SELECTIVE ESTROGEN RECEPTOR MODULATORS
Raloxifene is an estrogenic agent that reduces the risk of vertebral fracture.
recommended dose is 60 mg (tablet) orally once daily. It is the only SERM approved
in the United States that is indicated for the treatment and prevention of osteoporosis
In a randomized controlled trial including almost 7,000 postmenopausal women,
raloxifene 60 mg or 120 mg daily for 3 years increased BMD in the femoral neck
(2.1% and 2.4%, respectively) and spine (2.6% and 2.7%, respectively) compared to
placebo (p < 0.001 for all comparisons).
106 Women ages 31 to 80 were included with
or without a previous vertebral fracture. The incidence of new vertebral fracture was
10.1% for placebo, 6.6% for raloxifene 60 mg/day, and 5.4% for raloxifene 120
mg/day. Compared to placebo, the risk of new vertebral fracture was 0.7 (95% CI,
0.5–0.8) for raloxifene 60 mg/day and 0.5 (95% CI, 0.4–0.7) for raloxifene 120
mg/day and risk reduction was similar regardless of preexisting fracture. There were
no significant differences in total nonvertebral fractures. Serious adverse events
included venous thromboembolism 0.3% for placebo and 1.0% for each 60-mg and
120-mg groups (RR 3.1; 95% CI 1.5–6.2). Other common and significantly different
adverse effects included influenza-like syndrome, hot flashes, leg cramps, and
peripheral edema. Subjects enrolled in this 3-year raloxifene trial above by Ettinger
106 were eligible to participate in a 1-year extension with no raloxifene and then
a 4-year continuation which included raloxifene 60 mg daily for the raloxifene
107 The primary outcome of the 4-year extension was invasive breast cancer
and included roughly 4,000 women from the original trial. Raloxifene reduced the
risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16; 95% CI
0.09, 0.30). During the 1-year extension with no raloxifene, BMD decreased
significantly. It increased as raloxifene was restarted and was maintained. Vertebral
fracture risk was maintained 4 years after randomization, but was not measured in the
4-year extension trial. Bone mineral density was measured in US sites only in the 4-
year extension trial and included 386 women in the final analysis.
years on raloxifene, BMD in the femoral neck increased 1.9% from baseline and 3%
from placebo (p = 0.30). BMD in the lumbar spine increased 4.3% from baseline and
2.2% from placebo (p = 0.045). The safety of raloxifene after 7 years was similar to
3 years. (see Case 110-2, Question 8, for additional information about raloxifene.)
Bisphosphonates are the major pharmacologic group of medications for the
treatment of osteoporosis. A meta-analysis of seven randomized controlled trials,
approximately 3,700 participants, comparing raloxifene and alendronate was
conducted to determine the efficacy and safety of the two medications in
109 The length of the trials was at least 12 months and the
majority of trials included were of good quality. The raloxifene dose in each trial
was 60 mg daily. The alendronate dose varied and included were two trials at 70 mg
each week, four trials at 10 mg daily, and one trial at 5 mg daily. There were no
statistical differences found between raloxifene and alendronate in the risk of
vertebral fractures, nonvertebral fractures, or total fractures within a follow-up
period of 12 to 24 months. There were no significant differences in upper GI
disorders, venous thromboembolism, or vasodilation. There was a significantly
higher rate of diarrhea found in the alendronate group and significant increase in
vasomotor events found in the raloxifene group. In a subgroup analysis, there was a
higher risk of upper GI disorders for alendronate compared to raloxifene in patients
over 65 years of age and for alendronate administered daily compared to raloxifene.
Raloxifene has a unique benefit and risk profile when compared to other treatments
for osteoporosis. Raloxifene decreases the risk of vertebral fractures by 34% to 44%
compared to placebo, but no significant differences are found in the risk of total
110 No differences in the rate of vertebral or nonvertebral
fracture risk have been found in head-to-head trials comparing raloxifene and
109,110 The safety and efficacy of raloxifene have been studied in a
randomized controlled trial up to 7 years. Significant adverse effects include an
increase in venous thromboembolism; myalgias, cramps, and limb pain; and hot
flashes. The FDA has issued a boxed warning regarding the increased risk of deep
vein thrombosis and pulmonary embolism while taking raloxifene and a warning of
increased risk of death due to stroke in postmenopausal women with documented
coronary heart disease or those at increased risk for coronary events.
estrogen therapy, it is necessary to continue raloxifene therapy to maintain increases
Bisphosphonates, such as alendronate, risedronate, ibandronate, or zoledronic acid,
can be used as an alternative to raloxifene to prevent fractures due to osteoporosis.
