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Contributors
RobeRt A. AdleR, Hunter Holmes McGuire VA Medical of Internal Medicine, Katholieke Universiteit Leuven, Leuven,
Center and Virginia Commonwealth University School of Belgium
Medicine, Richmond, VA, USA
Adele l. boSkey, Starr Chair in Mineralized Tissue Research and
Director, Musculoskeletal Integrity Program, Hospital for Special
MAtthew R. Allen, Departments of Anatomy and Cell Biology,
Surgery, New York; Professor of Biochemistry, Weill Medical College
Indiana University School of Medicine, Indianapolis, IN, USA
of Cornell University; Professor, Field of Physiology, Biophysics and
ShReyASee AMin, Division of Rheumatology, College of Systems Biology, Graduate School of Medical Sciences of Weill
Medicine, Mayo Clinic, Rochester, MN, USA Medical College of Cornell University; Professor, Field of Biomedical
Engineering, Sibley School, Cornell Ithaca; Adjunct Professor,
diAnA M. Antoniucci, University of California, San School of Engineering, City College of New York, NY, USA
Francisco; Physicians Foundation of California Pacific Medical
RoGeR bouillon, Laboratory of Experimental Medicine
Center, Division of Endocrinology, Diabetes and Osteoporosis,
and Endocrinology (LEGENDO), Katholieke Univeriteit Leuven
San Francisco, CA, USA
(KUL), Leuven, Belgium
AndRe b. ARAujo, New England Research Institutes, Inc., dAvid b. buRR, Departments of Anatomy and Cell Biology
Watertown, MA, USA and Orthopaedic Surgery, Indiana University School of Medicine;
Department of Biomedical Engineering, IUPUI, Indianapolis, IN,
lAuRA A.G. ARMAS, Creighton University Osteoporosis
USA
Research Center, Omaha, NE, USA
Melonie buRRowS, Department of Orthopaedics, University
GiAMpieRo i. bARoncelli, Department of Obstetrics, of British Columbia; Centre for Hip Health and Mobility,
Gynecology and Pediatrics, 2nd Pediatric Unit, ‘S. Chiara’ Hospital, Vancouver, Canada
Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
Filip cAllewAeRt, Center for Musculoskeletal Research,
SilvAno beRtelloni, Department of Obstetrics, Gynecology Leuven University Department of Experimental Medicine,
and Pediatrics, 2nd Pediatric Unit, ‘S. Chiara’ Hospital, Azienda Katholieke Universiteit Leuven, Leuven, Belgium
Ospedaliero-Universitaria Pisana, Pisa, Italy
GeeRt cARMeliet, Laboratory of Experimental Medicine
and Endocrinology (LEGENDO), Katholieke Univeriteit Leuven
ShAlendeR bhASin, Section of Endocrinology, Diabetes
(KUL), Leuven, Belgium
and Nutrition, Boston University School of Medicine and Boston
Medical Center, Boston, MA, USA luiSellA ciAnFeRotti, Department of Endocrinology and
Metabolism, University of Pisa, Pisa, Italy
john p. bilezikiAn, Department of Medicine, Division of
Endocrinology, Metabolic Bone Diseases Unit, College of Physicians juliet coMpSton, University of Cambridge School of
Clinical Medicine, Cambridge, UK
and Surgeons, Columbia University, New York, NY, USA
FeliciA coSMAn, Regional Bone Center Helen Hayes Hospital,
neil c. binkley, University of Wisconsin, School of Medicine
West Haverstraw, New York; Department of Medicine, Division of
and Public Health, Madison, WI, USA
Endocrinology, Metabolic Bone Diseases Unit, College of Physi-
cians and Surgeons, Columbia University, New York, NY, USA
Steven boonen, Center for Musculoskeletal Research,
Department of Experimental Medicine, Katholieke Division of SeRGe cReMeRS, Division of Endocrinology, Department of
Geriatric Medicine, Leuven University Hospital, Department Medicine, Columbia University, New York, NY, USA
ix
x contributors
k. ShAwn dAviSon, Laval University, Quebec City, PQ, Canada deboRAh t. Gold, Duke University Medical Center, Durham,
NC, USA
dAvid w. deMpSteR, Department of Pathology, College of
Physicians and Surgeons, Columbia University, New York, NY, USA X. edwARd Guo, Department of Biomedical Engineering,
