The World Health Organization along with several leading osteoporosis
organizations developed the WHO Fracture Risk Assessment tool (FRAX) that can
be used alone or with BMD to identify fracture risk.
44 FRAX is a computerizedbased algorithm created for different populations available online at
http://www.shef.ac.uk/FRAX. The FRAX algorithm incorporates ethnicity as well
as clinical risk factors (e.g., age, smoking, physical inactivity, height, weight, prior
fracture, parental history of hip fracture, long-term use of glucocorticoids, and
comorbid conditions that have been associated with decreases in BMD) to calculate
10-year fracture risk. FRAX has been validated in 11 different cohorts and is a
valuable tool that provides information on absolute risk instead of relative risk by
taking into account the impact of risk factors on fracture and death. As with many
tools, there are some limitations to FRAX. The algorithm excludes certain variables
such as vitamin D deficiency, bone turnover markers, and falls. It does not take into
account multiple fractures and may underestimate risk.
FRAX should not replace clinical judgment for treatment and is intended to be
used in postmenopausal women and men over age 50. It has not been validated in
patients who have been on or who are receiving medication therapy for
CASE 110-2, QUESTION 2: Based on the information that you have obtained, does M.J. have osteoporosis
or is she at risk for developing osteoporosis?
M.J. is 62 inches tall and weighs 50 kg. She has a T-score of −2.0 (DXA
measurement of the spine) and a Z-score of −1.0. Using the FRAX risk assessment
tool for the US population (http://www.shef.ac.uk/FRAX) without a T-score of the
femoral neck, M.J.’s 10-year probability of a hip fracture is 0.5% and her 10-year
probability of a major osteoporosis-related fracture is 5.1%. M.J’s T-score is
consistent with osteopenia or low bone mass.
Techniques for Measuring Bone Mineral Density
Technique Abbreviation Measurement Sites
Dual-energy X-ray absorptiometry DXA Hip, spine, total body
Peripheral quantitative computed
Quantitative ultrasound QUS Heel, tibia, patella
Quantitative computed tomography QCT Spine, hip
Single-energy X-ray absorptiometry SXA Heel
M.J.’s risks include low bone mass, low body mass, a family history of
osteoporosis, history of smoking, and medication that increases the risk of
CASE 110-2, QUESTION 3: What preventive measures would help decrease M.J.’s likelihood of developing
M.J. goes for walks occasionally and should begin a consistent exercise program
appropriate for her age and physical condition. Postmenopausal women who
incorporated aerobic and weight-bearing exercise showed some improvements in
BMD and reduced the risk of fractures as compared to those who did not exercise.
Weight-bearing exercise and resistance training may improve strength, muscle mass,
flexibility, balance, and decrease M.J.’s risk for falls.
Similar to T.J., it is important for M.J. to have a well-balanced diet rich in fruits and
vegetables, low-fat dairy products, whole grains, fish, and nuts to provide adequate
calcium and nutrients needed for bone health.
The recommended daily allowance of calcium for women ages 51 to 70 is 1,200
33 M.J’s total calcium intake from diet and supplementation is about 1,000
mg/day and should be increased so that she incorporates 1,200 mg/day of calcium in
her diet. She can do this by choosing calcium-containing foods (Table 110-3) and by
taking a supplement if she cannot get adequate calcium from her diet (Table 110-4).
It is important for M.J. to have adequate vitamin D intake in her diet. The
recommended daily allowance of vitamin D for women between 51 and 70 age is
600 IU/day, and for women over age 70, the recommended daily allowance is 800
IU/day. The NOF recommends 800 to 1,000 IU/day for men and women over age 50.
Expert consensus opinion has made recommendations for serum 25(OH) vitamin D
33 Levels less than 20 ng/mL (50 nmol/L) suggest insufficiency,
whereas levels of 29 to 32 ng/mL(70 to 80 nmol/L) suggest adequate stores. There is
currently limited evidence to attempt to achieve serum 25(OH) vitamin D levels
above 60 ng/mL (150 nmol/L). (For further information, see Case 105-1, Question 2.)
A serum 25(OH) vitamin D level should be drawn and M.J. should receive a vitamin
D supplement to achieve a serum 25 (OH) vitamin D level of 30 ng/mL (75 nmol/L)
if the level is found to be insufficient.
Although calcium and vitamin D are important for bone health, they should not be
used instead of drug therapy to treat osteoporosis, but used as part of an overall plan
CASE 110-2, QUESTION 4: Because a rapid rate of bone loss is seen during menopause when estrogen
An estimated 10% to 15% of a woman’s bone mass is estrogen dependent.
Estrogens are important in bone formation, resorption, and maintaining bone mass
while menopause is associated with a decrease in estrogen and an increase in bone
The National Osteoporosis Risk Assessment Study and the Million Women Study,
both large observational studies by design, found that EPT or ET provided significant
relative risk reductions in fracture.
47,48 These results were confirmed by the Women’s
Health Initiative (WHI) with both the EPT and ET arms, showing significant risk
reductions in hip, vertebral, and total fractures compared with placebo.
