111. Osteoporosis Prevention,
Diagnosis, and Therapy
National
Institutes of Health
Consensus Development Conference Statement
March 27-29, 2000
This statement was originally published as:
Osteoporosis Prevention, Diagnosis, and
Therapy. NIH Consens Statement 2000 March 27-29;
17(1): 1-36.
For making bibliographic reference to consensus
statement no. 111 in the electronic form displayed here,
it is recommended that the following format be used:
Osteoporosis Prevention, Diagnosis, and
Therapy. NIH Consens Statement Online 2000 March
27-29; [cited year, month, day]; 17(1): 1-36.
NIH Consensus Statements are prepared
by a nonadvocate, non-Federal panel of experts, based on
(1) presentations by investigators working in areas
relevant to the consensus questions during a 2-day public
session; (2) questions and statements from conference
attendees during open discussion periods that are part of
the public session; and (3) closed deliberations by the
panel during the remainder of the second day and morning
of the third. This statement is an independent report of the panel and is
not a policy statement of the NIH or the Federal Government.
The statement reflects the panelís assessment of medical knowledge
available at the time the statement was written. Thus, it provides
a "snapshot in time" of the state of knowledge on the conference topic.
When reading the statement, keep in mind that new knowledge is
inevitably accumulating through medical research.
Introduction
1.
What is osteoporosis and what are its
consequences?
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 is the optimal evaluation and treatment of
osteoporosis and fractures?
5.
What are the directions for future research?
Conclusions
Consensus
Development Panel
Speakers
Planning
Committee
Conference
Sponsors
Conference
Cosponsors
Introduction
The National Institutes of Health (NIH) sponsored a
Consensus Development Conference on Osteoporosis
Prevention, Diagnosis, and Therapy on March 27-29,
2000.
Osteoporosis is a major threat to 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 disorder.
Osteoporosis, once thought to be a natural part of
aging among women, is no longer considered age or
gender-dependent. It is largely preventable due to the
remarkable progress in the scientific understanding of
its causes, diagnosis, and treatment. Optimization of
bone health is a process that must occur throughout the
lifespan in both males and females. Factors that
influence bone health at all ages are essential to
prevent osteoporosis and its devastating
consequences.
To clarify the factors associated with prevention,
diagnosis, and treatment, and to present the latest
information about osteoporosis, the NIH organized this
conference. After 1 1/2
days of presentations and audience discussion addressing
the latest in osteoporosis research, an independent,
non-Federal consensus development panel weighed the
scientific evidence and wrote this draft statement that
was presented to the audience on the third day. The
consensus development panel's statement addressed the
following key questions:
- What is osteoporosis and what are its
consequences?
- How do risks vary among different segments of the
population?
- What factors are involved in building and
maintaining skeletal health throughout life?
- What is the optimal evaluation and treatment of
osteoporosis and fractures?
- What are the directions for future research?
The primary sponsors of this meeting were the National
Institute of Arthritis and Musculoskeletal and Skin
Diseases and the NIH Office of Medical Applications of
Research. The conference was cosponsored by the National
Institute on Aging; National Institute of Diabetes and
Digestive and Kidney Diseases; National Institute of
Dental and Craniofacial Research; National Institute of
Child Health and Human Development; National Institute of
Nursing Research; National Institute of Environmental
Health Sciences; National Heart, Lung, and Blood
Institute; NIH Office of Research on Women's Health; and
Agency for Healthcare Research and Quality (formerly the
Agency for Health Care Policy and Research).
1. What is
osteoporosis and what are its consequences?
Osteoporosis is defined as 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. Bone density is
expressed as grams of mineral per area or volume and in
any given individual is determined by peak bone mass and
amount of bone loss. Bone quality refers to architecture,
turnover, damage accumulation (e.g., microfractures) and
mineralization. A fracture occurs when a failure-inducing
force (e.g., trauma) is applied to osteoporotic bone.
Thus, osteoporosis is a significant risk factor for
fracture, and a distinction between risk factors that
affect bone metabolism and risk factors for fracture must
be made.
It is important to acknowledge a
common misperception that osteoporosis is always the
result of bone loss. Bone loss commonly occurs as men and
women age; however, an individual who does not reach
optimal (i.e., peak) bone mass during childhood and
adolescence may develop osteoporosis without the
occurrence of accelerated bone loss. Hence sub-optimal
bone growth in childhood and adolescence is as important
as bone loss to the development of osteoporosis.
Currently there is no accurate measure of overall bone
strength. Bone mineral density (BMD) is frequently used
as a proxy measure and accounts for approximately 70
percent of bone strength. The World Health
Organization (WHO) operationally
defines osteoporosis as bone density 2.5 standard
deviations below the mean for young white adult women. It
is not clear how to apply this diagnostic criterion to
men, children, and across ethnic groups. Because of the
difficulty in accurate measurement and standardization
between instruments and sites, controversy exists among
experts regarding the continued use of this diagnostic
criterion.
Osteoporosis can be further characterized as either
primary or secondary. Primary osteoporosis can occur in
both genders at all ages but often follows menopause in
women and occurs later in life in men. In contrast,
secondary osteoporosis is a result of medications, other
conditions, or diseases. Examples include
glucocorticoid-induced osteoporosis, hypogonadism, and
celiac disease.
The consequences of osteoporosis
include the financial, physical, and psychosocial, which
significantly affect the individual as well as the family
and community. An osteoporotic fracture is a tragic
outcome of a traumatic event in the presence of
compromised bone strength, and its incidence is increased
by various other risk factors. Traumatic events can range
from high-impact falls to normal lifting and bending. The
incidence of fracture is high in individuals with
osteoporosis and increases with age. The probability that
a 50-year-old will have a hip fracture during his or her
lifetime is 14 percent for a white female and 5 to 6
percent for a white male. The risk for African Americans
is much lower at 6 percent and 3 percent for 50-year-old
women and men, respectively. Osteoporotic fractures,
particularly vertebral fractures, can be associated with
chronic disabling pain. Nearly one-third of patients with
hip fractures are discharged to nursing homes within the
year following a fracture. Notably, one in five patients
is no longer living 1 year after sustaining an
osteoporotic hip fracture. Hip and vertebral fractures
are a problem for women in their late 70s and 80s, wrist
fractures are a problem in the late 50s to early 70s, and
all other fractures (e.g., pelvic and rib) are a problem
throughout postmenopausal years. The impact of
osteoporosis on other body systems, such as
gastrointestinal, respiratory, genitourinary, and
craniofacial, is acknowledged, but reliable prevalence
rates are unknown.
