OFFICERS
President
William D. Leslie, MD, CCD
Winnipeg, Manitoba (CANADA)
President-Elect
John A. Shepherd, PhD, CCD
San Francisco, CA (USA)
Vice President
John J. Carey, MB, BCh, MS,
CCD
Galway (Ireland)
Treasurer
Kate T. Queen, MD, CCD
Waynesville, NC (USA)
Secretary
Anita Colquhoun, MRT(N), CDT
Toronto, Ontario (CANADA
Immediate Past President
Diane C. Krueger, BS, CBDT
Madison, WI (USA)
Executive Director & CEO
Peter D. Brown
Middletown, CT (USA)
July 15, 2015
The United States Preventive Services Task Force
540 Gaither Road
Rockville, Maryland 20850
Re: Draft Research Plan for Osteoporosis: Screening
On behalf of the International Society for Clinical Densitometry, we
appreciate the opportunity to comment on the USPSTF Draft Research
Plan for Osteoporosis: Screening. The ISCD is a multidisciplinary, nonprofit
organization that was founded in June of 1993 with approximately over
3,000 members in more than 70 countries. ISCD provides a central
resource for a number of scientific disciplines with an interest in the
assessment of musculo- skeletal health. The Society is the only one of its
kind worldwide with membership of physicians, technologists, other allied
health providers and scientists representing 30 disciplines including family
practice, internal medicine, obstetrics, gynecology, endocrinology,
gerontology, nephrology, orthopedics, pediatrics, radiology and
rheumatology.
The ISCD’s mission is to advance excellence in the assessment of skeletal
health. As such, the ISCD offers comprehensive educational courses in
bone densitometry and vertebral fracture assessment (VFA) as well as
certification in dual energy X-ray absorptiometry (DXA) acquisition and
interpretation for technologists and physicians. The ISCD now also offers
facility accreditation to demonstrate to healthcare providers, payors and
patients that a DXA testing facility meets accepted standards
BOARD OF DIRECTORS
Robert D. Blank, MD, PhD, CCD
Milwaukee, WI (USA)
Bruno Muzzi Camargos, MD, CCD,
CDT
Belo Horizonte (Brazil)
Beatrice Edwards, MD, FACP, MPH,
CCD
Houston, TX (USA)
Ronald C. Hamdy, MD, CCD
Johnson City, TN (USA)
Kyla K. Kent, CBDT
Redwood City, CA (USA)
E Michael Lewiecki, MD, FACP,
FACE, CCD
Albuquerque, NM (USA)
Sarah L. Morgan, MD, RD, CCD
Birmingham, AL (USA)
Christopher R. Shuhart, MD, CCD
Seattle, WA (USA)
Joon-Kiong Lee MD, FRCS, CCD
The Organization periodically holds Position Development Conferences, to
address a variety of issues in the field, using a process whereby an
international panel of experts makes recommendations based on reviews
of the scientific literature by task forces associated with their Scientific
Advisory Committee. Recommendations that are approved by the ISCD
Board of Directors become Official Positions; of the ISCD. See attached for
ISCD Official Positions.
Proposed Analytic Framework
ISCD Comments on Analytic Framework
The International Society for Clinical Densitometry welcomes the
opportunity to comment on the framework for the upcoming USPSTF
review of osteoporosis screening and treatment study. We are particularly
grateful for the chance to comment early in the process, while the research
questions are still being framed.
In reviewing the key questions in the draft research plan, we note
that the major focus of the review is on the utilization of bone density and
the efficacy and potential harm of therapeutic agents approved for
Petaling Jaya (MALAYSIA)
prevention and treatment with fracture de-emphasized by its placement last
in the flow diagram. Current thinking among clinical experts is that fracture
is the critical outcome and that the focus of any review should be focused
on strategies for identification of fracture risk and strategies for prevention
of fracture. In this light, we suggest that the key questions and outcomes
be framed so as to emphasize the primary importance of fractures.
Inherent in any analysis should be consideration of both the risks of
screening and treatment intervention and the risks of not screening and
treating. As currently written, the analytic framework focuses exclusively on
harms of therapeutic intervention and does not address the risks
associated with a failure to intervene with effective therapy.
In light of this, we suggest that, while the role of bone mineral
density (BMD) testing in determining fracture risk is important, the key
questions and outcomes should be framed to emphasize the primary
importance of fractures. This recommendation is consistent with the
USPSTF, who began moving toward a fracture risk-based
conceptualization in its 2011 recommendations, as embodied in the use of
FRAX to estimate fracture risk in determining which women under age 65
should be screened for osteoporosis.
We believe that the fracture risk conceptualization should be
applied uniformly in conducting the upcoming study. Fracture risk is
continuous, not graded, so imposing a BMD T-score threshold for
determining which patients should receive various assessments or
treatments is ultimately retrogressive. While there is no doubt that the risk
of fracture increases as BMD decreases, other things being equal, more
low trauma fractures occur in individuals who do not meet the densitometric
definition of osteoporosis than occur in those who do.
For these reasons, we believe that the analytic framework should
be altered. Specifically, we object to dichotomous paths being followed on
the basis of bone mass measurement. The analytic framework should
incorporate the continuous nature of risk and recognize that global fracture
risk assessment, not simple bone mass measurement, should be the
primary goal of any diagnostic intervention. The analytic framework should
also explicitly address ascertainment of prior fracture, since this is the
single most robust predictor of future fracture risk.
We recognize that this recommendation runs counter to the thought
processes that dominated the field during its formative years in the 1980s
and 1990s. Although it may have been reasonable to view bone density as
a surrogate for fracture, much information has been gained in the
succeeding decades that points to the complexity underlying fracture risk.
One good example is type 2 diabetes mellitus where measurement of bone
density systematically underestimates fracture risk. This highlights the point
that other indicators of fracture risk in addition to bone density are needed
to explain this complexity.
Additionally, we recommend the age of this cohort be changed in
the analytic framework to asymptomatic adults age 50 years and above
(from age > 40 years) without known reasons for secondary osteoporosis.
We recommend this because it is the minimum age included in most
osteoporosis and post-fracture quality measures, as well as the prevalence
data for osteoporosis and low bone mass per the CDC National Health and
Nutrition Examination Survey.
Key Question 1
Does screening (clinical risk assessment, bone measurement testing,
or both) for osteoporosis (defined as a T-score of ≤−2.5), low bone
mass (defined as a T-score of −1 to −2.5), or high fracture risk reduce
fractures and fracture-related morbidity and mortality in
asymptomatic adults age 40 years and older without known reasons
for secondary osteoporosis?
ISCD Comments on Key Question 1
We propose that Key Question 1 be rephrased as follows:
Does screening (clinical risk assessment, bone measurement testing, or
both) for high fracture risk reduce fractures and fracture-related morbidity
and mortality in asymptomatic adults age 50 years and older without known
reasons for skeletal fragility?
Since the publication of the USPSTF Recommendation Statement
Osteoporosis: Screening (January 2011), there has been increased
emphasis by clinical experts in bone health towards expanding the criteria
and individualizing the assessment for fracture risk as opposed to
screening for osteoporosis. As phrased, Key Question 1 de-emphasizes
the importance of fracture as the important endpoint by focusing on bone
density. We recommend that Key Question 1 be rephrased to emphasize
the importance of fracture as an endpoint. We also think that the the term
“asymptomatic adults” should be explicitly defined to include history of low
trauma fracture in individuals age 50 years and older. In particular, we wish
to include studies in populations that have suffered prior low trauma
fractures and are at increased risk of future fracture, independent of Tscore. These would include persons with wrist fractures following falls from
standing height and those with prevalent vertebral fractures.
Wrist fractures often fail to be recognized as sentinel events as
such individuals are usually asymptomatic following fracture healing but
remain at elevated risk for subsequent fractures, including hip fractures. It
is estimated that between one half and two thirds of vertebral fractures do
not come to medical attention at the time of their occurrence. However,
either a history of significant height loss (> 1.5 inches) or a similar
discrepancy between stated and measured height are both scenarios in
which screening for BMD and the presence of prevalent vertebral fractures
is clinically warranted. We therefore recommend that assessment for
vertebral fractures also be considered within the USPSTF definition of
“screening,” and that these clinical findings should be studied explicitly in
as a part of the analysis for Key Question 1. If USPSTF chooses not to
include vertebral fracture assessment in the definition of screening, then
we believe it to be imperative that the USPSTF explicitly state that these
individuals are outside the scope of the screening guidelines. It should be
noted that it is somewhat redundant to define osteoporosis as
asymptomatic; osteoporosis is an asymptomatic disease that increases the
risk of fracture; it is fracture, not osteoporosis that cause symptoms (e.g.,
pain, disability, loss of independence).
Every fragility fracture suffered by a patient increases the risk of
both future fracture and premature mortality. It is widely recognized that a
prior fracture is a significant risk factor for future fractures; in a metaanalysis of 11 international cohorts, it was noted that suffering a fracture
doubles the risk of subsequent fractures. Additionally, the evidence review
for the USPSTF Recommendation Statement Osteoporosis: Screening
(January 2011) included published papers through 2009 and concluded
that “although methods to identify persons at risk for osteoporotic fractures
are available and medications to reduce fractures are effective, no trials
directly evaluate screening effectiveness, harms, and intervals.” We urge
the USPSTF to include in the proposed research plan and evidence review
more recent published papers noted above which expand screening criteria
and individualize screening intervals so we can encourage the shift in the
healthcare professional focus to fracture risk assessment and prevention.
With regard to screening intervals, the continuous nature of fracture risk
highlights why recommendations for screening intervals should be based
on an individual’s fracture risk and not only by age.
Key Question 2
a. What is the accuracy and reliability of validated risk
assessment approaches to identify adults who are at increased
risk for osteoporosis, low bone mass, or high fracture risk?
b. What is the evidence to support the use of different thresholds,
based on risk assessment, for identifying patients who should
have bone measurement testing?
c. What is the evidence to determine risk assessment and bone
measurement screening intervals?
d. How well do peripheral dual energy x-ray absorptiometry and
qualitative ultrasound predict fracture risk?
ISCD Comments on Key Question 2:
We propose that key question 2 be rephrased as follows:
a. What is the accuracy and reliability of validated risk assessment
approaches to identify adults who are at increased risk for fracture?
b. What is the evidence to support the use of different intervention
thresholds, based on estimated fracture risk for identifying patients who
should be treated to prevent fracture?
c. What is the evidence to determine risk assessment and bone
measurement screening intervals and how do these vary according to
baseline fracture risk?
d. How well do peripheral dual energy x-ray absorptiometry and qualitative
ultrasound predict fracture risk?
This question focuses on the use of bone measurement technology
without considering other elements routinely used to assess fracture risk.
We recommend this question be refocused to expand the criteria used to
screen, diagnose and treat osteoporosis. Limiting the clinical diagnosis of
osteoporosis to a T-score-based criterion obtained from DXA or qualitative
ultrasound creates uncertainty about the use of the term osteoporosis in
the diagnosis of older women and men who have already sustained lowtrauma fractures and have T-scores > −2.5. Another group that is not
included is the individual who is considered at high risk based on absolute
fracture risk calculations from FRAX or other algorithms. A failure to identify
such patients as having osteoporosis may contribute to the welldocumented underdiagnoses and under treatment of this disease, limiting
our ability to reduce the burden of fractures.
Other clinical tools that augment T-score-based identification of
patients with high fracture risk are essential diagnostic tools, and perform
best when used in conjunction with bone mass measurement. We note
that FRAX is improved with BMD measurements and that adding BMD
testing to clinical risk factors for risk assessment increased prediction of
fractures, especially hip fractures, in younger populations. Another study
compared estimates produced by the FRAX tool with and without BMD
included in the FRAX score calculation, and found that FRAX scores
without BMD measurements were lower for women in all age groups
compared with their inclusion in the calculation. For men, the predicted
probability without BMD was lower in the age group 50 to 59, similar in the
age group 60 to 69, and higher in men over 70. The wide spread adoption
of FRAX in clinical practice suggests that it is important to include this tool
in your assessment.
Another element to this question should examine what fracture
types allow a diagnosis of osteoporosis. The International Society for
Clinical Densitometry’s position is that any low trauma fracture, defined as
fracture occurring in the context of a fall from standing height or lesser
trauma, is sufficient to establish a diagnosis of osteoporosis, regardless of
BMD.
Although our primary concern is the under diagnoses of
osteoporosis in individuals 50 years and older who suffer a fracture, we
acknowledge that fractures that occur with a high level of trauma may or
may not have been influenced by the level of bone strength. Therefore, in
this situation an evaluation, including BMD testing, is needed to help
determine the role that reduced bone mass may have played. Care should
be taken to avoid making a diagnosis of osteoporosis if the fractures truly
resulted solely from the trauma.
Regarding Vertebral Fracture Assessment (VFA), several studies
have found that adding VFA to a BMD scan leads to detection of otherwise
unnoticed vertebral fractures, broadening the group of individuals who may
benefit from osteoporosis treatment. VFA performed at the same time as
BMD resulted in changes to the treatment plan in 31 percent of 117
patients evaluated. Ferrar, et al followed 674 women for 6 years and found
that those who had a baseline fracture were at 8-fold increased risk of a
subsequent fracture relative to women with no baseline fracture.
Also, we recommend that the USPSTF consider emerging
assessment technologies that contribute to fracture risk prediction. There is
a growing literature on the predictive power of Trabecular Bone Score, as
well as on engineering models based on CT scans of the hip.
Key Question 3
What are the harms of screening (clinical risk assessment, bone
measurement testing, or both) for osteoporosis, low bone mass, or
high fracture risk?
a. What is the effectiveness of pharmacotherapy for the treatment
of osteoporosis (defined as a bone mass T-score of ≤−2.5),
specifically in reducing fracture-related morbidity and
mortality?
b. What is the effectiveness of pharmacotherapy for the
prevention of osteoporosis in persons with low bone mass
(defined as a T-score of −1.0 to −2.5), specifically in reducing
fracture-related morbidity and mortality?
c. What is the effectiveness of pharmacotherapy for the
prevention of osteoporosis in persons with low bone mass or
for the treatment of osteoporosis by subgroup, specifically in
postmenopausal women, premenopausal women, men,
younger age groups (age <65 years), and older age groups
(age ≥65 years)?
d. What is the effectiveness of pharmacotherapy for the reduction
of fracture-related morbidity and mortality in patients with low
bone mass, as measured by peripheral dual energy x-ray
absorptiometry or qualitative ultrasound?
ISCD Comments on Key Question 4:
We propose that key question 4 be rephrased as follows:
a. What is the effectiveness of pharmacotherapy for the reduction of
fracture-related morbidity and mortality in those who have suffered a past
low trauma fracture and/or have a bone mass T-score < -2.5?
b. What is the effectiveness of pharmacotherapy for the reduction of
fracture-related morbidity and mortality in those with high fracture risk but
without prior fractures or with a bone mass T-score > -2.5?
c. What is the effectiveness of pharmacotherapy for the prevention of
fractures by subgroup, specifically in postmenopausal women,
premenopausal women, men, younger age groups (age <65 years), and
older age groups (age ≥65 years)?
d. What is the effectiveness of pharmacotherapy for the reduction of
fracture-related morbidity and mortality in patients with high fracture risk, as
measured by peripheral dual energy x-ray absorptiometry or qualitative
ultrasound?
e. What is the evidence to support the use of different intervention
thresholds based on risk assessment for identifying patients who should be
treated to prevent fracture?