Previously, ET or EPT would have been considered first-line treatment for the
prevention of osteoporosis in a postmenopausal woman such as M.J., who has an
intact uterus and is at risk for osteoporosis based on risk factors and T-score. In the
Women’s Health Initiative (WHI), conjugated equine estrogen (CEE) alone and CEE
with medroxyprogesterone (CEE+MPA) were shown to decrease the risk of hip,
vertebral, and total fractures in postmenopausal women; however, the intervention
phases were ended early because coronary heart disease (CHD), stroke, deep vein
thrombosis (DVT), pulmonary embolism (PE), and breast cancer were significantly
increased in the CEE + MPA group and rates of stroke were significantly increased
in women on CEE alone (also see Chapter 51, The Transition Through
49,50 The findings from the WHI do not support the use of ET or EPT for
the prevention of osteoporosis. Since the publication of the Heart and
Estrogen/Progestin Replacement Study (HERS) I and HERS II and the NIH Women’s
Health Initiative (WHI), healthcare providers are less likely to prescribe ET or EPT
for the sole purpose of osteoporosis prevention or to continue its use after a women
no longer needs EPT or ET for postmenopausal symptoms such as hot flushes.
EPT is approved for the prevention of osteoporosis in postmenopausal women
with a uterus and ET is approved for postmenopausal women without a uterus.
When prescribed for osteoporosis prevention, ET and EPT should be used at the
lowest effective doses and the shortest duration indicated. Longer therapy should
only be prescribed in women who have failed other osteoporosis therapies, or when
other osteoporosis therapies are contraindicated and when it can be determined that
the benefits outweigh the risks. M.J. does not have bothersome symptoms of
menopause; therefore, ET or EPT would not be appropriate at this time.
Contraindications to Estrogen Use
CASE 110-2, QUESTION 5: If M.J. developed bothersome symptoms of menopause, would ET or EPT be
appropriate to treat symptoms and prevent osteoporosis?
Contraindications to EPT or ET include pregnancy; active or history of deep vein
thrombosis or pulmonary embolism; active or recent (e.g., within the past year)
arterial thromboembolic disease (e.g., stroke, myocardial infarction); undiagnosed
abnormal genital bleeding; known, suspected, history of breast cancer; known or
suspected estrogen-dependent neoplasia; liver dysfunction or disease; or known
hypersensitivity to the product or any of its ingredients.
should be used with caution in those with a history of asthma, diabetes mellitus,
migraine, epilepsy, systemic lupus erythematous, porphyria, and hepatic
hemangiomas. Patients on EPT or ET are at increased risk for cancer, including
endometrial (if not on EPT), breast (for EPT), and ovarian cancer as well as
increased cardiovascular events, thromboembolic disease, stroke, gallbladder
disease, and dementia (also see Chapter 51, The Transition Through Menopause).
M.J. stated that she has a strong family history of breast cancer, and starting EPT
or ET would not be the treatment of choice for the prevention of osteoporosis.
CASE 110-2, QUESTION 6: Should a bisphosphonate be considered for the prevention of osteoporosis in
postmenopausal women such as M.J.?
NAMS recommends adding osteoporosis drug therapy in postmenopausal women
who have had a vertebral or hip fracture, in postmenopausal women with a BMD of
−2.5 or worse at the lumbar spine, femoral neck, or total hip, and in postmenopausal
women with a T-score of −1.0 to −2.5 who have a 10-year fracture risk of 20%
(spine, hip, shoulder, wrist) or risk of 3% (hip) calculated using FRAX.
Bisphosphonates, analogs of pyrophosphate, are considered first-line therapy for the
prevention and treatment of osteoporosis in postmenopausal women. Alendronate
(excluding effervescent tablets), ibandronate, risedronate-immediate release, and
zoledronic acid are indicated for osteoporosis prophylaxis in postmenopausal
women like M.J, whereas other agents are indicated for osteoporosis treatment and
Alendronate, ibandronate, risedronate, pamidronate, and zoledronic acid are
aminobisphosphonates with a greater selectivity for the antiresorptive surfaces of the
bone due to changes in the nitrogen-containing side chain of the compounds.
Bisphosphonates have high affinities for bone hydroxyapatite and can be
incorporated into bone. They concentrate in mineral tissue and interfere with the
osteoclast-mediated bone resorption to cause osteoclast apoptosis, decreased bone
turnover, resulting in decreased fracture rates in postmenopausal women who are at
Because of their incorporation into bone, bisphosphonates have long half-lives,
estimated to be 1 to 10 years. Unlike etidronate (a nonaminobisphosphonate),
aminobisphosphonates do not inhibit bone mineralization, which could lead to
Bisphosphonates-Bone Mineral Density Efficacy in Postmenopausal Women
In a Cochrane review that included randomized controlled trials (RCTs) of
alendronate for the primary and secondary prevention of osteoporotic fractures in
postmenopausal women taken for at least 1 year, alendronate was compared to
placebo with or without calcium and vitamin D.
57 Trials were considered primary
prevention trials if the women had an average T-score within 2 SD of the mean, or if
the prevalence of vertebral fracture was less than 20% at baseline. Secondary
prevention trials were defined as women having a bone density at least 2 SD below
peak bone mass or a previous vertebral compression fracture or age greater than 62
years. Clinically, important improvements were seen with vertebral fractures
although not statistically significant for primary prevention. In secondary prevention
studies, alendronate 10 mg daily led to clinically and statistically significant
reductions in hip, wrist, vertebral, and nonvertebral fractures.