Hip fracture has a profound impact on quality of life,
as evidenced by findings that 80 percent of women older
than 75 years preferred death to a bad hip fracture
resulting in nursing home placement. However, little data
exist on the relationship between fractures and
psychological and social well-being. Other
quality-of-life issues include adverse effects on
physical health (impact of skeletal deformity) and
financial resources. An osteoporotic fracture is
associated with increased difficulty in activities of
daily life, as only one-third of fracture patients regain
pre-fracture level of function and one-third require
nursing home placement. Fear, anxiety, and depression are
frequently reported in women with established
osteoporosis and such consequences are likely
under-addressed when considering the overall impact of
this condition.
Direct financial expenditures for treatment of
osteoporotic fracture are estimated at $10 to $15 billion
annually. A majority of these estimated costs are due to
in-patient care but do not include the costs of treatment
for individuals without a history of fractures, nor do
they include the indirect costs of lost wages or
productivity of either the individual or the caregiver.
More needs to be learned about these indirect costs,
which are considerable. Consequently, these figures
significantly underestimate the true costs of
osteoporosis.
2. How do
risks vary among different segments of the
population?
Gender/Ethnicity
The prevalence of osteoporosis,
and incidence of fracture, vary by gender and
race/ethnicity. White postmenopausal women experience
almost three-quarters of hip fractures and have the
highest age-adjusted fracture incidence. Most of the
information regarding diagnosis and treatment is derived
from research on this population. However, women of other
age, racial, and ethnic groups, and men and children, are
also affected. 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; however,
differences in bone geometry, frequency of falls, and
prevalence of other risk factors appear to play a role as
well.
Both men and women experience an age-related decline
in BMD starting in midlife. Women experience more rapid
bone loss in the early years following menopause, which
places them at earlier risk for fractures. In men,
hypogonadism is also an important risk factor. Men and
perimenopausal women with osteoporosis more commonly have
secondary causes for the bone loss than do postmenopausal
women.
African American women have higher bone mineral
density than white non-Hispanic women throughout life,
and experience lower hip fracture rates. Some Japenese
women have lower peak BMD than white non-Hispanic women,
but have a lower hip fracture rate; the reasons for which
are not fully understood. Mexican American women have
bone densities intermediate between those of white
non-Hispanic women and African American women. Limited
available information on Native American women suggests
they have lower BMD than white non-Hispanic women.
Risk Factors
Risks associated with low bone
density are supported by good evidence, including large
prospective studies. Predictors of low bone mass include
female gender, increased age, estrogen deficiency, white
race, low weight and body mass index (BMI), family
history of osteoporosis, smoking, and history of prior
fracture. Use of alcohol and caffeine-containing
beverages is inconsistently associated with decreased
bone mass. In contrast, some measures of physical
function and activity have been associated with increased
bone mass, including grip strength and current exercise.
Levels of exercise in childhood and adolescence have an
inconsistent relationship to BMD later in life. Late
menarche, early menopause, and low endogenous estrogen
levels are also associated with low BMD in several
studies.
Although low BMD has been established as an important
predictor of future fracture risk, the results of many
studies indicate that clinical risk factors related to
risk of fall also serve as important predictors of
fracture. Fracture risk has been consistently associated
with a history of falls, low physical function such as
slow gait speed and decreased quadriceps strength,
impaired cognition, impaired vision, and the presence of
environmental hazards (e.g., throw rugs). Increased risk
of a fracture with a fall includes a fall to the side and
attributes of bone geometry, such as tallness, hip axis,
and femur length. Some risks for fracture, such as age, a
low BMI, and low levels of physical activity, probably
affect fracture incidence through their effects on both
bone density and propensity to fall and inability to
absorb impact.
Results of studies of persons with osteoporotic
fractures have led to the development of models of risk
prediction, which incorporate clinical risk factors along
with BMD measurements. Results from the Study of
Osteoporotic Fractures (SOF), a large longitudinal study
of postmenopausal, white non-Hispanic women, suggest that
clinical risk factors can contribute greatly to fracture
risk assessment. In this study, 14 clinical risk factors
predictive of fracture were identified. The presence of
five or more of these factors increased the rate of hip
fracture for women in the highest tertile of BMD from 1.1
per 1,000 woman-years to 9.9 per 1,000 woman-years. Women
in the lowest tertile of BMD with no other risk factors
had a hip fracture rate of 2.6 per 1,000 woman-years as
compared with 27.3 per 1,000 woman-years with five or
more risk factors present. A second model, derived from
the Rotterdam study, predicted hip fractures using a
smaller number of variables, including gender, age,
height, weight, use of a walking aid, and current
smoking. However, these models have not been validated in
a population different from that in which they were
derived.
Secondary Osteoporosis
A large number of medical disorders are associated
with osteoporosis and increased fracture risk. These can
be organized into several categories: genetic disorders,
hypogonadal states, endocrine disorders, gastrointestinal
diseases, hematologic disorders, connective tissue
disease, nutritional deficiencies, drugs, and a variety
of other common serious chronic systemic disorders, such
as congestive heart failure, end-stage renal disease, and
alcoholism.
The distribution of the most common causes appears to
differ by demographic group. Among men, 30 to 60 percent
of osteoporosis is associated with secondary causes; with
hypogonadism, glucocorticoids, and alcoholism the most
common. In perimenopausal women, more than 50 percent is
associated with secondary causes, and the most common
causes are hypoestrogenemia, glucocorticoids, thyroid
hormone excess, and anticonvulsant therapy. In
postmenopausal women, the prevalence of secondary
conditions is thought to be much lower, but the actual
proportion is not known. In one study, hypercalciuria,
hyperparathyroidism, and malabsorption were identified in
a group of white postmenopausal osteoporotic women who
had no history of conditions that cause bone loss. These
data suggest that additional testing of white
postmenopausal women with osteoporosis may be indicated,
but an appropriate or cost-effective evaluation strategy
has not been determined.
Glucocorticoid use is the most common form of
drug-related osteoporosis, and its long-term
administration for disorders such as rheumatoid arthritis
and chronic obstructive pulmonary disease is associated
with a high rate of fracture. For example, in one study,
a group of patients treated with 10 mg of prednisone for
20 weeks experienced an 8 percent loss of BMD in the
spine. Some experts suggest that any patient who receives
orally administered glucocorticoids (such as Prednisone)
in a dose of 5 mg or more for longer than 2 months is at
high risk for excessive bone loss.
People who have undergone organ transplant are at high
risk for osteoporosis due to a variety of factors,
including pretransplant organ failure and use of
glucocorticoids after transplantation.
