NR566 Final Exam Study Guide: Weeks 9-18
Advanced Pharmacotherapeutics for Cardiovascular,
Endocrine, Respiratory, and Hematologic Disorders
Week 5 to Week 8 Week 9 &10 Week 11 &12 Week 13& 14 Week
15&16 Week 17&18
- Prevention of osteoporosis with hormone replacement therapy Tara (p.433)
Hormone therapy reduces postmenopausal bone loss and thereby decreases the risk for
osteoporosis and related fractures. Therapy is lifelong and the risk for harm is increased.
Hormone therapy should only be considered for women with significant risk for osteoporosis,
and only when that risk outweighs the risks of hormone therapy.
Supporting Studies and Evidence
Women's Health Initiative (WHI) Trials (2002, 2004): Use of MHT for menopausal symptoms
declined substantially after publication of the WHI trials. Subsequent studies have shown that
initiation of MHT within 10 years of the final menstrual period (FMP) and age < 60 years is
associated with a favorable balance of benefit vs. risk . MHT has been shown to maintain or
increase BMD in early postmenopausal women and to prevent fracture in women who do not
have osteoporosis . However, benefits last only as long as therapy continues. When therapy is
discontinued, very rapid bone loss ensues with a 4.5-6% loss at the lumbar spine (LS) within one
year . The 5-year follow-up of the WHI cohorts showed that fracture rates after MHT
discontinuation returned to that of the placebo . The rapid loss that occurs with estrogen
discontinuation can be mitigated with alendronate 10 mg daily when initiated within 3 months
of discontinuation — a gain of 3.2% in 12 months was seen instead .
,Kronos Early Estrogen Prevention Study (KEEPS) and Postmenopausal Estrogen/Progestin
Interventions (PEPI) Trial: Both trials noted therapy increased BMD at both the hip and spine .
The WHI noted a reduction in vertebral, hip, and nonvertebral fractures, with meta-analyses
suggesting 5 to 7 years of treatment is required to reduce fracture risk significantly . The PEPI
trial specifically noted therapy increased BMD at both the hip and spine .
4-Year Randomized Controlled Trial of HRT + Bisphosphonate (Wimalawansa, 1998): This
landmark 4-year prospective randomized study of 72 postmenopausal women (mean age 64.9
years) with established osteoporosis demonstrated the additive effect of etidronate and HRT. In
patients who received combined therapy, BMD increased in the lumbar spine by 10.4% (P <
0.001) and in the hip by 7.0% (P < 0.001) at 4 years. For patients treated with intermittent
cyclical etidronate (ICE), these increases were 7.3% (P < 0.001) and 0.9% (P < 0.05), and with
HRT alone, the increases were 7.0% (P < 0.001) and 4.8% (P < 0.01) in the vertebrae and femora,
respectively. The control group treated with calcium and vitamin D alone lost 2.5% (P < 0.05)
and 4.4% (P < 0.01) of BMD in the vertebrae and femora, respectively, after 4 years . Patients
who received combined therapy had significantly higher BMD in both the vertebrae and femora
(P < 0.05) compared with patients treated with HRT or etidronate alone. Height loss was
significantly less in all three active treatment groups compared with the control group .
Timing of Initiation: Subgroup analysis noted the timing of hormonal therapy influences risks
and benefits, with more favorable effects in those under age 60 or within 10 years of
menopause . The Endocrine Society solely recommends estrogen therapy in postmenopausal
women at high risk of fractures with a prior hysterectomy, who are under 60, 10 years past
menopause, low risk for deep venous thromboses, no prior myocardial infarction or stroke, no
diagnosis of breast cancer, those with bothersome vasomotor symptoms, those willing to take
menopausal hormone therapy, and for whom bisphosphonates or denosumab are
contraindicated . The AACE recommends cyclic or daily progestin in addition to estrogen in
patients with a uterus to prevent endometrial hyperplasia; however, their advice is for
treatment to be used at the lowest dose and for the shortest time necessary . MHT should be
used in the lowest dose and for the shortest period necessary to control menopausal symptoms
. When hormonal therapy is discontinued, skeletal benefits are lost after a few months, with a
decrease in BMD of around 6% within the first year (and by 2 years returns to the level of a
woman who has never taken estrogen), and bone turnover markers return to levels seen
pretreatment within a few months .
