Handbook of Parathyroid Diseases A Case Based Practical

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Foreword

Hyperparathyroidism has undergone a dramatic shift in clinical presentation from

the cases typically seen in the first two thirds of the previous century, following
recognition of the disease in the late 1920s and its successful treatment by surgical
removal of the overactive parathyroid gland. The disease, as then identified, was
characterized by overt signs and symptoms of bone, renal, and other organ dysfunc-
tion, such as severe osteitis fibrosa and kidney stones. Hyperparathyroidism, as rec-
ognized today, has largely transformed into a milder but more frequently recognized
disorder, often termed asymptomatic hyperparathyroidism to reflect the virtual
absence of symptoms typically associated with the disease.
Despite much progress in definition of the physiology of calcium homeostasis, as
well as the genetic pathogenesis of hyperparathyroidism, its diagnosis, and surgical
management, uncertainty persists about optimum management of asymptomatic
hyperparathyroidism. The disease may remain clinically stable for many years and
bone mineral density, although often reduced from that of euparathyroid subjects of
the same age, may remain remarkably constant for many years. These findings led
in recent years to the view that medical monitoring may be sufficient in these
patients, rather than recommending surgery. For several reasons, however, the pen-
dulum seems to be swinging back toward the view that surgical correction rather
than medical monitoring may be appropriate in many of these patients because of
concern about subtle organ deterioration, even in the absence of overt symptoms.
This volume presents 17 chapters dealing with fundamental and clinical issues
pertinent to disease recognition, pathogenesis and pathophysiology, and surgical
and medical management. Chapters 5, 6, and 9 focus particularly on the disease
features that are central to the key management decision, surgery versus medical
monitoring. Guidelines felt useful have been developed through several consensus
meetings of experts in the field. These deal with (1) criteria for formally recom-
mending surgery and (2) criteria to be followed if medical observation is elected.
Also reviewed is the current status of medical therapies, should disease manifesta-
tions require efforts of intervention rather than mere medical monitoring in patients
who are medically unsuitable or unwilling to undergo surgical correction.

vii
viii Foreword

Concerns about eventual skeletal deterioration as well as subtle neuropsychiatric

and cardiovascular features of even mild hyperparathyroidism, coupled with clear
evidence of improved bone density with surgery and suggestive but still somewhat
inconclusive evidence regarding the presence and reversibility with surgery of neu-
ropsychiatric and cardiovascular features is leading most endocrinologists and sur-
geons to now favor surgery. The possibility of medical monitoring, however, is still
regarded as an option awaiting further study of the presence and reversibility of
subtle disease features.
One chapter deals with hypoparathyroidism, a deficiency rather than excess of
parathyroid action. Hypoparathyroidism has long been unusual among endocrine
deficiency disorders, in that replacement therapy with the missing hormone is not
offered because of the need for parenteral therapy and the short half life of hormone
after administration. Effective current therapies are reviewed. There is however,
renewed interest in exploring treatment with recently available, longer acting form
of parathyroid hormone.

John T. Potts, Jr., MD

Jackson Distinguished Professor of Clinical Medicine
Harvard Medical School
Director of Research and Physician-in-Chief Emeritus
Massachusetts General Hospital
Preface

The purpose of the Handbook of Parathyroid Diseases is to present a concise yet

comprehensive overview of our current knowledge in the area of parathyroid function,
hormone regulation, and medical and surgical management of disease states. Many
advances have been made in particular over the past decade in our understanding of
molecular biology, physiology, genetics, cell signaling, hormone regulation, imaging,
surgical, and pharmacologic intervention. These advances are conveyed to the prac-
titioner in an easy-to-read format which is both practical and user friendly. This
book will be of great value to students, residents, and physicians in endocrinology,
surgery, radiology, nuclear medicine, pediatrics, primary care, internal medicine,
biochemistry, and pathology. The handbook will educate the reader using a case-based
approach presenting current evidence in the field. The material is presented in easy-
to-read and understandable language with liberal use of tables and textboxes when-
ever possible. Complex concepts are conveyed in simple and clear language. Leading
national and international experts have contributed to this state-of-the-art book
which is unique in its depth of knowledge and practicality.