They have multiple administration options available and may be beneficial in
enhancing adherence in certain patients. (see Case 110-2, Question 7 to address the
use of aminobisphosphonates in the treatment of postmenopausal osteoporosis: A
table of medications and doses can be found in Table 110-8).
Alendronate was the first bisphosphonate approved for the treatment of
postmenopausal osteoporosis in 1995 and available as a daily or weekly tablet.
Many clinical trials have been published regarding the use of bisphosphonates in the
treatment of osteoporosis. In a Cochrane review of 11 randomized controlled trials,
approximately 12,000 postmenopausal women who had previous fracture or whose
BMD was greater than 2 SD below the mean, alendronate reduced the risk of
vertebral fracture (NNT 16), nonvertebral fracture (NNT 50), wrist fracture (NNT
50), and hip fracture (NNT 100).
57 Compared to placebo, alendronate reduces the
risk of vertebral fracture by 40% to 64%, nonvertebral fracture, 11% to 49%, and
hip fracture, 21% to 55%, over 3 years.
57,110 Alendronate is well tolerated and
adverse events reported in clinical trials were similar to placebo. Adverse reactions
reported in postmarketing surveillance and outside of clinical trials suggest
alendronate is strongly associated with upper gastrointestinal events.
alendronate is slightly better tolerated than daily alendronate, but the risk of
gastrointestinal intolerance exists and may lead to development of esophagitis,
esophageal ulcers, esophageal stricture or perforation, gastric or duodenal ulcers,
and possibly esophageal cancer. Adverse effects are greater in patients who lie down
after taking oral bisphosphonates, who fail to swallow the medication with a full
glass (6–8 ounces) of water, or who continue to take the medication after developing
symptoms suggestive of esophageal irritation.
As similar gastrointestinal events have been reported with other oral
the FDA requires a medication guide to be provided at the time
these medications are dispensed.
77 A medication guide will address issues that are
specific to bisphosphonates and are intended to help patients better understand
treatment, adverse effects, and adherence. (see Case 110-2, Question 7 for additional
information on adverse effects)
Risedronate is available as an oral tablet in four different doses: administered
daily, weekly, monthly, or 2 consecutive days monthly.
risedronate significantly reduces the rate of vertebral, nonvertebral, and hip
110,112 Most trials used doses of 5 mg daily. Although they were not of high
quality, in head-to-head trials comparing different dosing schedules, there were no
statistical differences in the dosing regimens.
110 Comparing risedronate to placebo,
the reduction in the risk of vertebral fracture ranged from 39% to 69%, even among
subgroups with mild-to-severe renal impairment. The reduction in the risk of
nonvertebral fracture ranged 19% to 60% and the reduction in the risk of hip fracture
from 26% to 40%. Adverse events reported in clinical trials were similar to
Ibandronate is available as a daily or monthly tablet and a 3-mg quarterly
111 Compared to placebo, daily oral ibandronate significantly
decreases vertebral risk fracture 52% to 62% over 3 years.
significant decreases in nonvertebral or hip fracture have been found using
114 However, in a subgroup analysis of two noninferiority trials, higher
doses of ibandronate (150 mg once monthly, 3 mg IV quarterly, and 2 mg IV every 2
months) reduced the risk of nonvertebral fracture compared to lower doses of
ibandronate HR 0.620 (0.395–0.973).
Alendronate or risedronate would be the oral bisphosphonate treatment of choice
due to the reduction of vertebral, nonvertebral, and hip fracture.
Zoledronic acid is available as a 5 mg intravenous infusion given over a 15-minute
period once yearly for the treatment of osteoporosis.
It significantly reduces the risk
of vertebral (NNT 14), nonvertebral (NNT 38), and hip fracture (NNT 98) similarly
to that achieved by alendronate or risedronate.
115,116 Zoledronic acid was associated
with atrial fibrillation in a large trial of postmenopausal women diagnosed with
osteoporosis, but not in a subsequent study of postmenopausal women with recent hip
It is less likely to cause gastrointestinal symptoms than oral
bisphosphonates; however, it is associated with injection reactions such as fever
(18%), myalgia (9%), and flu-like symptoms (8%) that typically resolve within 3
days but can last up to 2 weeks. There is an increased risk of hypocalcemia
following an injection compared to placebo. Zoledronic acid is contraindicated in
patients with acute renal impairment, patients with creatinine clearance less than 35
mL/minute, and patients with hypocalcemia.