Hyperthyroidism is a well-described risk factor for
osteoporosis. In addition, some studies have suggested
that women taking thyroid replacement may also be at
increased risk for excess bone loss, suggesting that
careful regulation of thyroid replacement is
important.
Children and Adolescents
Several groups of children and adolescents may be at
risk for compromised bone health. Premature and low birth
weight infants have lower-than-expected bone mass in the
first few months of life, but the long-term implications
are unknown.
Glucocorticoids are now commonly used for the
treatment of a variety of common childhood inflammatory
diseases, and the bone effects of this treatment need to
be considered when steroid use is required chronically.
The long-term effects on bone health of intermittent
courses of systemic steroids or the chronic use of
inhaled steroids, as are often used in asthma, are not
well described.
Cystic fibrosis, celiac disease, and inflammatory
bowel disease are examples of conditions associated with
malabsorption and resultant osteopenia in some
individuals. The osteoporosis of cystic fibrosis is also
related to the frequent need for corticosteroids as well
as to other undefined factors.
Hypogonadal states, characterized clinically by
delayed menarche, oligomenorrhea, or amenorrhea, are
relatively common in adolescent girls and young women.
Settings in which these occur include strenuous athletic
training, emotional stress, and low body weight. Failure
to achieve peak bone mass, bone loss, and increased
fracture rates have been shown in this group. Anorexia
nervosa deserves special mention. Although hypogonadism
is an important feature of the clinical picture, the
profound undernutrition and nutrition-related factors are
also critical. This latter point is evidenced, in part,
by the failure of estrogen replacement to correct the
bone loss.
Residents of Long-Term Care Facilities
Residents of nursing homes and other long-term care
facilities are at particularly high risk of fracture.
Most have low BMD and a high prevalence of other risk
factors for fracture, including advanced age, poor
physical function, low muscle strength, decreased
cognition and high rates of dementia, poor nutrition,
and, often, use of multiple medications.
3. What
factors are involved in building and maintaining skeletal
health throughout life?
Growth in bone size and strength
occurs during childhood, but bone accumulation is not
completed until the third decade of life, after the
cessation of linear growth. The bone mass attained early
in life is perhaps the most important determinant of
life-long skeletal health. Individuals with the highest
peak bone mass after adolescence have the greatest
protective advantage when the inexorable declines in bone
density associated with increasing age, illness, and
diminished sex-steroid production take their toll. Bone
mass may be related not only to osteoporosis and
fragility later in life but also to fractures in
childhood and adolescence. Genetic factors exert a strong
and perhaps predominant influence on
peak bone mass, but physiological,
environmental, and modifiable lifestyle factors can also
play a significant role. Among these are adequate
nutrition and body weight, exposure to sex hormones at
puberty, and physical activity. Thus, maximizing bone
mass early in life presents a critical opportunity to
reduce the impact of bone loss related to aging.
Childhood is also a critical time for the development of
lifestyle habits conducive to maintaining good bone
health throughout life. Cigarette smoking, which usually
starts in adolescence, may have a deleterious effect on
achieving bone mass.
Nutrition
Good nutrition is essential for normal growth. A
balanced diet, adequate calories, and appropriate
nutrients are the foundation for development of all
tissues, including bone. Adequate and appropriate
nutrition is important for all individuals, but not all
follow a diet that is optimal for bone health.
Supplementation of calcium and vitamin D may be
necessary. In particular, excessive pursuit of thinness
may affect adequate nutrition and bone health.
Calcium is the specific nutrient most important for
attaining peak bone mass and for preventing and treating
osteoporosis. Sufficient data exist to recommend specific
dietary calcium intakes at various stages of life.
Although the Institute of Medicine
recommends calcium intakes of 800 mg/day for children
ages 3 to 8 and 1,300 mg/day for children and adolescents
ages 9 to 17, only about 25 percent
of boys and 10 percent of girls ages 9 to 17 are
estimated to meet these recommendations. Factors
contributing to low calcium intakes are restriction of
dairy products, a generally low level of fruit and
vegetable consumption, and a high intake of low calcium
beverages such as sodas. For older adults, calcium intake
should be maintained at 1,000 to 1,500 mg/day, yet only
about 50 to 60 percent of this population meets this
recommendation.
Vitamin D is required for optimal calcium absorption
and thus is also important for bone health. Most infants
and young children in the United States have adequate
vitamin D intake because of supplementation and
fortification of milk. During adolescence, when
consumption of dairy products decreases, vitamin D intake
is less likely to be adequate, and this may adversely
affect calcium absorption. A recommended vitamin D intake
of 400 to 600 IU/day has been established for adults.
Other nutrients have been evaluated for their relation
to bone health. High dietary protein, caffeine,
phosphorus, and sodium can adversely affect calcium
balance, but their effects appear not to be important in
individuals with adequate calcium intakes.
Exercise
Regular physical activity has numerous health benefits
for individuals of all ages. The specific effects of
physical activity on bone health have been investigated
in randomized clinical trials and observational studies.
There is strong evidence that physical activity early in
life contributes to higher peak bone mass. Some evidence
indicates that resistance and high impact exercise are
likely the most beneficial. Exercise during the middle
years of life has numerous health benefits, but there are
few studies on the effects of exercise on BMD. Exercise
during the later years, in the presence of adequate
calcium and vitamin D intake, probably has a modest
effect on slowing the decline in BMD. It is clear that
exercise late in life, even beyond 90 years of age, can
increase muscle mass and strength twofold or more in
frail individuals. There is convincing evidence that
exercise in elderly persons also improves function and
delays loss of independence and thus contributes to
quality of life. Randomized clinical trials of exercise
have been shown to reduce the risk of falls by
approximately 25 percent, but there is no experimental
evidence that exercise affects fracture rates. It also is
possible that regular exercisers might fall differently
and thereby reduce the risk of fracture due to falls, but
this hypothesis requires testing.
Gonadal Steroids
Sex steroids secreted during puberty substantially
increase BMD and peak bone mass. Gonadal steroids
influence skeletal health throughout life in both women
and men. In adolescents and young women, sustained
production of estrogens is essential for the maintenance
of bone mass. Reduction in estrogen production with
menopause is the major cause of loss of BMD during later
life. Timing of menarche, absent or infrequent menstrual
cycles, and the timing of menopause influence both the
attainment of peak bone mass and the preservation of BMD.
Testosterone production in adolescent boys and men is
similarly important in achieving and maintaining maximal
bone mass. Estrogens have also been implicated in the
growth and maturation of the male skeleton. Pathologic
delay in the onset of puberty is a risk factor for
diminished bone mass in men. Disorders that result in
hypogonadism in adult men result in osteoporosis.