, Guideline Positioning: Estrogen/hormone therapies, although never specifically approved for
osteoporosis use, are approved for the prevention of postmenopausal osteoporosis . Current
clinical guidelines focus on treatment of osteoporosis to prevent fractures, with scant attention
to prevention of osteoporosis. In the absence of long-term clinical prevention trials, clinicians
must use their knowledge of bone physiology with respect to estrogens and bisphosphonates to
make informed clinical decisions for perimenopausal women. On average, women who enter
menopause with a T-score of -1.5 or lower and lose 10% of their BMD over 10 years will develop
osteoporosis .
Meds are: raloxifene (Evista), bisphosphonates (e.g., alendronate [Fosamax]), calcitonin
(Miacalcin), and teriparatide (Forteo).
Pharmacologic Agents — Supporting Evidence
Raloxifene (Evista): The principal efficacy study for raloxifene in postmenopausal osteoporosis is
the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a Phase III randomized trial
(GGGK). The Continuing Outcomes Relevant to Evista (CORE) study, a 4-year continuation of
MORE involving 4,011 women, demonstrated continued skeletal effects at 8 years, with
significant reductions in new vertebral and nonvertebral osteoporotic fractures . Raloxifene is
indicated for the treatment and prevention of osteoporosis in postmenopausal women . A
specified secondary endpoint demonstrated a statistically significant decrease in the proportion
of patients who reported any incident fracture (new vertebral or osteoporotic nonvertebral) in
both raloxifene treatment groups compared with placebo .
Bisphosphonates (Alendronate/Fosamax): The Fracture Intervention Trial (FIT) consisted of two
studies in postmenopausal women: the Three-Year Study of patients who had at least one
baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone
density but without vertebral fractures . The FOSIT (Fosamax International Trial) study was a
multinational, placebo-controlled, randomized trial of the effects of alendronate on bone
density and fracture risk in postmenopausal women with low bone mass . When combined with
HRT, alendronate increased lumbar spine BMD more than placebo when each was added to
hormone replacement therapy . The Early Postmenopausal Intervention Cohort (EPIC) study
evaluated prevention of bone loss with alendronate in postmenopausal women under 60 years
of age .
Advanced Pharmacotherapeutics for Cardiovascular,
Endocrine, Respiratory, and Hematologic Disorders
Week 5 to Week 8 Week 9 &10 Week 11 &12 Week 13& 14 Week
15&16 Week 17&18
- Prevention of osteoporosis with hormone replacement therapy Tara (p.433)
Hormone therapy reduces postmenopausal bone loss and thereby decreases the risk for
osteoporosis and related fractures. Therapy is lifelong and the risk for harm is increased.
Hormone therapy should only be considered for women with significant risk for osteoporosis,
and only when that risk outweighs the risks of hormone therapy.
Supporting Studies and Evidence
Women's Health Initiative (WHI) Trials (2002, 2004): Use of MHT for menopausal symptoms
declined substantially after publication of the WHI trials. Subsequent studies have shown that
initiation of MHT within 10 years of the final menstrual period (FMP) and age < 60 years is
associated with a favorable balance of benefit vs. risk . MHT has been shown to maintain or
increase BMD in early postmenopausal women and to prevent fracture in women who do not
have osteoporosis . However, benefits last only as long as therapy continues. When therapy is
discontinued, very rapid bone loss ensues with a 4.5-6% loss at the lumbar spine (LS) within one
year . The 5-year follow-up of the WHI cohorts showed that fracture rates after MHT
discontinuation returned to that of the placebo . The rapid loss that occurs with estrogen
discontinuation can be mitigated with alendronate 10 mg daily when initiated within 3 months
of discontinuation — a gain of 3.2% in 12 months was seen instead .
,Kronos Early Estrogen Prevention Study (KEEPS) and Postmenopausal Estrogen/Progestin
Interventions (PEPI) Trial: Both trials noted therapy increased BMD at both the hip and spine .
The WHI noted a reduction in vertebral, hip, and nonvertebral fractures, with meta-analyses
suggesting 5 to 7 years of treatment is required to reduce fracture risk significantly . The PEPI
trial specifically noted therapy increased BMD at both the hip and spine .