The controversial atrial fibrillation results in the zoledronic acid trials prompted
79 Following an analysis of clinical trials comparing
alendronate, ibandronate, risedronate, and zoledronic acid to placebo, the FDA
stated there was no clear association of risk for atrial fibrillation in male and female
patients treated with bisphosphonate drugs.
Both intravenous (IV) and oral bisphosphonates are associated with osteonecrosis
of the jaw (ONJ) and atypical fractures. (see Case 110-2, Question 7 for additional
information on adverse effects)
M.B. has been diagnosed with osteoporosis and her risk of recurrent fracture is
high. Bisphosphonates are effective for secondary prevention after a first fracture.
Oral alendronate as previously prescribed or oral risedronate would be the
bisphosphonate of choice for M.B.
CASE 110-3, QUESTION 4: What other possible alternatives or additive therapies for the treatment of
postmenopausal osteoporosis are available for M.B.?
Calcitonin decreases bone resorption and bone turnover.
from salmon is 40 to 50 times more potent than human calcitonin.
and an injectable formulation are available and indicated for the treatment of
osteoporosis in women who have been postmenopausal for at least 5 years.
Injectable calcitonin is also indicated for the treatment of hypercalcemia and Paget
disease. Calcitonin is only recommended for the treatment of osteoporosis when
alternatives are not suitable and can be considered third-line treatment.
Fracture reduction has not been shown in quality clinical trials.
Common nasal symptoms from nasal administration include rhinitis, nasal sores,
irritation, itching, sinusitis, and epistaxis.
119 Local skin reactions (10%) are common
118 Nausea with or without vomiting (10%) and flushing
(2%–5%) can occur at initiation of therapy, but subsides over time. Other adverse
effects include arthralgia, headache, and back pain. More severe adverse effects
associated with calcitonin salmon include serious hypersensitivity, hypocalcemia,
and malignancy. Injectable calcitonin should be refrigerated when not in use and
nasal spray refrigerated until it is opened for use; thereafter, it is stable for 30 days at
room temperature. Calcitonin nasal spray should be used in alternate nostrils daily.
Due to calcitonin salmon’s weak efficacy, alternative treatments should be used for
the treatment of osteoporosis.
Denosumab is a human monoclonal antibody that binds to RANKL, a regulator of
23 Denosumab is administered by subcutaneous injection
every 6 months and inhibits bone turnover with a rapid onset. Denosumab
significantly increases BMD in the lumbar spine, total hip, and at the femoral neck
120 This effect dissipates quickly and BMD returns to
approximately baseline levels within 12 months of discontinuation.
In a large randomized, placebo-controlled, multicenter trial that included 7,868
postmenopausal women with osteoporosis, denosumab 60 mg subcutaneously every 6
months was compared to placebo for a duration of 36 months.
the primary outcome of new clinical vertebral fracture, 2.3% versus 7.2% (RR 0.32;
95% CI 0.26 to 0.41; p < 0.001). Denosumab slightly reduced the cumulative risk of
new hip fracture, 0.7% versus 1.2% (HR, 0.60; 95% CI, 0.37 to 0.97; p = 0.04), and
also reduced the cumulative risk of nonvertebral fracture, 6.5% versus 8.0% (HR
0.80; 95% CI, 0.67 to 0.95; p = 0.01). Eczema occurred in 3% of patients receiving
denosumab and 1.7% for placebo (p < 0.001). A serious skin infection occurred in
12 patients (0.3%) receiving denosumab and only one patient receiving placebo (p =
0.002). Other adverse effects were similar in both groups.
In two head-to-head clinical trials comparing denosumab to weekly alendronate,
denosumab was associated with greater increases in BMD at the hip, lumbar spine,
femoral neck, and radius at 12 months.
122,123 Similar findings have been published
comparing denosumab to monthly ibandronate.
significantly higher at the total hip, femoral neck, and lumbar spine in
postmenopausal women receiving denosumab than in those receiving ibandronate.
Palacios et al. pooled data from two trials comparing denosumab 60 mg
subcutaneously every 6 months to either ibandronate or risedronate, 150 mg once
125 Postmenopausal women with low bone mineral density and
suboptimal adherence with prior oral bisphosphonate therapy were included in the
trials. A treatment satisfaction questionnaire at baseline was compared to 6 and 12
months. Satisfaction improved in all patients, but was significantly higher in the
denosumab group (p < 0.001). Qualitative measures of effectiveness, side effects,
convenience, and overall satisfaction were greater in patients who transitioned to
denosumab. The clinical outcome of fracture was not reported and the comparison of
fracture risk between denosumab and oral bisphosphonates cannot be made.