Medications Approved for Prevention and Treatment in Postmenopausal
Class Medication Prevention Treatment
Bisphosphonates Alendronate 5 mg PO daily
Alendronate/cholecalciferol 70 mg/2,800 IU PO
Zoledronic acid 5 mg IV every other year 5 mg IV yearly
Raloxifene 60 mg PO daily 60 mg PO daily
Polypeptide hormone Calcitonin Not indicated 100 IU IM or SC once
Monoclonal antibody Denosumab Not indicated 60 mg SC every 6 months
Parathyroid hormone Teriparatide Not indicated 20 mg SC once daily
Estrogen Conjugated estrogen When other treatments
Estrogen + progestin When other treatments
0.45 mg/20 mg PO daily Not indicated
A 2-year multicenter study of postmenopausal women age 45 to 59 was conducted
to compare the efficacy and tolerability of alendronate to EPT.
randomized to receive placebo, alendronate 2.5 mg/day or alendronate 5 mg/day, or
open-label EPT, unless contraindicated decreases in BMD of the lumbar spine were
noted in the placebo group, whereas 2% and 2.7% increases were seen in the
alendronate 2.5 and 5 mg/day groups, respectively, after the first year. Forty percent
of women who were in the placebo group lost 2% of bone mineral density at the hip
as compared to only 10% in the alendronate 2.5 mg and 6% in the alendronate 5-mg
groups. Hip BMD increased at 2 years by 1.9% (EPT) and 1.3% (alendronate 5 mg)
in the United States cohort. In the European cohort, women on EPT had significantly
greater increases in total body BMD as compared to those on alendronate 5 mg/day.
Alendronate 2.5 and 5 mg/day were well tolerated with adverse effects similar to
placebo. The adverse effects of EPT could not be directly compared to alendronate
because the EPT arm was open label. Alendronate and EPT both increase BMD,
therefore decreasing the acceleration of bone loss in postmenopausal women without
osteoporosis. Alendronate is an effective alternative to EPT without the well-known
In a double-blind, placebo-controlled phase II/III study, oral ibandronate 2.5 mg/day
in early postmenopausal women without osteoporosis resulted in significantly
increased BMD in the lumbar spine (1.9%) as compared to placebo (−1.9%) and
total hip (1.2%) as compared to placebo (−0.6%) after 2 years.
2.5 mg/day significantly reduced biochemical turnover markers.
MOBILE, a randomized controlled, noninferiority study, included 1,609
postmenopausal women ages 55 to 80 with osteoporosis and compared daily
ibandronate (2.5 mg/day) to three different monthly regimens; ibandronate 50 mg
given on 2 consecutive days/month, 100 and 150 mg once monthly.
regimens were at least as effective as daily ibandronate after 1 year. At 2 years, the
mean increase in BMD of the lumbar spine seen in the ibandronate 50 mg on 2
consecutive days/month was (5.3%), ibandronate 100 mg/month (5.3%), and
ibandronate 150 mg/month (6.4%) as compared to ibandronate 2.5 mg taken daily
(4.8%). Increases were seen in the total hip, trochanter, and femoral neck with
ibandronate 150 mg/month being the most significant.
In a 5-year long-term extension (MOBILE LTE), increases in BMD that were
achieved during the MOBILE study were maintained, and further increases were seen
61 Minor changes were seen in the femoral neck and trochanter.
Overall adverse effects of monthly ibandronate were similar to daily ibandronate.
Benefits in BMD changes and decreases in bone turnover markers were greatest for
Ibandronate has also been studied as an intravenous (IV) formulation of 3 mg
62 One-year results from the dosing intravenous
administration (DIVA) study improved BMD in the lumbar spine (4.5% vs. 3.5%)
and the total hip (2.1% vs. 1.5%) to a similar if not greater degree than daily oral
In a double-blind, placebo-controlled study, early postmenopausal women age 40 to
61 with normal BMD for age, received 2 years of risedronate treatment or placebo.
Women who received risedronate 5 mg/day for 2 years had BMD increases of 1.4%
from baseline in the lumbar spine as compared to a 4.3% loss in the placebo group.
There was an increase of 2.6% at the femoral trochanter at 2 years and 1.3% at the
femoral neck at 9 months with risedronate 5 mg/day as compared to a decrease of
2.4% at the femoral neck and 2.8% at the trochanter with placebo.
In a study of postmenopausal women who were at least 50 years of age, were
postmenopausal for 5 or more years, and had osteoporosis, 75 mg of risedronate on 2
consecutive days a month (2CDM) was as safe and effective as risedronate 5 mg/day
64 At 2 years, lumbar spine BMD increases of 4.2% in the 2CDM and
65 There were no statistically significant differences
in BMD changes of lumbar spine, proximal femur, and bone turnover markers.
Adverse effects in both groups were similar.
In a study that compared risedronate 5 mg/day and 150 mg/month in
postmenopausal women with osteoporosis, similar increases in lumbar spine BMD
from baseline were observed (3.4% and 3.5%, respectively) after 1 year and no
difference in the new incidence of vertebral fractures.
in biochemical bone turnover markers. Adverse effects were similar, with a higher
incidence of constipation in the 5 mg/daily group and diarrhea in the 150 mg/monthly
Zoledronic acid is an intravenous bisphosphonate that was initially approved for
osteoporosis treatment and later received FDA approval for osteoporosis prevention
In a 2-year study of zoledronic acid for the prevention of bone loss in
postmenopausal women with low bone mass, 581 women were randomized to
receive zoledronic acid 5 mg IV at baseline and 12 months (2 × 5 mg), zoledronic
acid 5 mg IV at baseline only and placebo at 12 months, or placebo at baseline and at
67 At 2 years, BMD was significantly increased in the lumbar spine in the
(2 × 5 mg; 5.18%), (5 mg 4.42%) as compared to placebo (−1.32%). At 2 years,
BMD also increased at the proximal femur sites (2 × 5 mg; total hip 2.91%, femoral
neck 2.2%, trochanter 4.83%) (5 mg; total hip 2.28%, femoral neck 1.64%,
Zoledronic acid infusion for osteoporosis prophylaxis is administered every other
year as compared to yearly when treating osteoporosis.