Hamilton, ON, Canada Aliya A. Khan, MD

San Francisco, CA, USA Orlo H. Clark, MD

ix
Contents

1 Mechanisms Underlying Extracellular

Calcium Homeostasis ............................................................................. 1
Edward M. Brown
2 Preoperative Parathyroid Imaging
for the Endocrine Surgeon .................................................................... 19
Elizabeth G. Grubbs, Beth S. Edeiken, Maria K. Gule,
Brett J. Monroe, Edmund Kim, Thinh Vu,
and Nancy D. Perrier
3 Primary and Secondary Hyperparathyroidism
Testing and Assays ................................................................................. 41
Jean-Hugues Brossard and Pierre D’Amour
4 Symptomatic Primary Hyperparathyroidism
Medical Therapy .................................................................................... 55
Ghada El-Hajj Fuleihan
5 Surgical Management of Primary Hyperparathyroidism .................. 75
Meei J. Yeung and Janice L. Pasieka
6 Primary Hyperparathyroidism: Asymptomatic
Medical Management ............................................................................ 93
Aliya A. Khan
7 Surgical Management of Asymptomatic Primary
Hyperparathyroidism ............................................................................ 103
Rachel Farkas, Jacob Moalem, and Orlo H. Clark
8 Nonclassic, Extraskeletal Manifestations of Primary
Hyperparathyroidism ............................................................................ 123
Nancy D. Perrier, Storm Weaver, Swaroop Gantela,
and D. Sudhaker Rao

xi
xii Contents

9 Secondary Hyperparathyroidism ......................................................... 141

Naifa Lamki Busaidy, Amit Lahoti, and David A. Hanley
10 Secondary Hyperparathyroidism: Surgical......................................... 159
John Yoo and J.E.M. Young
11 Tertiary Hyperparathyroidism Pathogenesis,
Clinical Features, and Medical Management ...................................... 181
D. Sudhaker Rao, and Dolores Shoback
12 Surgical Treatment of Persistent Hyperparathyroidism
After Renal Transplantation ................................................................. 199
Frederic Triponez and Pieter Evenepoel
13 Bone Density and Fracture Risk
in Primary Hyperparathyroidism ........................................................ 215
E. Michael Lewiecki and Paul D. Miller
14 Genetic Aspects of Hereditary Hyperparathyroidism ........................ 229
Alberto Falchetti, Francesca Giusti, Loredana Cavalli,
Tiziana Cavalli, and Maria Luisa Brandi
15 Hypoparathyroidism and Hypocalcemic States .................................. 245
Laura Masi and Maria Luisa Brandi
16 Molecular Pathogenesis of Primary Hyperparathyroidism ............... 257
Kelly Lauter and Andrew Arnold
17 Cost-Effectiveness of Parathyroidectomy for Primary
Hyperparathyroidism ............................................................................ 271
Kyle Zanocco and Cord Sturgeon

Index ................................................................................................................ 277

Contributors

Andrew Arnold, MD Center for Molecular Medicine, University of Connecticut,

School of Medicine, Farmington, CT, USA
Maria Luisa Brandi, MD Department of Internal Medicine,
University of Florence, Centro di Riferimento Regionale sui Tumori Endocrini
Ereditari, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
Jean-Hugues Brossard, MD Department of Medicine, Centre de recherche,
Centre hospitalier de l’Université de Montréal (CHUM)-Hôpital Saint-Luc,
Université de Montréal, Montreal, QC, Canada
Edward M. Brown, MD Division of Endocrinology, Diabetes and Hypertension,
Department of Medicine, Harvard Medical School, Brigham and Women’s
Hospital, Boston, MA, USA
Naifa Lamki Busaidy, MD, FACP Department of Endocrine Neoplasia
& Hormonal Disorders, University of Texas M. D. Anderson Cancer Center,
Houston, TX, USA
Loredana Cavalli, MD Department of Internal Medicine, University of Florence,
Florence, Italy
Tiziana Cavalli, MD Department of Internal Medicine, University of Florence,
Florence, Italy
Orlo H. Clark, MD, FACS Department of Surgery, University of California,
San Francisco, San Francisco, CA, USA
Pierre D’Amour, MD, FRCPC Department of Medicine, University of Montreal,
Montreal, QC, Canada
Beth S. Edeiken, MD Department of Diagnostic Radiology,
The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Pieter Evenepoel, MD Department of Medicine, Division of Nephrology,
University of Leuven, Leuven, Belgium