Denosumab is approved for the treatment of postmenopausal women with
osteoporosis who are at high risk for fracture.
120 Common adverse reactions include
back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and
cystitis. Serious infections including cellulitis can occur when taking denosumab as
well as skin rash and eczema. There is a risk of hypocalcemia with treatment.
Adequate supplementation of calcium and vitamin D, at least 1,000 mg of calcium
and 400 IU of vitamin D daily, is recommended. Hypocalcemia must be corrected
the initiation of treatment serious hypersensitivity reactions, pancreatitis,
osteonecrosis of the jaw (ONJ), and atypical femur fractures have all been reported.
Denosumab is available as prefilled syringes that should be stored in the refrigerator
at 2°C to 8°C (36°F–46°F). It should be left out and brought to room temperature for
administration. It is recommended that a healthcare provider administers denosumab
by subcutaneous injection in the upper arm, upper thigh, or abdomen.
Endogenous parathyroid hormone (PTH) regulates the level of calcium in the blood.
Even a small decrease in calcium will cause secretion of PTH. It acts on the kidneys
to conserve calcium and stimulate the production of calcitriol, which increases the
absorption of calcium. PTH stimulates bone formation and bone resorption, but also
increases the movement of calcium from the bone to the blood. Hyperparathyroidism
is uncontrolled overactivity and the continuous secretion of PTH. Excessive PTH
causes bone breakdown by osteoclasts and has been shown to contribute to bone loss
and bone fragility. A controlled intermittent injection, however, promotes bone
formation, increasing BMD and bone size. Teriparatide is a human recombinant
fragment of the first 34 amino acids of parathyroid hormone (PTH 1-34), which
produce most of its chief biologic effects.
It is available as a multidose pen, given
as a daily 20 mcg subcutaneous injection, and approved for the treatment of
postmenopausal women with osteoporosis who are at high risk for fracture.
Early clinical trials in humans were stopped prematurely because animal data
showed increased incidence of osteosarcoma at high doses and long duration.
boxed warning for the potential risk of osteosarcoma appears in the manufacturer’s
package information and a medication guide is required to be dispensed with
127 conducted one of the early randomized placebo-controlled trials
using teriparatide that was terminated early. The trial enrolled 1,637 postmenopausal
women who had been in menopause at least 5 years and sustained at least one
moderate or two mild vertebral fractures. Patients were randomized to a daily
subcutaneous injection of 20, 40 mcg, or placebo and completed an average of 18
months of therapy. Teriparatide (PTH) 20 and 40 mcg reduced new vertebral
fractures by 65% and 69%, respectively, and reduced new nonvertebral fractures by
53% and 54%, respectively. BMD increased significantly in the lumbar spine (9%
and 13%) and femoral neck (3% and 6%) for the 20 and 40 mcg doses, but decreased
by 2% at the radius in patients taking 40 mcg. Nausea and headache were significant
compared to placebo for patients taking the 40 mcg dose, whereas dizziness and leg
cramps were significant for patients taking the 20 mcg dose. Hypercalcemia
happening at least once during the first 4 to 6 hours after injection occurred in 2% of
women in the placebo group, in 11% of women in the 20 mcg group, and 28% of
women in the 40 mcg group. The dose of PTH in these patients was decreased by half
after the first incidence of hypercalcemia. PTH increased serum calcitriol and serum
uric acid, and slightly decreased serum magnesium, but approximately 5 weeks after
treatment was terminated, serum calcium, magnesium, and uric acid returned to or
A meta-analysis of randomized placebo-controlled trials had similar results; PTH
decreased vertebral fracture risk by 63% (RR = 0.37; 95% CI: 0.28–0.48) and
nonvertebral fracture risk by 38% (RR = 0.62; 95% CI: 0.46–0.82).
reduced the incidence of new and worsening back pain (OR = 0.68, 95% CI: 0.53–
0.87). Adverse effects of nausea and hypercalcemia following injection were
A subgroup analysis of the European Study of Forteo (EUROFORS) included 503
patients who received teriparatide in a 2-year, randomized controlled, open-label
clinical trial of 868 postmenopausal women with established osteoporosis.