Oral bisphosphonates are first-line and most commonly prescribed medications for
the prevention and treatment of osteoporosis. The decision to start medication
therapy for the prevention of osteoporosis prevention in postmenopausal women
should involve both the patient and physician. A BMD of the femoral neck may help
to better determine a more accurate FRAX 10-year risk score. M.J. has multiple risk
factors for osteoporosis but pharmacologic therapy is not indicated at this time.
The incorporation of bisphosphonates into bone results in a reservoir of available
drug that is slowly released over time.
68,69 The peak effect of reducing bone turnover
markers occurs in 3 to 6 months and continues for months to years with
discontinuation. Approval studies in the United States were for 3 to 4 years;
however, extension studies suggest longer efficacy.
No consensus is currently available on how long to continue bisphosphonate
therapy. In the Fracture Intervention Trial Long-term Extension (FLEX) of the
original Fracture Intervention Trial (FIT), the effects of continuing alendronate were
compared to the effects of stopping alendronate after 5 years of treatment.
Statistically significant bone loss occurred (2% to 3% more than those who took
alendronate for 10 years) when women were switched to placebo after 5 years of
alendronate therapy; however, BMD remained well above FIT baseline. A gradual
rise was seen in biochemical markers of bone turnover and there were no significant
differences seen in clinical or nonvertebral fractures. There was a slightly higher risk
of clinically detected vertebral
fractures, in the placebo group (women who had discontinued alendronate therapy
after 5 years) compared to the groups who continued alendronate, suggesting that
women at high risk for vertebral fracture or with T-scores less than −3.5 may benefit
from continued bisphosphonate therapy.
The long-term effects of risedronate 5 mg/daily on bone were studied in women
biopsies of the iliac crest that were taken at 3 and 5 years, changes in bone mineral
and collagen were preserved in the risedronate groups as compared to maturation
that was observed with placebo. The FLEX and VERT-NA studies suggest that
women with good response to bisphosphonate therapy who are not at high risk for
fracture may be able to take a “drug holiday” (e.g., 1-year off therapy) after 3 to 5
74 Women who are able to reach a T-score of greater than −2.5
may be able to discontinue therapy for several years.
The length of therapy should be a decision made based on the benefits of therapy,
adverse effects, and safety of bisphosphonates (see Contraindications and Adverse
In a NAMS Practice Pearl, the authors describe a guide to
bisphosphonate drug holidays according to fracture risk.
mild risk—treat for 3 to 5 years then consider a drug holiday; moderate risk—treat
for 5 to 10 years then consider a 3- to 5-year drug holiday; and high risk—treat for
10 years then consider a drug holiday for 1 to 2 years. For high-risk patients on drug
holiday, treat with a nonbisphosphonate such as raloxifene or teriparatide.
CASE 110-2, QUESTION 7: What are the potential adverse effects of bisphosphonates?
Common adverse effects associated with the use of oral bisphosphonates include
gastrointestinal symptoms, such as acid regurgitation, dysphagia, abdominal
distension, gastritis, nausea, dyspepsia, flatulence, diarrhea, and constipation.
common esophageal adverse effects, such as esophagitis, esophageal ulcers, and
erosions, have occurred and have rarely been followed by esophageal stricture or
75,76 The risk of severe esophageal adverse effects is reported to be
increased in patients who do not take bisphosphonates with 6 to 8 ounces of water,
do not remain upright after taking bisphosphonates, or in those who develop
esophageal irritation and continue to take bisphosphonates (see Dosing section). A
medication guide will address issues that are specific to bisphosphonates and are
intended to help patients better understand treatment, adverse effects, and
In addition, hypocalcemia, musculoskeletal pain, headaches and rash
Both intravenous (IV) and oral bisphosphonates are associated with osteonecrosis
of the jaw (ONJ), a serious but rare adverse event.
series of cancer patients receiving IV bisphosphonates. Risk factors for
osteonecrosis of the jaw include the diagnosis or previous history of cancer; invasive
dental procedures; concurrent use of chemotherapy, corticosteroids, or angiogenesis
inhibitors; poor oral hygiene; preexisting dental disease or infection; and anemia and
coagulopathy. The risk of ONJ increases at higher doses and with duration of
Bisphosphonates are associated with atypical fractures of the femoral shaft.
warning is included in the manufacturers’ information for all bisphosphonate drugs
that are indicated for the prevention or treatment osteoporosis. A safety review of
oral bisphosphonates and atypical subtrochanteric femur fractures by the FDA is also
80 A clear connection has not been found. The mechanism of action is not
clear; however, bone is normally subject to microdamage with every day stresses
and this initiates bone remodeling.
81 Antiresorptive agents may oversuppress bone
turnover causing microdamage to accumulate which may lead to brittle bone and an
increased risk of fracture. Lee et al.
