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Main entry under title:

The genetics of osteoporosis and metabolic bone disease / edited by Michael J. Econs.
p. cm.
Includes bibliographical references and index.
ISBN 0-89603-702-9 (alk. paper)
1. Bones—Metabolism—Disorders—Genetic aspects. 2. Osteoporosis—Genetic aspects.
I. Econs, Michael J.
[DNLM: 1. Osteoporosis—genetics. 2. Bone Diseases, Metabolic—genetics. 3. Genetic
Predisposition to Disease. 4. Hereditary Diseases. WE 250 G328 2000]
RC931.M45 G46 2000
616.7'16042—dc21
99-058332
 Preface
The explosive growth in the field of molecular biology over the
last two decades has started to make a great impact on clinical medicine.
Genes have been cloned for diseases that were poorly understood only
a decade ago. Additionally, investigators are increasingly aware that
there are strong genetic components to complex disorders, such as
osteoporosis, that are not classically thought of as genetic disorders.
New insights into the pathogenesis of metabolic bone diseases have
been obtained from investigations into the molecular biology of these
diseases and new therapies will become available based on these new
insights.
In The Genetics of Osteoporosis and Metabolic Bone Disease, I have
assembled an internationally renowned group of experts to write the
various chapters. Each of the authors is an expert in his/her field who
is currently performing research on the content of their chapter and have
made important contributions to the understanding of the clinical fea-
tures and pathophysiology of metabolic bone disease and genetics.
The first part of The Genetics of Osteoporosis and Metabolic Bone Disease
addresses issues related to genetic contributions to the development of
osteoporosis and the many factors that must be considered when
searching for genes that predispose to osteoporosis. The second sec-
tion addresses recent advances in the clinical and molecular biological
aspects of inherited metabolic bone disorders. The last section reviews
the latest techniques for finding genes that predispose to metabolic
bone diseases.
Michael J. Econs, MD
 Dedications

This book is dedicated to Lee Win Liu, MD, who has made many
sacrifices as I have pursued genes that cause metabolic bone disease.
She has worked with me on numerous reunions of families with meta-
bolic bone disorders. These family reunions have almost always oc-
curred during weekends or holidays.
The book is also dedicated to Robert and Steven Econs, who have
enriched our lives beyond what we could ever have imagined.

vi
 Contents
Preface ......................................................................................................... v
Contributors .............................................................................................. ix
1 • Genetic and Environmental Determinants of Variance
in Bone Size, Mass, and Volumetric Density
of the Proximal Femur ................................................................ 1
Ego Seeman
2 • How to Determine If, and by How Much,
Genetic Variation Influences Osteoporosis? ......................... 29
John L. Hopper
3 • Vitamin D Receptor Gene Polymorphisms
and Bone Mineral Homeostasis .............................................. 45
Serge Ferrari, René Rizzoli, and Jean-Philippe Bonjour
4 • Type 1 Collagen Polymorphisms
and Osteoporosis ....................................................................... 61
Stuart H. Ralston
5 • Osteogenesis Imperfecta ............................................................... 75
Paul A. Dawson and Joan C. Marini
6 • Vitamin D-Dependent Rickets Type I and Type II .................. 95
Sachiko Kitanaka and Shigeaki Kato
7 • Inherited Phosphate Wasting Disorders .................................. 111
Michael J. Econs and Kenneth E. White
8 • X-Linked Nephrolithiasis/Dent’s Disease
and Mutations in the ClC-5 Chloride Channel .................. 133
Steven J. Scheinman and Rajesh V. Thakker
9 • Genetics of Tumoral Calcinosis ................................................. 153
Kandaswamy Jayaraj and Kenneth Lyles
10 • Fibrous Dysplasia and the McCune–Albright Syndrome ........ 163
Lee S. Weinstein