Patients were divided into three subgroups based on previous treatment with
antiresorptive medications. Changes in BMD were analyzed in patients who were
treatment-naïve (n = 84), patients pretreated with antiresorptive medication (AR)
who had no evidence of inadequate treatment response (n = 134), and patients
pretreated showing an inadequate response to AR treatment (n = 285) at 6, 12, 18,
and 24 months. The mean BMD decreased at the total hip and femoral neck in the
first 6 months of treatment with teriparatide in patients who were previously treated
with AR, but not in patients who were treatment-naïve. There was an increase from
baseline of BMD at the femoral neck at 12 months and at the hip by 18 months. At 24
months, changes in BMD were significant in all three subgroups at the lumbar spine,
total hip, and femoral neck. Gains in BMD were greatest for treatment-naïve patients.
Significant increases in BMD at the lumbar spine, total hip, and femoral neck
occurred between 18 and 24 months.
Teriparatide has a unique mechanism of action that makes it attractive to combine
with other medications to treat osteoporosis. Teriparatide has been given safely in
combination with denosumab for 12 months along with a 12-month extension in a
small trial (n = 94) of postmenopausal women.
130,131 At 12 months, all groups had a
significant change in BMD, but the combination resulted in greater increases in BMD
than with either medication alone. At 24 months, BMD continued to increase, but the
increase in hip and femoral neck BMD from teriparatide was significantly higher than
in the first year and when compared to the second 12 months of denosumab. Overall
increases in BMD at the femoral neck (6.8%), total hip (6.3%), and spine (12.9%)
are greater from the combination of teriparatide and denosumab than can be achieved
from either drug alone. BMD of the distal radius increased at 24 months, but a
decrease in BMD from baseline occurred in the teriparatide group. Medications
were well tolerated. Mild hypercalcemia was reported in the first 12 months but did
not occur in the second 12 months. Serious adverse effects were reported, but all
were judged unrelated to the medications.
Teriparatide in combination with alendronate does not have the same results.
The combination of teriparatide and alendronate increased BMD at the radius, but
decreased BMD at the lumbar spine, femoral neck, and total hip compared to
teriparatide alone. However, the addition of teriparatide to alendronate in women on
long-term therapy instead of switching to teriparatide resulted in increased BMD at
18 months compared to teriparatide alone.
When combined with zoledronic acid, BMD in the lumbar spine improved
significantly over zoledronic acid alone, but was not different than teriparatide
134 BMD in the total hip was increased in the combination group and
significantly different from teriparatide alone, but not different from zoledronic acid
Teriparatide may have a slight benefit in combination with bisphosphonates and
more significant effects when combined with denosumab, but more information is
needed to determine the effect on fracture risk.
Teriparatide has been used to treat and promote healing of bisphosphonate- or
denosumab-induced osteonecrosis of the jaw.
135,136 Weekly administration at different
doses is being explored for the prevention of vertebral fractures.
Initial administration of teriparatide should be given when the patient can sit or lie
down as orthostatic hypotension may occur with the initial doses.
pens are stable for up to 28 days, including the first injection. The remaining
medication should be discarded after 28 days. Teriparatide should be stored under
refrigeration at 2°C to 8°C (36°F–46°F) and injected immediately on removal from
refrigeration. After use, the pen should be recapped and protected from light. Safety
with teriparatide is limited beyond 2 years and therapy is not recommended for
longer than 2 years at this time.
Adverse effects reported include hypercalcemia, leg cramps, nausea, and
dizziness. Orthostatic hypotension may occur within 4 hours of administration and
spontaneously resolves after a few minutes to hours for the first several doses.
Patients should immediately sit or lie down if symptoms occur.
Glucocorticoid-Induced Osteoporosis
QUESTION 1: D.J. is a 56-year-old male who was diagnosed with Crohn disease 10 years ago. D.J. has
including his risks and outline patient-specific goals for him.
Glucocorticoid therapy, such as prednisone, is a common cause of osteoporosis.
The risk of fracture increases at the start of therapy, within 3 to 6 months, and
decreases after discontinuation.
139 Fracture risk increases with dose and duration of
Glucocorticoids contribute to bone loss resulting in osteoporosis by reducing the
lifespan of osteoblasts and increasing osteocyte apoptosis.
bone formation, decreased bone volume, and lead to rapid bone loss.
D.J. is at risk for substantial loss of bone mass due to a high dose of medication
for an extended period of time. The goal while he is on glucocorticoid therapy would
be to minimize bone loss. D.J. would be a candidate for pharmacologic therapy for
the prevention of osteoporosis while taking prednisone. The minimum threshold for
risk of osteoporosis according to National Osteoporosis Foundation (NOF) is 5 mg
prednisone daily for 3 months.