81 conducted a meta-analysis that included nine
observational studies and one randomized controlled trial, a total of 658,497
patients. The results were statistically significant for increased risk of
subtrochanteric or diaphyseal fracture with bisphosphonate use (adjusted odds ratios
[AOR] = 1.99, 95% confidence intervals [CI] = 1.28–3.10), subtrochanteric fractures
AOR = 2.71 (95% CI = 1.86–3.95), and diaphyseal fractures AOR = 2.06 (95% CI =
1.70–2.50). The analysis was limited by the multiple study designs, varying lengths
of follow-up, and different patient populations leading to a high heterogeneity. The
pooled results of combined subtrochanteric or diaphyseal fracture and
subtrochanteric fracture results had significant heterogeneity (84.3% and 83.6%,
respectively). The results for diaphyseal fracture had moderate heterogeneity
(29.7%). The overall risk is low compared to osteoporotic fracture. In a nested
case–control study of 52,595 women 68 years and over who took at least 5 years of
bisphosphonate therapy, the subtrochanteric or femoral shaft fracture occurred in 71
(0.13%) during the subsequent year and 117 (0.22%) within 2 years.
were similar to the meta-analysis. Compared with no use or transient use, the use of
bisphosphonates for 5 years or longer was associated with a significantly increased
risk of atypical hip or femur fracture (odds ratio [OR] = 2.74; 95% CI, 1.25–6.02).
Duration less than 5 years was not associated with increased risk of fracture.
Additional adverse effects reported with zoledronic aced are pyrexia, headache,
pain in extremity, flu-like illness, and eye inflammation.
Currently, there is not enough evidence to hold bisphosphonate therapy in patients
who should be treated for osteoporosis or osteoporosis prevention; however, if a
patient has prodromal pain in the thigh or leg or has suffered an atypical fracture
while on bisphosphonate therapy, it would be reasonable to discontinue therapy and
Alendronate is approved for the prevention of osteoporosis in doses of 5 mg PO
daily and 35 mg PO weekly. Alendronate is also available with cholecalciferol in a
70 mg/2,800 IU and 70 mg/5,600 IU PO weekly tablet. Ibandronate is approved at
2.5 mg PO daily and 150 mg PO monthly. Risedronate is approved at 5 mg PO daily,
35 mg PO weekly, and 75 mg PO on 2 consecutive days each month and 150 mg PO
monthly. The delayed-release formulation of risedronate is not indicated for the
prevention postmenopausal osteoporosis. Zoledronic acid is indicated at 5 mg IV
every 2 years over no less than 15 minutes.
83 Selecting the appropriate dosing option
may improve adherence to therapy.
Oral bisphosphonates are poorly absorbed and after an overnight fast when taken
with water approximately 50% will be absorbed through the gut and 50% will be
excreted in urine. Patients should be instructed to take most bisphosphonates with 6
to 8 ounces of water early in the morning on arising and at least 30 minutes (60
minutes for ibandronate) before ingesting food, beverage, or other medications.
Risedronate is also available as a 35-mg delayed-release tablet that should be taken
once weekly after breakfast. Patients should not lie down, but should stay fully
upright for at least 30 minutes (60 minutes for ibandronate) after ingesting an oral
bisphosphonate to prevent esophageal irritation or ulceration and to ensure
appropriate bioavailability. With all bisphosphonates, patients should ingest
adequate calcium and vitamin D, but should not take the calcium or vitamin D at the
same time as the oral bisphosphonates because they may decrease the absorption of
A diagnosis of GERD, as seen in M.J., may preclude the use of oral
bisphosphonate therapy for prevention of osteoporosis
due to gastric irritation. Zoledronic acid for prevention of osteoporosis is an
alternative. Using the information available for M.J. (T-score of −2.0 at lumbar
spine, Z-score −1.0, estimated 10-year probability of hip fracture 0.5%, and
estimated 10-year probability of major osteoporosis-related fracture 5.1%), therapy
is not indicated at this time.
The current guidelines from the NOF and NAMS recommend pharmacologic
therapy be reserved for those patients with a hip or vertebral fracture, individuals
with a T-score of −2.5 or less at the femoral neck or spine once secondary causes
have been excluded, and individuals with low bone mass with a 10-year probability
of at least 3% risk of hip fracture or at least 20% risk of major osteoporotic
1,32 At this time, M.J. should maintain adequate intake of calcium and vitamin
D, as well as implement an exercise program and continue to avoid risk factors for
Contraindications and Precautions
Hypocalcemia should be corrected before beginning therapy and all patients on
bisphosphonates should receive adequate calcium and vitamin D through diet and/or
supplements. Patients on loop diuretics should be monitored for hypocalcemia.
Patients receiving zoledronic acid should be appropriately hydrated, the infusion
given over no less than 15 minutes, then followed by a 10 mL of normal saline
78 To reduce the incidence of acute-phase reaction symptoms, acetaminophen
Although no dosage adjustments are recommended for patients with mild renal
insufficiency, alendronate and zoledronic acid are not recommended in patients with
creatinine clearance less than 35 mL/minute and ibandronate and risedronate are not
recommended in patients with creatinine clearance <30 mL/minute.
