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Osteoporosis
Progress
and Promise
Progress
and Promise
From the National Institute of Arthritis and Musculoskeletal and Skin
Diseases
About Osteoporosis
Osteoporosis is a skeletal disorder characterized by compromised bone
strength predisposing to an increased risk of fracture. Bone strength
reflects the integration of two main features: bone density and bone
quality. Osteoporosis is the most common of the bone diseases that
affect Americans. Although it is the underlying cause of most fractures
in older people, the condition is silent and undetected in many cases
until a fracture occurs.
Osteoporosis is a major health risk for 28 million Americans. In the
United States today, 10 million individuals already have osteoporosis
and 18 million more have low bone mass, placing them at increased risk
for this disease. American women are four times more likely to develop
osteoporosis than men. One out of every two women and one in eight men
over 50 will have an osteoporosis-related fracture in her or his
lifetime. Osteoporosis may be attributed to three factors: (1)
accelerated bone loss at menopause in women or as men and women age; (2)
suboptimal bone growth during childhood and adolescence resulting in
failure to reach peak bone mass; and (3) bone loss secondary to disease
conditions, eating disorders, or certain medications and medical
treatments.
Osteoporosis is responsible for more than 1.5 million fractures
annually, including 300,000 hip fractures, approximately 700,000
vertebral (spinal) fractures, 250,000 wrist fractures, and more than
300,000 fractures at other sites. In the presence of osteoporosis,
fractures can occur from normal lifting and bending, as well as from
falls. Furthermore, osteoporotic fractures, particularly vertebral
fractures, can be associated with disabling pain.
Of all the fractures, hip fractures have the greatest morbidity and
socioeconomic impact. One in five patients is no longer alive 1 year
following an osteoporotic hip fracture. This means people can and do die
as a result of hip fractures. Fifty percent of those people experiencing
a hip fracture will be unable to walk without assistance, and 28 percent
will require long-term care. The burden of health care costs due to
osteoporotic fractures is estimated to be $10 to $15 billion per year.
Research has enhanced our knowledge about how to maintain a healthy
skeleton throughout life. This has led to progress in understanding the
causes, prevention, diagnosis, and treatment of osteoporosis. Every
research advance brings us closer to eliminating the pain and suffering
caused by this disease.
Addressing Osteoporosis: A Collaborative Approach
Substantial efforts are underway at the Federal level to address this
serious public health problem. Recognizing that significant advances
have been made since the National Institutes of Health (NIH) hosted an
osteoporosis consensus development conference in 1984, the Office of
Medical Applications of Research (OMAR) and the National Institute of
Arthritis and Musculoskeletal and Skin Diseases (NIAMS) were primary
sponsors of the Consensus Development Conference on Osteoporosis
Prevention, Diagnosis, and Therapy that was held in March 2000. The
consensus panel issued a statement based upon information that addressed
five questions: (1) What is osteoporosis and what are its components?
(2) How do risks vary among different segments of the population? (3)
What factors are involved in building and maintaining skeletal health
throughout life? (4) What are the optimal evaluation and treatment of
osteoporosis and fractures? and (5) What are the directions for future
research?
Several components of the NIH are currently supporting basic and/or
clinical research on osteoporosis and related bone diseases. NIAMS has
taken the lead in initiating the Federal Working Group on Bone Diseases.
This group provides a forum for sharing information among NIH institutes
and other Federal agencies to enhance communication and to coordinate
research efforts.
The Study of Osteoporotic Fractures (SOF), supported by NIAMS and the
National Institute on Aging (NIA) and involving more than 9,000
Caucasian women 65 years or older, described risk factors for hip,
wrist, and spine fractures. The study demonstrated that bone mineral
density predicts hip and other types of fractures, and also provided
evidence that women with low bone density have an increased risk of
stroke, as well as evidence of a relationship between bone mineral
density and breast cancer incidence. The NIH Women's Health Initiative
currently supports the largest study of osteoporosis and fractures ever
conducted. This study will determine the usefulness of calcium and
vitamin D supplements, and may lead to new public health initiatives to
optimize the intake of these nutrients in the U.S. population.
While osteoporosis in women has received substantial attention, less
scrutiny has been devoted to osteoporosis in men. Perhaps this is
because men tend to have a higher peak bone mass at maturity and a more
gradual reduction in sex hormones, resulting in a later development of
osteoporosis. Yet, an estimated one-third of hip fractures worldwide
occur in men. The cause and pathology of osteoporosis in men is now
receiving research attention under a seven-center grant supported by
NIAMS, NIA, and the National Cancer Institute (NCI).