Columbia University, New York, NY, USA
john A. eiSMAn, Bone and Mineral Research Program, Garvan
Institute of Medical Research; University of New South Wales; St pAtRick hAentjenS, Center for Outcomes Research, University
Vincent’s Hospital, Sydney, NSW, Australia Hospital Brussels, Vrije Universiteit Brussel, Brussels, Belgium
GhAdA el-hAjj FuleihAn, Calcium Metabolism and Osteo- johAn hAlSe, Department of Endocrinology and Internal
porosis Program, American University of Beirut Medical Center, Medicine, Aker University Hospital, Oslo; Spesialistsenteret
Beirut, Lebanon Pilestredet Park, Oslo, Norway
eRik Fink eRikSen, Department of Endocrinology and Internal
dAvid j. hAndelSMAn, Department of Andrology, ANZAC
Medicine, Aker University Hospital, Oslo; Spesialistsenteret
Research Institute, Concord Hospital, University of Sydney,
Pilestredet Park, Oslo, Norway
Sydney, NSW, Australia
MuRRAy j. FAvuS, Section of Endocrinology, Diabetes, and
elizAbeth M. hAney, Oregon Health and Science University,
Metabolism, University of Chicago, Chicago, IL, USA
Portland, OR, USA
dieteR FelSenbeRG, Zentrum Muskel- & Knochenforschung,
dAvid A. hAnley, University of Calgary, Calgary, AB, Canada
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin,
Freie Universität & Humboldt-Universität Berlin, Berlin, Germany
RobeRt p. heAney, Creighton University Osteoporosis
Research Center, Omaha, NE, USA
SeRGe FeRRARi, Service of Bone Diseases, Department of
Rehabilitation and Geriatrics, WHO Collaborating Center for
RAvi jASujA, Section of Endocrinology, Diabetes and Nutrition,
Osteoporosis Prevention, Geneva University Hospital, Geneva,
Boston University School of Medicine and Boston Medical Center,
Switzerland
Boston, MA, USA
dAvid p. FyhRie, David Linn Chair of Orthopaedic Surgery,
helenA johAnSSon, WHO Collaborating Centre for
Lawrence J. Ellison Musculoskeletal Research Center, Department
Metabolic Bone Diseases, University of Sheffield Medical School,
of Orthopaedic Surgery, The University of California, Davis; The
Sheffield, UK
Orthopaedic Research Laboratories, Sacramento, CA, USA
john A. kAniS, WHO Collaborating Centre for Metabolic Bone
pAtRick GARneRo, INSERM Research unit 664 and Synarc,
Diseases, University of Sheffield Medical School, Sheffield, UK
Lyon, France
jeAn-MARc kAuFMAn, Ghent University Hospital,
luiGi GennARi, Deparment of Internal Medicine, Endocrine,
Department of Endocrinology and Unit for Osteoporosis and
Metabolic Sciences, and Biochemistry, University of Siena, Italy
Metabolic Bone Diseases, Gent, Belgium
piet GeuSenS, Department of Internal Medicine, Subdivision
of Rheumatology, Maastricht University Medical Center, RobeRt klein, Bone and Mineral Unit, Oregon Health &
Science University and Portland VA Medical Center, Portland,
Maastricht, The Netherlands; Biomedical Research Institute,
OR, USA
University Hasselt, Belgium
vicente GilSAnz, Director, Childrens Imaging Research StAvRoulA kouSteni, Division of Endocrinology,
Program, Childrens Hospital Los Angeles, Professor of Radiology Department of Medicine, College of Physicians and Surgeons,
and Pediatrics, University of Southern California, Los Angeles, Columbia University, New York, NY, USA
CA, USA
diAne kRueGeR, University of Wisconsin, Madison, WI, USA
MonicA GiRotRA, Memorial Sloan-Kettering Cancer Center;
kiShoRe M. lAkShMAn, Section of Endocrinology, Dia-
Joan and Sanford I. Weill Medical College of Cornell University,
betes, and Nutrition, Division of Endocrinology & Metabolism,
New York, NY, USA
Boston University School of Medicine, Boston Medical Center,
AndReA GiuSti, Department of Gerontology & Musculo- Boston, MA, USA
Skeletal Sciences, Galliera Hospital, Genoa, Italy
thoMAS F. lAnG, Professor in Residence, Department of
AndReA GiuStinA, Department of Endocrinology & Radiology and Biomedical Imaging, and Joint Bioengineering
