to  suggests  using  intravenous  response  of  the  respond  by  increased  that  there  calcium  must  gastro-intestinal  i s no  excretion,  active  tract. but  excretion  of  8 calcium into the g a s t r o - i n t e s t i n a l t r a c t i n response to r a i s e d blood l e v e l s .  Christiansen, i n 1937,  (13),  using r a b b i t s , r a t s ,  and goats, could f i n d no active g a s t r o i n t e s t i n a l excretion on intravenous calcium loads. balance study on men  McCance and Widdowson (41), i n t h e i r  given a d d i t i o n a l intravenous calcium load,  noted that excretion of the calcium was v i a the urine rather than the feces.  Baylor, et a l (7)  gave intravenous calcium  and observed f e c a l and u r i n a r y excretion.  They found no change  i n the f e c a l calcium content. Having considered b r i e f l y the general responses  of the  kidney versus the g a s t r o i n t e s t i n a l t r a c t to intravenous calcium, loads, we turn to the question of the fate of intravenous calcium, and i n p a r t i c u l a r , i t s r e t e n t i o n i n the body.  In  1924,  Salvesen and Hastings (56) noted the r e t e n t i o n of calcium G r e v i l l e , i n 1931  following intravenous loading. the rapid disappearance  (22) noted  of calcium following intravenous  i n j e c t i o n and found that t h i s rapid disappearance  from the  blood occured even i n eviscerated and nephrectomized dogs, and concluded that the i n i t i a l  rapid f a l l of blood calcium  due to uptake into the skeleton.  was  More r e c e n t l y , many authors  have used calcium infusions and have noted the recovery i n the urine over the next 24 hours as measured above the c o n t r o l excretion.  Recovery has ranged from 20% - 60% of the dose i n  various s e r i e s (38,52,31,9).  Laszlo, i n 1951  (57) r e l a t e d  urine calcium recovery to bone metabolism, stating that high recovery i n d i c a t e d o s t e o l y t i c processes, low recovery, osteoblastic processes.  Others have used the calcium tolerance  9 test  as  regard  a  general  to  osteoporosis  suggested bone a  that  mineral  short  calcium these  study  an  as  It  of  and  the of  of  the  hoped  that  in  the  kidney  of  the  fluid  and  al  of  calcium, plasma the  to  analysis  of  of  normal of  the  might  be  acute on  the  i n both  normal  diseases.  The  cases  known h i g h  blood  the  (17).  attempt  excretion of  to  the  Frequent establish  load;  i s responsible by  kidney  calcium  bone  this  level  condition  i n an  on  of  the  the  of  (14)  rates  level  the  parathyroid  presumably  et  might g i v e information  plasma  which  for  flow.  this  done  new  existing  plasma  between  because  in  of  e x c r e t i o n by  Further  rate  man  of  calcium  chosen  i n the  dose,  to  been  extension  Copp  response  adaptation  with  e x t r a - r e n a l mechanism part  mixing  an  infusion  that  plasma  normal  were  was  the  load.  the  test  clinically sampling  by  sampling  bone-blood  subjects  disease  done  shown  extracellular  was  found urine  role  that  of  and  has  down  calcium  t h e s i s was  follow  calcium  measure  Paget's  flow  work  laying  plasma  kinetics  to  r e g u l a t i n g the  subjects  a  I t has  i n  (33).  able  infusion  to  particularly  (61,58).  controlled, rapid  a  intravenous factors  of  of  frequent  intravenous  "compartment"  due  in this  i n r e s t o r i n g the  suggested  derived  be  with  This  metabolism,  osteomalacia  tests  calcium  were  bone  levels  these  Using  level.  important  curves  on  pigs.  workers  after  high  reported  gluconate,  calcium is  the  during  investigations and  and  of  r e t e n t i o n may  at  time  The  dogs  indicator  skeletal  and  for  uptake.  to  the At  plasma the study retention the  same  10 time, and  the  might  plasma  changes be  i n phosphorus  related  calcium  i n time  levels.  and  and  citrate  could  amplitude to the  "be  followed  changes  i n  11  METHODS  Subjects:  The ranging  experimental  i n age  ambulatory  from  and  series  nineteen  i n good  comprised  to  general  20  adult,  eighty-three condition at  male p a t i e n t s ,  years. the  A l l were  time  of  the  study.  Cases Metabolic  number  ward  were p a t i e n t s Hospital,  intervals  Of  from  i n the  Clinical  tests  from  nine  the  series,  widespread  to  eight  mineral  Paget's  confirmed  by  following  thyroidectomy,  X-ray.  hypoparathyroidism. of  a  osteoporosis pages  28  18  were  hospitalized  General  Hospital.  Investigation Unit  on  the  The at  others  Shaughnessy  were days  done to  on  nine  subjects,  at  s e v e r a l months f o l l o w i n g  infusion.  i n regard  removal  and  Vancouver  infusion  ranging  initial  normal  the  15  Vancouver.  Repeat  the  of  13,  and  on  29.  and  Case  X-ray.  11  18  were  metabolism.  disease  Case  parathyroid  subjects  of  had  Five  bone  was  13  had  of  Case the  be suffered  deformans)  hypoparathyroidism idiopathic  studied before  adenoma.  to  subjects  (Osteitis  developed  case  Details  considered  14  was  cases  and  after  diagnosed  are  given  as on  12 Administration of Calcium: Calcium was given as calcium gluconate 10% (Nadeau) and the dosage was  c a l c u l a t e d as 10 mg.  The 10% s o l u t i o n contained 9*3 mg.  calcium per kg. body weight. Ca per cc.  The required  amount of calcium gluconate was made up to a standard volume of 180 cc. with d i s t i l l e d water, and was mixed thoroughly. The s o l u t i o n was  administered intravenously into the a n t e c u b i t a l  v e i n at a constant rate of 3 cc per minute from a graduated burette, to make a standard i n f u s i o n rate of 10 mg.  Ca/Kg/hr.  f o r one hour. In most cases, the i n f u s i o n was and 10:30  a.m.  c a r r i e d out between  In two cases, numbers 11(b) and 13,  9:30  a two hour  i n f u s i o n was done, using double the dose and volume, but the same rate of flow, and running from 9:30  a.m.  to 11:30  a.m.  Diet: The e a r l i e r t e s t s were done i n the f a s t i n g state: that i s , patients were allowed water ad l i b i t u m on the day of the t e s t , but d i d not eat u n t i l f i v e or s i x hours a f t e r the i n f u s i o n - at about 3:00 p.m., Case 5 was and on low (150  when they resumed a standard h o s p i t a l d i e t .  studied both on high (1500 mg calcium per  day)  mg calcium per day) calcium d i e t .  Later cases consumed a standard h o s p i t a l d i e t at the normal meal times on the day of the t e s t , the calcium content being approximately 500 mg. per day and being the same on the control days before and a f t e r the t e s t .  13 Collection  5  of  cc. blood  venipuncture a  Samples:  single  i n t h e arm  vein.  heparinized  Blood  transferred  with  parafilm.  four by  sample. 15  30  minute  following cases,  C a r e was  and  one  The intervals  o f one  following  the infusion.  