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BONE
HEALTH
A New Drug in a New Class for Postmenopausal
Osteoporosis
Raymond E. Cole, DO, CCD
Denosumab is expected to receive FDA approval soon for the treatment
of postmenopausal osteoporosis (PMO). This article reviews
the clinical trials supporting the safety and efficacy data of this
new drug.
While the currently available PMO treatments from a variety of drug
classes are effective in reducing the risk of subsequent fracture,
they have some limitations. For example, some individuals are unable
to adhere to the somewhat complex bisphosphonate oral dosing regimen,
have gastrointestinal intolerance to an oral bisphosphonate, or are
reluctant to take a long-acting IV bisphosphonate. Known risks and
limitations are associated with hormones, selective estrogen receptor
modulators, and teraparatide daily injections. Thus, the availability
of denosumab, the first human monoclonal antibody for PMO, will provide
a new option for pharmacologic management from a new drug class.
Denosumab will be administered as a 60-mg subcutaneous (SC) injection
every 6 months.
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DENOSUMAB: MECHANISM OF ACTION
Denosumab is a human monoclonal antibody that inhibits
the activation of hyperactive bone-resorbing osteoclasts. It does
so by specifically targeting RANKL.1-3 RANKL is a cytokine
essential for the formation, function, and survival of osteoclasts.
Denosumab has a high affinity and specificity for RANKL. By binding
to RANKL, denosumab inhibits the RANKL-RANK interaction, resulting
in decreasing osteoclast differentiation, activation, and survival.
This decreases bone resorption, as demonstrated by a rapid and sustained
decrease in bone turnover markers, and increases bone mineral density
(BMD).4,5
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CLINICAL TRIALS AND EFFICACY DATA
The FREEDOM trial (Fracture REduction Evaluation of Denosumab in
Osteoporosis every 6 Months) was an international, 3-year, randomized,
placebo-controlled study in which 7,868 women with PMO received either
60 mg SC denosumab (n=3,902) or placebo (n=3,906) every 6 months.6
The primary efficacy endpoint was new vertebral fractures at 36 months.
The secondary endpoints were hip and nonvertebral fractures. All
study participants were between ages 60 and 90 (mean, 72.3). The
mean baseline T score was -2.8 at the lumbar spine. All patients
received 1,000 mg of elemental calcium and 400 to 800 IU of vitamin
D daily.
The results demonstrated that women with PMO receiving an SC injection
of denosumab twice-yearly experienced a 68% reduction in risk for
a new radiographic vertebral fracture compared to placebo (61% year
1, 78% year 2, 65% year 3 [P<.001]). They experienced a 40% reduction
in risk for hip fracture (P=.04) and a 20% reduction (P=.011) in
risk for a nonvertebral fracture. Over the 3 years, women treated
with denosumab experienced significant increases in BMD (9.2% at
the lumbar spine and 6% at the total hip). The serum C-telopeptide
(sCTX) bone marker demonstrated an 86% decrease at one month and
72% over 3 years.
The STAND trial (Study of Transitioning from AleNdronate to Denosumab)
was a
1-year, phase 3, double-blind, active-controlled, double-dummy noninferiority
study in 504 postmenopausal women who were previously being treated
with alendronate.7,8 (Noninferiority trials are intended to show
that the effect of a new treatment is not worse than that of a control.)
The primary endpoint was change in BMD at the total hip after 12
months. Subjects were randomized to receive 60 mg SC denosumab every
6 months or continue 70 mg oral alendronate weekly. All subjects
were given supplements of 1,000 mg calcium and at least 400 IU of
vitamin D daily. At 12 months, denosumab was noninferior to alendronate,
with subjects transitioning to denosumab demonstrating a significant
increase in BMD at the total hip (0.85% difference [P<.0001])
and spine (1.18% difference [P<.0001]).
The DECIDE trial (Determining Efficacy: Comparison of Initiating
Denosumab versus alEndronate) was a 1-year, phase 3, double-blind,
double-dummy, noninferiority study in 1,189 postmenopausal women
with lumbar spine or total hip T score of -2.0 or less, to compare
the efficacy of treatment with denosumab versus alendronate.9 The
subjects were randomized to receive SC denosumab 60 mg every 6 months
plus weekly oral placebo (n=594) or 70 mg oral alendronate weekly
plus SC placebo injections every 6 months (n=595). All subjects were
instructed to take at least 500 mg supplemental calcium per day,
with the dose of vitamin D supplementation adjusted according to
baseline serum 25-hydroxyvitamin D level. The primary endpoint was
percent change from baseline of the total hip BMD at 12 months. The
mean baseline lumbar spine T score was -2.6. At 12 months, there
was a significantly greater increase in BMD with denosumab compared
with alendronate at the total hip (denosumab 3.5% vs alendronate
2.6% [P<.0001]), and 1.1% at the lumbar spine.