CASE 110-4, QUESTION 2: What medications are available to prevent osteoporosis in D.J.?
Alendronate, risedronate, and zoledronic acid are FDA-approved for the treatment of
glucocorticoid-induced osteoporosis (GIOP). Risedronate and zoledronic acid are
approved for the prevention of GIOP. The American College of Rheumatology
(ACR) published guidelines for the prevention and treatment of glucocorticoidinduced osteoporosis.
141 For postmenopausal women and men ages 50 years and
over, alendronate, risedronate, and zoledronic acid are all recommended in patients
receiving glucocorticoid doses of 7.5 mg/day if the duration is at least 3 months.
Bisphosphonates increase BMD and prevent bone loss in patients treated with
Alendronate 5- and 10-mg doses for 48 weeks were found to increase BMD in the
lumbar spine, femoral neck, and trochanter while it decreased in placebo in patients
on long-term glucocorticoids, with no significant difference in fracture rate.
completed trial, 389 of 560 patients were still receiving daily prednisone 7.5 mg and
eligible to continue a 12-month extension.
143 At the end of the 12-month extension,
BMD increased at the lumbar spine, femoral neck, and trochanter significantly in the
alendronate groups and decreased in the placebo group. Although only a small
number of vertebral fractures occurred, the difference was significant for alendronate
(0.7%) versus placebo (6.8%; p = 0.026). Alendronate at a dose of 70 mg weekly is
also more effective than placebo at increasing BMD in patients taking
144 Risedronate 5 mg daily for 48 weeks preserved BMD at the
lumbar spine while it decreased in placebo in patients who were started on long-term
145 No significant difference in fracture rate was found. In a 1-year
noninferiority trial of zoledronic acid 5 mg IV, one dose, versus risedronate 5 mg
oral daily, BMD was increased in the lumbar spine 4.06% versus 2.71%,
146 Zoledronic acid was noninferior and superior to
risedronate. In a study of men on glucocorticoids for at least 1 year, zoledronic acid
had similar results and significantly increased BMD at the lumbar spine and total hip
Although daily doses of alendronate and risedronate are approved for the
indication of glucocorticoid-induced osteoporosis, weekly doses are more frequently
used in clinical practice and significantly reduce the incidence of fracture.
doses also improve adherence. (see Case 110-4, Question 4: Adherence)
Teriparatide is also approved for the treatment GIOP. A 36-month trial conducted by
Saag et al. compared teriparatide 20 mcg subcutaneously daily versus alendronate 10
148 The study included 400 men and women, primarily with
rheumatologic conditions. Teriparatide increased spinal BMD 7.2% versus 3.4% in
the alendronate group after 18 months of therapy. Hip BMD increased 3.8% in the
teriparatide group versus 2.4% in the alendronate group. Differences between groups
were noted as early as 6 months. At 36 months, teriparatide continued to increase
BMD in the spine, hip, and femoral neck to a greater extent than alendronate. There
were fewer vertebral fractures in the teriparatide group (1.7%) than in the
alendronate group (7.7%; p = 0.007). No significant difference in nonvertebral
fractures was found between groups. A small (n = 95), 18-month trial compared
teriparatide 20 mcg subcutaneously daily to risedronate 35 mg weekly in men who
were with a minimum of 3 months prior glucocorticoid use (median 6.4 years).
Significant increases in BMD from baseline were found for both treatment groups,
but a significantly greater increase occurred with teriparatide (16.3% versus 3.8%; p
= 0.004). No vertebral fractures occurred during the trial. A total of five patients in
the risedronate group (10.6%) developed new clinical fractures while no fractures
occurred in the teriparatide group (p = 0.056).
Denosumab is not approved for the treatment of GIOP, but increases BMD and
reduces bone turnover in patients on long-term glucocorticoids.
CASE 110-4, QUESTION 3: What recommendations should D.J.’s clinician share with him for preventing
Adequate dietary calcium and vitamin D are essential. Supplementation is
recommended if needed to maintain dietary calcium 1,200 to1,500 mg daily and
vitamin D 800 to 1,000 IU daily.
141 Lifestyle changes are encouraged in patients and
include smoking cessation, reduced alcohol intake, and regular exercise.