xiii
xiv Contributors

Alberto Falchetti, MD Department of Internal Medicine, University of Florence,

Florence, Italy
Rachel Farkas, MD Department of Surgery, University of Rochester
Medical Center, Rochester, NY, USA
Ghada El-Hajj Fuleihan, MD, MPH Calcium Metabolism and Osteoporosis
Program, WHO Collaborating Center for Metabolic Bone Disorders,
Department of Medicine, American University of Beirut-Medical Center,
Riad El Solh, Beirut, Lebanon
Swaroop Gantela, MD Human Neuroimaging Laboratory, Baylor College
of Medicine, Houston, TX, USA
Francesca Giusti, MD Department of Internal Medicine, University of Florence,
Florence, Italy
Elizabeth G. Grubbs, MD Department of Surgical Oncology,
Unit 1484, The University of Texas M. D. Anderson Cancer Cente,
Houston, TX, USA
Maria K. Gule, MD Department of Surgical Oncology, Unit 1484,
The University of Texas M. D. Anderson Cancer Cente, Houston, TX, USA
David A. Hanley, MD, FRCPC Department of Medicine, University of Calgary,
Calgary, AB, Canada
Aliya A. Khan, MD, FRCPC, FACP, FACE Department of Endocrinology
and Metabolism, McMaster University, Hamilton, ON, Canada
Edmund Kim, MD Department of Nuclear Medicine, The University of Texas
M. D. Anderson Cancer Center, Houston, TX, USA
Amit Lahoti, MD Section of Nephrology, Department of General Internal
Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Kelly Lauter, BA, MD Center for Molecular Medicine,
University of Connecticut, School of Medicine, Farmington, CT, USA
E. Michael Lewiecki, MD, FACP, FACE Department of Medicine, New Mexico
Clinical Research and Osteoporosis Center, Albuquerque, NM, USA
Laura Masi, MD Department of Medicine, University of Florence,
Centro di Riferimento Regionale sui Tumori Endocrini Ereditari,
Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
Paul D. Miller, MD Colorado Center for Bone Research, Lakewood, CO, USA
Jacob Moalem, MD Department of Surgery, University of Rochester Medical
Center, Rochester, NY, USA
Brett J. Monroe, MD Department of Diagnostic Radiology,
The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Contributors xv

Janice L. Pasieka, MD, FRCSC, FACS Department of Surgery and Oncology,

Divisions of General Surgery and Surgical Oncology, University of Calgary, North
Tower, Foothills Medical Center, Calgary, AB, Canada
Nancy D. Perrier, MD, FACS Department of Surgical Oncology, Unit 1484,
The University of Texas M. D. Anderson Cancer Cente, Houston, TX, USA
D. Sudhaker Rao, M.B.B.S., FACP, FACE Bone & Mineral Metabolism,
Bone & Mineral Research Laboratory, Henry Ford Medical Center, New Center
One, Henry Ford Hospital, Detroit, MI, USA
Dolores Shoback, MD Endocrine Research Unit, San Francisco
Department of Veterans Affairs Medical Center, University of California,
San Francisco, CA, USA
Cord Sturgeon, MD Section of Endocrine Surgery, Department of Surgery,
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Frederic Triponez, MD Thoracic and endocrine surgery,
University Hospital of Geneva, Geneva, Switzerland
Thinh Vu, MD Department of Diagnostic Radiology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX, USA
Storm Weaver, MD Department of Surgical Oncology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX, USA
Meei J. Yeung, MD, FRACS Department of Surgery, Monash University
Endocrine Surgery Unit, Melbourne, Australia
John Yoo, MD, FRCS(C), FACS Department of Otolaryngology-Head
and Neck Surgery, University of Western Ontario, London, ON, Canada
J.E.M. Young, BSc, MD, FRCS, FACS Department of Surgery,
McMaster University, Hamilton, ON, Canada
Kyle Zanocco, MD Section of Endocrine Surgery, Department of Surgery,
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Chapter 1
Mechanisms Underlying Extracellular Calcium
Homeostasis