The DEFEND trial (Denosumab in postmenopausal women with low bone
mass) was a 1-year, phase 3 trial that examined 332 postmenopausal
women with osteopenia who were randomized to receive either denosumab
60 mg SC once every 6 months or placebo.10 The primary endpoint was
the percent change in lumbar spine BMD at 24 months. Other endpoints
included change in BMD at the hip, radius, and total body, and bone
turnover markers. All subjects received calcium and vitamin D supplementation.
Lumbar spine BMD increase was 6.5% in the denosumab-treated groups
(≤5 or >5 years from menopause) versus -0.6% in the similarly
aged placebo groups. BMDs at the hip, radius, and total body were
significantly higher in the denosumab-treated women. Bone turnover
markers in denosumab-treated women rapidly declined and remained
low throughout the study.
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SIDE EFFECTS AND SAFETY DATA
In the FREEDOM trial, the overall rates of adverse events (AEs)
were similar in both the placebo and denosumab groups (93%).6 Rates
of serious AEs were 25.8% for denosumab and 25.1% for placebo. The
most common AEs were arthralgia, back pain, upper respiratory tract
infection, and hypertension. There were no significant differences
in the overall incidence of cancer, cardiovascular events, deaths,
delayed fracture healing, hypocalcemia, falls, or local reactions
to the injection. There were no reported cases of osteonecrosis of
the jaw. There was no significant difference in the overall incidences
of cellulitis, with 47 (1.2%) in the denosumab group and 36 (0.9%)
in the placebo group. However, there was a difference in the incidence
of cellulitis as a serious AE, with 12 (0.3%) in the denosumab group
and one (<0.1%) in the placebo group (P=.002).
In both the STAND and DECIDE trials, the overall rates of AEs were
similar at 77.9% and 80.9%, respectively, in the denosumab groups
and 78.7% and 80.9% in the placebo groups.7-9 Serious AEs, including
infections and neoplasms, were not significantly different in either
trial.
In the DEFEND trial, the overall rates of AEs were similar in both
the placebo and denosumab groups, although constipation, sore throat,
and rash were reported more frequently in the denosumab group.10 Rates of serious AEs were 11% for denosumab and 5.5% for placebo.
Overall rates of infection were similar at 60% in the denosumab group
and 61% with placebo; however, there was an increase in serious AE
infections associated with hospitalization (8 in the denosumab group
and 1 in the placebo group). Neoplasms occurred in 4 subjects in
the denosumab group and 1 in the placebo group. No deaths were reported
in the study.
As a result of these AEs, most likely there will be a black box warning
on the denosumab label. The FDA Advisory Committee for Reproductive
Health Drugs (ACRHD) recommended that denosumab be limited to women
who have a history of fracture or are at high risk for fracture,
and that other treatments should be prescribed first until more long-term
safety data are available. The ACRHD also recommended a stringent
safety monitoring plan and Risk Evaluation and Mitigation Strategy,
which includes a medication guide and health care provider communications
plan. The FDA usually follows the recommendation of the ACRHD for
drug approval.
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DISCUSSION: PLACE IN CLINICAL THERAPY
Several clinical effects of denosumab differentiate it from other
PMO treatments.7-10 Denosumab has a quick onset of action, demonstrating
efficacy in as early as one month. It demonstrates a rapid increase
in BMD and decrease in bone markers, suggesting rapid fracture protection.
Upon initiation of treatment, it lowers markers of bone turnover
more rapidly than oral bisphosphonates. The efficacy is sustained
for the entire duration of treatment; however, once treatment is
discontinued, there is a rapid decrease in BMD and increase in bone
markers. This suggests that fracture protection efficacy may be rapidly
lost upon discontinuation of treatment. Long-term efficacy and safety
data in this regard are not yet available.
It is worthwhile to note there have been no head-to-head fracture
trials comparing denosumab to other treatments such as the bisphosphonates;
therefore, comparisons of fracture efficacy cannot be made. In addition,
other indications for denosumab are currently being investigated.
NEWS UPDATE |
Editor’s note: On October 16,
2009, the FDA issued a Complete Response Letter for denosumab, requesting
further information on the postmarketing surveillance plan before completing
its review of applications for product approval. |
The author reports no actual or potential conflict of interest in relation to this article.
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Raymond Cole, DO, CCD, is Clinical Assistant
Professor, Department of Internal Medicine, Michigan State University
College of Osteopathic Medicine, East Lansing; and Director,
Osteoporosis Testing Center of Michigan, Brooklyn, MI.
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