Growth Hormone and Body Composition
Growth hormone and insulin-like growth factor-I, which
are maximally secreted during puberty, continue to play a
role in the acquisition and maintenance of bone mass and
the determination of body composition into adulthood.
Growth hormone deficiency is associated with a decrease
in BMD. Children and youth with low BMI are likely to
attain lower-than-average peak bone mass. Although there
is a direct association between BMI and bone mass
throughout the adult years, it is not known whether the
association between body composition and bone mass is due
to hormones, nutritional factors, higher impact during
weight-bearing activities, or other factors. There are
several observational studies of fractures in older
persons that show an inverse relationship between
fracture rates and BMI.
4. What is
the optimal evaluation and treatment of osteoporosis and
fractures?
The goals for the evaluation of
patients at risk for osteoporosis are to establish the
diagnosis of osteoporosis on the basis of assessment of
bone mass, to establish the fracture risk, and to make
decisions regarding the needs for instituting therapy. A
history and physical examination are essential in
evaluating fracture risks and should include assessment
for loss of height and change in posture . Laboratory
evaluation for secondary causes of osteoporosis should be
considered when osteoporosis is diagnosed. The most
commonly used measurement to diagnose osteoporosis and
predict fracture risk is based on assessment of BMD which
is principally determined by the mineral content of bone.
BMD measurements have been shown to correlate strongly
with load-bearing capacity of the hip and spine and with
the risk of fracture. Several different techniques have
been developed to assess BMD at multiple skeletal sites
including the peripheral skeleton, hip, and spine. The
World Health Organization (WHO) has selected BMD
measurements to establish criteria for the diagnosis of
osteoporosis. A T-score is defined as the number of
standard deviations (SD) above or below the average BMD
value for young healthy white women. This should be
distinguished from a Z-score, which is defined as the
number of SD above or below the average BMD for age- and
gender-matched controls. According to the WHO definition,
osteoporosis is present when the T-score is at least
minus 2.5 SD. Although T-scores were based originally on
assessment of BMD at the hip by dual-energy X-ray
absorptiometry (DXA), they have been applied to define
diagnostic thresholds at other skeletal sites and for
other technologies. Experts have expressed concern that
this approach may not produce comparable data between
sites and techniques. Of the various sampling sites,
measurements of BMD made at the hip predict hip fracture
better than measurements made at other sites while BMD
measurement at the spine predicts spine fracture better
than measures at other sites.
Newer measures of bone strength, such as ultrasound,
have been introduced. Recent prospective studies using
quantitative ultrasound (QUS) of the heel have predicted
hip fracture and all nonvertebral fractures nearly as
well as DXA at the femoral neck. QUS and DXA at the
femoral neck provide independent information about
fracture risk, and both of these tests predict hip
fracture risk better than DXA at the lumbar spine. In
general, clinical trials of pharmacologic therapies have
utilized DXA, rather than QUS, for entry criterion for
studies, and there is uncertainty regarding whether the
results of these trials can be generalized to patients
identified by QUS to have high risk of fracture.
Over the past year, several professional organizations
have been working on establishing a standard of
comparability of different devices and sites for
assessing fracture risk. With this approach, measurements
derived from any device or site could be standardized to
predict hip fracture risk. However, the values obtained
from different instruments cannot be used to predict
comparable levels in bone mass. Limitations in precision
and low correlation among different techniques will
require appropriate validation before this approach can
be applied to different skeletal sites and to different
age groups.
It has been suggested that the diagnosis and treatment
of osteoporosis should depend on risk-based assessment
rather than solely on the assessment of a T-score.
Consideration of risk factors in conjunction with BMD
will likely improve the ability to predict fracture risk.
This approach needs to be validated in prospective
studies and tested in appropriate randomized clinical
trials.
In addition to the effects of
bone mass, bone micro architecture, and macrogeometry,
bone strength is also affected by the rate of bone
remodeling. Bone remodeling can be assessed by the
measurement of surrogate markers of bone turnover in the
blood or urine. These markers include bone-specific
alkaline phosphatase and osteocalcin, which are indices
of bone formation, and the urinary levels of
pyridinolines and deoxypyridinolines and serum and urine
levels of type I collagen telopeptides (CTX and NTX),
which are indices of bone resorption. The level of these
markers may identify changes in bone remodeling within a
relatively short time interval (several days to months)
before changes in BMD can be detected. However, according
to available data, marker levels do not predict bone mass
or fracture risk and are only weakly associated with
changes in bone mass. Therefore, they are of limited
utility in the clinical evaluation of individual
patients. Despite these limitations, markers have been
shown in research studies to correlate with changes in
indices of bone remodeling and may provide insights into
mechanisms of bone loss.
Who Should Be Evaluated?
The value of bone density in
predicting fracture risk is established, and there is
general consensus that bone density measurement should be
considered in patients receiving glucocorticoid therapy
for 2 months or more and patients with other conditions
that place them at high risk for osteoporotic fracture.
However, the value of universal screening, especially in
perimenopausal women, has not been established. There are
several unknown factors with this approach.
First, the number of women evaluated and treated would
need to be high in order to prevent a single fracture.
For example, in white women aged 50-59, an estimated 750
BMD tests would be required to prevent just one hip or
vertebral fracture over a 5-year period of treatment.
Second, the value has not been established for the common
practice of beginning preventive drug therapy in the
perimenopausal period for the purpose of preventing
fractures later in life.
Until there is good evidence to support the
cost-effectiveness of routine screening, or the efficacy
of early initiation of preventive drugs, an
individualized approach is recommended. A bone density
measurement should be considered when it will help the
patient decide whether to institute treatment to prevent
osteoporotic fracture. In the future, a combination of
risk factor evaluation and bone density measurements may
increase the ability to predict fracture risk and help
with treatment decisions. Until assessment by randomized
clinical trials is conducted, individual decisions
regarding screening could be informed by the preliminary
evidence that the risk for fracture increases with age,
and with an increased number of additional risk
factors.
What Are the Effective Medical Treatments?
In the past 30 years, major
strides have been made in the treatment of osteoporosis.
Evidence-based reports systematically reviewing the data
from randomized clinical trials, including meta-analyses
for each of the major treatments, are available and
permit conclusions regarding the role of each modality of
osteoporosis therapy.