CASE 110-2, QUESTION 8: Should a SERM such as raloxifene, be considered for the prevention of
Selective Estrogen Receptor Modulators (SERMs)
Raloxifene is a benzothiophene second-generation selective estrogen receptor
modulator with both agonist and antagonist action on select estrogen target
84,85 Raloxifene binds to estrogen receptors (ER) resulting in estrogen agonist
effect in bone and lipid metabolism and estrogen antagonist effect in breast and
85 Tamoxifen is also a SERM, but differs from raloxifene in that it
has agonistic effects on endometrial tissue and raloxifene does not. Tamoxifen is
indicated for the prophylaxis and treatment of breast cancer and is not indicated for
postmenopausal osteoporosis prevention. Raloxifene’s agonist activity on bone tissue
is believed to effect osteoclastogenesis, leading to a reduction in bone resorption and
a decreased rate of bone turnover, increasing BMD.
postmenopausal women age 45 to 60 with normal to low bone mineral density,
patients were randomized to receive raloxifene 30, 60, 150 mg, or placebo daily for
86 Significant increases in BMD of the lumbar spine (1.6%, placebo −0.8%),
hip (1.6%, −0.8%), femoral neck (1.2%, placebo −1.3%), and total body (1.4%,
placebo −0.6%) were observed, along with decreases in bone turnover markers,
serum concentrations of total cholesterol, and LDL. No significant differences were
observed in endometrial thickness.
Jolly et al. conducted a 2-year extension study of two 3-year prospective,
randomized, double-blind, placebo-controlled trials of raloxifene for the prevention
of postmenopausal osteoporosis.
87 The study included 328 women from the initial
1,145 core study age 45 to 60. After 5 years of therapy with raloxifene 60 mg daily,
bone turnover markers decreased, BMD of the lumbar spine increased (2.8%), and
total hip BMD (2.6%) as compared to placebo. In women with osteopenia of the
lumbar spine, 2.5% developed osteoporosis in the lumbar spine as compared to
18.5% of those who took placebo. There were significant reductions in total
cholesterol and LDL, but not HDL or triglycerides. No significant endometrial
differences were reported as compared to placebo. Women with osteopenia who
took raloxifene 60 mg daily for 5 years were 87% less likely to progress to
osteoporosis at the lumbar spine then those on placebo. Women with normal BMD
were 77% less likely to progress to osteopenia after 5 years of raloxifene 60 mg
daily. There was a statistically significant increase in the incidence of hot flashes
(raloxifene 28.8%; placebo 16.8%).
The Efficacy of Fosamax versus Evista Comparison Trial (EFFECT) was a
randomized, double-blind clinical trial including 487 postmenopausal women with
low bone density of the spine or hip (T-score ≤ 2.0). Efficacy and tolerability of
alendronate were compared to raloxifene.
88 Patients were randomly assigned to
either alendronate 70 mg weekly and daily placebo identical to raloxifene or
raloxifene 60 mg daily and weekly placebo identical to alendronate for 12 months.
After 1 year, increases in BMD were greater for alendronate than raloxifene in the
lumbar spine (4.8% vs. 2.2%, respectively; p < 0.001) and total hip (2.3% vs. 0.8%,
respectively; p < 0.001). Tolerability and GI effects were similar in both groups;
however, significantly higher reports of vasomotor symptoms came from the
In other clinical trials, women who took raloxifene had an increased risk of deep
vein thrombosis (DVT) and pulmonary embolism (PE).
A paradox still exists regarding how raloxifene can decrease vertebral fractures
by up to 41% while increasing BMD by only 2% to 3%, rates that are lower than
those noted for ET, EPT, or alendronate.
In addition, raloxifene has not been
observed to have a significant effect on hip fractures when compared to other agents.
The antifracture effect of raloxifene on vertebral fractures may occur secondary to
normalization of the high turnover rate of cancellous bone, which then prevents
further disruption of bone microarchitecture.
91 This may occur through raloxifene
binding at estrogen β-receptor sites that are predominantly in cancellous bone,
whereas α-receptors are predominantly in cortical bone. Thus, bone type and
estrogen receptors are different in the hips compared with vertebrae. In addition, a
less potent antiresorptive agent, such as raloxifene, may help prevent vertebral
fractures but not hip fractures because the threshold for preventing osteoclast activity
in cancellous bone (which is predominant in vertebrae) may be lower than in cortical
bone (which predominates in hips). For these reasons, it may require a more potent
antiresorptive agent to increase BMD in the hips.
Raloxifene might be considered for osteoporosis prevention in a woman such as
M.J., even with her strong family history of breast cancer. This latter
recommendation is based on results from the MORE trial.
noted in risk for invasive breast cancer in postmenopausal women with osteoporosis
(mean age, 66.5 years) who received raloxifene for 3 years. A total of 7,705 women
were assigned to raloxifene groups (60 mg twice daily or 60 mg daily) or a placebo
group. Of those enrolled in either raloxifene group (n = 5,129), only 13 cases of
breast cancer were reported versus 27 that occurred in the 2,576 women in the
placebo group. Postmenopausal women over 50 with low bone mass such as M.J. are
candidates for osteoporosis prevention therapy if they have a 10-year hip fracture
probability of 3% or greater or a 10-year major osteoporosis-related fracture
probability of 20% or greater based on the WHO FRAX.
Raloxifene 60 mg PO daily is indicated for the prevention of osteoporosis in
Raloxifene 60 mg once daily can be taken without regard for food.
approximately 60% absorbed and undergoes
extensive glucuronide conjugation, resulting in a 2% absolute bioavailability. Some
circulating raloxifene glucuronide conjugates are converted back to the parent
compound. Raloxifene and its monoglucuronide conjugates are highly protein-bound.
Raloxifene is primarily excreted in feces, with less than 0.2% excreted unchanged
and less than 6% eliminated in urine as glucuronide conjugates. There appear to be
Adverse effects of raloxifene include an increased risk for venous thromboembolic
disease, flu syndrome, headache, hot flashes, nausea, diarrhea, flatulence,
gastroenteritis, leg cramps, peripheral edema, arthralgia, neuralgia, sinusitis,
bronchitis, rash, sweating, and conjunctivitis.
