Current Topics In Osteoporosis

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^•Osteoporosis

"&^$% jfEditors
"||j|t Hong-wen Deng
f v jp': Creighton University, USA
'^ Xi'an Jiaotong University, P R China &
^/'•'it Hunan Normal University, PR China

f | Yao-zhong Liu
:v
' -. $• U' Creighlon University, USA

(- Associate Editors
|, Chun-yuan Guo
R; P&G Pharmaceuticals, USA
m Di Chen
JK University of Rochester Medical Center, USA

II ^ ^ World Scientific
^ f p ^ W JERSEY • LONDON • SINGAPORE • BEIJING • S H A N G H A I • HONG KONG • TAIPEI • CHENNAI
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CURRENT TOPICS IN OSTEOPOROSIS

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 FOREWORD

Osteoporosis has been termed a "disease of civilization", although

"industrialization" might be more apt. The disease is apparently less
common in predominantly agrarian and labor-intensive societies. The
reasons are varied and include factors as divergent as shorter life-span,
the osteotrophic effect of physical work, and simple medical under-
reporting of osteoporotic fractures. Osteoporosis has also been termed a
Gompertzian disorder, meaning that risk and prevalence rise
geometrically with age. The reasons are that the factors leading to bony
fragility are, for the most part, cumulative in their effect. As a result,
social or economic changes that lead to increases in life expectancy will
increase Gompertzian diseases as well. For this reason alone, if not for
others, osteoporosis will become an increasing problem in the nations of
East and Southeast Asia. It has been estimated, in fact, that by 2050,
there will be 6.3 million hip fractures annually, worldwide, with over
half of those in Asia.
Because osteoporotic fractures are disabling and resource-consuming,
they create heavy demands on the health care systems of nations with
high proportions of elderly. For example, in a country such as Finland,
roughly 40% of hospital bed days are accounted for by osteoporotic
fractures. Thus, prevention of osteoporotic fractures becomes of
paramount importance.
One of the more common medical myths is that, in order to prevent
and treat a disorder, one first must understand its cause. But the history
of medical advances reveals that this is rarely the case. Instead, empirical
approaches that are partially effective develop first, leading to better
diagnostic distinctions, better understanding of pathogenesis, and
ultimately, to more precise, efficacious therapies. It is a circular, iterative
process. That has certainly been the case for osteoporosis.

v
vi Foreword

First recognized as a distinct disease around the turn of the 20th

century, osteoporosis was characterized, as its very name indicated, by a
decreased amount of bony tissue in skeletal structures. This led to
development of sophisticated technology for measurement of bone mass;
but widespread application of this technology soon revealed that
knowing the mass or density of bone was not enough. In 1990, at the
Consensus Conference in Copenhagen, osteoporosis was redefined for
the first time in 90 years as a disease, not of low bone mass, but of
increased skeletal fragility. Low bone mass was retained in the
definition, but relegated to the status of a risk factor, that is, one of
several causes of fragility. This redefinition reflected a growing
understanding of the importance of factors as varied as fall patterns and
bone quality in influencing whether a person might suffer an osteoporotic
fracture. Nevertheless, the bone mass paradigm for osteoporosis had
enormous momentum, reinforced by the ability to measure mass in the
clinic with an accuracy and precision better than found in the
corresponding measures available to most other fields of medicine.
The reduced bone mass originally considered integral to the condition
was judged to be the result of excessive, unbalanced bone resorption - a
model that led naturally to the development and utilization of
antiresorptive drugs, most notably the bisphosphonates. As an instance of
the iterative character of evolving medical understanding, it soon became
apparent that these agents were more efficacious than they should have
been, had their action been primarily to alter bone loss. Moreover, as we
looked more closely at their effect, we found that the bisphosphonates
reduced fracture risk within a few months of starting treatment, before
any appreciable mass difference could accumulate. This led to a
realization that these agents were acting primarily by reducing bone
remodeling activity and that remodeling was, itself, a fragility factor. Up
till then, remodeling had been largely ignored, partly because it was
difficult to measure in the clinic with any precision, and partly because
remodeling had been considered to be a process that strengthened bone
by repairing micro-damage, not a source of weakness.
The difficulty in measuring remodeling with precision is still to some
extent with us, although the technology of bone remodeling biomarkers
is improving steadily and, given time, could rival the accuracy and
 Foreword vii