Edward M. Brown

Keywords Calcium • PTH • Calcitonin • Vitamin D • 1,25(OH)2D3 • Calcium-sensing

receptor • Calcium regulation by kidney • Bone • Intestine • Parathyroid chief cells
• Fibroblast growth factor-23 • Phosphate • Calcium-binding protein • Calbindin
• Magnesium • RANKL • Osteoprotegrin • Phosphatonins • Osteocyte • Osteoblast
• Osteoclast • Alpha klotho

Calcium (Ca2+) is indispensable for all living things. In complex, multicellular

organisms, calcium serves key roles in both the intra- and extracellular spaces [1].
In humans and other mammals, for example, notable extracellular roles of calcium
ions include promoting plasma membrane integrity and serving as an important
cofactor in proteins, such as adhesion molecules, clotting factors, and secreted
enzymes (i.e., trypsin) [1]. It is also an essential component, along with phosphate
ions, of the mineral phase of bone [2, 3]. The combination of a collagenous matrix
and its associated insoluble mineral phase confers upon bone both hardness and
strength, thereby enabling the skeleton to protect vital internal structures (i.e., the
brain and heart) and to facilitate ambulation and other directed movements [2].
Intracellular Ca2+ likewise serves numerous critical roles [4], including activating
exocytosis (the so-called stimulus-secretion coupling) and muscle contraction
(“stimulus-contraction coupling”) and participating in the propagation of action
potentials in some nerve cells. Ca2+ serves more generally as a key intracellular
second messenger [3, 5], regulating a host of cellular processes (mitosis, energy
metabolism, gene expression, cell death, etc.) through its interaction with intracel-
lular Ca2+ sensors, such as calmodulin [6].

E.M. Brown, M.D. (*)

Division of Endocrinology, Diabetes and Hypertension, Department of Medicine,
Harvard Medical School, Brigham and Women’s Hospital, EBRC 223A,
221 Longwood Ave., Boston, MA 02115, USA
e-mail: [email protected]

A.A. Khan and O.H. Clark (eds.), Handbook of Parathyroid Diseases: 1

A Case-Based Practical Guide, DOI 10.1007/978-1-4614-2164-1_1,
© Springer Science+Business Media, LLC 2012
2 E.M. Brown

The numerous roles of Ca2+ in living organisms highlight the importance of

ensuring adequate and stable Ca2+ concentrations in bodily fluids in order to provide
a sufficient source of Ca2+ for both its extracellular and intracellular functions (extra-
cellular Ca2+ is the ultimate source of all intracellular Ca2+) [7]. Tetrapods (animals
with four extremities, e.g., birds, mammals, amphibians, and reptiles) have evolved
a finely tuned homeostatic system designed to maintain near constancy of the extra-
cellular ionized calcium concentration (Cao2+) [2, 7, 8]. The purpose of this chapter
is to provide an overview of how this system functions under normal circumstances.
This provides a backdrop for subsequent chapters detailing various aspects of pri-
mary hyperparathyroidism (PHPT), a hypercalcemic disorder caused by hyperfunc-
tion of one or more parathyroid glands [9]. Indeed, a key aspect of PHPT is abnormal
Cao2+ sensing by pathological parathyroid tissue, which “resets” the Cao2+ homeo-
static system to maintain varying degrees of hypercalcemia [10–12]. While not a
major focus of this chapter, recent important advances have taken place in our
understanding of phosphate homeostasis [13, 14]. Since several of the key regula-
tors of phosphate metabolism, e.g., fibroblast growth factor-23 (FGF-23) and alpha-
klotho (a-klotho), also modulate Cao2+ homeostasis, these interactions are covered
briefly, stressing the essential and intimate links that have been emerging between
these two homeostatic systems.