Contraindications and Potential Drug Interactions
Raloxifene carries a boxed warning and is contraindicated in patients with active
venous thromboembolism or a past history of venous thromboembolism due to
87 Raloxifene is contraindicated in women who are pregnant, plan to
become pregnant, and those nursing. Raloxifene should be used with caution during
periods of prolonged immobilization, in patients with a history or risk of stroke,
moderate or severe renal impairment, and in patients with hepatic impairment. The
coadministration of cholestyramine may decrease the absorption of raloxifene and
should be avoided. Prothrombin time should be monitored when starting or
discontinuing raloxifene in patients taking warfarin. Raloxifene is over 95% bound to
plasma proteins and may affect highly protein-bound medications.
Bazedoxifene is a third-generation SERM and is available only in a combination
product with conjugated estrogen.
prevention of postmenopausal osteoporosis in women with an intact uterus. Due to
the boxed warnings (endometrial cancer, cardiovascular disorders, and probable
dementia) and adverse events associated with estrogen, its use is limited to the
shortest duration possible. The manufacturer suggests that nonestrogen agents be
considered when using the medication for the sole purpose of osteoporosis
prevention (see section on ET).
mg/day in divided doses with meals and Vitamin D 1,000 IU daily, both of which were started after
Does M.B. exhibit any clinicalsigns of osteoporosis?
There are few clinical signs of osteoporosis. It is usually asymptomatic until a
fracture occurs. M.B. exhibits a loss of 1.5 inches in height and mild kyphosis. She
also has mild back pain. There are other causes of kyphosis, but M.B. may exhibit
kyphosis due to compression fractures associated with osteoporosis. (see Case 110-
2, Question 1, for further information about osteoporosis clinical signs and
CASE 110-3, QUESTION 2: What changes, if any, should be made to MB’s treatment plan?
A treatment plan for M.B. should be aimed at preventing further bone loss and
minimizing falls, which could lead to fractures. It is important for M.B. to continue
calcium and vitamin D in her diet and maximize her physical function by
incorporating exercise in her treatment plan. M.B has experienced a previous fracture
and likely vertebral compression due to osteoporosis. She is at a higher risk for a
subsequent fracture. The benefits of pharmacologic treatment using a different
medication or reinitiating alendronate should be discussed with MB, along with
Vertebral fractures are a common consequence of osteoporosis and associated with a
decreased health-related quality of life (HRQOL).
symptoms and may go unrecognized at the time of the fracture. The risk of an
additional vertebral fracture within a year of the incident fracture is 5 times higher
compared to postmenopausal women with no previous vertebral fracture.
physical symptoms resulting from vertebral fractures become more evident with each
93 They are associated with loss of height, pain, decreased mobility, and
mortality. The risk of recurrent fracture is also high at other sites such as the hip and
wrist. A large, random cohort of almost 40,000 U.S. Medicare beneficiaries, who
were not enrolled in a prescription benefit plan, were evaluated for the occurrence of
a second fracture or death using data from 1999 to 2006.
second fracture and subsequently died were only counted in the second fracture
category, although a time to event analysis was performed including the risk of
second fracture with death. The 5-year risk of second fracture and the 5-year risk of
For persons ages 65 to 74 years: the 5-year rate of death after a hip or clinical
vertebral fracture was highest in patients with dementia (64.7%; 61.8%,
respectively) and chronic kidney disease (76.7%; 65.2%); the rate of death after a
wrist fracture was highest in patients with dementia (56%) and heart failure (33.3%),
and with chronic kidney disease only slightly lower (31.6%); the 5-year rate of death
was highest after hip fracture in all patients (38.1%) than for clinical vertebral
fracture (29.3%) or wrist fracture (13.1%); the 5-year rate of death among men was
higher than women after all incident fractures such as hip fracture (48.7% vs.
33.1%), clinical vertebral fracture (38.5% vs. 25.3%), and wrist fracture (17.3% vs.
12.3%); and the 5-year rate of second fracture was higher in women than in men such
as hip fracture (27.2% vs. 17.7%), clinical vertebral fracture (37.4% vs. 24.5%),
and wrist fracture (21.1% vs. 17.6%). With each decade over the age of 65, there
was greater than a 20% higher risk of death than the previous decade (e.g., after hip
fracture, the 5-year risk of death was 38.1% for ages 65–74, 49% for ages 75–84,
and 63.7% for ages 85 and older). The increase was not as large for a second
fracture. In the majority of subcategories, the 5-year risk of death or subsequent
fracture was greater than 20%. Patients’ ages 65–74 without comorbidity and who
experienced a wrist fracture had less than 20% risk of death or subsequent fracture.
Calcium and vitamin D supplementation in combination can improve bone density as
well as prevent incident fractures in postmenopausal women with osteoporosis.
is difficult, however, to find evidence to support the benefit of supplements for
treatment of secondary prevention of fracture in older patients diagnosed with
increased BMD of the lumbar spine compared to baseline after 1 year, whereas
BMD of the lumbar spine decreased compared to baseline in the placebo group.