vii
viii Contents

11 • The Molecular Basis for Parathyroid Hormone Resistance

in Pseudohypoparathyroidism ............................................. 179
Michael A. Levine
12 • Fibrodysplasia Ossificans Progressiva ..................................... 211
Eileen M. Shore, John G. Rogers, Roger Smith,
Francis H. Gannon, Martin Delatycki, J. Andoni
Urtizberea, James Triffitt, Martine Le Merrer,
and Frederick S. Kaplan
13 • Disorders Resulting from Inactivating or Activating
Mutations in the Ca2+o-Sensing Receptor ............................ 237
Edward M. Brown
14 • Multiple Endocrine Neoplasia Type 1 (MEN1) ...................... 275
Rajesh V. Thakker
15 • The Ret Signaling System and Its Role in Hereditary
Medullary Thyroid Carcinoma ............................................. 295
Robert F. Gagel and Gilbert Cote
16 • Genetics of Paget’s Disease of Bone.......................................... 309
Frederick R. Singer and Robin J. Leach
17 • Osteopetrosis ................................................................................. 319
L. Lyndon Key, Jr.
18 • Hypophosphatasia ....................................................................... 335
Michael P. Whyte
19 • Jansen and Blomstrand: Two Human Chondrodysplasias
Caused by PTH/PTHrP Receptor Mutations ........................... 357
Harald Jüppner and Caroline Silve
20 • Genetic Linkage Analysis in Human Disease ......................... 377
Suzanne M. Leal and Marcy C. Speer
21 • The Identification of Disease Genes
in a Candidate Region ............................................................. 415
Fiona Francis and Tim M. Strom
22 • Finding Mutations in Disease Genes ........................................ 431
Peter S. N. Rowe
Index ...................................................................................................... 447
 Contributors
JEAN-PHILIPPE BONJOUR • Division of Bone Diseases, WHO Collaborating
Center for Osteoporosis and Bone Diseases, Department of Internal
Medicine, University Hospital, Geneva, Switzerland
EDWARD M. BROWN • Endocrine-Hypertension Division, Department
of Medicine, Brigham and Women’s Hospital, Boston, MA
GILBERT COTE • Associate Professor of Medicine, Section of Endocrine
Neoplasia and Hormonal Disorders, University of Texas M. D.
Anderson Cancer Center, Houston, TX
PAUL A. DAWSON • Section on Connective Tissue Disorders, Heritable
Disorders Branch, NICHD, NIH, Bethesda, MD
MARTIN DELATYCKI • Victorian Clinical Genetics Service, Murdoch
Institute, Royal Children’s Hospital, Flemington Road, Parkville,
Victoria, Australia
MICHAEL J. ECONS • Departments of Medicine and Medical and Molecular
Genetics, Indiana University School of Medicine, Indianapolis, IN
FIONA FRANCIS • Institut Cochin de Génétique Moléculaire, INSERM U.
129, CHU Cochin Port-Royal, Paris, France
SERGE FERRARI • Division of Bone Diseases, WHO Collaborating Center
for Osteoporosis and Bone Diseases, Department of Internal
Medicine, University Hospital, Geneva, Switzerland
ROBERT F. GAGEL • Section of Endocrine Neoplasia and Hormonal
Disorders and Department of Internal Medicine Specialties,
University of Texas M.D. Anderson Cancer Center, Houston, TX
FRANCIS H. GANNON • Department of Orthopaedic Surgery, Pathology
and Laboratory Medicine, University of Pennsylvania School
of Medicine, Philadelphia, PA
JOHN L. HOPPER • The University of Melbourne, Melbourne, Australia
KANDASWAMY JAYARAJ • GRECC, VAMC, Division of Geriatrics, Duke
University Medical Center, Durham, NC
HARALD JÜPPNER • Endocrine Unit, Department of Medicine and
Children’s Service, Massachusetts General Hospital and Harvard
Medical School, Boston, MA