Key Elements of Cao2+ Homeostasis

The Cao2+ homeostatic system has three essential elements. Figure 1.1 shows how
these elements function in a coordinated manner to maintain near constancy of
Cao2+. The first component is one or more Cao2+ sensors that detect perturbations in
Cao2+ from its normal level [7, 8]. The best characterized Cao2+-sensing mechanism
is the extracellular calcium-sensing receptor (CaSR), a G protein-coupled receptor
that is expressed in many, if not all, of the tissues participating in Cao2+ homeostasis
[15, 16]. These include the parathyroid hormone (PTH)-secreting parathyroid chief
cells [15], calcitonin (CT)-secreting thyroidal C cells [17], and various cell types in
kidney [18], intestine [19, 20], and bone [21]. The CaSR’s functions in these tissues
are described in more detail subsequently.
The second key element of the Cao2+ homeostatic mechanism are hormones that
are directly or indirectly regulated by Cao2+ sensors and modulate Ca2+ transport into
or out of the extracellular fluid (ECF). The first of these is PTH, which acts on the
kidney to increase distal tubular reabsorption of Ca2+ and proximal tubular synthesis
of 1,25(OH)2D3 as well as on bone to stimulate net release of skeletal Ca2+ (accom-
panied in an obligatory manner by phosphate) [2]. Vitamin D3 is synthesized in the
skin and also absorbed from the diet in the small intestine; it then undergoes
largely unregulated 25-hydroxylation in the liver prior to its precisely regulated
1-hydroxylation in the kidney [22]. The synthesis of 1,25(OH)2D3 is stimulated by
PTH, hypocalcemia, and hypophosphatemia and inhibited by hypercalcemia,
hyperphosphatemia, and 1,25(OH)2D3 itself [2, 22]. The latter, therefore, feeds back
1 Mechanisms Underlying Extracellular Calcium Homeostasis 3

Fig. 1.1 Schematic representation of the system maintaining Cao2+ homeostasis. In response to
hypocalcemia, PTH is released into the circulation (plus indicates stimulation). It acts on the kid-
ney to promote increased distal tubular reabsorption of Ca2+, enhanced synthesis of 1,25(OH)2D3
from the 25(OH)D3 that is produced in the liver, and phosphaturia. The 1,25(OH)2D3 formed in the
kidney stimulates intestinal absorption of Ca2+ and phosphate and acts with PTH to increase net
release of Ca2+ from bone. Increased influx of Ca2+ into the ECF from bone and intestine, coupled
with reduced loss of Ca2+ via the kidney, restores Cao2+ to normal. In addition to the actions of the
Cao2+-regulating hormones just described (i.e., PTH and 1,25(OH)2D3), Ca2+ and phosphate them-
selves exert direct actions on the tissues and organs involved in Cao2+ homeostasis, as indicated by
the arrows from these ions to the respective target tissue. Many of the actions of Cao2+ are mediated
by the CaSR. In addition to the actions of PTH and 1,25(OH)2D3 that are illustrated, FGF-23 (not
shown) is stimulated by hyperphosphatemia and 1,25(OH)2D3 and, in turn, promotes phosphaturia,
inhibits the 1-hydroxylation of 25-hydroxyvitamin D, and reduces the secretion of PTH (see text
for additional details). Reproduced in modified form with permission from Brown EM. Mechanisms
underlying the regulation of parathyroid hormone secretion in vivo and in vitro. Curr Opin Nephrol
Hypertens. 1993; 2: 541–51

on its own synthesis in a negative manner. 1,25(OH)2D3 is the most biologically

active form of vitamin D3 in the body. Its sequential, regulated synthesis enables it
to act as the second major Cao2+-elevating hormone (along with PTH) by increasing
intestinal Ca2+ (and phosphate) absorption and activating bone resorption [2, 22].
CT is a potent hypocalcemic hormone in some species, such as rodents, primarily
owing to its capacity to inhibit bone resorption [23]. Its importance in Cao2+ homeo-
stasis in humans is probably marginal [24], although in pharmacological doses it
has found some utility in treating hypercalcemia, Paget disease of bone, and osteo-
porosis prior to the advent of the much more efficacious bisphosphonates [25, 26].
The third component of the Cao2+ homeostatic system is the cells within kidney,
bone, and intestine that effect vectorial transport of Ca2+ into or out of the ECF.
4 E.M. Brown

Fig. 1.2 Segments of the nephron relevant to Cao2+ homeostasis and their contribution to Ca2+
reabsorption along the entire length of the renal tubule (see text for details). Passive reabsorption
of Ca2+ in the proximal tubule (PT), which is largely unregulated, accounts for 60–70% of Ca2+
reabsorption while regulated reabsorption in CTAL and DCT (as well as the connecting tubule
(CT) just distal to the DCT) comprises 20 and 10%, respectively. At most, ~5% of Ca2+ is reab-
sorbed in the collecting duct (CD). Courtesy of S.C. Hebert, M.D.