Metabolic Diseases, Leiden University Medical Center, Leiden, Graduate Group, University of California, San Francisco, San
The Netherlands Francisco, CA, USA
SteFAn GoeMAeRe, Ghent University Hospital, Department bRuno lApAuw, Ghent University Hospital, Department of
of Endocrinology and Unit for Osteoporosis and Metabolic Bone Endocrinology and Unit for Osteoporosis and Metabolic Bone
Diseases, Gent, Belgium Diseases, Gent, Belgium
Contributors xi
joAn M. lAppe, Creighton University Osteoporosis Research SteFAno MoRA, Departments of Radiology and Pediatrics,
Center, Omaha, NE, USA Childrens Hospital Los Angeles, Los Angeles, California, USA;
Laboratory of Pediatric Endocrinology, BoNetwork, San Raffaele
benjAMin z. ledeR, Endocrine Unit, Department of Medicine, Scientific Institute, Milan, Italy
Massachusetts General Hospital and Harvard Medical School,
Boston, MA, USA tuAn v. nGuyen, Bone and Mineral Research Program, Garvan
Institute of Medical Research; University of New South Wales; St
willeM leMS, Department of Rheumatology, Vrije Universiteit Vincent’s Hospital, Sydney, NSW, Australia
Amsterdam; VU Medisch Centrum, Amsterdam, The Netherlands
AndeRS oden, WHO Collaborating Centre for Metabolic Bone
X. SheRRy liu, Departments of Medicine and Biomedical Diseases, University of Sheffield Medical School, Sheffield, UK
Engineering, College of Physicians and Surgeons, Columbia
University, New York, NY, USA clAeS ohlSSon, Center for Bone Research, Department
of Medicine, Sahlgrenska Academy, University of Gothenburg,
Shi S. lu, Regional Bone Center, Helen Hayes Hospital, West Gothenburg, Sweden
Haverstraw, New York, NY, USA
teRence w. o’neill, Epidemiology arc Unit, University of
Manchester, Manchester, UK
heAtheR M. MAcdonAld, Schulich School of Engineering,
University of Calgary, Calgary, Canada
eRic S. oRwoll, Bone and Mineral Unit, Oregon Health &
Science University, Portland, OR, USA
chRiStA MAeS, Laboratory of Experimental Medicine and
Endocrinology (LEGENDO), Katholieke Universiteit Leuven
SocRAteS e. pApApouloS, Department of Endocrinology &
(KUL), Leuven, Belgium
Metabolic Diseases, Leiden University Medical Center, Leiden,
The Netherlands
Ann e MAloney, Maine Medical Center Research Institute,
Scarborough, ME, USA
René Rizzoli, Division of Bone Diseases [WHO Collaborating
Center for Osteoporosis Prevention] Department of Rehabilitation
peGGy MAnnen cAwthon, San Francisco Coordinating
and Geriatrics, Geneva University Hospitals and Faculty of Medicine,
Center, California Pacific Medical Center Research Institute, San
Geneva, Switzerland
Francisco, CA, USA
cliFFoRd j. RoSen, Maine Medical Center Research Institute,
clAudio MARcocci, Department of Endocrinology and
Scarborough, ME, USA
Metabolism, University of Pisa, Pisa, Italy
MARtin RunGe, Aerpah Clinic Esslingen, Esslingen, Germany
lynn MARShAll, Department of Medicine, Bone and Mineral
Unit, Department of Public Health and Preventive Medicine,
john t. SchouSboe, Park Nicollet Health Services,
Oregon Health & Science University, Portland, OR, USA
Minneapolis; Division of Health Policy & Management, School of
Public Health, University of Minnesota, MN, USA
GheRARdo MAzziotti, Department of Medical and Surgical
Sciences, University of Brescia, Italy
eGo SeeMAn, Endocrine Centre, Heidelberg Repatriation
Hospital/Austin Health, Department of Medicine, University of
euGene v. MccloSkey, WHO Collaborating Centre for
Melbourne, Melbourne, Victoria, Australia
Metabolic Bone Diseases, University of Sheffield Medical School,
Sheffield, UK
MARkuS j. Seibel, Bone Research Program, ANZAC Research
Institute, The University of Sydney, Sydney, NSW, Australia
heAtheR A. MckAy, Department of Orthopaedics, University of
British Columbia; Centre for Hip Health and Mobility; Department
deboRAh e. SellMeyeR, Metabolic Bone Center, The Johns
of Family Practice, University of British Columbia, Vancouver,