ix
x Contributors

FREDERICK S. KAPLAN • Department of Orthopaedic Surgery, University

of Pennsylvania School of Medicine, Philadelphia, PA
SHIGEAKI KATO • Institute of Molecular and Cellular Biosciences,
The University of Tokyo, Tokyo, Japan
L. LYNDON KEY, JR. • Department of Pediatrics, General Clinical Research
Center, Medical University of South Carolina, Charleston, SC
SACHIKO KITANAKA • Institute of Molecular and Cellular Biosciences,
The University of Tokyo, Tokyo, Japan
ROBIN J. LEACH • Department of Cellular and Structural Biology,
University of Texas Health Science Center at San Antonio,
San Antonio, TX
SUZANNE M. LEAL • Rockefeller University, New York, New York
MARTINE LEMERRER • Hospital Necker, Paris, France
MICHAEL A. LEVINE • Division of Pediatric Endocrinology, Department
of Pediatrics, The Johns Hopkins University School of Medicine,
Baltimore, MD
KENNETH LYLES • GRECC, VAMC, Division of Geriatrics,
Duke University Medical Center, Durham, NC
JOAN C. MARINI • Section on Connective Tissue Disorders, Heritable
Disorders Branch, NICHD, NIH, Bethesda, MD
STUART H. RALSTON • Bone Research Group, Department of Medicine
and Therapeutics, University of Aberdeen, Scotland, UK
RENÉ RIZZOLI • Division of Bone Diseases, WHO Collaborating Center
for Osteoporosis and Bone Diseases, Department of Internal
Medicine, University Hospital, Geneva, Switzerland
JOHN G. ROGERS • Victorian Clinical Genetics Service, Murdoch Institute,
Royal Children’s Hospital, Victoria, Australia
PETER S. N. ROWE • Dept of Biochemistry and Molecular Biology,
University of London, Royal Free Hospital Medical School,
Hampstead, London, UK
STEVEN J. SCHEINMAN • Department of Medicine, SUNY Upstate Medical
University, Syracuse, NY
EGO SEEMAN • Austin and Repatriation Medical Centre, University
of Melbourne, Melbourne, Australia
CAROLINE SILVE • INSERM U. 426, Faculté de Médecine Xavier Bichat,
Paris, France
FREDERICK R. SINGER • John Wayne Cancer Institute at St. John’s Health
Center, Santa Monica, CA
EILEEN M. SHORE • Department of Orthopaedic Surgery, Department
of Genetics, University of Pennsylvania School of Medicine,
Philadelphia, PA
Contributors xi

ROGER SMITH • Medical Research Council Bone Research Laboratory,

University of Osvord, Nuffield Orthopaedic Centre, Headington,
Oxford, UK
MARCY C. SPEER • Department of Medicine, Duke University Medical
Center, Durham, North Carolina
TIM M. STROM • Abteilung Medizinische Genetik, Kinderklinik, Ludwig-
Maximilians-Universität, Muenchen, Germany
RAJESH V. THAKKER • MRC Molecular Endocrinology Group, MRC
Clinical Sciences Centre, Imperial College School of Medicine,
Hammersmith Hospital, London, UK
JAMES TRIFFITT • Medical Research Council Bone Research Laboratory,
University of Osvord, Nuffield Orthopaedic Centre, Headingdon,
Oxford, UK
J. ANDONI URTIZBEREA •Association Francaise Contre les Myopathies,
Evry, France
LEE S. WEINSTEIN • Metabolic Diseases Branch, National Institute of
Diabetes, Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, MD
KENNETH E. WHITE • Department of Medicine, Indiana University School
of Medicine, Indianapolis, IN
MICHAEL P. WHYTE • Metabolic Research Unit, Shriners Hospital for
Children and, Division of Bone and Mineral Diseases, Washington
University School of Medicine, St. Louis, MO
The Proximal Femur: Size, Mass, Density 1

CHAPTER 1

Genetic and Environmental

Determinants of Variance in Bone
Size, Mass, and Volumetric Density
of the Proximal Femur
Ego Seeman