Calcium and vitamin D intake modulates age-related
increases in parathyroid hormone (PTH) levels and bone
resorption. Randomized clinical trials have demonstrated
that adequate calcium intake from diet or supplements
increase spine BMD and reduce vertebral and nonvertebral
fractures. Low levels of 25-OH vitamin D are common in
the aging population, and significant reductions in hip
and other nonvertebral fractures have been observed in
patients receiving calcium and vitamin D3 in prospective
trials. The maximal effective dose of vitamin D is
uncertain, but thought to be 400 to 1,000 IU/day. There
is consensus that adequate vitamin D and calcium intakes
are required for bone health. The therapeutic effects of
most of the clinical trials of various drug therapies for
osteoporosis have been achieved in the presence of
calcium and vitamin D supplementation among control and
intervention groups. Optimal treatment of osteoporosis
with any drug therapy also requires calcium and vitamin D
intake meeting recommended levels. The preferred source
of calcium is dietary. Calcium supplements need to be
absorbable and should have USP designation.
Physical activity is necessary for bone acquisition
and maintenance through adulthood. Complete bed rest and
microgravity have devastating effects on bone. Trials of
exercise intervention show most of the effect during
skeletal growth and in very inactive adults. Effects
beyond those directly on bone, such as improved muscular
strength and balance, may be very significant in
fracture-risk reduction. Trials in older adults have
successfully used various forms of exercise to reduce
falls. High-impact exercise (weight training) stimulates
accrual of bone mineral content in the skeleton. Lower
impact exercises, such as walking, have beneficial
effects on other aspects of health and function, although
their effects on BMD have been minimal.
Randomized placebo-controlled trials (RCTs) of cyclic
etidronate, alendronate, and risedronate analyzed by a
systematic review and meta-analysis have revealed that
all of these bisphosphonates increase BMD at the spine
and hip in a dose-dependent manner. They consistently
reduce the risk of vertebral fractures by 30 to 50
percent. Alendronate and risedronate reduce the risk of
subsequent nonvertebral fractures in women with
osteoporosis and adults with glucocorticoid-induced
osteoporosis. There is uncertainty about the effect of
anti- resorptive therapy in reducing nonvertebral
fracture in women without osteoporosis. In RCTs, the
relative risk of discontinuing medication due to an
adverse event with each of the three bisphosphonates was
not statistically significant. The safety and efficacy of
this therapy in children and young adults has not been
evaluated. Since subjects in clinical trials may not
always be representative of the community-based
population, an individual approach to treatment is
warranted.
Hormone replacement therapy (HRT) is an established
approach for osteoporosis treatment and prevention. Many
short-term studies and some longer term studies with BMD
as the primary outcome have shown significant efficacy.
Observational studies have indicated a significant hip
fracture reduction in cohorts of women who maintain HRT
therapy; still there is a paucity of trials with
fractures as the endpoint. HRT trials have shown
decreased risk of vertebral fractures, but there have
been no trials of estrogen with hip fracture as the
primary outcome.
The development of selective estrogen receptor
modulators (SERMs) has been an important new thrust in
osteoporosis research. The goal of these agents is to
maximize the beneficial effect of estrogen on bone and to
minimize or antagonize the deleterious effects on the
breast and endometrium. Raloxifene, a SERM approved by
the FDA for the treatment and prevention of osteoporosis,
has been shown to reduce the risks of vertebral fracture
by 36 percent in large clinical trials. Tamoxifen, used
in the treatment and prevention of breast cancer, can
maintain bone mass in postmenopausal women. However,
effects on fracture are unclear.
There is a great deal of public interest in natural
estrogens, particularly plant-derived phytoestrogens.
These compounds have weak estrogen-like effects, and
although some animal studies are promising, no effects on
fracture reduction in humans have been shown. Salmon
calcitonin has demonstrated positive effects on BMD at
the lumbar spine, but this effect is less clear at the
hip. Other than a recently completed randomized
controlled trial of nasal calcitonin, no analysis of
fracture risk is available. The PROOF study revealed a
significant reduction in vertebral fracture risk at the
200 IU dose but not at the 100 IU or 400 IU dose. The
absence of dose response, a 60 percent dropout rate, and
the lack of strong supporting data from BMD and markers
decrease confidence in the fracture risk data from this
trial. Nonpharmacologic interventions directed at
preventing falls and reducing their effect on fractures
have been promising. These include studies to improve
strength and balance in the elderly, as well as using hip
protectors to absorb or deflect the impact of a fall.
Multifactorial approaches to preventing falls, as well
as improving bone mass through combinations of
interventions, suggest promising new directions.
Should the Response to Treatment Be
Monitored?
Several approaches have been introduced for the
monitoring of patients receiving therapies for
osteoporosis. The goals of monitoring are to increase
adherence to treatment regimens and determine treatment
responses. Many individuals do not continue prescribed
therapy or do not adhere to a treatment protocol, even
when enrolled in formal clinical trials. Monitoring by
densitometry or measurements of bone markers have not
been shown to be effective in improving compliance, and
more research is needed about how to improve adherence to
treatment protocols.
The best tests for monitoring treatment response would
reflect the largest changes with the least error, and
these assessment tools are not readily available. The
Fracture Intervention Trial (FIT) reveals an additional
problem with monitoring, the statistical phenomenon of
regression to the mean. In this study, the larger the
bone loss in the first year, the greater the gain the
next year, for both the placebo and active treatment
groups. Therefore, physicians should not stop or change
therapies with demonstrated efficacy solely because of
modest loss of bone density or adverse trends in markers
of bone turnover.
Orthopaedic Management of Osteoporotic
Fractures
While proximal femur (hip) fractures comprise nearly
20 percent of all osteoporotic fractures, this injury is
among the most devastating of all the osteoporotic
fractures and is responsible for the greatest expenditure
of health care resources. The 1-year mortality rate
following hip fracture is about 1 in 5. As many as
two-thirds of hip fracture patients never regain their
preoperative activity status. Early surgical management
of hip fractures is associated with improved outcomes and
decreased perioperative morbidity.
The adverse health, functional and quality of life
effects of vertebral (spine) fractures are commonly
underestimated, and such fractures are associated with
increased mortality. The occurrence of a single vertebral
fracture substantially increases the likelihood of future
fractures and progressive kyphotic deformity. Due to the
challenges of reconstruction of osteoporotic bone, open
surgical management is reserved only for those rare cases
that involve neurologic deficits or an unstable spine.
Recently, there has been a burgeoning interest in two
"minimally invasive" procedures for management of acute
vertebral fractures, vertebroplasty and kyphoplasty,
which involve the injection of polymethylmethacrylate
bone cement into the fractured vertebra. Anecdotal
reports with both techniques claim frequent acute pain
relief; however, neither technique has been subjected to
a controlled trial to demonstrate the benefits over
traditional medical management. Furthermore, the
long-term effect of one or more reinforced rigid
vertebrae on the risk of fracture of adjacent vertebrae
is unknown for both of these procedures.
Several issues are critically important to the
orthopaedic management of acute osteoporotic fractures.
It is most important to avoid the misconception that the
only treatment required of an osteoporotic fracture is
management of the acute fracture itself. Management
during the perifracture period must consider blood clot
prevention (mechanical or pharmacologic) in patients who
will have delayed ambulation, the avoidance of substances
that may inhibit fracture repair (nicotine,
corticosteroids), and the frequent need for supplemental
caloric intake. Finally, since less than 5 percent of
patients with osteoporotic fractures are referred for
medical evaluation and treatment, more aggressive
diagnostic and therapeutic intervention of this
population represents an opportunity to prevent
subsequent fractures. Physicians treating the acute
fracture should initiate an outpatient evaluation of the
patient for osteoporosis and a treatment program, if
indicated, or refer the patient for an osteoporosis
assessment.
5. What are
the directions for future research?
The following questions, issues, and concerns should
be addressed:
- Peak bone mass is an important factor in
determining long-term fracture risk. Strategies to
maximize peak bone mass in girls and boys are
essential, including how to identify and intervene in
disorders that can impede the achievement of peak bone
mass in ethnically diverse populations, and, to
determine how long these interventions should last.
More research regarding the risks for fracture in
chronic diseases affecting children is needed. What is
the impact of calcium deficiency and vitamin D
deficiency in childhood, and can it be reversed? How
does gonadal steroid insufficiency, pubertal delay, or
undernourishment impact bone mass? What is known about
the use of bisphosphonates or other agents in the
treatment of children with osteoporosis?
- Genetic factors leading to osteoporosis are being
identified. These factors may relate to bone mass
acquisition, bone remodeling, or bone structure.
Pharmacogenetic approaches for identifying and
targeting specific genetic factors predisposing to
osteoporosis need to be developed.
- Glucocorticoid use is a common cause of secondary
osteoporosis and associated fractures. What is the
impact of glucocorticoid-induced osteoporosis in
adults and children? What are the mechanisms of
disease? What novel approaches can be taken to
stimulate bone formation in this condition?
Development of glucocorticoids that avoid effects on
the skeleton are needed.
- Secondary causes of osteoporosis are prevalent. A
number of risk factors have been identified, including
specific disease states and medication use. How should
patients be identified for diagnosis and treatment of
osteoporosis? What is known about the use of
bisphosphonates or other agents in young adults with
secondary osteoporosis? What is known about the causes
of osteoporosis in perimenopausal women? How should
they be monitored for treatment response? Are
therapies for improving bone mass in postmenopausal
women effective in secondary causes?
- There is a need for prospective studies of gender,
age, and ethnically diverse individuals to provide
data that will permit more accurate fracture risk
identification in these populations. Fracture risk is
a combination of bone-dependent and bone-independent
factors. Bone-independent factors include muscle
function and cognition, which also contribute to falls
leading to fractures. A comprehensive assessment of
bone-dependent and bone-independent factors should be
included. There is a need for a comprehensive
assessment of a validated risk assessment tool. What
is the best way to identify patients in need of
treatment for osteoporosis? An algorithm should be
constructed that incorporates risk factors for
fracture in addition to assessment of bone density.
What is the best use of surrogate markers of bone
turnover to determine osteoporosis, and how does this
impact on fracture risks?
- Quality of life is significantly impaired by
osteoporosis. Future research should characterize and
validate quality-of-life tools in patients across
gender, age, and race or ethnicity. It will be
important to identify effects of fracture risk and
intervention on quality of life. Quality of life
should be incorporated as an outcome in clinical
trials evaluating fracture risk and therapy. In
addition, the psychosocial and financial effects of
osteoporosis on caregivers and family dynamics should
be considered.
- There are no available data to suggest which
asymptomatic patients should have screening
bone-density tests done or when screening is
justified. Information regarding screening guidelines
is important to obtain.
- Neuropsychiatric disorders may cause or be the
result of osteoporosis. Specific psychiatric
disorders, including depression and anorexia nervosa,
are associated with osteoporosis or clinical
fractures. Medications used to treat psychiatric or
neurologic disorders may cause osteoporosis, and the
diagnosis of osteoporosis may have psychological
implications. Research efforts into the relationship
between neuropsychiatric disorders and fracture risk
should be strongly encouraged.
- There is an urgent need for randomized clinical
trials of combination therapy, which includes
pharmacologic, dietary supplement, and lifestyle
interventions (including muscle strengthening,
balance, and management of multiple drug use, smoking
cessation, psychological counseling, and dietary
interventions). Primary outcomes would be fractures,
and secondary outcomes would include quality of life
and functional capability. Cost-effectiveness
evaluation should be considered in such a trial.
- What is the optimal evaluation and management of
fractures? What diagnostic and management paradigm
should be employed? What are the long-term
consequences of osteoporosis and clinical fractures on
nonskeletal body systems? What measures can be taken
to prevent subsequent fractures?
- Anabolic agents that stimulate bone formation,
such as PTH and fluoride, have been evaluated.
Meta-analysis of fluoride therapy revealed no
protective effects on fracture risk. PTH peptides are
the most promising but are still in clinical trials.
Other factors, including growth hormones, are under
investigation. There is a critical need to develop and
assess anabolic agents that stimulate bone
formation.
- Assure accessibility to treatment for people
regardless of income and geography.
- There is a need to determine the most effective
method of educating the public and health care
professionals about the prevention, diagnosis and
treatment of osteoporosis.
- There is a need to improve the reporting of BMD
and fracture risk so it is understandable to medical
specialists and can be explained to patients.
- Study is needed to determine the efficacy and
safety of long-term administration of various drug
interventions in maintaining BMD and preventing
fractures.
- Trials of dietary supplements are needed.
- Study is needed to understand the influence of
nutrition on micronutrients and non-patentable medical
interventions.
- Study is needed to understand cost-effectiveness
and effectiveness of programs encouraging bone
health.
- Study of interventions examining the long-term
effects of fractures on health, function and quality
of life is needed.
Conclusions
Question 1
- Osteoporosis occurs in all populations and at all
ages. Though more prevalent in white postmenopausal
females, it often goes unrecognized in other
populations.
- Osteoporosis is a devastating disorder with
significant physical, psychosocial, and financial
consequences.
Question 2
- The risks for osteoporosis, as reflected by low
bone density, and the risks for fracture overlap but
are not identical.
- More attention should be paid to skeletal health
in persons with conditions known to be associated with
secondary osteoporosis.
- Clinical risk factors have an important, but as
yet poorly validated, role in determining who should
have BMD measurement, in assessing risk of fracture,
and in determining who should be treated.
Question 3
- Adequate calcium and vitamin D intake are crucial
to develop optimal peak bone mass and to preserve bone
mass throughout life. Supplementation of these two
components in bioavailable forms may be necessary in
individuals who do not achieve recommended intake from
dietary sources.
- Gonadal steroids are important determinants of
peak and lifetime bone mass in men, women, and
children.
- Regular exercise, especially resistance and
high-impact activities, contributes to development of
high peak bone mass and may reduce the risk of falls
in older individuals.
Question 4
- Assessment of bone mass, identification of
fracture risk, and determination of who should be
treated are the optimal goals when evaluating patients
for osteoporosis.
- Fracture prevention is the primary goal in the
treatment of patients with osteoporosis.
- Several treatments have been shown to reduce the
risk of osteoporotic fractures. These include
therapies that enhance bone mass and reduce risk or
consequences of falls.
- Adults with vertebral, rib, hip, or distal forearm
fractures should be evaluated for the presence of
osteoporosis and given appropriate therapy.
Consensus
Development Panel
Anne Klibanski, M.D.
Panel and Conference Chair
Professor of Medicine
Harvard Medical School
Chief
Neuroendocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Lucile Adams-Campbell, Ph.D.
Director and Professor of Medicine
Howard University Cancer Center
Washington, DC
Tamsen Bassford, M.D.
Associate Dean for Student Affairs
Assistant Professor of Family and Community Medicine
Department of Family and Community Medicine
Health Sciences Center
University of Arizona
Tucson, Arizona
Steven N. Blair, P.E.D.
Director
Epidemiology and Clinical Applications
The Cooper Institute
Dallas, Texas
Scott D. Boden, M.D.
Associate Professor of Orthopaedic Surgery
Director, The Emory Spine Center
Emory University School of Medicine
Decatur, Georgia
Kay Dickersin, Ph.D.
Associate Professor
Department of Community Health
Brown University
Providence, Rhode Island
David R. Gifford, M.D., M.P.H.
Assistant Professor of Medicine and Community Health
Center for Gerontology and Health Care Research
Brown University
Providence, Rhode Island
Lou Glasse, M.S.W.
President Emeritus
Older Women's League
Poughkeepsie, New York
Steven R. Goldring, M.D.
Associate Professor of Medicine
Chief of Rheumatology
Beth Israel Deaconess Medical Center
Harvard Medical School and New England Baptist Bone and
Joint Institute
Boston, Massachusetts
Keith Hruska, M.D.
Ira M. Lang Professor of Medicine and Cell Biology
Department of Medicine
Washington University
St. Louis, Missouri
Susan R. Johnson, M.D., M.S.
Professor of Obstetrics and Gynecology and
Epidemiology
University of Iowa Colleges of Medicine and Public
Health
Iowa City, Iowa
Laurie K. McCauley, D.D.S., Ph.D.
Associate Professor
Department of Periodontics/Prevention/Geriatrics
University of Michigan
Ann Arbor, Michigan
William E. Russell, M.D.
Associate Professor of Pediatrics and Cell Biology
Director, Division of Pediatric Endocrinology
Vanderbilt University Medical Center
Nashville, Tennessee
Speakers
Douglas C. Bauer, M.D.
Assistant Professor of Medicine
University of California, San Francisco
San Francisco, California
John Paul Bilezikian, M.D.
Professor of Medicine and Pharmacology
Chief, Division of Endocrinology in the Department of
Medicine
College of Physicians and Surgeons
Columbia University
New York, New York
Dennis M. Black, Ph.D.
Professor
Department of Epidemiology and Biostatistics
University of California, San Francisco
San Francisco, California
Mark E. Bolander, M.D.
Consultant
Division of Orthopedic Research
Department of Orthopedic Surgery
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
Mary L. Bouxsein, Ph.D.
Instructor
Department of Orthopaedic Surgery
Orthopaedic Biomechanics Laboratory
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Ann Cranney, M.D., M.Sc.
Assistant Professor
Division of Rheumatology
Ottawa Hospital, Civic Campus
Ottawa, Ontario
Canada
Steven R. Cummings, M.D.
Professor of Medicine, Epidemiology, and
Biostatistics
Assistant Dean for Clinical Research
Department of Medicine
University of California, San Francisco
San Francisco, California
Jerome C. Donnelly, D.M.D.
Harker Heights, Texas
Bess Dawson-Hughes, M.D.
Professor of Medicine
Chief
Calcium and Bone Metabolism Laboratory
Jean Mayer USDA Human Nutrition Research Center on
Aging
Tufts University
Boston, Massachusetts
Lorraine A. Fitzpatrick, M.D.
Professor of Medicine
Endocrine Research Unit
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
Deborah T. Gold, Ph.D.
Associate Research Professor
Department of Psychology and Behavioral Science
Duke University Medical Center
Durham, North Carolina
Gordon Guyatt, M.D.
Professor
McMaster University
Health Sciences Centre
Hamilton, Ontario
Canada
Robert P. Heaney, M.D.
John A. Creighton University Professor
Professor of Medicine
Department of Medicine
Creighton University
Omaha, Nebraska
Mark Helfand, M.D., M.P.H.
Director, Evidence-Based Practice Center
Associate Professor of Internal Medicine and Medical
Informatics and Outcomes Research
Oregon Health Sciences University
Portland, Oregon
C. Conrad Johnston, Jr., M.D.
Distinguished Professor
School of Medicine
Indiana University
Indianapolis, Indiana
John A. Kanis, M.D.
Professor
Center for Metabolic Bone Diseases
Medical School
University of Sheffield
Sheffield, South Yorkshire
United Kingdom
Douglas P. Kiel, M.D., M.P.H.
Associate Professor of Medicine
Harvard Medical School Division on Aging
Associate Director of Medical Research
Research and Training Institute
Hebrew Rehabilitation Center for Aged
Boston, Massachusetts
Nancy E. Lane, M.D.
Associate Professor of Medicine
Division of Rheumatology
San Francisco General Hospital
University of California, San Francisco
San Francisco, California
Robert Lindsay, M.D., Ph.D.
Chief of Internal Medicine
Regional Bone Center
Helen Hayes Hospital
West Haverstraw, New York
Thomas A. Lloyd, Ph.D.
Professor of Clinical Epidemiology
Department of Health Evaluation Science
Hershey Medical Center
Pennsylvania State University College of Medicine
Hershey, Pennsylvania
Robert A. Marcus, M.D.
Professor of Medicine
Stanford University
VA Medical Center
Palo Alto, California
L. Joseph Melton III, M.D.
Michael M. Eisenberg Professor
Department of Health Sciences Research
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
Heidi D. Nelson, M.D., M.P.H., F.A.C.P.