Addressing Osteoporosis: The NIAMS Research Agenda
NIAMS leads the Federal research effort on osteoporosis and related bone
diseases and, NIH-wide, is responsible for about one-third of the
funding for research in this area. This funding exceeded $136 million in
FY 1999. NIAMS-supported research ranges from basic studies to clinical
and translational research, as well as early intervention and prevention
projects such as "Camp Calcium," a novel program for
adolescent girls. The goal of the Camp Calcium program is to determine
how much calcium growing girls need in their diets so that they can
develop the strongest possible bones, which will help reduce their
chance of getting osteoporosis later in life.
Overall, significant advances in preventing and treating osteoporosis
are available today, as the direct result of research focused on (1)
determining the causes and consequences of bone loss at cellular and
tissue levels; (2) assessing risk factors; (3) developing strategies to
maintain and even enhance bone density; and (4) exploring the roles of
such factors as hormones, calcium, vitamin D, drugs, and exercise on
bone mass.
Selected Scientific Advances
Identification of a gene essential for the formation of bone. Through a
convergence of efforts by investigators around the world, research has
shown that normal skeletal development--in both mice and
humans--requires two active copies of the gene Cbfa1. This discovery is
expected to open a number of exciting new research areas.
Finding that estrogen causes "programmed cell death" in cells
that are responsible for degradation of bone (osteoclasts). By paving
the way for future assessment of whether drugs can also affect the
programmed cell death of osteoclasts (thereby making them potentially
useful as bone-protecting treatments), this discovery represents an
exciting link between basic research and tangible patient benefit.
Finding that one of a collection of molecules created by researchers
(called peptidomimetics) successfully blocks part of the bone resorption
process. This is the first clear indication that a particular synthetic
antagonist may be effective in the prevention of osteoporosis. The
finding may hold promise for combating bone loss in women who cannot
tolerate estrogen.
Patient-based research showing that elderly women who already had
several spine fractures at the start of a study experienced the greatest
health benefit from calcium supplementation (both in terms of reducing
the rate of new spine fractures and stopping bone loss). This finding
has clear implications for developing and targeting new preventive
strategies.
Low-dose estrogen study. Because estrogen is currently the first line of
defense for osteoporosis but has known side effects, it is critical to
find the lowest effective dose that will preserve and even add bone. A
recent study supported by NIAMS tested the usefulness of daily low-dose
estrogen plus progesterone in women over age 65 and found that these
women showed significant increases in spine, forearm, and total body
bone mineral density. This study provides proof that low-dose estrogen
can be an effective preventive and therapeutic option.
Study of osteoporotic fractures (SOF). The development of
risk-prediction models for osteoporotic fractures that incorporate
clinical risk factors along with bone mineral density measurements is an
important advance in identifying persons at greatest risk for fractures
and for whom intervention measures may be suitable. The SOF, a study of
postmenopausal Caucasian women, led to the identification of 14 clinical
risk factors. Possession of five or more of these factors greatly
increased the risk of fracture in the women in the study.
Secondary osteoporosis. Information regarding the diseases, physical
states, medical treatments, and drugs that can lead to the development
of secondary osteoporosis is now available to physicians. The
information alerts physicians to the appropriate use of treatment, the
monitoring of patients at risk, and, where possible, the use of
intervention measures to prevent the development of osteoporosis. For
example, it is generally agreed that patients on glucocorticoid therapy
for 2 months or longer and patients whose conditions place them at high
risk for osteoporotic fractures should be considered for bone density
measurement.
Screening in the general population. Because there is a lack of
sufficient evidence regarding the cost-effectiveness of routine
screening or the efficacy of early initiation of preventive drugs, an
individualized approach is recommended for testing for bone loss.
Testosterone study. Circulating levels of testosterone are known to
decline in men as they age, leading to bone loss. A recent clinical
trial of testosterone supplementation in a group of older men with low
hormone levels revealed little difference in bone mineral density
between the placebo- and testosterone-treated men, indicating that
hormone therapy to replace bone mass is not necessary for most older
men.
Gene for osteoporotic fractures. A recent study showed that women 65 and
older with the apolipoprotein E (APOE*4) gene on chromosome 19 were
nearly twice as likely as those without the gene to suffer hip and wrist
fractures. Women with this gene experience weight loss that contributes
to bone loss and may have reduced levels of vitamin K, which stimulates
bone formation and reduces bone-cell loss.
Body mass index. Suboptimal bone growth in childhood and adolescence is
as important as bone loss to the development of osteoporosis. Growth
hormone and insulin-like growth factor-I, which are secreted the most
during puberty, play a role in acquiring and maintaining bone mass and
in determining body composition into adulthood. Children and youth with
low body mass index (BMI) are likely to have a lower-than-average peak
bone mass. There is a direct association between BMI and bone mass
throughout the adult years, and several studies of fractures in older
persons have shown an inverse relationship between fracture rates and
BMI.