Hopkins Bayview Medical Center, Baltimore, MD, USA
Canada
elizAbeth ShAne, Columbia University College of Physi-
chRiStiAn MeieR, Division of Endocrinology, Diabetes and cians & Surgeons, New York, NY, USA
Clinical Nutrition, University Hospital Basel, Basel, Switzerland
jAy R. ShApiRo, Bone and Osteogenesis Imperfecta Programs,
pAul d. MilleR, University of Colorado Health Sciences Kennedy Krieger Institute; Department of Physical Medicine and
Center, Medical Director, Colorado Center for Bone Research, Rehabilitation, Johns Hopkins University, Baltimore, MD, USA
Lakewood, CO, USA
Shonni j. SilveRbeRG, Division of Endocrinology,
biSMRutA MiSRA, College of Physicians and Surgeons, Department of Medicine, College of Physicians and Surgeons,
Columbia University, New York, NY, USA Columbia University, New York, NY, USA
xii contributors
StuARt l. SilveRMAn, Cedars-Sinai/UCLA and the OMC kAtRien venken, Center for Musculoskeletal Research,
Clinical Research Center, Los Angeles, CA, USA Leuven University Department of Experimental Medicine,
Katholieke Universiteit Leuven, Leuven, Belgium
RAjAn SinGh, Section of Endocrinology, Diabetes and
Nutrition, Boston University School of Medicine and Boston lieve veRlinden, Laboratory of Experimental Medicine and
Medical Center, Boston, MA, USA Endocrinology (LEGENDO), Katholieke Universiteit Leuven
(KUL), Leuven, Belgium
eMily M. Stein, Columbia University College of Physicians &
Surgeons, New York, NY, USA AnneMieke veRStuyF, Laboratory of Experimental Medicine
and Endocrinology (LEGENDO), Katholieke Universiteit Leuven
thoMAS w. StoReR, Section of Endocrinology, Diabetes (KUL), Leuven, Belgium
and Nutrition, Boston University School of Medicine and Boston
QinGju wAnG, Endocrine Centre, Heidelberg Repatriation
Medical Center, Boston, MA, USA
Hospital/Austin Health, Department of Medicine, University of
Melbourne, Melbourne, Victoria, Australia
pAwel Szulc, INSERM Research Unit 831, Hôspital Edouard
Heriot, Lyon, France
connie M. weAveR, Department of Foods and Nutrition,
Purdue University, West Lafayette, IN, USA
MAhMoud tAbbAl, Calcium Metabolism and Osteoporosis
Program, American University of Beirut Medical Center, Beirut,
FeliX w. wehRli, Department of Radiology, University of
Lebanon
Pennsylvania, Philadelphia, PA, USA
youRi tAeS, Ghent University Hospital, Department of Sunil j. wiMAlAwAnSA, Professor of Medicine, Endo-
Endocrinology and Unit for Osteoporosis and Metabolic Bone
crinology & Metabolism; Director, Regional Osteoporosis Center,
Diseases, Gent, Belgium
Department of Medicine, Robert Wood Johnson Medical School,
New Brunswick, NJ, USA
chARleS h. tuRneR, Department of Orthopaedic Surgery,
Indiana University School of Medicine, Indianapolis; Department of kRiStine M. wiRen, Bone and Mineral Unit, Oregon Health &
Biomedical Engineering, IUPUI, IN, USA Science University; Portland VA Medical Center, Portland,
OR, USA
lieSbeth vAndenput, Center for Bone Research, Department
of Medicine, Sahlgrenska Academy, University of Gothenburg, RoGeR zebAze, Department of Endocrinology and Medicine,
Gothenburg, Sweden Austin Health, University of Melbourne, Melbourne, Victoria,
Australia
diRk vAndeRSchueRen, Center for Musculoskeletal
Research, Leuven University Department of Experimental huA zhou, Regional Bone Center, Helen Hayes Hospital, West
Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Haverstraw, New York, NY, USA
Foreword
The field of osteoporosis has grown enormously over the last shorter in duration with surrogate, instead of fracture, end-
4 decades, with a focus upon the issues that relate to skeletal points. With this smaller database, it nevertheless appears
health in women. It was only about 15 years ago that the sci- that men respond to available pharmacological approaches
entific community began to acknowledge that osteoporosis to osteoporosis in a similar manner to women (Section 10).