precision of bone mass measurement. The importance of quantifying

remodeling is underscored by recent advances in skeletal
histomorphometry, which have revealed that mean bony remodeling
rates double across menopause in women, and triple by the time a
woman reaches her mid 60s. These increases in remodeling are not
related to need for mechanical repair, and their net mechanical effect is a
weakening of the skeleton.
Thus osteoporotic fractures are now understood to be occurring in a
context of exaggerated remodeling that confers no mechanical benefit.
Antiresorptives are precisely the right form of therapy to reverse this
abnormal situation. In fact, it has been suggested that osteoporosis be
redefined once again, now as a disease of increased bony fragility due to
increased remodeling. Low bone mass thus becomes not the cause of the
fracture, nor even of the fragility, but a determinant of which individuals
with high remodeling will be most prone to fracture.
But even so, the bone mass technological juggernaut continues its
unstoppable downhill roll. Four years after the 1990 redefinition, a WHO
panel defined treatment cut-off values for osteoporosis exclusively in
terms of bone mass measurement. Specifically, the diagnosis
"osteoporosis" was applied to individuals with a bone density value
(BMD) more than 2.5 standard deviations below the young adult mean.
This reflected not so much a turning of the field's back on the 1990
definition as the need to establish international guidelines for diagnosis
and treatment in the absence of a well-developed technology for the
addition of other undoubted risk factors into the assessment of individual
patient risk. Advances in remodeling measurement will almost surely
lead to changes in the WHO diagnostic criteria. Already it is recognized
that the combination of high remodeling and low bone mass are much
more strongly predictive of fracture than is low BMD alone.
But even as the field expands into a better understanding of the
pathogenetic role of exaggerated remodeling, the final answer will still
elude us. Not every woman experiences an increase in bony remodeling
after menopause. Why do some and not others? We do not know. One of
the factors hypothesized to underlie the mid-life rise in bone remodeling
is a combination of low calcium intake and low vitamin D status. Since
both lead to increased parathyroid gland activity, this explanation has
viii Foreword

considerable face validity. Parathyroid hormone is known to be the

principal systemic determinant of the amount of bone remodeling
activity. But as we have gained more experience with these problems, it
has turned out that not everyone with inadequate vitamin D status
develops a parathyroid response. Why do some and not others? We do
not know.
As we make finer and finer distinctions, other such questions
continue to arise. Hence, as we have gained more experience with this
disorder and developed better treatments, it has become clear that
osteoporosis is a more complex disorder than we could have imagined.

Robert P. Heaney, M.D.

Creighton University
Omaha, Nebraska, USA
 TABLE OF CONTENTS

Foreword v
Chapter 1 Epidemiology of Osteoporosis 1
EMCLau
Chapter 2 The Social and Financial Costs of 17
Osteoporosis
Elaine King and Gang Li
Chapter 3 Pathogenesis of Osteoporosis in Asian and 26
Caucasian Women
Yunbo Duan
Chapter 4 Nutrition and Osteoporosis 67
Robert P Heaney
Chapter 5 Bone Adaptation to Mechanical Loading: How 118
Does Bone Sense the Need for Change to
Loading from Exercise?
K Shawn Davison, C J R Blimkie,
R A Faulkner, and L Giangregorio
Chapter 6 The Diagnosis of Osteoporosis in 144
Postmenopausal Women
M Janet Barger-Lux and Robert R Recker
Chapter 7 Biochemical Markers of Bone Turnover: 158
Assay Methods and Clinical Application
Chun-Yuan Guo
Chapter 8 Bone Marrow Adipogenesis in Osteoporosis 178
Chao Wan and Gang Li
Chapter 9 Statistical Methods in Osteoporosis Research 201
Ying Lu and Hua Jin