Nutritional studies. It is known that calcium is essential for building
strong bones and reducing fracture risk. Vitamin D is required for
optimal calcium absorption by the body. Both substances should be part
of any osteoporosis treatment. Recent studies have shown that while some
substances, such as high dietary protein, caffeine, phosphorus, and
sodium, can adversely affect calcium balance, their effects appear not
to be important in individuals who have an adequate calcium intake.
Gender/ethnicity. Caucasian postmenopausal women experience almost
three-quarters of hip fractures. However, women of other age, racial,
and ethnic groups, as well as men and children, are also affected by
osteoporosis. Much of the difference in fracture rates among these
groups appears to be explained by differences in peak bone mass and rate
of bone loss. Differences in bone geometry, frequency of falls, and
presence of other risk factors also appear to play a role.
New drugs. Bisphosphonates and selective estrogen receptor modulators (SERMs)
are fairly recent prevention and treatment options for osteoporosis.
Randomized placebo-controlled trials and meta-analysis of
bisphosphonates (etidronate, alendronate, and risedronate) show that all
increase bone mineral density at the spine and hip in a dose-dependent
manner and reduce the risk of vertebral fractures by 30 to 50 percent.
In large clinical trials, raloxifene, a SERM recently approved by the
Food and Drug Administration, reduced the risk of vertebral fracture by
36 percent.
Exercise and falls. There is some evidence that childhood exercise,
particularly resistance and high-impact exercise (such as weight
training), contributes to higher peak bone mass. While there are health
benefits to low-impact exercise, such as walking, it has minimal benefit
for bone mineral density. Acknowledging that falls are a major risk
factor for osteoporotic fractures, researchers conducted randomized
clinical studies of exercise during adulthood and later in life that
showed that the conditioning, balance-enhancing, and muscle-building
effects of exercise reduce falls by approximately 25 percent.
Ultrasound. Clinical trials of drug therapy for osteoporosis have most
often used dual photon x-ray absorptiometry (DXA) to measure bone
mineral density. Studies of the less cumbersome and less expensive
quantitative ultrasound (QUS) of the heel show that QUS predicts hip
fracture and other nonvertebral fractures nearly as well as DXA at the
femoral neck.
Biomarkers. Biomarkers of bone remodeling (formation and breakdown),
such as alkaline phosphatase and osteocalcin (serum markers) and
pyridinolines and deoxypyridinolines (urinary markers), are of limited
utility in evaluating individual patients because they do not predict
bone mass or fracture risk. However, research studies show that
biomarkers correlate with changes in indices of bone remodeling and may
provide insights into the mechanisms of bone loss.
Current and Planned Initiatives
In the past decade, there has been an explosion of basic and clinical
research in osteoporosis. However, many fundamental advances in
molecular and cellular biology, immunology, genetics, and bioengineering
have not yet been applied to skeletal biology. In addition, research on
SERMs holds promise for reducing bone loss in postmenopausal women
without adverse effects on other organs. Vast opportunities exist to
expand the current knowledge base, continuing in a diverse approach to
osteoporosis. Initiatives that may serve as springboards for further
research include:
Multicenter clinical intervention studies on combination therapies for
osteoporosis. Because pharmaceutical companies tend to focus resources
on bringing individual drugs to market, Federal support is needed to
test combinations of drugs, as well as possible exercise and nutritional
modifications to various drug combinations. Lower doses and combinations
of effective agents may reduce the side effects and risks associated
with current individual drug treatments, and may improve overall
responsiveness. These studies will also generate information on
osteoporosis in men, children, adolescents, and those who have diseases
and conditions that put them at high risk for osteoporosis, moving
beyond postmenopausal women, the group on whom most private sector
research has been concentrated.
The bone density, biomarkers, and physical activity component of the
National Health and Nutrition Examination Survey (NHANES) IV. National
Health and Nutrition Examination Surveys have been conducted
periodically since the 1960s, through household interviews and physical
examinations provided in specially designed mobile examination centers,
and with data collection periods ranging from 3 to 6 years. NHANES IV is
planned as a continuous survey, and new data collection began in 1999.
NIAMS is specifically interested in information from three tests to be
included in the exam: dual photon x-ray absorptiometry (DXA),
measurements of markers of bone resorption in urine and blood samples,
and assessment of musculoskeletal strength in participants aged 50 and
over.