1. Introduction
The genetic and environmental factors responsible for age, gender and race
specific differences in bone fragility and fracture rates of the proximal femur are
unknown. There are several possible reasons.
First, the phenotype is inadequately defined. Areal bone mineral density
(BMD), the surrogate measure of bone fragility used as a predictor of fracture, is
a summation of the modeling and remodeling that occurs during growth and aging
on the periosteal and endosteal (endocortical, intracortical, trabecular) surfaces of
bone. The differing and largely independent modeling and remodeling on these
surfaces — during growth, aging, and disease, in men and women, and in different
races, suggests the surfaces are regulated differently. Areal BMD is an ambiguous
phenotype as it is the net result of the bone added and removed from these sur-
faces. Its use obscures the pathogenetic basis of bone fragility rather than reveal-
ing it. Insight into the regulators of the bone surface remodeling is unlikely to be
obtained until the age, gender, and race specific means and variances of these
specific phenotypes are described and quantified. Potential genetic and environ-
mental factors hypothesized to explain the variances can then be investigated.
Second, there is no experimental evidence to support the notion that gender
and racial differences in areal BMD are responsible for the corresponding gender
and racial differences in fracture rates. Gender and racial differences in areal
BMD are likely to be largely accounted for by corresponding differences in bone

The Genetics of Osteoporosis and Metabolic Bone Disease

Ed.: M. J. Econs © Humana Press Inc., Totowa, NJ

1
2 Seeman

size. Little evidence exists for gender or racial differences in volumetric BMD. If
volumetric BMD does differ, its structural basis (differences in cortical thickness,
true cortical density, trabecular number, or thickness) is largely undefined, except
for evidence to support greater trabecular thickness in blacks than whites.
Third, a causal relationship is assumed to exist between gender, racial,
and secular differences in hip axis length (HAL) and corresponding differ-
ences in hip fracture rates. This association has not been tested in a prospec-
tive study. Gender, racial, and secular differences in HAL are likely to be
due to corresponding differences in leg length. Adjustments by total height
may over- or underestimate gender and racial differences in HAL depending
on the comparisons made because leg length is greater in men than women,
and greater in blacks than whites or Asians.
Fourth, the search for genetic factors has not been driven by specific
testable hypotheses concerning any age-, gender-, or race-specific biologi-
cal process such as periosteal apposition, endocortical remodeling. Lack of
knowledge of the structural differences that are responsible for the differ-
ences in bone fragility between genders and races hampers attempts to find
genes that are responsible for these differences.
What Is the Problem — Hip Fractures?
Hip fractures are the most serious consequence of bone fragility in terms of
morbidity, mortality, and financial burden (1,2). The incidence of hip fractures:
1. increases with advancing age in women and men,
2. is higher in women than men,
3. is higher in whites than blacks or Asians,
4. varies from country to country,
5. varies more between countries than between genders, and
6. secular trends in hip fracture incidence have been variously reported to
increase, decrease, or remain unchanged during the past 50 yr (1).
Assuming accurate case ascertainment, these gender-, race-, country-, and
time-specific estimates of hip fracture incidence are likely to reflect differences
in the incidence of falls, the severity of trauma, and underlying bone fragility. This
chapter is confined to the discussion of the genetic and environmental factors that
may account for differences in bone fragility that may, in turn, contribute to this
perplexingly diverse epidemiology of hip fractures.
What Are the Questions?
What are the structural elements that contribute to bone strength of the
proximal femur? Do they differ according to age, gender, and race? What are the
age-,gender-, and race-specific genetic and environmental factors that account for
the variance in these structures, i.e., between young and old, women and men, and
between races? Do the differences in these structures, and the differences in
The Proximal Femur: Size, Mass, Density 3