ix
x Foreword

Chapter 10 Prevention and Treatment of Postmenopausal 261

Osteoporosis
Lu Amy Sun andArkadi Chines
Chapter 11 Novel Potential Drug Targets for the 291
Anti-Resorptive Treatment of Osteoporosis
Jia Ke Xu, Shek Man Chim and
Ming Hao Zheng
Chapter 12 Male Osteoporosis 334
Lu Amy Sun andArkadi Chines
Chapter 13 Osteoporosis and Osteoarthritis 347
Yuqing Zhang
Chapter 14 Osteoporosis in Pediatrics 362
Horacio Plotkin and Richard Lutz
Chapter 15 Genetics of Osteoporosis 415
Volodymyr Dvornyk, Yao-Zhong Liu,
Hui Shen, Yong-Jun Liu and Hong-Wen Deng
Chapter 16 Pharmacogenetics and Pharmacogenomics of 445
Osteoporosis
Donghai Xiong, Ji-Rong Long, Sun Xiao,
Hong-Wen Deng
Chapter 17 Studying Osteoporosis at the Whole-Genome 464
Level: Problems and Prospects
Volodymyr Dvornyk, Peng Xiao,
Yong-Jun Liu, Hui Shen and Hong-Wen Deng
Chapter 18 Animal Models and Study Design for 499
Osteoporosis Research
Hua Zhu Ke and Xiao Jian Li
Chapter 19 Prevention and Treatment of Osteoporosis 513
with Traditional Herbal Medicine
Ling Qin, Ge Zhang, Yenyu Shi,
Kwongman Lee, Pingcheung Leung
Appendix An Introduction to Hologic Technology 533
Subject Index 535
 CHAPTER 1

EPIDEMIOLOGY OF OSTEOPOROSIS

E. M. C. Lau

Department of Community & Family Medicine,

The Chinese University of Hong Kong, 4/F School of Public Health,
Prince of Wales Hospital, Shatin, N.T., Hong Kong

The epidemiology of osteoporosis is reviewed in this article. Attempts

were made to answer the following questions:

1. How should osteoporosis be defined?

2. How can risk factors and BMD measurements be applied to diagnose
osteoporosis?
3. How do the rates for osteoporotic fractures vary by country, sex, age
and time?
4. What are the cost for osteoporosis in terms of direct and indirect
cost, morbidity and mortality?

According to the WHO criteria, osteoporosis can be defined as bone

mineral density (BMD) of 2.5 standard deviation or more below the
young normal mean. BMD measurements are predictive of fracture
risks. Hip fracture is by far the most costly of osteoporotic fracture;
and the rates are highest in Caucasians, intermediate in Asians and
lowest in Blacks. Risk factors could be used to assist in decision in
prescribing BMD measurements.

1
2 E. M. C. Lau

Research agenda
Further studies aimed at refining the use of risk factors and BMD in
predicting fractures.
Further study on the cost-effectiveness of primary and secondary
prevention of hip and other fractures.
Studies on the various aspects of epidemiology of osteoporosis in
Asian populations.

Summary
Bone mineral density measurements and risk factors can be used to
predict osteoporotic fractures. The important osteoporotic fractures are
hip fracture, vertebral fracture and forearm fracture. The incidence of
hip fracture is highest in Caucasians, intermediate in Asians and lowest
in Negroid populations. The incidence of hip fracture increases
exponentially with age in both sexes, but remains higher in women than
men throughout life. Most vertebral fractures are clinically silent but are
associated with much morbidity. Hip fracture is associated with
extremely high direct cost in developed countries; and the cost is on the
rise in developing countries.

Introduction
Osteoporosis can be defined as a "systematic skeletal disease
characterized by low bone mass, and microarchitectural deterioration of
bony tissue, with a consequent increase in bone fragility and
susceptibility to fractures" [1]. As fragility fractures are the main public
health consequence of osteoporosis, diagnostic criteria should be such
that they are predictive of fractures.