Recognizing that fracture risk is a continuous variable mandates the
rephrasing of key question 4. The goal of intervention is not to prevent or
treat osteoporosis--it is to prevent fractures. This approach is already in
use for cardiovascular disease, where no one thinks of “prevention of
dyslipidemia” or “treatment of dyslipidemia” as the primary endpoint, but as
prevention of myocardial infarctions. Deciding which patients benefit from
such therapy should not be based solely on densitometric classification, but
on a global assessment of risk. This must include past fracture history, age
and other factors that contribute to risk, TBS. With regard to screening
intervals, fracture risk increases exponentially, not linearly, with age.
Indeed, it has been found that the average fracture risk “doubling time” is
much more rapid than would be expected from age-related BMD loss
alone. This means that while longer screening intervals may be
appropriate for younger individuals, the frequency of reassessment should
increase in older individuals or as individuals approach the guidelinesbased intervention threshold.
Key Question 5
What are the harms associated with pharmacotherapy for the
prevention of osteoporosis in persons with low bone mass or for the
treatment of osteoporosis?
ISCD Comments on Key Question 5:
We propose that key question 5 be rephrased as follows: What are
the harms associated with pharmacotherapy for the prevention of low
trauma fracture?
Proposed key question 5 should be broadened. There are “harms”
associated with treatment, but also with failure to treat. The question as
written is rather one-sided and is likely to result in conclusions that do not
accurately reflect the risks that confront a patient at risk of low trauma
fracture. Death, loss of independence and chronic pain are just a few of the
sequalae of hip fracture. We recognize that inclusion of fracture risk in this
evaluation may lower the use of osteoporosis medications for prevention
purposes; this may be appropriate until outcomes data are developed that
provide an accurate assessment of their impact on a long-term fracture
risk. There are a number of efficacious medications available to treat
osteoporosis and low bone mass which are widely prescribed and highly
effective at preventing secondary fractures with the potential to reduce hip
fractures by up to 50 percent, but there are limited data about long-term
outcomes in patients at lower risk.
We recognize that the perception of risk associated with antiresorptive agents has risen over the past decade with the identification of
osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). We
would remind you, however, that while the relative risk of patients with
AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is
low, ranging from 3.2 to 50 cases per 100,000 person-years. This risk
should be factored into and balanced with the risks associated with
fracture. The other rare side effect regarding the use of these medications
is osteonecrosis of the jaw (ONJ). The risk of ONJ associated with oral
bisphosphonate therapy for osteoporosis is low, estimated between 1 in
10,000 and <1 in 100,000 patient-treatment years. While this is a serious
side-effect, it is important to balance the risks of the therapy with risks of
non-treatment in this discussion.
Contextual Question 1
What is the evidence from modeling studies about different risk
thresholds for identifying patients who should have bone
measurement testing?
ISCD Generally Agrees, See Comments:
This is an important question. We recommend, however, that you
think of fracture risk as a continuous variable that rises over the course of a
lifetime. The goal of diagnostic and therapeutic intervention is to identify
those individuals who have greater risk of fracture and then to reduce that
risk. A continuous risk gradient does not naturally lend itself to the
establishment of thresholds, especially when some elements of risk are not
readily amenable to measurement.
Contextual Question 2
What is the evidence from modeling studies about the effectiveness
of screening strategies (screening, risk assessment, or bone
measurement) that use a) different ages at which to start and stop
screening and b) different screening intervals?
ISCD Generally Agrees, See Comments:
We urge the same caution with regard to this question as to the
prior one. We are reluctant to establish age-based, as opposed to riskbased, criteria for screening strategies.
ISCD Comments on the Draft Research Approach:
We encourage the USPSTF to review all data that bear on the Key
Questions, and not to constrain its search to data published since
November 1, 2009. This is particularly important as the therapeutic
paradigm shifts to include both densitometric and risk-based criteria. For
example, vertebral fracture assessment (VFA) is a powerful screening tool
for asymptomatic vertebral fractures that falls within the scope of USPSTF
review, but much of the published data emerged before November 2009
and might not be included in the search strategy.
William D. Leslie, MD, MSc, FRCP, CCD
ISCD President
E Michael Lewiecki, MD, FACP, FACE, CCD
ISCD Public Policy Chair
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