| Recommendation #1: Monitor sex differences and similarities for
all musculoskeletal diseases and conditions, including diagnosis and
treatment, which affect both sexes. |
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• What are the common musculoskeletal, immunologic, and neurologic
disorders and injuries in which diagnostic markers or therapeutics need to be
different in men and women? Are diagnostic parameters sex-dependent in
diseases common to men and women? Is their pathophysiology different?
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• What are the unifying principles in musculoskeletal disease that are
sex-invariant?
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• Are there unexpected consequences of sexual dimorphism in the
musculoskeletal system?
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• Are there sex and gender differences that are not predictable based on
hormonal status? What are their origins?
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| Recommendation #2: Longitudinal and cross-sectional studies of
musculoskeletal diseases and conditions should be conducted and designed so
that results can be analyzed by sex. |
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• Why do each of the sex-specific diseases exhibit their specificity?
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• Are there sexually dependent differences in bone and soft-tissue
growth, development, and properties that are independent of differences in
growth rate? What are the molecular bases for these differences?
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• When is the variance in bone traits, such as cortical thickness,
trabecular number, and thickness, established? What are the genetic
determinants of this variance?
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• Are there sex and gender differences in the treatment success for
musculoskeletal medicines and surgeries?
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• What is the impact of sex and gender across the lifespan on surgical
outcomes? Sports injuries? Outcomes of trauma and sepsis?
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| Recommendation #3: Make sex-specific data in musculoskeletal
diseases and conditions more readily available. |
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• What are the normative values for important diseases that have a major
sex-gender component?
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• Is there epidemiological information in existing databases that can be
mined to provide information about sex-specific disease traits and management?
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• Are standard laboratory techniques used in musculoskeletal research
valid for male and female cells and tissues?
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| Recommendation #4: Mine cross-species information and develop
relevant in vivo and in vitro models that incorporate the biological clock.
Stratify both human and animal studies of musculoskeletal diseases and
conditions based on sex. |
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• Is there equivalence of puberty and menopause in animals and do animals
demonstrate the same life-cycle behaviors as humans? Do sex-specific
differences in animal models reflect differences in humans?
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• What are the most appropriate models for evaluating sex-specific
differences in specific musculoskeletal diseases?
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| Recommendation #5: Expand research on sex differences in neural
organization and function, pain, and analgesia with respect to musculoskeletal
diseases and conditions. |
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• Are there sexual differences in response to neurologic injury?
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• Why is there a dichotomy between the neuroprotective effects of
estrogen in animal models of experimental ischemia and the results from recent
clinical trials that suggest estrogen increases stroke risk? Are we
overdosing? Should estrogen be considered for an acute stroke trial?
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• Why should sexually dimorphic pain mechanisms exist? Do the COX-2 and
NSAIDs agents affect male and female cell biology similarly?
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• What is the basis for the differences in response to anesthesia in men
and women? At which loci in the brain are male and femalespecific circuitry
different from one another? At which point are they convergent?
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• How does neuromuscular development differ in males and females and how
are those differences affected by life cycle?
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| Recommendation #6: Promote research on sex differences at the
molecular, cellular, and tissue levels with specific emphasis on
musculoskeletal diseases and conditions. |
| Molecular and Cell Biology |
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• What is the molecular basis of sexual dimorphic cell behavior,
including response to injury, growth and development, response to estrogens
and androgens, and tissue-engineering constructs? What in addition to estrogen
and androgen (including cytokines and growth factors) determines the sexual
dimorphic behavior of cells and tissues?
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• Are there fundamental differences between male and female donor cells
that must be taken into consideration when producing musculoskeletal tissues
under bioreactor and other tissue-engineering conditions? Are there
sex-specific differences in host response to tissues produced using cells from
a different sex donor?
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• What is the basis for the differences between male and female cells in
culture? Are sex-specific differences in cells genetically determined by
imprinting or are they adaptations to the hormonal environment of the donor or
cell culture conditions?
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• Are stem cells, like more differentiated cells, subject to age, hormone
status, and sex-specific constraints? Is there a difference between embryonic,
fetal, or adult stem cells? Are their sex-specific differences in host
responses to tissues produced using cells from a different sex donor?
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• What are the components of the cell-death pathway that differ between
males and females?
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Tissue Properties
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• At the tissue and organ levels, what are the relative sex-dimorphic
responses on bone size, shape, and mass and the variance in these. Do these
vary with age and/or time? What is the basis for this variation?
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• How are adaptation and remodeling processes regulated in males and
females? How are these related to fracture and injury risk?
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• How do groups of mutations in musculoskeletal tumors affect the
sex-specific biology of the tumor? Are there hormonal differences in bone
metastases? Are there animal and in vitro models of spontaneous metastasis to
bone? Do the sex hormones affect bone metastases?
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• Does accelerated bone turnover from estrogen deprivation augment
cancer-induced osteolysis and lead to the accelerated deterioration of bone
structural properties?
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• Do single gene mutations affecting bone mass have different effects in
men and women?
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• How does the observation that males and females inherit bone traits
differently affect bone properties and fracture risk? What is the basis for
this difference in inheritance?
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• How do the differences in male and female development manifest
themselves in injury patterns? Do systemic androgens produce similar effects
on post-cranial muscle fibers and their motor neurons? What is the mechanism
of these effects?
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• How does change in estrogen levels impair the osteogenic response to
exercise? What common distal pathways in bone are affected by both estrogen
and exercise? Is stimulation of the estrogen receptor necessary for these
shared responses?
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• What strategies show potential for effectively reducing impact loads to
prevent fracture, and which should be tested further in clinical trials or
used in clinical practice? Which strategies of fall prevention are most
effective? Will certain strategies be more effective for women or men?
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• What is the biological basis for the observed impaired ability in women
to recover balance after a perturbation as measured in controlled experiments
in motion analysis laboratories? Do these differences relate to greater fall
rates in women or to greater injury rates when women do fall?
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• Is there a sexually dimorphic response toward implant materials
(biosynthetic, metal, or composite)? How does the immune response toward these
implants differ?
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