intervals  to complete  test. urine  Nearly  voiding  was  analyzed  of  and  were  urine  during,  hour  hour,  and  period  the b o t t l e . of calcium,  day.  and  followed  A l lurine phosphate  at  time  out  at  the start  exact  24  longer  of the hour  time  samples  and  were  o r s i x hours  control  The  hours  citrate.  bottles  after  then  samples  carried  a fractionated  to the test  each  t a k e n , i n some  f o r five  were  sealed  of  were  was  of  were  citrate.  Patients:  patients  objective  before  on  f o r content  The or  prior  marked  Observation  24  were  the infusion,  phosphate  clean  Collections  a  plasma  time  A l lblood  inorganic  before,  a l l cases had  collection  18 h o u r s .  into  The  f o r the s i x or seven samples  from  to dry  the exact  before  by  usually  tubes which  the i n f u s i o n  Further  voided  hour  samples  samples  calcium,  patients  and c e n t r i f u g e d .  during  the following  f o r total  a t once,  taken to note  hour  i n dry syringes  to the infusion,  d r y specimen  control  the infusion.  during  analyzed  tubes  samples  collected  transferred,  to clean,  Pour  minute  were  opposite  was  centrifuge  then  blood  samples  were  observed c a r e f u l l y  response to hypercalcemia.  a t t h e end o f i n f u s i o n  ECG  f o r any  subjective  tracings  i n the f i r s t  ten  were  cases.  done  14 A n a l y t i c a l Methods: Plasma calcium was  analyzed "by the Copp m o d i f i c a t i o n of  the photometric t i t r a t i o n method of Lehmann (39). calcium was determined  Urine  i n the same manner a f t e r p r e c i p i t a t i o n  of the phosphate and p r o t e i n by Horner's method (32). and urine inorganic phosphates were determined the method of Taussky and Shorr (63). c i t r a t e s were determined Pincus and Lugovoy (46).  Plasma  according to  Plasma and urine  according to the method of Natelson, In some cases, glomerular  filtration  rate was measured independently using the i n u l i n clearance procedure.  15 RESULTS  Observation  The the  of the  Subjects:  p a t i e n t s were  infusion.  hypercalcemia,  There  were  no  aside  from  a  two  of the normal  was  interesting  the  disappearance  irritability  observed  feeling  calcium  was  the  infusion  and near  not  show  cardiac effect  Plasma  any  constant tested  at  The  cases  average  It  neuromuscular signs),  the time  and t h e  that  tracings,  the  done  i n 10  plasma before  cases, d i d  hypercalcemia.  resting  The  o f 13-90  Despite  of cases,  patient  i n normal with  However,  varied level  mg%,  was  case which  plasma  significantly  remained  variation  8.83  had  when r e -  i n the cases  considerably i n  the variation  the control  d i d not vary  one  subjects  little  of hypoparathyroidism  level  operatively.  I ) .  levels  5*65 a n d 6.55 mg%. control  levels  (Table  the control The  two  calcium  later  tests.  types  to  i n  hypoparathyroidism,  of the infusion  due  9*4-9 - 0.0? mg%,  weeks  di'sease,  a  of  of  ECG  induced  Calcium:  Control  as  t h e end  after  of the infusion.  and Trousseau's  a b o v e 8 mg%.  and  "lightheadedness"  cases  of well-being during  elevated  of  the end  of objective signs  during  reactions to the  sensation  i n t h e two  (Chvostek's  general  untoward  subjects near  to note  carefully  - 0.36  calcium  of  Paget s 1  subsequent  mg%  (Table I I ) .  levels  as  of hyperparathyroidism f e l l  t o 9-35  i n levels calcium on  i n the  levels  the day  mg%  of  of the  low had  postdifferent each test.  16  The  uniform  calcium  was  period,  reaching  off  rapidly  3.05 In  mg%  rise a  peak  4.15  mg%  disease,  response  During  to  level a  a  second  parathyroid  f e l l  was  more  after f a l l  to  the  the  Urine  1,  2,  of  plasma  about  At  one  no  and  falling  the  a  normal did  half  3.10  The  mg%  mg%. of  a  mg%.  i n the and  plasma thereafter  calcium  curves  for  hours level  appeared  calcium  curves  II).  plasma  twenty-four  plasma  III).  6.20  and  removal  plasma  i n the  and  3.00  rose  from  (Table  Ca/Kg.  hours,  The  I  mg% mg%  drop  s i x to  the  and  0.25  5.25  rose  ranged  (Tables  after  f o r the  shown  peak  subject  i n i t i a l  and  time  -  mg.  control level.  as  infusion,  of  calcium  one to  infusion  1.84  week  of  the  the  20  load  throughout  the  rise  infusion  hypoparathyroid  3,  of  c o n t r o l and  rate  a  infused  response  normal,  hyperparathyroid  cases  4).  Calcium:  Rates the  showed  infusion,  emerged,  disease,  (Figures  averaged  given  an  control level  Typical patterns  infusion  Paget's  the  subject's  smooth.  rise  of  normals,  the  returning  infusion.  below  be  rapid for  slowly,  the  to  the  end  the  to  calcium  hyperparathyroid  infusion  adenoma,  a l l cases  the  In  two-hour  Following calcium  at  cases  i n the  of  plasma  above the  hypoparathyroid  calcium  of  level 10  i n the  thereafter.  to  Paget's  The in  a  response  mg%  urine  rose  e x c r e t i o n were  post-infusion hourly  calcium  above  i n the  urine  the  normal  measured  collection  excretion increased "threshold" plasma cases  (Table  I).  i n mg/min  as  the  level,  periods.  The  plasma  calcium  which  Increased  for  was  urine  about calcium  17 excretion was not observed i n cases of Paget's disease where the r i s e i n plasma calcium l e v e l was very small.  (Figures 6, 7, 8)  (Table I I ) . The net retention of calcium by the body was determined by subtracting from the i n f u s i o n dose the excess excretion of the test day above that of the control day. expressed as percentage of dose retained. retention v a r i e d from 37-64%.  Results were In normal cases, the  Some cases of Paget*s disease  and of hypoparathyroidism showed almost complete r e t e n t i o n . Phosphorus: In the normal subjects, the c o n t r o l l e v e l of plasma phosphorus was 3.24 - 0.14 mg%.  Patients with Paget's disease  had control l e v e l s averaging 3*15 - 0.18 mg%, which was not s i g n i f i c a n t l y d i f f e r e n t from the normals.  The two  hypoparathyroid cases had control phosphorus l e v e l s of 5*13 0.60 mg%.  The hyperparathyroid subject had a c o n t r o l plasma  phosphorus of 2.20 mg% pre-operatively and 3.50 mg% one week a f t e r the parathyroid adenoma had been removed. Plasma phosphorus rose i n response to the calcium i n f u s i o n but the r i s e was always delayed 1/2 - 1 hour i n comparison to the r i s e i n calcium l e v e l .  In normals, the r i s e averaged  1.00 - 0.08 mg% while i n Paget's disease the r i s e was only 0.18 - 0.13 mg%.  There was l i t t l e or no peak observed i n the  normal plasma phosphorus curve; but i n cases of hypoparathyroidism the plasma phosphorus rose to a d e f i n i t e peak 2.40 mg% above the  18  control change  level  and  then  i n phosphorus  The increased, plasma  level  to  was  phosphorus  and  to  returned normal  d i d not  show  normal  rose as  levels. a  normal.  