D.J. is a candidate for bisphosphonate therapy. He should receive an oral
bisphosphonate such as alendronate 70 mg weekly or risedronate 35 mg weekly
while taking prednisone. He should be counseled on the proper administration and
adverse effects of bisphosphonates and receive a medication guide with the
medication. (see Case 110-2, Question 8).
D.J. should choose 1 day of the week he will remember to take his medication. It
should be taken in the morning on an empty stomach with a full glass of water. He
should remain upright and not eat or drink anything for at least 30 minutes after taking
CASE 110-4, QUESTION 4: How does adherence affect prevention or treatment of osteoporosis?
Osteoporosis is a major public health concern, but is an asymptomatic disease
until fracture occurs. Although many medications used to treat osteoporosis have the
convenience of less frequent dosing, adherence is not optimal.
adherence of osteoporosis medication include dosing frequency, side effects of
medications, comorbid conditions, knowledge about osteoporosis, and cost.
Adherence in clinical trials does not typically reflect real-world patients. Of 18
randomized controlled trials that reported rates of adherence, the majority reported
over 90%. Of 59 observational studies, adherence was substantially lower: 10 of 13
adherence studies reported rates below 50%; in studies using data from health plans,
35% to 52% of patients had an adherence rate of 80% or above; and in several
marketing scans, adherence above 80% ranged from 23% to 49%, and only 33.5%
In a meta-analysis of bisphosphonate adherence including 15 observational studies
(n = 704, 134), the overall risk of fracture was estimated to be 46% higher when low
adherence was compared to high adherence.
152 This meta-analysis was limited by
heterogeneity and differences in the observational study designs.
A systematic review that included two separate searches of male osteoporosis
included 18 studies related to adherence, and 37 studies related to cost.
systematic review also included mostly observational studies and did not pool the
data. Over a 1-year period, only 32% to 64% of men were above 80% adherent to
medication above. Overall clinical outcomes were worse with nonadherence. The
overall cost associated with osteoporotic fractures in men is not as high as in women,
but four studies that explored direct and indirect costs found the overall cost per
fracture in men is higher than in women.
Oral bisphosphonates are first-line agents for prevention and treatment of
osteoporosis. Weekly doses improve adherence compared to daily doses; monthly
doses do not improve adherence compared to weekly doses and monthly adherence
Although the consequence of poor adherence is an estimate, it makes sense that
promoting adherence will improve the effect of bisphosphonates, and is important to
achieve the results that are reported in clinical trials.
men develop osteoporosis. Should he be tested for osteoporosis?
The National Osteoporosis Foundation (NOF) estimates that 9.9 million
Americans have osteoporosis and that 2 million are men.
The prevalence in men increases later in life, with the greatest increase seen at age
10 The age-adjusted prevalence of osteoporosis at either the femoral neck or
lumbar spine differs by race (4% non-Hispanic white men; 9% other races) as does
the prevalence of low bone mass (24% non-Hispanic black men; 39% non-Hispanic
white men). Approximately 80,000 men will break a hip each year and mortality
rates after hip fracture are higher in men than in women.
In an Endocrine Society Clinical Practice Guideline for Osteoporosis in Men,
24 suggest BMD testing for all men age 70 and greater, men with a history
of fracture after age 50, and in men age 50 to 69 with conditions or disease states
such as delayed puberty, alcohol abuse, smoking, hypogonadism,
hyperparathyroidism, hyperthyroidism, COPD, and glucocorticoid or GNRH agonists
J.B. is over age 70, and should have a DXA of the spine and hip to measure
24,92, When a spine or hip BMD is not possible and in men receiving androgen
deprivation therapy (ADT) or with hyperparathyroidism, a DXA of the forearm may
The same WHO criteria that were established for women are used to diagnose
osteoporosis in men (T-score < or equal to −2.5).
a decrease in hormones. Is hormone loss the same cause of osteoporosis in men?
Many risk factors contribute to osteoporosis in men (Table 110-1); however, a
decrease in androgen and estrogen production is the primary hormonal contributor to
the development of osteoporosis in this population.
Androgen production, specifically serum testosterone concentrations, decreases with
age. These decreased concentrations are thought to decrease bone formation and
increase resorption. Testosterone has been linked to decreases in BMD, whereas
dihydrotestosterone has not been linked.
159 Despite testosterone’s importance for
skeletal health in men, research now suggests that estrogen may play a more
important role in skeletal biology. Two genes, estrogen receptor α and aromatase, are
required for estrogen effects; ER-α is found on osteoblasts, osteoclasts, and stem
cells in bone. Aromatase is present in osteoblasts and stem cells in bone. The
absence of these genes results in an inability to convert androgen into estrogen.