When stratified for age, the effect of treatment in lumbar spine in patients was greater
in patients aged <70 years than those aged >70 years (p < 0.05). BMD in the lumbar
spine increased in the group aged <70 years and decreased in the age group aged >70
years. No significant changes were shown for BMD of the hip. Patients who were
older in this trial had a higher rate of previous hip fracture and demonstrated poorer
physical performance, which is a limitation in the applicability of the subgroup
analysis. A large randomized controlled trial of 5,292 women ≥70 years of age who
experienced a low-trauma osteoporotic fracture were randomly assigned 800 IU
, 1,000 mg calcium, oral vitamin D3
with calcium (1,000 mg/day), or placebo and followed between 24 and 62 months.
No statistically different results were found between the intervention groups in the
incidence of all fractures, radiographically confirmed fractures, hip fractures, other
types of fracture; death; time to fracture or death; or falls. Although well designed,
there were very few measurements of baseline concentration of 25OHD, no reports
of BMD, and patients in this trial reported only moderate adherence.
Sufficient dietary calcium and vitamin D is a universal recommendation for elderly
patients with osteoporosis. Maintaining serum 25OHD levels above 30 ng/mL (75
nmol/L) is an important goal as low levels of vitamin D are associated with an
1,99,100 The dietary goal for all patients with osteoporosis is to
eat a well-balanced diet rich in fruits and vegetables, low-fat dairy products, whole
grains, fish, and nuts. She should try to maintain her BMI between 20 and 25 kg/m2
patients like M.B., it is important to ensure vitamin D levels are adequate and dietary
intake of calcium is at least 1,200 mg/day. If M.B. does not achieve this from her
diet, the supplements she is currently taking would be recommended. Intestinal
absorption of calcium carbonate is dependent on stomach acid. There is some
controversy on whether gastric acid secretion is decreased with aging and if patients
who are older should take calcium citrate instead of calcium carbonate.
carbonate supplements are the form most often associated with constipation, which
can be problematic as gastric motility is decreased with aging.
should be used over calcium carbonate in patients with achlorhydria, a condition
common in the elderly, and in those patients who complain of constipation. M.B.
should continue taking her calcium carbonate in divided doses with meals. If there is
a question of absorption due to lower gastric acid or complaints of constipation,
M.B. could switch calcium products to calcium citrate. (see Case 115-1, Questions 2
and 3, further discuss calcium requirements, supplementation, and product selection
Falls are common among older adults and the leading cause of fractures and injury,
103 One in three adults over the age of 65 years falls each year.
Fall-related fractures occur more often among older women than men, although men
are more likely to die from fall-related fractures than women. Pain and disability are
common results of falling as well as developing a fear of falling again. Those aged
75 and older are 5 times more likely to be admitted to a long-term care facility than
those between the ages of 65 and 75 years. Fall prevention that includes exercise
training is an important nonpharmacologic treatment for older patients with
osteoporosis. In a meta-analysis of 17 randomized controlled trials of various fall
prevention programs in community dwelling patients over 60 years of age, exercise
significantly reduced the rate of falls, including falls resulting in injuries or
104 A reduction of about 37% for all injurious falls was found, along with a
reduction of 43% for severe injurious falls, and 61% for falls resulting in fractures.
M.B. should include a regular weight-bearing and strengthening exercise routine
that is appropriate for her age and physical condition. Exercise helps maintain bone
mass, function, and agility. Older patients should be screened at least once per year
for fall risk to determine whether there are any underlying factors or medical
conditions associated with the risk of falls.
105 Any patient who presents to a clinician
after a fall should have a risk assessment as well. Patients at higher risk of falling
include those with deficits in gait and balance, foot problems, impairment of vision,
cardiovascular disease, postural hypotension, and vitamin D deficiency. Removal of
contributing factors and treating underlying medical conditions with the fewest
medications possible can reduce the risk of falling. Pharmacists have an important
role in optimizing medication therapy to decrease CNS effects or adverse effects
affecting cognition and blood pressure. The prevention of falls also includes
maintaining a safe environment, reducing tripping hazards, adding handrails inside
and outside the tub or shower and next to the toilet, and improving the lighting in the
Pharmacologic treatment is indicated in patients who have experienced a hip or
vertebral fracture, in those with T-scores < −2.5 at the femoral neck, total hip, or
lumbar spine, and in postmenopausal women and men age 50 and older with low
bone mass and high risk of fracture.
1 Agents approved for treatment of osteoporosis
include bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic
acid), calcitonin, denosumab, estrogen, raloxifene, and teriparatide. Drug therapy
decisions in a patient with osteoporosis or risk of fracture should be based on the
patient’s medical history, patient preferences, and a balance of the risks and benefits
of a medication. The goal of pharmacotherapy is to reduce the rate of fractures with
the least amount of adverse effects. Head-to-head trials are often the best evidence
for comparison, but this evidence is not always available. Osteoporosis diagnosis
and evaluation of bone health are based on bone mineral density assessment, which is
used to estimate fracture risk. When searching for the best therapy, it is important to
be mindful that the basis of treatment is the reduction of fractures. Trials reporting
BMD alone may not be sufficient to predict the effect on fractures.
CASE 110-3, QUESTION 3: What medications might be considered for the treatment of osteoporosis in
As discussed in Case 110-2, conjugated estrogen therapy has positive effects on
BMD and fracture rates, but is no longer recommended for the treatment of
osteoporosis. M.B. may have benefitted from years of using estrogen therapy,
preserving BMD, but the benefit of estrogen therapy on BMD only occurs while
taking it. Bone loss is accelerated once hormone therapy is stopped; thus, M.B. and
her physician should discuss whether she would benefit from another drug for
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