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Overview Page 2
MECHANISM OF ACTION AND EFFICACY EVALUATIONS OF NON-ESTROGEN OSTEOPOROSIS THERAPIES
The goal of osteoporosis therapy is to promote increases in BMD and reductions in the risk
of osteoporotic fracture. However, as previously mentioned, markers of bone turnover are
increasingly used to indicate bone quality and fracture risk. BMD maintenance and bone
quality is the result of balance between the bone synthesis activities of osteoblasts with the
bone resorption activities of osteoclasts. Estrogen is an important modulator of bone in
premenopausal women and works primarily through inhibiting resorption.[Hardman 1996]
Estrogen therapy is now recommended, in low doses and for short periods of time, only for
treatment of urogenital or vasomotor symptoms in peri- or postmenopausal women.[Writing Group for Women's Health Initiative Investigators]
However, ultra-low-dose formulations of estrogen are under investigation, and
one of these was recently approved for the prevention of osteoporosis in postmenopausal
women (Menostar®; Berlex). Ettinger et al conducted a placebo-controlled, double-blind trial
of very-low-dose transdermal estradiol (0.014 mg/d) in 417 women aged 60-80, with bone
mineral density z-scores of -2.0 or higher.[Ettinger 2004] Median plasma estradiol levels in
the treated group (n=208) increased from 4.8 pg/mL at baseline to 8.5 pg/mL at one year
and 8.6 pg/mL at two years (p<0.001). Lumbar-spine bone mineral density increased 2.6%
in the estradiol group and 0.6% in the placebo group (between-group difference 2.0%,
p<0.001). Mean total hip bone mineral density increased 0.4% in the estradiol group and
decreased 0.8% in the placebo group (between-group difference 1.2%, p<0.001).
Several classes of therapy are now used in the place of estrogen for prevention and
treatment of osteoporosis. These therapies work through inhibiting resorption and by
anabolic mechanisms.
ANTIRESORPTIVE THERAPIES
Selective Estrogen Receptor Modulators (SERMS)
SERMS include tamoxifen, indicated for adjuvant therapy to reduce the risk of breast cancer,
and raloxifene (Evista®; Lilly). Raloxifene is the only SERM indicated to prevent or treat osteoporosis.
Raloxifene is a non-hormonal agent that binds selectively to estrogen receptors
on many cells, producing activation of some estrogen pathways and blockage of others.
Raloxifene interactions with the estrogen receptor inhibit bone resorption. Raloxifene does
not have estrogen-like adverse effects on endometrial and breast tissue.[Evista PI]
The efficacy of raloxifene for prevention and treatment of osteoporosis was shown in the
Multiple Outcomes of Raloxifene Evaluation (MORE) trial.[Ettinger 1999] Raloxifene
treatment was associated with modest effects on bone density and was shown to produce
reductions in bone turnover markers. In addition, the risk of vertebral fractures was
reduced. There were no data for nonvertebral fractures from this trial. The MORE trial also
showed that raloxifene treatment produced significant reductions in the incidence of breast
cancer as well as cardiovascular and cerebrovascular disease.[Ettinger 1999]
Calcitonin
Calcitonin (Miacalcin®; Novartis) is a polypeptide hormone secreted by the thyroid gland. It
interacts directly with receptors on osteoclasts, inhibiting bone resorption.[Hardman 1996]
There are two dosage forms of salmon calcitonin, injectable (rarely used) and a nasal spray.
The nasal spray form was evaluated in the Prevent Recurrence of Osteoporotic Fractures
(PROOF) trial. In this large, double-blind, randomized, placebo-controlled trial, postmenopausal
women with established osteoporosis received 100, 200, or 400 IU calcitonin
daily by nasal spray. Lumbar-spine BMD was increased and markers of bone turnover
were decreased in all treatment groups compared with placebo (p<0.01 for all comparisons).
In this study, 200 IU per day significantly reduced the risk of new vertebral fractures by
33% overall and by 36% in patients with existing vertebral fractures. However, 100 IU and
400 IU per day reductions in fractures did not reach significance.[Chesnut 2000]
Results from this trial are problematic, due to the dropout of 59% of the patients before
the end of the trial and the lack of dose response in fracture reduction. In addition, the
PROOF study was only partially blinded, because physicians and patients were aware of
BMD measurements as the trial progressed.