In  some  cases  no  noted.  excretion of  approached  phosphorus  returned  the  The  linear  as  calcium  calcium  excretion  level  excretion rate  relation  to  plasma  in  of phosphorus  levels.  Citrate,:  Control in  the  normal  Paget's  disease, citrate  0.35  -  0.14  and  0.98  did  not  A  a  of  were  five  0.15  -  0.15  i n the  i n the  relation  and  to  0.20  patients  calcium mg%  hypoparathyroid during  -  subjects.  f o l l o w i n g the  plasma  cases.  infusion  i n Paget's  citrate  mg%  with  i n hypoparathyroid  the  out  calculation on  time  collections after  periods  could  so  the  that  mg% to  30  page  plotted against  hours  0.09  mg%  1.65  was  -  rising  disease, The  rate  infusion  but  levels.  Data:  corresponding urine  0.24  i n response  linear  sample  been worked (UY)  -  excretion rose  show  Treatment  mg%  concentration -  i n normals,  0.03  citrate  3.58  1.63  and  rose  mg%  -  citrate  subjects,  Plasma  of  plasma  be  lag  of »  the  the  made  from  the  from  mean p l a s m a a  straight  over  infusion  studied.  data  patient  When e x c r e t i o n r a t e s  interval, were  the  hourly  ended,  The kidney  at  periods to  level  line  was  periods least were  bladder  (P)  2  no.  i n  mg/min  over  the  obtained. for  five  at  be  Since  least  clearance  sufficiently could  has  long  neglected.  19 Where incomplete  emptying of the bladder was suspected, i t was  u s u a l l y found that the following period compensated f o r the low value.  This was checked by c a l c u l a t i n g excretion rate vs. plasma  calcium l e v e l on overlapping two hourly clearance periods.  The  l i n e a r r e l a t i o n s h i p of UV vs P was a constant f i n d i n g i n a l l cases where the plasma calcium had r i s e n above a "threshold" level.  The slope of the l i n e ku = UV/P i s dependent upon the  GFR and upon the d i f f u s i b l e f r a c t i o n of the plasma calcium, that i s , the f i l t e r e d load of calcium.  In the l a t e r cases,  where GFR was determined by the i n u l i n clearance  technique,  the d i f f u s i b l e f r a c t i o n was found to be 50 - 60% of the t o t a l plasma calcium.  The above can be summarized by the equation: UV = GFR x P x d - Tm  where  UV = excretion rate i n mg/min. GFR = glomerular f i l t r a t i o n rate (Ml/min) = i n u l i n clearance (Cin). P = mean plasma calcium over each time period i n mg%. d = d i f f u s i b l e f r a c t i o n of t o t a l plasma calcium. Tm = a constant = tubular reabsorption maximum (Mg. Ca/min). The dependence of excretion of calcium upon the plasma  calcium concentration suggested maximum.  a d e f i n i t e tubuler reabsorption  This appeared to correspond to the normal plasma  concentration i n the normal subjects, but i n the cases with a  20  low  control  the  Tm w a s  above  calcium  n o t exceeded  a p p r o x i m a t e l y 10  Plasma  smooth  fact  that  decline,  calcium  levels  decline  might  demonstrated  were  is  was  the rate  gave  this  a  Px  was  raised  found t o be  slower as  over  calcium finite  above  that  line  1 8 - 2 5 mg.  which  the normal  the further  Ca/Kg.  body  level  P / ^ t )  short  finite  plasma  (Figure  i n plasma  subjects  9).  calcium  i n urine, i t  calcium  weight.  as  (A  at a  excretion  o f t h e body  of  intervals.  calcium  "broke"  decline  In the normal  levels,  (Pm) o v e r  plasma  to calcium  the size  be drawn.  calcium  a  normal  the rate  time  o f decrease o f plasma  straight  to estimate  c u r v e s showed  suggested that  this  i s due e n t i r e l y  would  t h e n much  mean p l a s m a  1 mg%  one assumes  possible  which  calcium  calcium  t o the plasma  by i n t e g r a t i n g  (Px) about  below  at first,  approached,  the integrated  If level  the plasma  and h y p o p a r a t h y r o i d i s m )  mg%.  be r e l a t e d  intervals  level  unless  a l l t h e plasma  rapid  Plotting versus  (Paget's disease  Calcium Curves: The  time  level  pool  studied  from this  21  DISCUSSION For  the purpose of discussion, i t i s convenient  consider  a  This  been  has  exchange alters  simplified  using  on  exchange  comprising compartment  and  i s made u p  i s drained  calcium  to  This  fluids  a  by  The  plasma  complex  diffusible  fluid  be  t h e D o n n a n membrane  i s usually given  70%  as  In  addition to the f l u i d  is  bound  diverse single That  pools  of calcium  "calcium  portion,  there  components  have  compartment"  i s some d e l a y of the pool  i n the  of the t o t a l  t o m u s c l e , t e n d o n and  calcium  membranes been  calcium  concentration  equilibrium  plasma concentration of the soft  between  expected.  tissues  i n general.  grouped together  i n the mixing  being  interstitial  These as  f o r the purpose of t h i s  i s t o be  of  fraction.  of calcium  and  This  the remainder  the concentration dependent upon  and  oversimplified explanation.  Therefore, will  (45),  tissues.  the overall  p r o t e i n bound,  small  of  compartment"  o f McLean soft  excretion.  i s an  rates  with  compartment.  "calcium  and  calcium  the exchangeable f r a c t i o n  represent  i s partially  ionized, with  of a  and  are concerned  s o much w i t h  compartment"  i n body  i s assumed  transport  subdivisions of the  "calcium  compartment.  chiefly  and n o t  movement.  loading with  b e c a u s e we  i s i n equilibrium with  concentration  Plasma  the  proposed  to the  However,  somewhat  within  the calcium  calcium,  this  (6).  concentration  model  corresponding  in  concept  total  system f o r calcium  i n the a n a l y s i s of calcium  radioisotopes  occuring  The  bone  helpful  the model  effects  compartment  to  a  discussion.  plasma and  Studies  on  the  other  (45).  22 exchange have  of radiocalcium  indicated that  small  (3,64).  plasma that  mixing  In this  i s very  compartment  has been  plasma  calcium  It  apparent  was  occurred  of calcium  from  by t h e body,  i n the plasma  effect  the linear (P).  excretion  to a rapid infusion. "calcium  compartment"  through  the kidney  relation  This  from  of excretion by the kidney  gave  between  excretion  a definite  the "calcium  measure  compartment"  could  rate  The the  and  of the rate a t any given  Unless  maximum w a s  exceeded,  practically  a l l the filtered  reabsorbed  despite  a considerable  1 1 a , 1 0 a , 10b i n T a b l e s  The  presence  be important  change  the tubular  i n plasma  of a tubular  calcium  determined  of plasma reabsorption  load  was  level  I I and I I I ) .  reabsorption  i n the r e s t o r a t i o n of normal  intravenous  be  (UV) and plasma  threshold.  after  of the infused  represents  the renal  to  through  i n the skeleton.  a t any time  flowing  i n this  by the changes i n  above  (note  and  the bones.  