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

1290 deposition in bone, once a cause of renal osteodystrophy, is no longer
an issue since aluminum was removed from dialysis solutions.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Osteoporosis
Osteoporosis is a condition of low bone mass and
microarchitectural disruption that results in fractures
with minimal trauma. Osteoporosis is a major and growing
public health problem in developed nations. Many
women (30-50%) and men (15-30%) suffer a fracture
related to osteoporosis. Characteristic sites of fracture
include vertebral bodies, the distal radius, and the proximal
femur, but osteoporotic individuals have generalized
skeletal fragility, and fractures at sites such as ribs
and long bones also are common. Fracture risk increases
exponentially with age, and spine and hip fractures are
associated with reduced survival. Fractures of distal
forearm, foot, or ankle are not associated with increased
mortality (Teng et al., 2008).
Osteoporosis can be categorized as primary or secondary. In
1948, Albright and Reifenstein concluded that primary osteoporosis
included two separate entities: one related to menopausal estrogen
loss and the other to aging. This concept was extended by the
recognition that primary osteoporosis represents two fundamentally
different conditions: type I osteoporosis, characterized by loss of trabecular
bone owing to estrogen lack at menopause, and type II osteoporosis,
characterized by loss of cortical and trabecular bone in men
and women due to long-term remodeling inefficiency, dietary inadequacy,
and activation of the parathyroid axis with age. It is not clear,
however, that these two entities are truly distinct. Although many
osteoporotic women undoubtedly have experienced excessive
menopausal bone loss, it may be more appropriate to consider osteoporosis
as the result of multiple physical, hormonal, and nutritional
factors acting alone or in concert.
Secondary osteoporosis is due to systemic illness or medications
such as glucocorticoids or phenytoin. The most successful
approach to secondary osteoporosis is prompt resolution of the
underlying cause or drug discontinuation. Whether primary or
secondary, osteoporosis is associated with characteristic disordered
bone remodeling, so the same therapies can be used.
Paget’s Disease. Paget’s disease is characterized by single or multiple
sites of disordered bone remodeling. The etiology of the disease
is uncertain but is thought to be the result of infection with the
measles virus of the paramyxovirus family (Roodman and Windle,
2005). It affects up to 2-3% of the population >60 years of age. The
primary pathologic abnormality is increased bone resorption followed
by exuberant bone formation. However, the newly formed
bone is disorganized and of poor quality, resulting in characteristic
bowing, stress fractures, and arthritis of joints adjoining the involved
bone. Pagetic lesions contain many abnormal multinucleated osteoclasts
associated with a disordered mosaic pattern of bone formation.
Pagetic bone is thickened and has abnormal microarchitecture.
The altered bone structure can produce secondary problems, such as
deafness, spinal cord compression, high-output cardiac failure, and
pain. Malignant degeneration to osteogenic sarcoma is a rare but
lethal complication of Paget’s disease.
Renal Osteodystrophy. Bone disease is a frequent consequence of
chronic renal failure and dialysis. Pathologically, lesions are typical
of hyperparathyroidism (osteitis fibrosa), vitamin D deficiency
(osteomalacia), or a mixture of both. The underlying pathophysiology
reflects increased serum phosphate and decreased calcium, leading
to secondary events that strive to preserve circulating levels of
mineral ions at the expense of bone.
PHARMACOLOGICAL TREATMENT
OF DISORDERS OF MINERAL ION
HOMEOSTASIS AND BONE METABOLISM
Hypercalcemia
Hypercalcemia can be life threatening. Such patients
frequently are severely dehydrated because hypercalcemia
compromises renal concentrating mechanisms.
Thus, fluid resuscitation with large volumes of isotonic
saline must be early and aggressive (6-8 L/day). Agents
that augment Ca 2+ excretion, such as loop diuretics
(Chapter 25), may help to counteract the effect of
plasma volume expansion by saline but are contraindicated
until volume is repleted because they otherwise
will aggravate volume depletion and hypercalcemia.
Corticosteroids administered at high doses (e.g., 40-80
mg/day of prednisone) may be useful when hypercalcemia results
from sarcoidosis, lymphoma, or hypervitaminosis D (Chapter 42).
The response to steroid therapy is slow; from 1-2 weeks may be
required before plasma Ca 2+ concentration falls.
Calcitonin (CALCIMAR, MIACALCIN) may be useful in managing
hypercalcemia. Reduction in Ca 2+ can be rapid, although “escape”
from the hormone commonly occurs within several days. The recommended
starting dose is 4 units/kg of body weight administered subcutaneously
every 12 hours; if there is no response within 1-2 days, the
dose may be increased to a maximum of 8 units/kg every 12 hours.
If the response after 2 more days still is unsatisfactory, the dose may
be increased to a maximum of 8 units/kg every 6 hours. Calcitonin
can lower serum calcium by 1-2 mg/dL.
Intravenous bisphosphonates (pamidronate, zoledronate)
have proven very effective in the management of hypercalcemia (see
further discussion of bisphosphonates later in the chapter). These
agents potently inhibit osteoclastic bone resorption. Oral bisphosphonates
are less effective for treating hypercalcemia. Therefore,
pamidronate (AREDIA) is given as an intravenous infusion of 60-90 mg
over 4-24 hours; the more prolonged infusion (>4 hours) is reserved
primarily for patients with renal dysfunction. With pamidronate, resolution
of hypercalcemia occurs over several days, and the effect
usually persists for several weeks. Zoledronate (ZOMETA) has superseded
pamidronate because of its more rapid normalization of serum
calcium and longer duration of action.
Plicamycin (mithramycin, MITHRACIN) is a cytotoxic antibiotic
that also decreases plasma Ca 2+ concentrations by inhibiting
bone resorption. Reduction in plasma Ca 2+ concentrations occurs
within 24-48 hours when a relatively low dose of this agent is given