in men is also important. The first edition of Osteoporosis in Available clinical data support the efficacy of these therapies
Men, published in 2001, was a seminal event in that it called in men with both primary and secondary osteoporosis.
attention to the problem in an organized series of articles on Finally, Osteoporosis in Men, second edition provides
male skeletal health and bone loss. Now, with this second a view of the future, underscoring a number of unresolved
edition of Osteoporosis in Men, further progress in this area issues to be included in the agenda for future research in
is emphasized with particular emphasis on new knowledge this area. These include discussions related to an appropriate
that has appeared during the last decade. BMD-based definition for male osteoporosis, a further under-
Osteoporosis in men is heterogeneous with many eti- standing of the factors implicated in age-related bone loss and
ologies to consider besides the well known roles of aging idiopathic osteoporosis in men, and randomized-controlled
(Sections 1-4) and sex steroids (Sections 6-8). The roots of studies directly assessing fracture risk reduction, particularly
the problem in some individuals can be back dated to the for non vertebral fracture. In all these areas, more definitive
pre-pubertal and pubertal growth periods that determine the information is needed.
acquisition of peak bone mass. This thorough and comprehensive book integrates new,
In addition, Osteoporosis in Men, second edition, deals accessible and informative material in the field. It will
exhaustively with important clinical issues. Nutritional con- help investigators, as well as practitioners and students, to
siderations, the clinical and economic burden of fragility improve their understanding of male skeletal health and
fractures, and diagnostic approaches are particularly strong bone loss. The additional knowledge, assembled in such a
aspects of the text (Sections 5, 7, 9). These chapters tran- readable manner, should help us achieve one of our ultimate
scend, in part, the specific focus of the volume, making it a goals-better care of men with osteoporosis.
useful resource and a valuable reference for an audience not
necessarily well-informed in bone and mineral disorders. Gerolamo Bianchi, MD
The last section of Osteoporosis in Men, second edition, Department of Locomotor System
highlights therapeutic approaches. Treatment options are less Division of Rheumatology
well defined in men than in women because virtually all of Azienda Sanitaria Genovese
the clinical trials involving men have been much smaller and Genova, Italy
xiii
Preface to the Second Edition
The first edition of Osteoporosis in Men was published The increased scope of the book is the result of contribu-
in 1999, about 15 years after the earliest publications on the tions from prominent experts in the field, including many
subject. Over the past decade, we have witnessed a surge who contributed chapters to the first edition. New authors
of further interest in the subject of male osteoporosis. This also have provided novel insights for the second edition.
second edition of Osteoporosis in Men is, thus, timely. Editorial responsibilities were shared by the three of us.