The  level  this  presumably  concentration  levels  compartment,  was b y r e t e n t i o n o f p a r t  i n t h e compartment  from  that the  One was b y e x c r e t i o n  concentration  through  delay i s  concentration  i n response  two ways.  fluid  ignored.  as measured  the loss  and t h e other  and t h i s  i t i s assumed  of the calcium  concentration that  rapid  may b e  observed  i n at least  kidney,  load  and f a l l  and e x t r a c e l l u l a r  make u p a s i n g l e  any l a g due t o m i x i n g  rise  plasma  discussion,  and t i s s u e c a l c i u m  The  the  between  loading.  The r e n a l  maximum plasma  appears  levels  threshold  appears  23 t o b e i n t h e r a n g e o f 8.5 t o 10.0 mg% The to  normal  subjects  had a c o n s i s t e n t  t h e i r normal plasma l e v e l .  and  not  a t , or very  observed u n t i l  plasma l e v e l s  patient  when d e t e r m i n e d b e f o r e This  case  parathyroid  The After  case  level  of osteoporosis  This  of total  plasma calcium, level  threshold,  indicating  level  rate  a c i d o s i s , an  test.  increase  h i s low plasma  calcium.  GPR w i t h  much h i g h e r  subjects.  extra  If this load  a  diffusible  t h a n t h e 0.6 t h a t  In a subject  and a d i f f u s i b l e  o f 10 mg%.  a large  o f Ku i n c a s e s 7 ( a )  value  10.8 gms o f c a l c i u m  the capacity  excess calcium.  of  f o r by a h i g h  calcium  filtration  plasma calcium renal  may be i n d e p e n d e n t o f  suggests that  the high  to b e : t y p i c a l f o r the normal  total  tumour.  a n d h y p e r c a l c u r i a may h a v e b e e n due t o i n t e r f e r e n c e  i s suggested that  glomerular  removal o f the p a r a t h y r o i d  to correct hyperchloremic  9 ( a ) may be a c c o u n t e d  fraction  The  h a d a l o w Tm o n t h e f i r s t  normal t u b u l a r r e a b s o r p t i o n  It  e x c r e t i o n was  e x c e e d e d 8.5 t o 10.0 mg%.  t h e Tm f o r c a l c i u m  t h e Tm was o b s e r v e d .  with  increased  levels  function.  treatment  calcium  since  cases,  a p p e a r e d t o h a v e t h e same Tm f o r c a l c i u m  and a f t e r  suggests that  close  Some o f t h e P a g e t ' s d i s e a s e  below r e n a l t h r e s h o l d  hyperparathyroid  and  threshold  studied.  t h e two c a s e s o f h y p o p a r a t h y r o i d i s m h a d p l a s m a  apparently  in  i n the cases  with  fraction  p e r day a t a  i s r a i s e d above t h e  c a n be e x c r e t e d  i n a day,  o f a r e n a l mechanism t o d i s p o s e  A lowered  t u b u l a r maximum, a s i n r e n a l  o r a c i d o s i s ( a s shown i n c a s e  a normal  o f 0.6. o f  i s filtered level  appeared  14), can cause a h i g h  of diseases  excretion;  24 yet by  the  lowered  plasma curve  Tm  calcium  overswings  previously net  size was  calcium  curve  possible  to  had  kg.  level.  the  control  the  "calcium  tissue  i n the  cases  removing  calcium  Analysis  of  the  rate  of  f a l l ,  at  This  break-point  there  compartment" assumptions  Px,  the  where of  by  the  period  point  Tm  the  were  was  after  where  the  in  i t  estimated  to  be  18  between  Px  and  be  not  to  from fall  reasonable  since high  of  plasma  urine  calcium  excess  for  "calcium  Px  noted  the  (see  the  25  -  mg.  control soft  that  1  has  mg%  assumed  has  the  i n relation  to  not  other  i s bone  shown a  above  to  be  gastrointestinal  compartment"  curves  about  was  levels  i s suggested  plasma  was  i n the  excretion into  It  the  value  of  compartment".  excreted  level  (Px)  a  was  in  was  levels  plasma  terms  decrease  observed  plasma  compartment  f o r plasma  the  that  the  exceeded,  compartment  dividing  made  periods  to  were  mentioned  clearance  body  a  and  calcium  the  (41,7,13)-  demonstrated  plasma  of  "calcium  i n response  gradually,  when  each  in  appeared  calcium  hypercalcuria  falling  period  calcium.  into  body weight  The  of  calcium  occurring  fluid  long  level.  below  done  plasma  and  retained  was  The  The  The  size  for a  reserve  of  occurring during  the  This  skeletal  control level  estimate  of  preserved  normal.  fallen  This  he  f o r cases  investigated.  calculations). per  large  are  In  weight.  excretions  tract  the  of  may  account  broke.  concentration  Ca  the  a c c r e t i o n was levels  level  levels  past  calcium  body  may  approached  The  no  plasma  m o b i l i z a t i o n from  This  no  normal  the  been factor uptake.  change control  renal  i n  the  level.  thresholds  25 and  normal  open  to  plasma  question.  explanation. of  plasma  the of  In  The  upon  that  the  renal  renal  of  compartment"  directly  may  levels  as  a  and  affect Px,  upon  point  at i s  a l l levels directly of  the  the  calcium  and  that  the  i s  possible  Analysis  above  dependent  this  occurs  level.  process at  loss  threshold  calcium  removal  i s also  significance  cases,  plasma  another  "calcium removal  above  the  The  f o l l o w i n g i s advanced  normal  calcium  dependent shows  levels.  plasma  curve in  i t s rate calcium  level.  Whatever  the  significance  that  the  rate  of  into  the  bone  should  bone,  i n the  rate  of  into  the  was  flow  the  normal periods  in  by  of  of  weeks  calcium the  levels  Thus to  the  infusion  calcium  to  very in a  cases to  blood  given  bone  (17).  (Table  blood  Paget's  changes  that flow  up the  to  high quickly This  disease in  different of  and  disease twenty  Testing,  pattern  i n  studied,  i s reflected  quite  A  load  Paget's -  rate  level.  disease  That  i n the  flow GFR.  peak  disease.  revealed  compartment"  calcium  lower  activity  on  appears  times  i s  the  at  i s  subject general  intervals  control response  plasma to  II).  f a r , only loading  and  i t  "calcium  the  workers  bone  also  level,  the  Paget's  high  months,  and  upon  in a  of  other  of  Px  fluid  distribute  cases  of  the  e x c r e t i o n depends  result  quiescence  of  few  a  rate  response a  a l l the  the  dependent  would  views  from  that  tend  and  the  accompanied  to  would  bone,  with  be  s a m e way  observed  agrees  movement  of  the  have  changes  been  i n plasma  considered.  calcium  The  i n  phosphate  response and  26 citrate were  levels  also  i n the plasma  determined.  definite  pattern  response  was  In  calcium same  by  reaching  level.  In a l l cases,  delayed  until  the  near  normal  and then  i n plasma  The  a peak  until  same  citrate  levels,  the  plasma  calcium  returned  The of and  less  kidney  than  soft  equilibrium which either of the  with  storage  calcium  compartment  rise  of circulatory  This  small  a tremendous  of calcium  changes  to a plateau  level  levels  reached  was  definite  seen i n  conclusions  i n t h e body  fluids  i si n  i n bone  v a r i a t i o n s i n plasma  mineral,  calcium,  or mobilization  blood  flow  bone  levels.  