genetic and environmental factors account for the age-,gender-, and racial-differ-
ences in hip fracture rates? What structural differences are found at the proximal
femoral between individuals with and without hip fractures? Have there been
secular changes in these structures that may explain secular trends in the age-,
gender-, and race-specific incidence of hip fractures?
The majority of these questions have no answers because:
1. there are methodological problems in measuring the phenotypes — the
specific structural elements responsible for bone strength,
2. there are methodological problems in identifying associations between
candidate genes and these structural elements, and
3. measuring the ‘‘dose’’ of an environmental exposure is difficult.
A most challenging problem is to demonstrate, by experimental design, that
the higher hip fracture rate in women than men, or in whites compared to other
racial groups is attributable to any gender or racial difference in a phenotype such
as bone mineral content (BMC), bone size, areal BMD, bone mineral apparent
density (BMAD), or volumetric BMD. Causality is usually inferred when the
observation is ‘‘consistent with’’ or ‘‘fits’’ the preconceived notion.
Defining Causality Using an Ambiguous Phenotype —
Vagaries of ‘‘Areal BMD’’
As fractures are uncommon annual events, fracture rates are exceedingly
difficult endpoints to use in the study of the pathogenesis or treatment of bone
fragility. As areal BMD predicts the breaking strength of bone in vitro, and
fractures in vivo, this surrogate endpoint of bone strength has been most widely
studied at this time. Although some insights have been obtained, areal BMD may
not be the appropriate phenotype needed to answer questions regarding the genetic
and environmental factors contributing to pathogenesis of bone fragility.
Areal BMD is a summation of the periosteal and endosteal (endocortical,
intracortical, trabecular) surface modeling and remodeling during growth and
aging. It is the summation or net result of the amounts of bone added to, and
removed from, these surfaces. As each of these surfaces is regulated differently
and responds differently to environmental factors, this integrated endpoint is
likely to obscure the ability to detect true causal relationships between genetic and
environmental factors and the modeling and remodeling behavior on these
surfaces. Areal BMD is incorrectly perceived to be an unambiguous and tightly
regulated phenotype. It is not. It is a ‘‘gemish,’’ a mixture, and failure to recognize
its limitations is likely to seriously mislead the thinking in the field.
The structural basis underlying the development of the macro-and
microarchitecture of the skeleton during growth and the loss of mass and struc-
tural integrity during aging, are not conveyed by the areal BMD measurement.
This phenotype has resulted in the following flawed notions (3):
1. Areal BMD increases during growth; it does not, bone size increases;
2. Peak areal BMD is higher in men than women; it is not, bone size is greater;
4 Seeman

3. Areal BMD is stable until menopause in women; it is not, bone loss at the
proximal femur is well documented before menopause;
4. Women lose more trabecular bone from the axial skeleton than men; no,
trabecular bone loss is similar in women and men (3);
5. Cortical bone loss is greater in women than men; no, net loss is greater
because endocortical resorption is greater and subperiosteal formation is less
in women than men;
6. Blacks have higher areal BMD than whites, who in turn have higher areal
BMD than Asians — this is largely (but not entirely) due to differences in
bone size rather than due to differences in volumetric BMD (3).
Growth in Femoral Width and Cortical Thickness
and The Constancy of Volumetric Density
The increase in size and bone mass of the proximal femur produces the
picture of increasing areal BMD during growth (Fig. 1, upper panels) (4). As the
femur increases in length and diameter, cortical thickness increases so that the
amount of bone within the growing bone increases in absolute terms (i.e., com-
pared with its value in grams in younger individuals) but the increase in external
size is matched by a commensurate increase in cortical thickness so that the
amount of bone in the bone, i.e., the volumetric BMD of the femur does not change
(Fig. 1, lower panels).
The increase in cortical thickness is achieved by expansion of periosteal
diameter with less expansion of the endocortical (medullary) diameter of long
bones such as the metacarpals and femur (5). (If the endocortical diameter and
periosteal diameter expanded in parallel, cortical thickness would not increase
despite the bone enlarging so that volumetric BMD would fall.) Endocortical
contraction occurs in females and perhaps to a lesser extent in males, in early
puberty with a sharp rise in cortical width so that by maturity, about 75% of
metacarpal cortical width is due to periosteal expansion while 25% is due to
endocortical contraction in females. Whether the pattern of development is simi-
lar at the femur is less certain. Provisional data suggests that the process is similar
at the femoral midshaft but endocortical (medullary) contraction occurs later than
at the metacarpal, consistant with the later growth and maturation of proximal
than distal limb segments (6) (Fig. 2). The clinical relevance of this regional
growth may emerge when exposure occurs to disease or risk factors; regions or
surfaces further from their peak may be affected more greatly than regions nearer
their peak. Medullary contraction may fail to occur at one or more sites depending
on the timing of exposure.
If volumetric BMD of the growing bone is constant from birth to adult-
hood, i.e., independent of age, then the position of an individual’s volumet-
ric BMD in the population distribution at any age is likely to be determined
prenatally. That is, the factors that determine whether an individual has a
femoral volumetric BMD at the 5th or 95th percentile are likely to be deter-
The Proximal Femur: Size, Mass, Density 5