Bisphosphonates
Bisphosphonates are synthetic analogues of pyrophosphate that work by binding preferentially
to hydroxyapatite in bone where active bone resorption is taking place under
osteoclasts. Bone resorption is inhibited at the sites where bisphosphonates are bound
and bone formation continues, resulting in net increases in bone mass at those sites.
[Fosamax PI] Two bisphosphonates are indicated for osteoporosis prevention and treatment
in the United States, alendronate (Fosamax®; Merck & Co.) and risedronate (Actonel®;
Procter & Gamble). To maximize absorption of bisphosphonates, they must be taken on an
empty stomach first thing in the morning with water only, and cannot be followed by any
food or drink for at least 30 minutes.[Fosamax PI]
Alendronate is the most potent available agent for prevention and treatment of osteoporosis.
It was studied in the Fracture Intervention Trial (FIT), a large, randomized, double-blind,
placebo-controlled study in patients with low BMD measurements. Patients who received
alendronate (5 mg/day, increased to 10 mg/day two years into the study) had increases in
BMD (average 7% to 9% at the spine and 5% to 8% at the hip compared to placebo). By
year 4, the risk of fracture in women with osteoporosis but no prior hip fractures was
reduced by 56%.[Black 2000] A meta-analysis of five studies of alendronate in postmenopausal
women showed an approximately 50% reduction in risk for hip fractures.[Karpf 1997]
Alendronate has recently become available in weekly formulations that are equivalent in
efficacy to daily formulations and may be associated with fewer esophageal and gastrointestinal
side effects.[Schnitzer 2000; Luckey 2003]
Risedronate produces moderate effects on BMD in the spine and hip and reduces the risk of
osteoporotic fractures. The Vertebral Efficacy with Risedronate Therapy (VERT) trials [Harris
1999; Reginster 2000], documented approximately 40% reductions in the risk of vertebral
fractures. These reductions were sustained for at least five years.[Harris 1999; Reginster
2000] Reductions in hip fractures were shown in a large study, the Hip Intervention Program
(HIP), that included over 9000 women. In women aged 70 to 79 years with severe osteoporosis
and other risk factors for fracture, a 40% reduction in the incidence of hip fractures
was seen by the third year in patients who received risedronate. However, in patients over 80
without proven osteoporosis but with other risk factors, risedronate-treatment groups had no
significant reduction in hip fractures.[McClung 2001] These results are surprising and
several explanations are possible, including the characteristics of the particular patient
population. Risedronate has also recently been approved for once-weekly dosing.
Anabolic Therapy
A recent addition to the armamentarium of non-estrogen therapies for osteoporosis is a
derivative of human parathyroid hormone (PTH). The recombinant form of PTH, consisting
of amino acids 1-34, was approved in 2002 as Forteo® (teriparatide; Lilly), a
subcutaneously administered injection. Once-daily administration of PTH stimulates
osteoblastic activity preferentially through specific receptors. Increases in bone mass and
strength, as well as increases in markers of bone turnover, are the result.[Forteo PI]
This agent was evaluated in 1637 postmenopausal women with prior vertebral fractures in
a randomized placebo-controlled trial. Patients who received 20 µg/d and 40 µg/d doses
of PTH had increased BMD overall and in the lumber spine and femoral neck specifically,
relative to placebo. New vertebral fractures occurred in 14% of women in the placebo group
and in 5% and 4%, respectively, of the women in the 20-µg group and the 40-µg group.
The risk of nonvertebral fractures was reduced by more than 50% in the two treatment
groups.[Neer 2001]
Summary
A meta-analysis of controlled trials provides an estimate of the comparative efficacy of
these therapies (with the exception of PTH) for prevention and treatment of osteoporosis.[Cranney 2002]
Although direct comparisons between trials are unreliable, strong data are
apparent for alendronate and risedronate as first-line therapy.[Cranney 2002] In addition,
a recent comparison across trials of antiresorptive therapies suggested that alendronate was
more effective than risedronate, calcitonin, raloxifene, and hormone therapy for reducing
the risk of vertebral and nonvertebral fractures. Significant differences were found between
alendronate and calcitonin for vertebral fractures and between alendronate and risedronate,
calcitonin, estrogen, and raloxifene for nonvertebral fractures.[Wehren 2004]
Conclusions
Recent events have increased the importance of non-estrogen therapies for patients with
osteoporosis. Bisphosphonates have emerged as significant first-line therapy for prevention
and treatment of osteoporosis in postmenopausal women. In particular, long-term
clinical experience and new long-term data with alendronate supports use of this agent for
many patients with or at risk for osteoporosis.
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