when  compartment"  compartment"  of this  was  except  of calcium  i n plasma  rose  i n a l l  "calcium  The bone  of  i n the  phosphorus  then  i n hypercalcemia,  (14).  The r i s e  t o i t sc o n t r o l  calcium  reserve  f a c t o r s i n the response t o acute  a  "calcium  wide  No  VII). with  a return t o normal  to normal.  t o a c t upon  rose  except  to a plateau  appears  VI,  phosphorus  calcium  by  a  a t about the  i n plasma  a rise  observations.  i n hypocalcemia  limiting  was  followed  i s a v a i l a b l e t o oppose by  rise  V,  to normal.  falling  show  that the  and c i t r a t e  the plasma  these  one gram  tissues.  (Tables  i n urine  also  i t appeared  not striking  the plasma  delayed  might  t o normal  and then  there  plasma  be d r a w n from  was  the i n i t i a l  the  could  f e l l  where  cases,  maintained  again.  this  t h e end o f the i n f u s i o n ;  hypoparathyroid  w h i c h was  However,  excretion returned  and c i t r a t e  mg%,  that  of phosphate  of hypoparathyroidism  2.40  excretion rates  nor conclusive  the excretion  as calcium  phosphate  hoped  of response.  excretion rates  time  cases  I t was  n e i t h e r marked  a l l cases,  and t h e i r  i s one o f  calcium  In normal  27 subjects,  the  kidney plays  of normal l e v e l s  an i m p o r t a n t  of plasma c a l c i u m a f t e r  c a l c i u m a p p e a r s t o be i n d e p e n d e n t i n the  cases  the  i n the  infusion. parathyroid  restoration The Tm f o r function  studied.  W . P . Neuman (47) excretion  of  role  explains  i n c a l c i u m homeostasis  the as  importance  o f bone  and  follows:  Bone c a n n o t be c o n s i d e r e d a s t a b l e s y s t e m i n w h i c h the i n o r g a n i c phase i s i n e r t . The t i s s u e f l u i d s o f a n a d u l t man l i t e r a l l y f l o w o v e r a c r e s o f a c t i v e inorganic surface. I t i s not s u r p r i s i n g that the i n o r g a n i c c o m p o s i t i o n of the body f l u i d s v a r i e s only s l i g h t l y . The a p p a r e n t s t a b i l i t y o f t h e s k e l e t o n c a n be a t t r i b u t e d o n l y t o e x t r e m e l y e f f i c i e n t e x c r e t o r y mechanisms w h i c h a u t o m a t i c a l l y balance v a r i a t i o n s i n inorganic intake.  28 CASE  HISTORIES:  G.S.S.  HI.  27  calcium July  diet  21,  J.B.A.  H2.  year  T.R.  A  37  Age  J . E . L . for  one  one  on  test H"7.  H8.  27.  on  low  p r i o r  for on  20  1  Normal  diet  '  21,  on a  to  high  test  on  one  week  d i e t ,  tested tested  July  of  23,1958.  August  and  6  years.  c a l c u l i .  p r i o r  to  test  Low c a l c i u m on August  mg/day)  (150  on h i g h  on  calcium diet  Gastrectomy  19,  1958.  disease  diet  24,  1958.  Tested  after  September  5,  mg/day)  (1500  Alkaline  years. test  test  Paget's  disease  o n N o v e m b e r 17  diet  for  1958  16 and  p e l v i s , before  38 K T J . years. November  KU.  97  disease  femora,  phosphatase  o n N o v e m b e r 10,  phosphatase  of  Normal  1954.  Widespread Paget's  before  before  renal  1958.  Alkaline  83  i n v e s t i g a t i o n  d i e t ,  Widespread Paget's  63*  1958.  Normal  calcium diet  September Age  negative  on normal  mg/day)  15,  77*  H.J.M.  diet  weeks  u l c e r ,  Acromio-clavicular separation.  after  Age  W.L.B.  two  man w i t h  Recurrent  (150  September  known  duodenal  1958.  week  and  old  Alcoholic.  49.  Age  E.O.B.  H6.  year  25,  week  1958  with, for  2)  cirrnhosis,  Age  V . J . S .  H5.  (gastric  60.  November H4.  airman  1958.  alcoholic H3.  old  known f o r  years.  16  and November  27,  Low  1958.  2  Diuril/day. H9.  H.W.E.  Age  74.  Bronchogenic removed  by  benemid, normal  cancer  disease  of  the  discovered  at  time  thoracotomy.  and  diet  Paget's  Normal  d i e t ,  p e l v i s of  and  test  d i u r i l ,  t i b i a .  and  l a t e r  d i g i t a l i s ,  colchicine before  test  on  J a n u a r y 9,  and benemid before  test  of  A p r i l  20,  1959; 1959-  salt gm  H10.  E . G . F . A g e 75« years.  1958.  19, Hll.  Normal  Widespread diet  before  Alkaline  19,  1959  hour  infusion  Age 44. Normal.  T.J.  thyroidectomy  hyperthyroidism. five  1959.  days  Signs of  later.  Two h o u r  One  infusion  diet  before  test  on March  hypoparathyroidism.  on March  diet  f o r two d a y s  (150  mg) o n d a y o f t e s t  July  23,  H.M.  A g e 39-  1959  previously.  after  diet  Age 18. Normal.  July  1959.  H17.  Wagstaffe.  H18.  Simpson.  Hyperchloremic  prior - June  to test, 1,  when  low calcium  Retested  on  of the h i p three  tested diet  before  diet  before  test  Age 48. H y p e r p a r a t h y r o i d .  on  July  of  parathyroid gland  on July  Normal  Age 4 5 . Normal  24, 1959.  acidosis.  then  1959.  dislocation  Elliott. 8,  hour  therapy.  Fracture Normal  Two  1959.  6,  R.H.B. A g e 4 8 . O s t e o p o r o s i s . Normal  H16.  Subtotal  Normal  Age 42. I d i o p a t h i c  infusion  H15.  February  1959.  2,  H14.  10, and  was 158 KU.  observed 25,  February  25  known f o r  1959-  M a r c h 4, A.D.M.  were  disease  on February  phosphatase  l o r toxic  hypoparathyroidism  H13.  test  M.B. A g e 3 0 . H y p o p a r a t h y r o i d . February  H12.  Paget's  Retested  Normal  on August  adenoma  7,  on August  test  on  on July  1959 1,  1959.  2,  diet  months  15,  before  after  1959. test  removal  1959*  H19.  Lutz.  Age 30.  Normal  diet  before  test  on August  4,  H20.  Cole.  Age 20. Normal  diet  before  test  on August  17,  1959. 1959.  SAMPLE C A L C U L A T I O N S :  Sample  C a l c u l a t i o n - IL-,  Determination  The  o f Ku and  slope  Tm  of the line  UV  graph  (Figure  6) and expressed  value  of this  slope  To  ( K u ) was  determine  appropriate  values  x  Tm,  0.610  from the  F o r H-2 t h e  mg/min/mg%.  b e l o w was  used,  and the  substituted.  UV  = GFR  UV  = 1.00 Mg/min when P  Ku  = GFR  d  = The d i f f u s i b l e  x d  determined  i n mg/min/mg%.  the equation  were  P  v s . P was  x d  -  Tm  = 0.610  =  11.15  Mg/min/Mg% or filtered  fraction  of plasma  calcium GFR  = Glomerular  GFR  and d were  .*.  The e q u a t i o n  filtration  rate  n o t measured  on t h i s  subject.  becomes:  1.00  = 0.6;10 x  Tm  =5*80  11.15 -  Tm  Mg/min  GFR If  the diffusible  of  the total  using  Ku GFR  plasma  = GFR x =  fraction  ( d ) i s assumed  calcium,  then,  d, x  100  =  102  Ml/min.  t o be  60%  TABLE  Subject  616  3(a)  547  3(b)  4  565 616  5(a)  715  5(b)  717  12 19 20 Mean ±S.E.M.  C A L C I U M V A L U E S FOR NORMAL S U B J E C T S  Plasma Ca (mg%) Control Infusion Plasma Peak Rise "Px" D o s e , mg L e v e l  2  16  I:  9.55 9.70  13.10 13.85 13.60  Control 24 H o u r Excretion  T e s t Day 24 h o u r Excretion  Mg  Mg  10.85 9.80 4.15  240  620  170  3.95  11.35  340  3-55  % Dose Renal Retained Threshold  Ku =  GFRxd Tm m^/min/Mg/min  G-FR Ml/min  9.55 9.70  .610  . 