Assistant Professor of Internal Medicine and Medical
Informatics and Outcomes Research
Oregon Health Sciences University
Portland, Oregon
Eric S. Orwoll, M.D.
Professor of Medicine
Oregon Health Sciences University
Portland, Oregon
Munro Peacock, M.D.
Professor of Medicine
General Clinical Research Center
Indiana University Medical Center
Indianapolis, Indiana
Robert R. Recker, M.D.
Chief, Endocrinology Division
Director, Osteoporosis Research Center
Professor of Medicine
Creighton University School of Medicine
Omaha, Nebraska
B. Lawrence Riggs, M.D.
Staff Consultant
Division of Endocrinology
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
Clifford J. Rosen, M.D.
Director
Maine Center for Osteoporosis Research
St. Joseph Hospital
Bangor, Maine
Elizabeth Shane, M.D.
Professor of Clinical Medicine
Department of Medicine
College of Physicians and Surgeons
Columbia University
New York, New York
Ethel S. Siris, M.D.
Madeline C. Stabile Professor of Clinical Medicine
Department of Medicine
College of Physicians and Surgeons
Columbia University
New York, New York
Anna Tosteson, Sc.D.
Associate Professor of Medicine and Community and Family
Medicine
Center for the Evaluative Clinical Sciences
Dartmouth Medical School
Lebanon, New Hampshire
Richard D. Wasnich, M.D., F.A.C.P.
Director
Hawaii Osteoporosis Center
Honolulu, Hawaii
Planning
Committee
Joan A. McGowan, Ph.D.
Planning Chair
Chief
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and
Skin Diseases
National Institutes of Health
Bethesda, Maryland
Janet S. Austin, Ph.D.
Director
Office of Communications and Public Liaison
National Institute of Arthritis and Musculoskeletal and
Skin Diseases
National Institutes of Health
Bethesda, Maryland
Douglas C. Bauer, M.D.
Assistant Professor of Medicine
University of California, San Francisco
San Francisco, California
Inese Z. Beitins, M.D., F.R.C.P.(C)
Director, Clinical Research
General Clinical Research Centers Program
National Center for Research Resources
National Institutes of Health
Bethesda, Maryland
John Paul Bilezikian, M.D.
Professor of Medicine and Pharmacology
Chief, Division of Endocrinology in the Department of
Medicine
College of Physicians and Surgeons
Columbia University
New York, New York
John Bowersox
Communications Specialist
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
Elsa A. Bray
Senior Analyst
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
Mona S. Calvo, Ph.D.
Expert Regulatory Review Scientist
Office of Special Nutritionals
Center for Food Safety and Applied Nutrition
U.S. Food and Drug Administration
Washington, DC
Bess Dawson-Hughes, M.D.
Professor of Medicine
Chief
Calcium and Bone Metabolism Laboratory
Jean Mayer USDA Human Nutrition Research Center on
Aging
Tufts University
Boston, Massachusetts
Martin Erlichman, M.S.
Senior Scientist
Center for Practice and Technology Assessment
Agency for Healthcare Research and Quality
Rockville, Maryland
John H. Ferguson, M.D.
Director (Retired)
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
Loretta P. Finnegan, M.D.
Medical Advisor to the Director
Office of Research on Women's Health
National Institutes of Health
Bethesda, Maryland
Stephen I. Katz, M.D., Ph.D.
Director
National Institute of Arthritis and Musculoskeletal and
Skin Diseases
National Institutes of Health
Bethesda, Maryland
Anne Klibanski, M.D.
Panel and Conference Chair
Professor of Medicine
Harvard Medical School
Chief
Neuroendocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Anne C. Looker, Ph.D.
Senior Research Epidemiologist
Division of Health Examination Statistics
National Center for Health Statistics
Centers for Disease Control and Prevention
Hyattsville, Maryland
Leo Lutwak, M.D., Ph.D.
Medical Officer
Division of Metabolic and Endocrine Drugs
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Rockville, Maryland
Ronald Margolis, Ph.D.
Senior Advisor for Molecular Endocrinology
Division of Diabetes, Endocrinology, and Metabolic
Diseases
National Institute of Diabetes and Digestive and Kidney
Diseases
National Institutes of Health
Bethesda, Maryland
Robert A. Phillips, Ph.D.
Chief, Radiological Devices Branch
Office of Device Evaluation
Center for Devices and Radiological Health
U.S. Food and Drug Administration
Rockville, Maryland
Geraldine B. Pollen, M.A.
Executive Secretary
Federal Working Group on Bone Diseases
National Institute of Arthritis and Musculoskeletal and
Skin Diseases
National Institutes of Health
Bethesda, Maryland
Pamela Gehron Robey, Ph.D.
Chief
Craniofacial and Skeletal Diseases Branch
National Institute of Dental and Craniofacial
Research
National Institutes of Health
Bethesda, Maryland
Michael Rosenblatt, M.D.
Harvard Faculty Dean
Senior Vice President for Academic Programs
Care Group
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Sherry S. Sherman, Ph.D.
Director
Clinical Endocrinology and Osteoporosis Research
National Institute on Aging
National Institutes of Health
Bethesda, Maryland
Judith M. Whalen, M.P.A.
Associate Director for Science Policy, Analysis, and
Communication
National Institute of Child Health and Human
Development
National Institutes of Health
Bethesda, Maryland
Karen Winer, M.D.
Medical Officer
Endocrinology, Nutrition, and Growth Branch
National Institute of Child Health and Human
Development
National Institutes of Health
Bethesda, Maryland
Conference
Sponsors
National Institute of Arthritis and Musculoskeletal
and Skin Diseases
Stephen I. Katz, M.D., Ph.D.
Director
Office of Medical Applications of Research
Stephen C. Groft, Pharm.D.
Acting Director
Conference
Cosponsors
National Institute on Aging
Richard J. Hodes, M.D.
Director
National Institute of Diabetes and Digestive and
Kidney Diseases
Allen M. Spiegel, M.D.
Director
National Institute of Dental and Craniofacial
Research
Harold C. Slavkin, D.D.S.
Director
National Institute of Child Health and Human
Development
Duane Alexander, M.D.
Director
National Institute of Nursing Research
Patricia A. Grady, Ph.D., R.N., F.A.A.N.
Director
National Institute of Environmental Health Sciences
Kenneth Olden, Ph.D.
Director
National Heart, Lung, and Blood Institute
Claude Lenfant, M.D.
Director
NIH Office of Research on Women's Health
Vivian W. Pinn, M.D.
Director
Agency for Healthcare Research and Quality
John M. Eisenberg, M.D., M.B.A.
Director