In the second edition, we have made major additions to As was the goal before, Osteoporosis in Men, Second
reflect increased areas of new knowledge, including genet- Edition, is meant to be useful to a broad audience, including
ics and inherited disorders. Previous topics are updated and students of the field as well as those already knowledgeable.
extended to make them timely also. New topics include: We have sought to summarize a compendium of informa-
tion intersecting general and specific areas of interest. This
l Important basic processes including bone biochemistry
volume will make apparent that information available con-
and remodeling
cerning osteoporosis in men still lags behind what we know
l Mechanical properties and structure
about osteoporosis in women. On the other hand, major
l Genetics and inherited disorders
advances in our understanding of the male skeleton in health
l Growth and puberty
and in disease are being translated into practical approaches
l Nutrition, including calcium, vitamin D, protein and
to their clinical management. We hope this second edition
other factors
provides a valuable reference source for you and that it also
l Sex steroids in muscle and bone
will serve to stimulate further advances in the field.
l Assessment of bone using DXA, CT, ultrasound, bio-
chemical markers
Eric Orwoll
l Sarcopenia and frailty
Portland, Oregon
l Diagnostic approaches
l Treatment approaches including bisphosphonates, parathy-
John Bilezikian
roid hormone, androgens and SARMS and newer agents.
New York, New York
A key element of the book continues to be sex differ-
ences in bone biology and pathophysiology that can inform Dirk Vanderschueren
our understanding of osteoporosis in both men and women. Leuven, Belgium
xv
1
Chapter
the Biochemistry of Bone: Composition
and Organization
Adele l Boskey
Starr Chair in Mineralized Tissue Research and Director, Musculoskeletal Integrity Program, Hospital for Special Surgery, New York;
Professor of Biochemistry, Weill Medical College of Cornell University; Professor, Field of Physiology, Biophysics and Systems Biology,
Graduate School of Medical Sciences of Weill Medical College of Cornell University; Professor, Field of Biomedical Engineering, Sibley
School, Cornell Ithaca; Adjunct Professor, School of Engineering, City College of New York, USA
IntroductIon tubular (long and short) bones such as the femur and digits,
respectively, and the flat bones, such as the calvaria in the
As detailed throughout this book, osteoporosis is charac- skull. Slightly better resolved, at the millimeter level, are the
terized by increased risk of fracture due to changes in the components of the bones, the cortices that surround the mar-
‘quality’ of bone [1]. To appreciate why bone becomes row cavity, the cancellous bone within the marrow cavity,
weaker or less resilient to fracture with age in both men the marrow cavity itself, the cartilaginous ends, etc. At the
and women and in individuals of different races, a gen- micrometer to millimeter level are the individual intercon-
eral knowledge of bone development and age-dependent necting struts of the trabeculae, the lamellae and the osteons
changes is necessary. In line with the theme of this book, that surround the vascular canals. The cells and the com-
it is noted that there are both age- and sex-dependent dif- posite matrices also can be visualized as part of this micro-
ferences in bone properties and composition, some related structure. Finally, at the nanometer level, bone consists of an
to the rate at which bones develop in boys and girls, some organic matrix made mainly from collagen fibrils and non-
related to the impact of genes on the X-chromosome which collagenous proteins, lipids, nanometer size mineral crystals
produce proteins important for bone development and/or (discussed below) and water. There is also heterogeneity
metabolism and some due to the direct effect of sex ster- in both the size of the collagen fibrils and the composition
oids on bone cells [2]. To appreciate the discrete differ- and sizes of the crystals deposited on this matrix [3, 4]. This
ences between bone structure and composition in men and heterogeneity is important for the mechanical competence
women this chapter reviews the basics of bone composi- of the tissue [5]. To understand the process of mineraliza-
tion and organization and the mineralization process from tion, knowledge of the cells and the extracellular matrices
the point of view of sexual dimorphism, where such differ- of bone is required.
ences between men and women are recognized. Emphasis
is placed on those factors that contribute to bone strength;
Bone cells
geometry, architecture, mineralization, the nature of the
organic matrix and tissue heterogeneity. Within the bone matrix are the cells that are responsible
for bone formation and bone turnover. Three key cells are
of mesenchymal origin – chondrocytes, osteoblasts and
osteocytes. The chondrocytes that form cartilage within the
Bone organIzatIon
epiphysial growth plates produce a matrix that can be min-
eralized, regulate the flux of ions that facilitate the miner-
Bone Heterogeneity
alization of that matrix and orchestrate the remodeling of
The structure of bone appears different depending on that matrix and its replacement by bone [6]. The other mes-
the scale at which it is examined. At the centimeter level, enchymal derived bone cells are the osteoblasts and osteo-
whole bone can be viewed as an organ, for example, the cytes [7]. As seen in the electron micrograph in Figure 1.1,
Copyright 22000190, Elsevier, Inc.