5.80  102  475  37 44  .600  5.60  100  47 54  10.30  • 545  5.40  91  .378  3-60  .560  5.30  63 94  9.55 9.40  12.90  3.35  11.75  290  635 570  12.45  3.05  10.95  210  570  50  10.25 10.00  13.20  10.95 11.90  645  60  10.25  .560  5.35  94  13.60  3.85 3.90  360  691 762  9.35 9.70  200  450  64  13.20  3.30  10.60  342  670  57  • 375 .650  3.75  9-90  10.75 9.90  63 108  670  8.85  12.20  258  8.85  .540  9.50  12.80  310  635 600  45  710  13.09  272  587  59 52  9.50  9.49  3.35 10.65 3.30 1 0 . 3 5 3.58 1 0 . 9 2  9-91  ±0.07  ±0.16  ±0.18  ±18  ±23  ±3  ±0.15  9.65  S.E.M.  =  ±0.10  Standard  error  of  the  6.05  90  .485  4.55 4.30  81  0.530  4.97  89  ±0.029 ± 0 . 2 7  mean  f—  1  TABLE I I :  Subject 6 7(a) 7(b) 8(a)  Plasma Ca (mg%) Control Infusion Plasma Dose, mg Level "Px" Peak Rise 5^7 886 886  9.05  10.90  10.95  12.85  9.15 7.00  11.85  8(b)  585 554  9(a)  756  9(b) 10(a)  715  8.35 9.50 8.20  736  10(b)  750  Mean ±S.E.M.  CALCIUM VALUES FOR SUBJECTS WITH PAGET'S DISEASE  8.35 9.90 11.10  Control Test Day Ku = 24 Hour 24 Hour % Dose Renal GFRxd Tm GFR Excretion Excretion Retained Threshold ml/min/ Mg/min Ml/ah wig 100  s5f  60  10.50  .475  4.2  125  200  91  110  150  1.25 .350  14.5 3.4  7.95  150  120  1.55 8.70 1.60 10.75 3.35 9.20  440  330  95 100 100  11.75 10.00  625  1165  45  72  1.85 10.50 1.90 11.80 2.70 10.45 1.35  8.65  11.55 9.60  0.95  8.65  10.00  8.83 ±0.36  10.68  8.35  -  79 210 59  -  -  9.90  -  9.50  2.16  20.0  360  27 95  8.20 8.65 8.65  -  -  -  -  35  80  1.35  8.95 9.20  85  100  93 98  1.84  3.15  191  282  84  1.06  10.5  177  ±0.45 ±0.25 ±0.18  ±67  ±115  ±8  ±0.42  ±1.3  ±69  ro  TABLE I I I :  CALCIUM VALUES EOR SUBJECTS WITH HYPOPARATHYROIDISM, HYPERPARATHYROIDISM, OR OSTEOPOROSIS  Plasma Ca (mg%) Control Infusion Plasma Case No. Dose, mg Level Peak Rise "Px"  Control Test Day Ku = 24 Hour 24 Hour % Dose Renal GFRxd Tm GER Excretion E x c r e t i o n Retained Threshold ml/min/ Mg/min Ml/min  Hypoparathyroid  11(a) * 11(b)  * 13  750 1500 1300  Mean is.E.M.  Mg  2.95 8.00 6.55 11.80) 5.25) 8.50 5.65 11.85) 6.20)10.00 6.27 11.83 5.73 8.83 ±0.29 ±0.02 ±0.44 ±0.61 6.60  9.55  Mg  55  92  65 53 ±8  ±128  95 95 71 87 ±8  40  183) 440)  312  8.50 8.50 10.00 9.00 ±0.50  .300 .920  2.40  0.610  8.90 5.65  50 153  Hyperparathyroid 18(a) (Pre-Op)  740  13.90 16.90 3.00 14.85  555  1030  36  9-70  .150  1.35  25  18(b) . (Post-Op)  740  9.35 12.45 3.10 9.30  78  145  91  9.30  .150  1.35  25  9.30 11.60 2.30 10.75 9.80 12.90 3.10 11.05  420 143  675 500  50 50  8.60  .575 .575  5.00  96 96  282  588 ±86  50  .575  5.40 ±0.40  Osteoporosis 14(a) 726 14(b)  726  9.55 12.25 2.70 10.90 ±0.25 ±0.65 ±0.40 ±0.15 *  +  -138  10.55 9.58 ±0.95  5.80  96  Dose was 10 Mg/kg/hr f o r two hours. VN  TABLE IV: PHOSPHORUS AND CITRATE VALUES FOR NORMAL SUBJECTS PHOSPHORUS  Control Case Plasma No. Level Mg%  Maximum Rise Mg%  CITRATE  Control 24 Hour Excretion mg  Test Day 24 Hour Excretion mg  2  3.60  1.00  360  495  3(a)  2.85 2.50  0.85 0.80  360 870  525 680  3.40  1.10  480  5(a)  3-50  1.25  5(b) 12  3.60  16  Control Plasma Level ' Mpf/o  Maximum Rise Mg%  Control 24 Hour Excretion mg  Test : 24 HoExcre' mg  1.45 1.00  0.55 0.00  140  160  360  430  510  2.50  0.00  660  620  710  650  1.60  0.60  660  600  0.90  1490  1375  0.00  950  700  3.80  1.00  1366  0.40  358  0.70  1250  254  3.50  965 2584  1.75 1.60  0.75 1.60  560  452  20  2.75 2.90  830  242  Hean  3.24  1.00  828  848  3(b) 4  19  ts.E.Ia.±0.14  ±0.08  ±151  ±216  -  -  -  -  -  -  -  -  1.65 ±.20  0.35  521  461  ±0.14  ±118  ±88  -  TABLE V:  PHOSPHORUS AND CITRATE VALUES FOR SUBJECTS WITH PAGET S DISEASE 1  PHOSPHORUS  Control Case Plasma No. Level 6  7(a) 7(b)  4.00  Maxim-urn Rise -1.00  8(a) 8(b) 9(a) 9(b) 10(a) 10(b)  2.75 3.00 2.10 3.00 3.50 3.10 3.20 3.70  -0.40 0.00 0.40 0.00 0.00  Mean  3.15  0.18  ±S.E.M.±0.18  Control 24 Hour Excretion Mg  0.65  885  0.70  710  0.55  400 622 680 400 800 560  ±0.13  632 ±62  CITRATE  Control Plasma Level  Maximum Rise  4.50  3.50  0.30 0.25  465  280  3.25  0.15  210  170  415 830  2.80  370  110  145  3.00  577 430  4.25  476  3.58 ±0.24  0.15 ±.15  367 350 300 ±63  436  3.75  -0.55 0.00 1.00 0.0  Test Day 24 Hour Excretion Mg 610 415  370 270  ±56  Control 24 Hour Excretion  Test Day 24 Hour Excretion  300  230  260 ±43  TABLE VI:  PHOSPHORUS AND CITRATE VALUES POR SUBJECTS WITH HYPOPARATHYROIDISM, HYPOPARATHYROIDISM, OSTEOPOROSIS PHOSPHORUS  Hypoparathyroidism  Control Plasma Level  CITRATE  Test Day Maximum Control 24 Hour 24 Hour Rise E x c r e t i o n Excretion Mg%  Control Plasma Level  Maximum Rise Mg%  Mean  .5.13  2.90  735  ±S.E.M.  -0.60  ±0.45  ±138  ±64  ±0.09  ±0.03  2.20 3.50  0.10 0.70  860  1020 52  -  -  -  -  Osteoporosis 14(a)  2.90  600-1000  830  720  600-800  14(b)  3.00  0.50 0.75  800  610  2.95  0.63  6.30  * 1Kb) * 13  5.75) 4.50)  1.40  620  2.45)  1010 575  3.35)  873 982)  1117) 1050  0.85  1.63  0.98  Test Day 24 Hour Excretion  202 327 132 220 ±57  11(a)  0.90 1.50 1.75  Control 24 Hour Excretion  Hyperparathyroidism 18(a)(Pre-Op) 18(b)(Post-OP)  Mean ± S.E.M.  ±0.05 *  ±0.11  700  3.70  -  720 ±110  0.90) 1.05)  0.80  -  -  291 403)  290) 347 ±55  -  Infused dose was 10 Mg/k/hr f o r two hours.  S.E.M.:  Standard error of the mean.  VN  0^  37  TABLE  VII:  DETAILED  DATA  Total C a Mg%  Time  8:00 8:30 9:00 9:30 9:45 10:00 10:15 10:30 11:00 11:30 12:00 1:00 2:00 3:00  PLASMA  a.m.  9-72 9.50 9-55 9.50 10.31 11.29 11.97 13.11 12.45 11.50 11.10  FROM A NORMAL  Total  3.58 3.91 3.83 3.70  1.77 1.29 1.29  3.61  1.45 1.29  3.53 3.58 3.95 4.33 4.61  10.47 10.28  -  -  Plasma Total Citrate Mpf/o  4.68 5.10 4-.57  10.80  P  SUBJECT  1.62  -  1.62  2.09  1.94 1.94  -  4.03 1.45  H2  38  TABLE  VIII:  Time  7:30-8:30  DETAILED URINE  Total C a Mg  Total P Mg  DATA  FROM A NORMAL  Ca Mg/min  P Mg/min  6.9  0.101  7.1 17.0  0.133  0.217 0.115  1.275 1.238  0.652 0.768  0.776 0.686  0.596 0.210  Ms  8:30-9:30 9:30-10:30  13.0  10:30-11:30  76.5  39.1 46.1 27.8  10.3  22.2  6.1  12.6 41.4  4.7 23-2  0.300  118.0  51.0  0.325  135.5  21.3  11:30-12:30 12:30-1:30  74.2  1:30-2:30  46.6 41.1  2:30-3:30 3:30-6:00  18.0 69.0  6:00-12:00 12:00-8:00  117-0  57.1  39.7  H2  Total Citrate  6.5 8.0 121.0  11.2  SUBJECT -  6.3 6.0  2.017  0.460  0.119  0.187 0.662  0.371  0.275 0.328 0.282  Citrate Mg/min  0.118 0.283 0.172 0.105 0.100 0.102 0.078 0.154 0.141 0.044  TABLE IX: ANALYSIS OF PLASMA CALCIUM CURVE - H2  Time  9:30 10:30 10:45 11:00 11:15 11:30 11:45 12:00 12:15 12:30 1:00 1:30 2:30 3:30  Pmg%  9-55 13-11 12.57 12.10 11.75 11.50 11.30 11.13 11.00 10.90 10.78 10.66  At(hxs)  Z\Pmg%  A  P A t  %  •54 .47 .35 .25 .20 .17 .13 .10 .12 .12  10.42  i  .24  .24 .24  10.25  i  .07  .17  % %  %  mg%  P mean '  2.16  12.84  1.88 1.00  12.34 11.93 11.63  .80  11.40  .68 .52  11.22 11.07 10.95  1.40  .40 .24  10.84  10.72 10.54 10.30  TABLE  X:  Time  DETERMINATION  E x c e s s Ca Excretion-mg  1 0 : 3 0 - 1 1 : 3 0  69.5  1 1 : 3 0 - 1 2 : 3 0  OF  A. mg%  DILUTION  VOLUME  Dilution Volume ( c c )  1.65  4 , 2 0 0  6 7 - 2  .60  1 1 , 2 0 0  1 2 : 3 0 - 1 : 3 0  39-6  . 