Definition
In 1994, an expert panel of the World Health Organization recommended
thresholds of bone mineral density in women to define osteoporosis [2],
that have been widely but not universally accepted by the international
 Epidemiology of Osteoporosis 3

scientific community and by regulatory agencies [3,4,5], Osteoporosis in

postmenopausal Caucasian women is defined as a value of bone mineral
density (BMD) or bone mineral content (BMC) more than 2.5 standard
deviations below the young average value (Fig 1). Severe osteoporosis
(established osteoporosis) uses the same threshold, but in the presence of
one or more fragility fractures.

Percent of population

O6 15 50 85 >99
Osteoporosis Low bone Normal i j !
mass • ! >
* X H j j 1 •

1 1 1 1 j 1 i i i i i i i i i

- 4 - 3 - 2 - 1 0 1 2 3 4
Bone mineral density (SD units ort-score)

Fig. 1 Diagnostic thresholds for women based on the distribution of bone mineral
density in the young healthy female population.

Predicting fracture risk

The association of BMD values and fracture risk has been studied in
several large cohort studies. DEXA measurements of the hip, spine,
forearm and calcaneus predict the risk of any fragility fracture in older
women similarly, each with a relative risk (RR) for any fracture of 1.5,
per age-adjusted standard deviation decrease. It is important to note that
4 E. M. C. Lau

the risk of specific types of fractures, especially hip fractures, is more

strongly predicted by measuring bone density at that site. The results of
the Study of Osteoporotic Fracture showed that the RR for hip fracture is
2.6 for each standard deviation decrease in age-adjusted BMD at the
femoral neck, while the RR is 1.5 for mid-radius [6].
BMD measurements are less accurate in predicting absolute risk than
the relative risk of fracture, for absolute risk changes marked with age
[7]. Absolute risks are important for decision making on therapeutic
interventions.
The National Osteoporosis Foundation (NOF) has issued clear
guidelines concerning the use of risk factors in predicting fracture [8]. It
was stated that risk factors for low bone density have limited value in
estimating a women's actual bone density [8]. However, risk factors
for fracture can be useful in identifying women at high risk of fractures
[9-12].
Five factors were selected by the NOF workgroup as being especially
useful in a clinical setting, because they are easily assessible and are
relatively common [8]. They were:

• Low bone mineral density;

• History of a prior fracture after age 40;
• History of a fracture at the hip, wrist, or vertebra in a first-degree
relative ("family history");
• Being in the lowest quartile in weight;
• Current cigarette smoking.

A simple counting method was recommended by the NOF, in which

practitioners will only need to determine whether a woman has had a
prior fracture, and then count whether she has none, one, two or more of
the remaining three clinical risk factors: family history of fracture,
relatively low body weight, and smoking [8]. This method is practicable.
There is a general lack of longitudind data on the relationship
between BMD measurements, risk factors and the risk of hip fracture
among Asian populations. However, cross-sectional studies
demonstrated that risk factors for hip fracture are similar to Caucasian
[13]. Moreover, the relationship between the relative risk of hip fracture
 Epidemiology of Osteoporosis 5

and diminishing BMD in Hong Kong Chinese were found to be similar

to Caucasians [14]. Hence much of the above recommendation in
Caucasian is probably applicable to Asian populations.

Fracture epidemiology
There is no universal definition of osteoporotic fractures. It is logical to
consider low energy fractures as being osteoporotic, for osteoporotic
individuals are more likely to fracture than their normal counterparts
[15]. Fractures of the hip, vertebra and forearm are considered to be
osteoporotic fractures. They share common epidemiological features:
the incidences are higher in women than in men, increases exponentially
with age, and occur at sites with a large proportion of trabecular bone
[16].
It is increasingly being recognized, however, that osteoporosis can
lead to fracture at other sites. These include fracture of the humerus,
ribs, tibia (in women), pelvis and other femoral fractures. Exclusion of
such fractures would lead to considerable underestimates in studying the
cost of osteoporosis.

Hip fracture

A. Geographical pattern

There is pronounced geographical variation in the incidence of hip

fracture, with rates being highest in Caucasians living in North Europe,
followed by rates in Caucasian living in North America. The rates are
intermediate in Asians and lowest in Black populations (Table 1) [17].
Moreover, the female to male ratio for hip fracture was 3:1 in
Caucasians, but 1:1 in Chinese and Bantu.
6 E. M. C. Lau

Table 1. Age-adjusted rate* of hip fracture per 100,000 population for females and
males, by ethnic group and year of study

Ethnic Site Year of Female Male Female to

group study male ratio
Blacks Maryland, USA 1979-1988 345 191 1.8
California, USA 1983-1984 241 153 1.6
Johannesburg, SA 1950-1964 26 29 1.3

Hispanics California, USA 1983-1984 219 97 2.3

Texas, USA 1980 305 128 2.4

Asians Hong Kong 1985 389 196 2.0

Hong Kong 1965-1967 179 113 1.6
Tottori, Japan 1986-1987 227 79 2.9
Okinawa, Japan 1984-1985 325 86 3.8
California, USA 1983-1984 383 116 3.3
Hawaii, USA 1979-1981 224 66 3.4
New Zealand 1973-1976 212 121 1.8
Singapore 1955-1962 83 111 0.7

Caucasian Sweden 1972-1981 730 581 1.3

Kuopio, Finland 1968 280 107 2.6
Malmo, Sweden 1950-1960 468 153 3.1
Norway 1983-1984 737 298 2.5
Edinburgh, 1978-1979 529 174 3.0
Scotland
Oxford, England 1983 603 114 5.3
California, USA 1983-1984 617 215 2.9
Hawaii, USA 1979-1981 645 205 3.1
New Zealand 1973-1976 466 139 3.4

* Rates were age- and gender-adjusted to the 1990 US non-Hispanic Caucasian

population.

Reproduced with permission from Villa ML, Nelson L (Ref 17).

 Epidemiology of Osteoporosis 7

The incidence of hip fracture also varies between subjects of the same
origins but living in different countries. In Europe, the incidences of hip
fracture vary more than 7 folds from one country to another [18,19].
There is some evidence that the incidence of hip fracture is raising
rapidly in developing Asian countries. For instance, in Hong Kong, a
highly urbanized city in China, the incidence of hip fracture had
increased by 200% in the last 3 decades [20]. A recent multi-national
study conducted in four Asian countries showed the incidence of hip
fracture to be directly proportional to economic developments. The
adjusted rates in Hong Kong and Singapore were almost identical to
American Caucasians (at 19 per 10,000), while the rate in Thailand and
Malaysia were 2/3 and 1/2 of the Hong Kong rates respectively [21].
With rapid economic development and aging of the population, hip
fracture will be a major health problem in Asia.
Indeed, Cooper et al [22] had projected that, by the year 2050, more
than half of all hip fractures in the world would occur in Asia. The
projected number of fractures will be 6.3 million, with 3.2 million in
Asia.

B. Secular trends

Recent research suggested that the incidence of hip fracture has

experienced either a leveling off or a slightly downturn in North America
and Europe. In Malmo, Sweden, Gullberg described a leveling off of hip
fracture incidence during the mid 80's [23]. Nungu reported that the age-
adjusted incidence of hip fracture remained at around 6/1000 population
in the Uppsala country of Sweden in the same period [24].
In the Canton of Vaud, Switzerland, Jequier et al found a slight
increase in hip fracture incidence in Swiss men, but not in women, from
1986 to 1991 [25]. In Siena, Italy, the incidence of hip fracture increased
slightly in men, but not in women from 1980 to 1991 [26].
The time trends for hip fracture in the UK from 1968 to 1986 was
studied by Spector et al, using data from the Hospital In Patient Enquiry
[27]. The standardized admission rates for hip fracture increased
tremendously from 1968 to 1980 in both sexes, after which the rates