Osteoporosis in Men All rights of reproduction in any form reserved.
Osteoporosis in Men
Osteoclasts
Osteoblast
Bone
50 Microns
FIgure 1.2 Transmission electron micrograph of an osteoclast
on the bone surface of a 70-year-old woman. The ruffled borders
0.5µm Osteocyte sealing the cell to the mineralized surface are indicated along with
the magnification. Courtesy of Dr Stephen B. Doty, Hospital for
Special Surgery, New York.
FIgure 1.1 Transmission electron micrograph showing oste-
oblasts lining the bone surface in an adult male Sprague-Dawley
rat. Inside the bone are the osteocytes, connected to one another
by canaliculae. The banded pattern of the collagen is also visible. in trabecular number, while in males there is a thinning of
Magnification is marked on the figure. Courtesy of Dr Stephen B.
trabeculae [13]. Some of the other functions of osteoblasts
Doty, Hospital for Special Surgery, New York.
and osteocyte proteins will be discussed later.
The cells responsible for the turnover of bone, the osteo-
clasts, are of hematologic and macrophage origin [14]. As
osteoblasts line the surface of the mineralized bone. They seen in the electron micrograph in Figure 1.2, these multi-
synthesize new matrix and regulate the mineralization and nucleated giant cells attach to the surface of the bone via a
turnover of that matrix. Once these osteoblasts become ‘ruffled border’. They receive signals from osteoblasts that
engulfed in mineral they become osteocytes and connect control bone remodeling and regulate the turnover of the
with one another by long processes (canaliculae) (see Figure mineralized matrix. They remove bone by producing acid
1.1). The osteocytes are the cells that sense mechanical sig- and couple that with the transport of chloride out of the
nals and then convey them through the matrix. Osteocytes cell. The acid dissolves the mineral (see below) and, after
produce many of the same proteins as osteoblasts, but the the mineral is removed, release proteolytic enzymes that
relative concentrations of these proteins are not the same degrade the matrix. During the dissolution of the matrix,
and the ways in which these cells use regulatory pathways signaling molecules communicate with the osteoblasts and
differ. As reviewed in detail elsewhere [8], the osteoblasts new bone formation is triggered. Androgens and estrogens
use the WNT/beta-catenin pathway [9] to regulate synthesis inhibit osteoclast activity to different extents [15] explain-
of new bone; the osteocytes use the WNT/beta-catenin path- ing some of the sexual dimorphism in osteoclast activity.
way to convey mechanical signals. Osteoblasts synthesize There are a number of other cells in bone, marrow stromal
more alkaline phosphatase, more type I collagen and more cells, pericytes, vascular endothelial cells, fibroblasts, etc that
bone sialoprotein than osteocytes, while osteocytes specifi- function as stem cells [16] but their properties are beyond the
cally produce sclerostin, a glycoprotein that is a WNT and scope of this chapter and will not be discussed here.
BMP antagonist, and produce high levels of dentin matrix
protein 1 [8]. Sclerostin, an osteocytes specific protein,
Skeletal development
inhibits osteoblast differentiation and, based on the sig-
nificant increase in bone mineral density in the sclerostin The shapes of male and female adult bones are different and,
knockout mouse [10], is believed to be important in deter- for archeologists, form the basis for the identification of sexes
mining the high bone mass phenotype [11]. This increase in in skeletal remains [17]. The early development of the skel-
bone mass was noted to be comparable for both sexes [10]. eton contributes markedly to these sexual differences. During
There is sexual dimorphism in the density of osteocytes, as development, bone structure changes in length and width and
females gain osteoclast lacunar density with increasing age, there is a concomitant alteration in tissue density, resulting in
while males show a decrease in this parameter [12]. This a bone that is optimally designed to bear the loads imposed
may explain why bone loss in women results in a decrease on it [18]. In the long and short tubular bones, endochondral