2 5  15,800  1 : 3 0 - 2 : 3 0  3 4 . 1  . 2 2  1 5 , 5 0 0  2 : 3 0 - 6 : 0 0  6 5 . 0  . 4 5  1 5 , 5 0 0  Normal  Ca mg.%  Time in Hours.  Figure  1:  Plasma for  calcium,  a normal  phosphorus  subject  and  citrate  Paget's Disease. H -  10 (o)  Ca mg,%  i  1  ' r  10  Renal  1  1  •  _P*  1  •  Threshold  _  J  Calcium  |  8  1  1 I  1 1 1  6  1  A ,  /  4-  o>- O  '  "X  'X^  \  x ' * - - x — X  •  Citrate  O''  'o  c  'O'  Phosphorus  . • °- - .  • . Q. •  2  I  1  10 m g . / k g . / h r .  •  0  Wi 1  1  2  4  i  •  i  6  i  8  Time in Hours.  Figure  2:  Plasma for  a  (Renal  calcium,  phosphorus and  subject with  Paget's  t h r e s h o l d was  citrate  disease  estimated  only)  Figure  3:  Plasma for  a  ( P x was e q u a l t o a t 8.30 Mg% w a s returned)  calcium,  phosphorus  subject with the renal the l e v e l  and  citrate  hypoparathyroidism  threshold. The l i n e drawn to which the plasma values  Hyperporathyroidism. (Pre-Op) H -18  Figure  4:  Plasma subject  (o)  calcium with  and phosphorus  f o ra  hyperparathyroidism  (Pre-operative)  Hyperparathyroidism - ( P o s t - O p . ) H - 18 (b)  Ca mg. % Calcium  6  4  Time  Figure  5:  Plasma subject  in Hours.  calcium with  and  phosphorus f o r a  hyperparathyroidism  (Post-operative)  Normal H-2 Ca mg./min. U V" M  1.5 -\  Ca  Figure  6:  mg. %  " P"  Variation of rate excretion  with  concentration  of urinary  plasma  calcium  calcium  i n a normal  subject  47  Hypoparathyroidism. Ca mg./min.  •  u  v  u  .  1-2  QJLil.  2.0 n  1.5 -  1.0 -  0.5 -  Figure  7:  V a r i a t i o n of rate excretion in  a  (Dose  with  subject was  10  of urinary  plasma  with  calcium  calcium  concentration  hypoparathyroidism  Mg/Kg/Hr.  f o r two  hours)  H -18 Ca mg./min. "UV"  8  10  12 Ca  mg.  14  %  " P  M  .  Figure  8:  Variation  of  rate  .  of u r i n a r y  calcium  16  with  plasma  with  hyperparathyroidism,  i  calcium  concentration P r e - and  excretion  i n a  subject  Post-operatively  ^  co  49  Figure  9:  Variation  of  rate  of decrease  plasma  calcium  concentration  plasma  calcium  concentration  i n with  50 BIBLIOGRAPHY  1.  A l b r i g h t , P . , E l l s w o r t h , R . , C a l c i u m and Phosphorus i n a Case of I d i o p a t h i c Hypoparathyroidism. J . C l i n . I n v e s t . 7:183, 1929.  2.  A l b r i g h t , P., R e i f e n s t e i n , E . C . , T h e P a r a t h y r o i d M e t a b o l i c Bone D i s e a s e ; W i l l i a m s and W i l k i n s Baltimore, 1948.  3.  Armstrong, W.D., Johnson, L . , Singer, R . I . , Lienke, M . , P r e m e r , M . L . , R a t e s o f T r a n s c a p i l l a r y Movement o f C a l c i u m and Sodium and o f C a l c i u m Exchange by t h e S k e l e t o n . A m . J . P h y s i o l . 171:641, 1952.  4.  Bauer, G . C . H . , Carlsson, A . , L i n d q u i s t , B . , E v a l u a t i o n of A c c r e t i o n , R e s o r p t i o n , and Exchange Reactions i n the Skeleton. Kgl. Pysiograf. S a l l s k . : L u n d N o r h a n d l , 25:1, 1955-  5.  B a u e r , G . C . H . , C a r l s s o n , A . , L i n d q u i s t , B . , Some of the Exchangeable Bone C a l c i u m . Acta. Physiol. Scandinavica, 35:67-72, 1955.  6.  Bauer, in  G.C.H.,  Ray, R . D . , Kinetics  M a n . J . Bone  and J o i n t  of  Surg.  Strontium  Studies  Glands and Company,  Properties  Metabolism  40:171-185, 1958.  7.  B a y l o r , C . H . , Van A l s t i n e , H . E . , Keutmann, E . H . , B a s s e t t , S.H. , Fate of Intravenous Calcium - E f f e c t on U r i n a r y Calcium, Phosphorus, Fecal Calcium, Phosphorus Balance. J . C l i n . I n v e s t . , 29:1167, 1950.  8.  B e r g s t r o m , W . H . , The S k e l e t o n M e t a b o l i s m , 5:433, 1956.  9.  Birkenhaeger, W . H . ,Hellendoorn, H . B . A . , Gerbrandy, J . , E f f e c t s of Intravenous Calcium Caerulinate on Calcium Metabolism. C l i n . Science, 18:45, 1959-  as  an E l e c t r o l y t i c  Reservoir.  10. B r o n n e r , F . , B e n d a , C E . , H a r r i s , R . S . , K r e p l i c h , C , C a l c i u m . M e t a b o l i s m i n a Case o f G a r g o y l i s m , studied 5 w i t h CaT . J . C l i n . I n v e s t . , 37:139, 1958. 11.  Bronner, F . , Harris, R . S . , Maletskos, C . J . , Berda, C E , , Studies i n Calcium Metabolism - Fate of Intravenous R a d i o c a l c i u m i n Humans. J . C l i n . I n v e s t . , 35: 1956.  12. C h e n ,  P.S., N e u m a n ,  W . F . , Renal  Excretion  A m . J . P h y s i o l . , 1 8 0 : 6 2 3 , 1955-  of  Ca by the Dog.  51 13.  Christiansen, H., Investigation of Excretion of Calcium. N u t r i t i o n Abstracts and Reviews, 6:722, 1 9 3 7 .  14. Copp, D.H., Calcium and Phosphorus Metabolism. Am. J . Med. 2 2 : 2 7 5 - 2 8 5 , 195715.  Dickens, P., C i t r i c Acid Content of Animal Tissues, with Reference to i t s Occurrence i n Bone and Tumour. Biochem. J . , 3 5 : 1 0 1 1 - 2 3 , 1941.  16. Dixon, T.F., C i t r i c Acid and Calcium Metabolism. J. Bone and Joint Surg., 33-B:268-71, 1 9 5 1 . 17.  Edholm, O.G., Howarth, S., Studies on Periphoral C i r c u l a t i o n i n O s t e i t i s Deformans. C l i n . Science, 1 2 : 2 7 7 , 1 9 5 3 .  18. Falkenheim, M., Neuman, W.F., Hodge, H.C., Phosphate Exchange as a Mechanism of Adsorption of Radiophosphorus by C a l c i f i e d Tissues. J. B i o l . Chem., 1 6 9 : 7 1 3 - 2 2 , 194-7. 19.  F i r s c h e i n , A., Martin, R., Mulryan, B.J., Strates, Neuman, W.F., Concerning the Mechanism of Action of Parathyroid Hormone - I-ion Gradients. J . Am. Chem. S o c , 80:1619, 1 9 5 8 .  20.  Freedman, P., Moulton, R., Spencer, A.G., E f f e c t of Intravenous Calcium Gluconate on Renal Excretion of Water and E l e c t r o l y t e s . C l i n . Science, 17:247, 1 9 5 8 .  21.  Freeman, S., B r i e f Resume of Calcium and Phosphorus Metabolism. Am. Acad, of Orth. Surg. Inst. Course Lect., 1955*  2 2 . G r e v i l l e , G.D., Study of Blood Calcium Following the Intravenous Use of Calcium S a l t s . Biochem. J . , 2 5 : 1 9 3 1 , 1 9 3 1 . 2 3 . Goldman, R., Bassett, S.H., E f f e c t of Intravenous Calcium Gluconate on Excretion of Calcium and Phosphorus i n Patients with Idiopathic Hypoparathyroidism.. J. C l i n . Endoc. and Metab., 14:278, 1 9 5 4 . 24. Handler, P., Conn, D.V., E f f e c t of Parathyroid Hormone on Renal Function. Am. J . P h y s i o l . , 169:188-193, 1 9 5 1 . 2 5 . Harrison, H.E., Harrison, H.C., The Uptake of Radiocalcium by the Skeleton; The E f f e c t of "Vitamin D and Calcium. J. B i o l . Chem., 1 8 5 : 8 5 7 - 8 6 7 , 1 9 5 0 .  52 26.  H a s t i n g s , A.B., S t u d i e s on A l t e r a t i o n o f C a l c i u m C o n c e n t r a t i o n i n Blood on the M o b i l i z a t i o n o f Calcium. T r a n s . M a c y C o n f . o n Me.tab. I n t e r r e l a t i o n s , p.38, 1951. -  27.  Hiatt, on J.  T h o m p s o n , D.D., Some E f f e c t s o f I n t r a v e n o u s Inorganic Phosphorus Metabolism. C l i n . I n v e s t . , 36:573, 1957-  Calcium  28.  