The major sites of hormonally regulated Ca2+ transport in the kidney are the cortical
thick ascending limb (CTAL) of Henle’s loop and the distal convoluted tubule
(DCT) (Fig. 1.2) [27, 28], where PTH and/or 1,25(OH)2D3 increase tubular reab-
sorption of Ca2+, thereby conserving bodily Ca2+ stores. In the proximal small intes-
tine and, to some extent, in the colon, 1,25(OH)2D3 increases transepithelial
absorption of Ca2+ [29]. This capacity to assimilate Ca2+ from the environment is a
critical component of the Cao2+ homeostatic system because the kidney cannot
completely reabsorb all Ca2+ filtered at the glomerulus, and there is some obligate
loss of Ca2+ into intestinal secretions. Adequate dietary Ca2+ is particularly key
during somatic growth because of the accompanying increase in requirements for
Ca2+ in the growing skeleton and soft tissues. The ability to regulate the fluxes of
Ca2+ into and out of the skeleton is also essential for maintaining Ca2+ homeostasis.
When dietary Ca2+ is limited, for example, skeletal Ca2+, mobilized in response to
increased circulating levels of PTH and 1,25(OH)2D3, becomes a critical internal
reservoir of Ca2+ to sustain normocalcemia [2].

Integrated Control of Cao2+ Homeostasis

The information presented to this point can be summarized by delineating the man-
ner in which the Cao2+ homeostatic system responds to hypo- or hypercalcemia.
A decrease in Cao2+ is detected by the CaSR in the parathyroid chief cells leading
1 Mechanisms Underlying Extracellular Calcium Homeostasis 5

Fig. 1.3 Sigmoidal relationship between serum-ionized calcium concentration and circulating
intact PTH (iPTH) levels in normal human subjects. Hypocalcemia was first induced by intrave-
nous administration of ethylenediaminetetraacetic acid (EDTA) and then hypercalcemia by infu-
sion of calcium gluconate; serum levels of calcium and iPTH were determined at frequent intervals.
Note the steepness of the slope at the midpoint of the curve. This midpoint is defined as the set
point, which is closely related to the level at which Cao2+ is set in vivo. The serum-ionized Ca2+ in
mM should be multiplied by 8 to yield mg/dl total Ca2+. See text for details. Reproduced with per-
mission from Brown EM [34]. Extracellular Ca2+ sensing, regulation of parathyroid cell function,
and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 1991; 71: 371–411

to an acute increase in PTH secretion. The steepness of the inverse sigmoidal

relationship between Cao2+ and PTH (Fig. 1.3) [11] ensures large changes in PTH
for small changes in Cao2+, thereby contributing to the narrow range over which
serum Ca2+ is maintained. The midpoint or set point of the Cao2+–PTH relationship,
in turn, is closely related to the level at which Cao2+ is “set” in vivo.
The increase in the circulating PTH level elicited by hypocalcemia stimulates
release of Ca2+ from bone and has at least three actions on the kidney: (1) promoting
phosphaturia in the proximal tubule, (2) increasing distal tubular reabsorption of
filtered Ca2+, and (3) enhancing renal synthesis of 1,25(OH)2D3 from 25(OH)D3 [2].
The first two of these are rapid, occurring within minutes, while the last requires
several hours of exposure to an elevated PTH level [30]. There is also PTH-
independent “buffering” of changes in extracellular calcium by bone through poorly
understood mechanisms, possibly involving the CaSR [31], that restore Cao2+ to its
baseline level following induced reductions or increases in the serum calcium con-
centration by administration of EGTA or calcium, respectively [32]. Thus, a brief
episode of hypocalcemia may be corrected solely through increased renal Ca2+ con-
servation and mobilization of Ca2+ from bone. More prolonged hypocalcemia, in
contrast, may necessitate a 1,25(OH)2D3-mediated increase in intestinal absorption