Replacement of estrogen in aromatase deficiency showed significant increases in
bone mass and markers of bone turnover normalized.
CASE 110-5, QUESTION 3: Should J.B. be given supplementation for hypogonadism if his testosterone
Hypogonadism may be a major contributor of bone loss in adult men and may
increase the risk of fracture.
If a complete history and physical activity suggest a
specific cause for osteoporosis, it would be appropriate for J.B.’s provider to order
more tests including serum testosterone levels and replace testosterone if indicated,
along with treatment for osteoporosis.
All men who are at risk for osteoporosis such as J.B. or who have osteoporosis
should receive 1,000 to 1,200 mg of calcium daily through their diet and
24 A 25(OH)D level should be drawn and if indicated,
J.B. should receive vitamin D to achieve a level of at least 30 ng/mL.
CASE 110-5, QUESTION 5: What therapies are available to treat osteoporosis in men?
FDA-approved therapies for men include bisphosphonates (alendronate,
risedronate, zoledronic acid), parathyroid hormone (teriparatide), and monoclonal
antibody (denosumab) (see Table 110-8). In a 2-year double-blind trial, 241 men
with osteoporosis were randomized to receive either alendronate 10 mg daily or
161 One-third of the population had low serum-free testosterone levels. BMD
increased by 7.1% versus 1.8% in the lumbar spine, 2.5% versus −0.1% in the
femoral neck, and 2% versus 0.4% in total body for alendronate and placebo groups,
respectively. The incidence of new vertebral fractures was less in the alendronate
group (0.8%) when compared with placebo (7.1%), and a smaller decrease in height
was observed in the alendronate group (0.6 mm) as compared to placebo (2.4 mm).
In a 2-year double-blind, placebo-controlled trial, 284 men were randomly
assigned in a 2:1 fashion to receive risedronate 35 mg weekly or placebo.
patients received calcium and vitamin D supplementation. Lumbar spine BMD
increased 4.5% over placebo in the risedronate group. There were no differences
between groups in vertebral and nonvertebral fractures, but bone turnover markers
were significantly lower in the risedronate group.
In a multicenter, double-blind, active-controlled, parallel-group study of
osteoporosis, 302 men age 25 to 85 were randomly assigned to receive once-yearly
zoledronic acid 5-mg IV infusion or oral alendronate 70 mg weekly and followed for
163 All patients received calcium and vitamin D supplementation. The results
of the study confirmed noninferiority of zoledronic acid to alendronate with similar
BMD response and suppression of bone turnover markers. BMD at the lumbar spine
increased by 6.1% in the zoledronic acid group versus 6.2% in the alendronate group
with other sites showing similar BMD increases between groups.
164 Patients received teriparatide 20 mcg
subcutaneously daily, 40 mcg subcutaneously daily, or placebo with calcium and
vitamin D supplementation for a median duration of 11 months. Lumbar spine BMD
increases were noted after 3 months with increases of 5.9% in the 20 mcg group and
9.0% in the 40 mcg group by study end. Increases were also seen in bone turnover
markers in the 20 and 40 mcg groups. The study was originally planned to be a 2-
year study, but it was stopped early after findings of osteosarcomas in rats during
In a systematic review and meta-analysis of antiresorptive and anabolic treatments
for osteoporosis in men, both classes of drugs increased BMD as compared to
placebo in men with osteoporosis.
165 More research is needed on vertebral and
nonvertebral fractures as a primary endpoint in studies that include men.
CASE 110-5, QUESTION 6: When is pharmacologic treatment recommended?
Pharmacologic therapy is indicated in men who are diagnosed with osteoporosis;
have low bone mass in addition to a 10-year risk of hip fracture ≥ 3% using WHO
FRAX; have had a hip or vertebral fracture without a major trauma; and those who
are on long-term glucocorticoid therapy >7.5 mg/day.
The Endocrine Society recommends monitoring DXA at the spine and hip every 1
to 2 years to evaluate treatment and bone turnover markers at 3 to 6 months after
J.B. should maintain adequate dietary calcium and vitamin D intake.
Supplementation is recommended if needed to maintain dietary calcium 1,200 mg
daily and vitamin D 600 IU. Lifestyle changes are encouraged in patients and include
smoking cessation, reduced alcohol intake, and regular exercise.
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT11e. Below are the key references and websites for this
chapter, with the corresponding reference number in this chapter found in parentheses
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