H o l l i n g e r , H.Z., P a t t e e , C . J . , R e v i e w o f N o r m a l and P h o s p h o r u s Metabolism. C a n . M e d . A s s o c . J . , 7 4 : 9 1 2 , 1956.  29.  H o l l i n g e r , H.Z., P a t t e e , C . J . , R e v i e w o f A b n o r m a l and P h o s p h o r u s M e t a b o l i s m - H y p e r c a l c e m i a . C a n . M e d . A s s o c . J . , 75:941, 1956.  Calcium  30.  H o l l i n g e r , H.Z., P a t t e e , C . J . , R e v i e w o f A b n o r m a l and Phosphorus M e t a b o l i s m - H y p o c a l c e m i a . C a n . M e d . A s s o c . J . , 77:45, 1 9 5 7 .  Calcium  31.  H o l o p a i n e n , T . , K o s k i n e n , H., E f f e c t o f I n t r a v e n o u s C a l c i u m Gluconate I n f u s i o n on t h e Calcium and Phosphorus E x c r e t i o n o f P a t i e n t s with Rheumatoid A r t h r i t i s . Acta Rheumatologica S c a n d . , 1:250-6, 1956.  32.  H o r n e r , W.H., T h e D e t e r m i n a t i o n o f C a l c i u m Material. J . L a b . C l i n . M e d . , 45:951-57, 1955-  33.  H o w a r d , J . E . , Some C u r r e n t C o n c e p t s o n M e c h a n i s m o f Calcification. J . B o n e a n d J o i n t S u r g . , 33-A:801-806, 1 9 5 1 .  34.  Howard,  J . E . ,C a l c i u m  Metabolism,  Bones  Calcium  i n Biological  and Calcium  Homeostosis, a Review o f C e r t a i n Current Concepts. J . C l i n . E n d o c . a n d M e t a b . , 17:1105-23, 195735«  H o w a r d , J . E . , H o p k i n s , T.R., C o n n o r , T . B . , R e s p o n s e t o Intravenous Calcium S a l t s i n Normal, Hyper-, and Hypoparathyroid Persons. J . C l i n . E n d o c , 13:1, 1953.  36.  J a h a n , I . , P i t t s , R.F., E f f e c t o f P a r a t h y r o i d Hormone on Renal Tubular Reabsorption o f Phosphorus and Calcium. Am. J . P h y s i o l . , 155:42, 1948.  37.  Kenny,  A.D., D r a s k o c z y ,  P.R.,  Goldhaber,  P.,  P r o d u c t i o n b y R e s o r b i n g Bone i n T i s s u e Am. J . P h y s i o l . , 1 9 7 : 5 0 2 , 195938.  Kyle,  L.H., Schaaf,  M.,  Erdman,  Citric  Acid  Culture.  L.A., The M e t a b o l i c  E f f e c t s of Intravenous Administration of J . L a b . C l i n . M e d . , 43:123-733, 1954.  Calcium.  53 3 9 . Lehmann, J . , A Photometric Method f o r Direct T i t r a t i o n of Calcium i n Serum with EDTA. Scand. J . C l i n , and Lab. Invest., 5 : 2 0 3 , 1 9 5 3 . 4-0. Lloyd, H.M. , Rose, G.A. , Ionized, Protein-Bound, and Oomplexed Calcium i n Plasma i n Primary Hyperparathyroidism. Lancet, 2(7059):1258, 1958. 41. McCance, R.A., Widdowson, E.M., The Fate of Calcium and Magnesium A f t e r Intravenous Administratioxi i n Normal Persons. Biochem. J . , 3 3 : 5 2 3 , 1 9 3 9 . 42. MacDonald, N.S., K i n e t i c Studies of S k e l e t a l Metabolism by External Counting of Injected Radioisotopes Radioisotope Osteogram. J. Lab. C l i n . Med., 52:541, 1 9 5 8 . 43. McLean, F.C., Bone. S c i e n t i f i c American,  192:84, 1955-  44. McLean, F . C , Hastings, A.B. , C l i n i c a l Estimation and S i g n i f i c a n c e of Calcium Ion Concentrations i n the Blood. Am.-J. Med. Sc., 189:606, 1 9 3 5 . 45. McLean, F . C , U r i s t , M.R. , Bone - An Introduction to the Physiology of S k e l e t a l Tissues. U n i v e r s i t y of Chicago Press, 1 9 5 5 . 46. Natelson, S., Pincus, J.B., Lugovoy, J.K., C i t r i c Acid Determination. J. B i o l . Chem., 1 7 5 : 7 4 5 , 194-8. 47. Neuman, W.F., Transactions of Macy Conference on Metabolism I n t e r r e l a t i o n s , 2:48, 1 9 5 0 . 48. Neuman, W.F., The Mechanism of Parathyroid Function. Journal Lancet, 7 8 : 1 9 0 - 1 9 6 , 1 9 5 8 . 49. Neuman, W.F., Mulryan, B.J., The Surface Chemistry of Bone. J. B i o l . Chem., 185:705-712, 1 9 5 0 . 50.  Neuman, W.F., Neuman, M.W., Emerging Concepts of the Structure and Functions of Bone. Am. J . Med., 22:123, 1957-  5 1 . Neuman, W.F., Neuman, M.W., Chemical Dynamics of Bone Mineral. U n i v e r s i t y of Chicago Press, 1 9 5 8 . 5 2 . Nordin, B.E.C, Fraser, R., Calcium Infusion Test: Renal Excretion data i n the Diagnosis of Osteomalacia. Lancet, 1:823, 1 9 5 6 .  54 53.  Patt, H . M . , Luckhardt, A . B . , Relationship Calcium to Parathyroid Secretion. E n d o c r i n o l o g y , 31:384, 1942.  54.  P l i m p t o n , C . A . , C a l c i u m M e t a b o l i s m i n H e a l t h and Disease. M e d . C l i n i c s o f N. A m e r i c a , 39:881-898, 1955-  55«  Poulos, P . P . , Renal Tubular Reabsorption E x c r e t i o n of C a l c i u m by the Dog. J . L a b . C l i n . M e d . , 49:253, 1957-  56.  Salvesen, A . , Hastings, A . , Mcintosh, J . F . , Effect of A d m i n i s t r a t i o n of C a l c i u m S a l t s on I n o r g a n i c Composition of the B l o o d . J . B i o l . C h e m . , 60:327-339, 1924.  57«  S c h i l l i n g , A . , L a s z l o , D . , Rate of U r i n a r y Calcium Excretion Following Its Intravenous Administration as an I n d i c a t o r o f Bone M e t a b o l i s m . P r o c . S o c . E x p . B i o l , a n d M e d . , 78:286, 1951.  58.  Schilling, A., Laszlo, D., Investigative Tools i n the Study of Calcium Metabolism i n Man: Balance Studies, the Calcium Tolerance Test, Radioactive Calcium. O r d . S u r g . , O r a l M e d . , O r a l P a t h . , 6:139-46, 1953-  59.  Schwartz, T . B . , Parathyroid Med. C l i n .  Laboratory Disease. N. A m e r i c a ,  Aids  in  the  of  a Low  and  Blood  Urinary  Diagnosis  of  43:497, 195945  60.  S i n g e r , L . , A r m s t r o n g , W . D . , The R e t e n t i o n o f Ca i n the S t a b l e Bone F r a c t i o n D u r i n g D i e t a r y C a l c i u m R e s t r i c t i o n . A r c h . B i o c h e m . a n d B i o p h y s . , 80:410-415, 1959-  61.  S p e n c e r , H . , H a u s i n g e r , A . , L a s z l o , D . , The Tolerance Test i n Senile Osteoporosis. J . Am. G e n i a t r i c s S o c , 2:19, 1954.  62.  Stein, R.O., Stein, M.L., Beller, H e a l t h and Disease. J . B . L i p p i n c o t t C o . , 1955•  63.  Taussky, H . H . , S h o r r , E . , M i c r o - C o l o r i m e t r i c Method Determination of Inorganic Phosphorus. J . B i o l . C h e m . , 2:675-685, 1953.  64.  Thomas, R . O . , L i t o v i t z , T . A . , R u b i n , M . I . , G e s c h i c k t e r , Dynamics o f C a l c i u m M e t a b o l i s m - Time D i s t r i b u t i o n Intravenous radiocalcium. A m . J . P h y s i o l . , 169:568-575, 1952.  65.  W i l l i a m s o n , B . J . , Freeman, S . , E f f e c t s of Acute Changes i n A c i d Base B a l a n c e o n R e n a l C a l c i u m E x c r e t i o n i n D o g s . A m . J . P h y s i o l . , 191:384, 1957-  66.  Wolff, A . V . , B a l l , S . M . , Effect of Intravenous S a l t s on Renal E x c r e t i o n i n the Dog. A m . J . P h y s i o l . , 158:205, 1949.  y  A.,  Calcium  L i v i n g Bone  in  for  Calcium  G.F., of  


Citation Scheme:


Citations by CSL (citeproc-js)

Usage Statistics



Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            async >
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:


Related Items