4-Year Randomized Controlled Trial of HRT + Bisphosphonate (Wimalawansa, 1998): This
landmark 4-year prospective randomized study of 72 postmenopausal women (mean age 64.9
years) with established osteoporosis demonstrated the additive effect of etidronate and HRT. In
patients who received combined therapy, BMD increased in the lumbar spine by 10.4% (P <
0.001) and in the hip by 7.0% (P < 0.001) at 4 years. For patients treated with intermittent
cyclical etidronate (ICE), these increases were 7.3% (P < 0.001) and 0.9% (P < 0.05), and with
HRT alone, the increases were 7.0% (P < 0.001) and 4.8% (P < 0.01) in the vertebrae and femora,
respectively. The control group treated with calcium and vitamin D alone lost 2.5% (P < 0.05)
and 4.4% (P < 0.01) of BMD in the vertebrae and femora, respectively, after 4 years . Patients
who received combined therapy had significantly higher BMD in both the vertebrae and femora
(P < 0.05) compared with patients treated with HRT or etidronate alone. Height loss was
significantly less in all three active treatment groups compared with the control group .
Timing of Initiation: Subgroup analysis noted the timing of hormonal therapy influences risks
and benefits, with more favorable effects in those under age 60 or within 10 years of
menopause . The Endocrine Society solely recommends estrogen therapy in postmenopausal
women at high risk of fractures with a prior hysterectomy, who are under 60, 10 years past
menopause, low risk for deep venous thromboses, no prior myocardial infarction or stroke, no
diagnosis of breast cancer, those with bothersome vasomotor symptoms, those willing to take
menopausal hormone therapy, and for whom bisphosphonates or denosumab are
contraindicated . The AACE recommends cyclic or daily progestin in addition to estrogen in
patients with a uterus to prevent endometrial hyperplasia; however, their advice is for
treatment to be used at the lowest dose and for the shortest time necessary . MHT should be
used in the lowest dose and for the shortest period necessary to control menopausal symptoms
. When hormonal therapy is discontinued, skeletal benefits are lost after a few months, with a
decrease in BMD of around 6% within the first year (and by 2 years returns to the level of a
woman who has never taken estrogen), and bone turnover markers return to levels seen
pretreatment within a few months .
, Guideline Positioning: Estrogen/hormone therapies, although never specifically approved for
osteoporosis use, are approved for the prevention of postmenopausal osteoporosis . Current
clinical guidelines focus on treatment of osteoporosis to prevent fractures, with scant attention
to prevention of osteoporosis. In the absence of long-term clinical prevention trials, clinicians
must use their knowledge of bone physiology with respect to estrogens and bisphosphonates to
make informed clinical decisions for perimenopausal women. On average, women who enter
menopause with a T-score of -1.5 or lower and lose 10% of their BMD over 10 years will develop
osteoporosis .
Meds are: raloxifene (Evista), bisphosphonates (e.g., alendronate [Fosamax]), calcitonin
(Miacalcin), and teriparatide (Forteo).
Pharmacologic Agents — Supporting Evidence
Raloxifene (Evista): The principal efficacy study for raloxifene in postmenopausal osteoporosis is
the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a Phase III randomized trial
(GGGK). The Continuing Outcomes Relevant to Evista (CORE) study, a 4-year continuation of
MORE involving 4,011 women, demonstrated continued skeletal effects at 8 years, with
significant reductions in new vertebral and nonvertebral osteoporotic fractures . Raloxifene is
indicated for the treatment and prevention of osteoporosis in postmenopausal women . A
specified secondary endpoint demonstrated a statistically significant decrease in the proportion
of patients who reported any incident fracture (new vertebral or osteoporotic nonvertebral) in
both raloxifene treatment groups compared with placebo .
Bisphosphonates (Alendronate/Fosamax): The Fracture Intervention Trial (FIT) consisted of two
studies in postmenopausal women: the Three-Year Study of patients who had at least one
baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone
density but without vertebral fractures . The FOSIT (Fosamax International Trial) study was a
multinational, placebo-controlled, randomized trial of the effects of alendronate on bone
density and fracture risk in postmenopausal women with low bone mass . When combined with
HRT, alendronate increased lumbar spine BMD more than placebo when each was added to
hormone replacement therapy . The Early Postmenopausal Intervention Cohort (EPIC) study
evaluated prevention of bone loss with alendronate in postmenopausal women under 60 years
of age .
