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

1300 cancer, and coronary events (coronary death, nonfatal myocardial
infarction, and hospitalized acute coronary syndromes other than
myocardial infarction) (Clemett and Spencer, 2000). The major drawback
of raloxifene is that it can worsen vasomotor symptoms.
Estrogen. There is an unambiguous relationship between estrogen
deficiency and osteoporosis. Postmenopausal status or estrogen deficiency
at any age significantly increases a patient’s risk for osteoporosis
and fractures. Likewise, overwhelming evidence supports
the positive impact of estrogen replacement on the conservation of
bone and protection against osteoporotic fracture after menopause
(Chapter 40). The outcome of the Women’s Health Initiative (WHI)
studies, however, strikingly altered the view of the therapeutic use of
HRT for long-term prevention or treatment of osteoporosis.
Significantly increased risks of heart disease and breast cancer were
found (Anderson et al., 2004; Cauley et al., 2003). The consensus
among experts now is to reserve HRT only for the short-term relief
of vasomotor symptoms associated with menopause. HRT should be
limited to osteoporosis prevention in women with significant ongoing
vasomotor symptoms who are not at an increased risk for cardiovascular
disease. An annual individualized risk-benefit reassessment
should be performed on these patients.
Calcium. The physiological roles of Ca 2+ and its use in the treatment
of hypocalcemic disorders were discussed earlier. The rationale for
using supplemental calcium to protect bone varies with time of life.
For preteens and adolescents, adequate substrate calcium is
required for bone accretion. Controlled trials indicate that supplemental
calcium promotes adolescent bone acquisition (Johnston et
al., 1992), but its impact on peak bone mass is not known. Higher
calcium intake during the third decade of life is positively related to
the final phase of bone acquisition (Recker et al., 1992). There is
controversy about the role of calcium during the early years after
menopause, when the primary basis for bone loss is estrogen withdrawal.
Although little effect of calcium on trabecular bone has been
reported, reduction in cortical bone loss with calcium supplementation
has been observed (Elders et al., 1994), even in populations with
high dietary calcium intake. In elderly subjects, supplemental calcium
suppresses bone turnover, improves BMD. Although some
studies found a concomitant decreases in the incidence of fracture
(Dawson-Hughes et al., 1997), three randomized trials found that it
did not reduce fracture rate in older women (Jackson et al., 2006).
Patients who are unable or unwilling to increase calcium by
dietary means alone may choose from many palatable, low-cost calcium
preparations. As noted previously, numerous oral calcium
preparations are available. The most frequently prescribed is carbonate,
which should be taken with meals to facilitate dissolution and
absorption. Traditional dosing of calcium is ~1000 mg/day, nearly
the amount present in a quart of milk. Adults >50 years of age need
1200 mg of calcium daily. More may be necessary to overcome
endogenous intestinal calcium losses, but daily intakes of ≥2000 mg
frequently are reported to be constipating.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Vitamin D and Its Analogs. Modest supplementation with vitamin D
(400-800 IU/day) may improve intestinal Ca 2+ absorption, suppress
bone remodeling, and improve BMD in individuals with marginal
or deficient vitamin D status. A prospective study found that neither
dietary calcium nor vitamin D intake was of major importance for
the primary prevention of osteoporotic fractures in women
(Michaelsson et al., 2003). However, supplemental vitamin D in
combination with calcium reduced fracture incidence in multiple
trials (Jackson et al., 2006). Several meta-analyses reported reduction
in the rate of fractures when vitamin D and calcium were taken
together. Because women commonly consume less than the recommended
intake of vitamin D, use of supplemental vitamin D or
increased consumption of such vitamin D–rich foods as dark fish
may be prudent.
The use of calcitriol to treat osteoporosis is distinct from
ensuring vitamin D nutritional adequacy. Here, the rationale is to
suppress parathyroid function directly and reduce bone turnover.
Calcitriol and the polar vitamin D metabolite 1α-hydroxycholecalciferol
are used frequently in Japan and other countries, but experience
in the U.S. has been mixed. Higher doses of calcitriol appear to
be more likely to improve BMD, but at the risk of hypercalciuria
and hypercalcemia; therefore, close scrutiny of patients and dose
modification are required. Restriction of dietary calcium may reduce
toxicity during calcitriol therapy (Gallagher and Goldgar, 1990). A
low incidence of hypercalciuric and hypercalcemic complications of
therapy in Japan may reflect relatively poor calcium intakes in that
country.
Calcitonin. Calcitonin inhibits osteoclastic bone resorption and modestly
increases bone mass in patients with osteoporosis; the largest
increases occurred in patients with high intrinsic rates of bone
turnover. One study showed that calcitonin nasal spray (200
units/day) reduced the incidence of vertebral compression fractures
by ~40% in osteoporotic women (Chesnut et al., 2000).
Thiazide Diuretics. Although not strictly antiresorptive, thiazides
reduce urinary Ca 2+ excretion and constrain bone loss in patients
with hypercalciuria. Whether they will prove to be useful in patients
who are not hypercalciuric is not clear, but data suggest that they
reduce hip fracture risk. No sustained effect is observed (Schoofs
et al., 2003). Hydrochlorothiazide, 25 mg once or twice daily, may
reduce urinary Ca 2+ excretion substantially. Effective doses of thiazides
for reducing urinary Ca 2+ excretion generally are lower than
those necessary for blood pressure control. For a more detailed discussion
of thiazide diuretics, see Chapter 25.
Anabolic Agents. Teriparatide. Teriparatide (FORTEO) is the only agent
currently available that increases new bone formation. It is FDAapproved
for treatment of osteoporosis for up to 2 years in both men
and postmenopausal women at high risk for fractures. Teriparatide
significantly decreased the incidence of vertebral (4-5% vs. 14%)
and nonvertebral fractures (3% vs. 6%) compared to placebo in a
prospective, randomized control study (FPT) (Neer et al., 2001).
Teriparatide increases predominantly trabecular bone at the lumbar
spine and femoral neck; it has less significant effects at cortical sites.
Although initial studies showed dose-dependent actions, and side
effects, because of concern (and black box label warning), teriparatide
is approved at the 20 μg dose, administered once daily by
subcutaneous injection in the thigh or abdominal wall. The most
common adverse effects associated with teriparatide include injection-site
pain, nausea, headaches, leg cramps, and dizziness.
Combination Therapies
Osteoporosis. Because teriparatide stimulates bone formation,
whereas bisphosphonates reduce bone resorption, it was predicted
that therapy combining the two would enhance the effect on BMD
more than treatment with either one alone. However, addition of