Fig. 1. Areal and volumetric bone mineral density (BMD) of the femoral shaft
versus age in males and females. (Adapted with permission from ref. 4.)

mined before birth — unless an individual’s volumetric BMD can change

percentiles. This does not occur for height unless there is illness or recovery
from illness. The structural differences responsible for femoral volumetric
BMD being in the 5th percentile compared to 95th percentile are not known.
Until these morphological differences between individuals within a decade
as well as across decades are defined, identifying the genetic and environ-
mental causes for these differences will be difficult.
The evidence that genetic factors may determine the variance in areal
BMD in old age is partly based on studies in mother-daughter pairs. Areal
BMD z scores or standardized deviations (SD, mean ± SEM) in 74 women
mean age 73 yr with hip fractures was about – 0.5 SD at the femoral neck,
– 1.0 SD at the femoral shaft, and – 0.4 SD at the lumbar spine (7). Respec-
tive z scores in 41 daughters mean age 44 yr, were – 0.4 SD, – 0.4 SD, and
+ 0.23 SD. The deficit at the femoral shaft in the daughters (relative to their
peers) was about half the deficit of the mothers (relative to their peers) —
consistent with the genetic hypothesis (8). Daughters of women with spine
fractures had deficits in areal BMD at the spine of about – 0.8 SD. The
deficits at the proximal femur were similar to those reported in daughters of
women with hip fractures (9). The differing temporal patterns of growth of
the axial and appendicular skeleton may be antecedents for deficits at the
femur but not spine, or deficits at both sites (3,6) .
6 Seeman

Fig. 2. Periosteal diameter of the third metacarpal and femoral midshaft increases
as age advances. Endocortical diameter increases and then contracts; earlier at the
metacarpal than femoral midshaft. (Adapted with permission from ref. 6.)

Differences in Bone Mass, Size,

and Volumetric Density
Patients with and without Fractures
As areal BMD measurement does not entirely adjust for bone size, it remains
possible that the resemblance in the areal BMD in the mother-daughter pairs may
be explained by resemblance in bone size, rather than resemblance in volumetric
BMD (and therefore cortical thickness, trabecular number, and thickness). Women
and men with spine fractures have smaller vertebral bone size than age- and
gender-matched controls (10,11). Men with hip fractures may have smaller femo-
ral neck width than controls while women with hip fractures may have larger
femoral neck width than controls (12). Thus, the lower areal BMD in women with
spine fractures and men with spine or hip fractures may be at least partly due to
the smaller bone size rather than reduced volumetric BMD. The lower areal BMD
in women with hip fractures (with larger bones) may be an underestimate — the
deficit in volumetric BMD may be less than the deficit in areal BMD.
The smaller size may be due to attainment of a smaller bone size during
growth, the failure of periosteal appositional growth during aging, or both. There
is less bone in the bone because peak bone mass attained during growth may be
reduced, and/or bone loss may have been excessive. The structural basis of less
bone in bone may be thinner cortices, fewer or thinner trabeculae, or reduced true
bone density of bony tissue. The observation that men with hip fractures have