Understanding the effects of therapeutic agents. While estrogen
continues to be an important hormone for the treatment of osteoporosis,
particularly in postmenopausal women, new treatment drugs have recently
been introduced into the marketplace that may prove helpful to a broader
population. These include alendronate, a bisphosphonate, and raloxifene,
a selective estrogen receptor modulator. Recent knowledge about the link
between bone and the cardiovascular system suggests that drugs commonly
used to reduce cholesterol may also have beneficial effects on the
skeleton. NIAMS is supporting research that examines the molecular and
cellular mechanisms by which currently used agents work in the hope of
advancing knowledge about their application to bone.
Animal models to study the bone matrix. There is growing evidence
suggesting that the bone matrix is a source of important biochemical
signals that influence the activity of bone cells, telling them where to
break down or form new bone. The identification of matrix components
that influence cell function could lead to new drugs that mimic these
signals. NIAMS supports research that uses new, genetically modified
mice as a model to examine the interaction between bone cells and the
bone matrix.
Control of osteoblast differentiation. Osteoblasts (bone-forming cells)
arise from precursor cells that differentiate to form different tissues.
Some osteoblasts differentiate further to become osteocytes, the cells
that are thought to be important for the response of bone to mechanical
loading. The complex balance between the generation of precursor cells,
their differentiation into osteoblasts and osteocytes, and ultimately
their death, determines the rate of new bone formation. NIAMS is
encouraging research that addresses the control of osteoblast
differentiation and the generation of genetic resources to advance this
research.
Effect of loading on bone development early in life. Bone mass during
adult life reflects the amount acquired during growth minus that which
is subsequently lost. Thus, maximizing peak bone mass may provide an
effective strategy to prevent osteoporosis. Two hundred prepubescent
children are participating in a study to determine the impact of
jumping, a high weight-bearing exercise, on the development of bone
mass. The study may show that implementing a specific bone-loading
program during childhood will enhance the development of both bone mass
and mineralization at an earlier age. This would provide a larger
foundation for mineralization and growth through adolescence, thereby
reducing the risk of future osteoporotic fractures.
Genetic analysis of bone mass. Although lifestyle and environmental
factors play a role, up to 75 percent of bone mineral density is
genetically determined. Researchers are employing a new method of
mapping genes that influence continuously varying traits, such as bone
mass. In mouse experiments, researchers have identified 17 candidate
genes that may influence the development of peak bone mass during
skeletal growth. The mapping of risk and protective genes in mice and
the development of unique animal models for isolating the effects of
those genes offer an important route to the possible identification of
risk and protective genes in humans. This would allow prediction of
individual--rather than general--risk, which in turn could lead to
effective targeting of prevention-based treatment strategies to
high-risk populations.
Understanding the molecular pathways that mediate PTH. Intermittently
administered parathyroid hormone (PTH) can stimulate increases in bone
mass. Although practical problems may limit the use of PTH in this way,
current research on the molecular pathways that mediate PTH action may
make it possible to derive a similar beneficial effect in other ways.
Information Dissemination and
Education Efforts
The NIH Osteoporosis and Related Bone Diseases-National Resource Center
(NIH ORBD-NRC) was created by NIAMS in 1994 in response to a groundswell
of interest by several voluntary and professional groups and key
congressional leaders. In addition to NIAMS, other Federal partners now
support the resource center. These include the National Institute on
Aging, as well as the National Institute of Child Health and Human
Development, the National Institute of Dental and Craniofacial Research,
the National Institute of Environmental Health Sciences, the NIH Office
of Research on Women's Health, and the Department of Health and Human
Services' Office of Women's Health, in cooperation with the National
Osteoporosis Foundation, the Paget Foundation, and the Osteogenesis
Imperfecta Foundation. The ORBD-NRC provides an important link to
resources and information on metabolic bone diseases. Its mission is to
expand awareness and enhance knowledge and understanding of the
prevention, early detection, and treatment of these diseases as well as
developing strategies for coping with them.
Osteoporosis can occur in all populations, but only recently have
efforts evolved to reach different ethnic populations. The NIH ORBD-NRC
has developed a partnership with the National Alliance for Hispanic
Health in a program to increase calcium consumption and physical
activity among Hispanic girls between the ages of 9 and 12. The
organizations are developing a culturally sensitive, age-appropriate
health education model that will be implemented in the fall of 2000. The
program is being designed for easy replication at the local level.
Through the resource center, collaborative efforts to enhance strategies
to promote bone health for women are being initiated through the
National Osteoporosis Education Campaign. The first step will be to
encourage teenage women to develop positive health behaviors (for
example, diet, exercise, calcium intake) that can have effects on bone
strength that last a lifetime.
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