DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

% change lumbar spine BMD
16
14
12
10
8
6
4
2
Teriparatide
PTH+ estradiol
Alendronate
Estradiol
Raloxifene
Calcitonin
0
Placebo
−2
0 6 12 18 24 30 36
Treatment duration, months
Figure 44–13. Relative efficacy of different therapeutic interventions
on bone mineral density of the lumbar spine. Teriparatide
(40 μg) (Neer et al., 2001), PTH (25 μg) + estradiol, alendronate
(10 mg), estradiol (0.625 mg/day), raloxifene (120 mg), calcitonin
(200 IU). Typical results with placebo treatment underscore the
inexorable bone loss without intervention. Some of the indicated
treatment interventions involved combination therapy, and
absolute comparisons should not be made. For additional references,
see legend to Figure 61-13 in the 11th edition of this text.
Until recently, antiresorptive drugs were the only agents
approved in the U.S. for treating osteoporosis. The increase in bone
density that they produce is variable and depends on the site and the
particular drug; generally, the increase is <10% after 3 years (Figure
44–12). This situation changed in 2002 when the FDA approved the
biologically active PTH fragment PTH(1–34) (teriparatide, FORTEO)
for use in treating postmenopausal women with osteoporosis and to
increase bone mass in men with primary or hypogonadal osteoporosis.
For a review and proposed guidelines for teriparatide/PTH use,
see Hodsman et al. (2005). This agent should be used only after consideration
of the risks (potential cause of osteosarcoma) and benefits
in patients refractory to bisphosphonates or at serious risk of fracture.
Therapeutic approaches likely will evolve considerably as newer treatment
paradigms are developed and combinations of antiresorptive
agents and PTH are introduced, and as the molecular physiology of
osteoblast and osteoclast function is elucidated (Grey et al., 2005).
Antiresorptive Agents. Bisphosphonates. Bisphosphonates are the
most frequently used drugs for the prevention and treatment of osteoporosis.
Second- and third-generation oral bisphosphonates alendronate
and risedronate have sufficient potency to suppress bone
resorption at doses that do not inhibit mineralization.
Alendronate (FOSAMAX), risedronate (ACTONEL), and ibandronate
(BONIVA) are approved for prevention and treatment of osteoporosis
and for the treatment of glucocorticoid-associated
osteoporosis. Multiple appropriate formulations are available.
Studies of daily treatment with alendronate established its efficacy
to increase bone mineral density, decrease bone turnover, and reduce
the risk of vertebral fracture among women with osteoporosis (Bone
et al., 2004; Liberman et al., 1995; Tonino et al., 2000; Tucci et al.,
1996). Similar results were obtained with risedronate (Delmas et al.,
2008). The results of 10-year daily treatment with 10 mg of alendronate
(with 500 mg of supplemental calcium) reported a 14%
increase of lumbar spine BMD, with smaller increments at the
trochanter, total hip, and femoral neck (Bone et al., 2004). On reduction
and discontinuation of treatment, BMD at the lumbar spine was
maintained. Although significant decreases of BMD occurred at the
total hip, femoral neck, and forearm, BMD at the lumbar spine,
trochanter, total hip, and total body remained significantly above
baseline values at year 10.
For patients in whom oral bisphosphonates cause severe
esophageal distress despite countermeasures, intravenous zoledronate
(RECLAST) or ibandronate offer skeletal protection without
causing adverse GI effects. For treatment of osteoporosis, ibandronate
(3 mg) is given intravenously every 3 months; zoledronate
is administered as 5 mg once yearly. Zoledronate is the first bisphosphonate
to be approved from once-yearly intravenous treatment of
osteoporosis. Intravenous ibandronate significantly increased BMD
of the lumbar spine. No fracture prevention data for intravenous
ibandronate are available. Zoledronate reduces both vertebral and
nonvertebral fractures (Black et al., 2007). Optimal duration of treatment
and long-term safety remain to be established. A 4-mg formulation
(ZOMETA) is available for intravenous treatment of hypercalcemia
of malignancy, multiple myeloma, or bone metastasis resulting from
solid tumors.
Denosumab. As described earlier, RANKL binds to its cognate receptor
RANK on the surface of precursor and mature osteoclasts, and
stimulates these cells to mature and resorb bone. OPG, which competes
with RANK for binding to RANKL, is the physiological
inhibitor of RANKL. Denosumab is an investigational human monoclonal
antibody that binds with high affinity to RANKL, mimicking
the effect of OPG, and thereby reducing the binding of RANKL
to RANK. Denosumab blocks osteoclast formation and activation. It
increases BMD and decreases bone turnover markers when given
subcutaneously once every 6 months. Denosumab, administered subcutaneously
at 60 mg doses every 6 months, resulted in 68%, 41%,
and 20% reductions in vertebral, hip and nonvertebral fractures,
respectively, in a phase III clinical trial (Cummings et al., 2008). In
the 3-year Fracture Reduction Evaluation with Denosumab and
Osteoporosis Every Six Months (FREEDOM) Trial, denosumab significantly
reduced morphometric vertebral fractures, and decreased
hip and nonvertebral fractures and changes in BMD and bone
turnover markers (Cummings et al., 2008). This novel therapy may
soon gain FDA approval.
Selective Estradiol Receptor Modulators (SERMs). Considerable work
has been undertaken to develop estrogenic compounds with tissueselective
activities. One of these, raloxifene (EVISTA), acts as an estrogen
agonist on bone and liver, is inactive on the uterus, and acts as an
anti-estrogen on the breast (Chapter 40). In postmenopausal women,
raloxifene stabilizes and modestly increases BMD and has been
shown to reduce the risk of vertebral compression fracture (Ettinger
et al., 1999). Raloxifene is approved for both the prevention and treatment
of osteoporosis. With the decreased use of estrogen for treating
osteoporosis, the SERM raloxifene would seem to be an ideal alternative
to HRT because raloxifene reduces the risk of vertebral fractures
(albeit without a positive effect on nonvertebral fractures), breast
1299
CHAPTER 44
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER