Chapter 35: Drug For Bone Disorders

Question 1

Biphosphanates

Answer 1

Bisphosphonates including alendronate [a-LEND-row-nate], ibandro-
nate [eye-BAN-dro-nate], risedronate [rih-SED-row-nate], and zoledronic
[zole-DROE-nick] acid are preferred agents for prevention and treat-
ment of postmenopausal osteoporosis. These bisphosphonates, along
with etidronate [e-TID-row-nate], pamidronate [pah-MID-row-nate], and
tiludronate [till-UH-droe-nate], comprise an important drug group used
for the treatment of bone disorders such as osteoporosis and Paget
disease, as well as for treatment of bone metastases and hypercalcemia
of malignancy.
1. Mechanism of action: Bisphosphonates decrease osteoclastic
bone resorption mainly through an increase in osteoclastic apop-
tosis (programmed cell death) and inhibition of the cholesterol bio-
synthetic pathway important for osteoclast function. The decrease
in osteoclastic bone resorption results in a small increase in bone
mass and a decreased risk of fractures in patients with osteoporo-
sis. The beneficial effects of alendronate persist over several years
of therapy (Figure 35.4), but discontinuation results in a gradual
loss of effects.
2. Pharmacokinetics: The oral bisphosphonates alendronate, rise-
dronate, and ibandronate are dosed on a daily, weekly, or monthly
basis depending on the drug (Figure 35.5). Absorption after oral
administration is poor, with less than 1% of the dose absorbed. Food
and other medications significantly interfere with absorption of oral
bisphosphonates, and specific guidelines for administration should
be followed to maximize absorption (Figure 35.5). Bisphosphonates
are rapidly cleared from the plasma, primarily because they avidly
bind to hydroxyapatite in the bone. Once bound to bone, they are
cleared over a period of hours to years. Elimination is primarily via
the kidney, and bisphosphonates should be avoided in severe renal
impairment. For patients unable to tolerate oral bisphosphonates,
intravenous ibandronate and zoledronic acid are alternatives.
3. Adverse effects: These include diarrhea, abdominal pain, and
musculoskeletal pain. Alendronate, risedronate, and ibandronate
are associated with esophagitis and esophageal ulcers. To mini-
mize esophageal irritation, patients should remain upright after
taking oral bisphosphonates. Osteonecrosis of the jaw has been
reported with bisphosphonates but is usually associated with
higher intravenous doses used for hypercalcemia of malignancy.
Although uncommon, use of bisphosphonates may be associ-
ated with atypical fractures. The risk of atypical fractures may
increase with long-term use of bisphosphonate therapy. Etidronate
is the only bisphosphonate that causes osteomalacia following long continuous use

Question 2

Selective estrogen receptor modulators

Answer 2

Selective estrogen receptor modulators
Lower estrogen levels after menopause promote proliferation and
activation of osteoclasts, and bone mass can decline rapidly. Estrogen
replacement is effective for the prevention of postmenopausal bone
loss. However, since estrogen may increase the risk of endome-
trial cancer (when used without a progestin in women with an intact
uterus), breast cancer, stroke, venous thromboembolism, and coro-
nary events, it is no longer recommended as a primary preventive
therapy for osteoporosis. Raloxifene [rah-LOX-ih-feen] is a selec-
tive estrogen receptor modulator approved for the prevention and
treatment of osteoporosis. It has estrogen-like effects on bone and
estrogen antagonist effects on breast and endometrial tissue. It is an
alternative for postmenopausal osteoporosis in women who are intol-
erant to bisphosphonates. Raloxifene increases bone density without
increasing the risk of endometrial cancer. In addition, it decreases the
risk of invasive breast cancer and also reduces levels of total and low-
density lipoprotein cholesterol. Adverse effects include hot flashes, leg
cramps, and a risk of venous thromboembolism similar to estrogen.

Question 3

Calcitonin

Answer 3

Calcitonin
Salmon calcitonin [cal-SIH-toe-nin] is indicated for the treatment of
osteoporosis in women who are at least 5 years postmenopausal. The
drug reduces bone resorption, but it is less effective than bisphospho-
nates. A unique property of calcitonin is the relief of pain associated with
osteoporotic fracture. Therefore, calcitonin may be beneficial in patients
with a recent vertebral fracture. It is available in intranasal and parenteral
formulations, but the parenteral formulation is rarely used for the treat-
ment of osteoporosis. Common adverse effects of intranasal administra-
tion include rhinitis and other nasal symptoms. Resistance to calcitonin has been observed with long-term use in Paget disease. Because of a
potential increased risk of malignancy with calcitonin, this agent should
be reserved for patients intolerant of other drugs for osteoporosis.

Question 4

Denosumab

Answer 4

Denosumab
Denosumab [den-OH-sue-mab] is a monoclonal antibody that tar-
gets receptor activator of nuclear factor kappa-B ligand and inhibits
osteoclast formation and function. Denosumab is approved for the
treatment of postmenopausal osteoporosis in women at high risk of
fracture. It is administered via subcutaneous injection every 6 months.
Denosumab has been associated with an increased risk of infections,
dermatological reactions, hypocalcemia, osteonecrosis of the jaw,
and atypical fractures. It should be reserved for women at high risk
of fracture and those who are intolerant of or unresponsive to other
osteoporosis therapies.

Question 5

Teriparatide

Answer 5

Teriparatide
Teriparatide [ter-ih-PAR-a-tide] is a recombinant form of human para-
thyroid hormone that is administered subcutaneously daily for the
treatment of osteoporosis. Teriparatide is the first approved treatment
for osteoporosis that stimulates bone formation. Other drugs for osteo-
porosis inhibit bone resorption. Teriparatide promotes bone formation
by stimulating osteoblastic activity. Teriparatide has been associated
with an increased risk of osteosarcoma in rats. The safety and efficacy
of this agent have not been evaluated beyond 2 years. Teriparatide
should be reserved for patients at high risk of fractures and those who
have failed or cannot tolerate other osteoporosis therapies.

Question 6

DRUGS FOR OSTEOPOROSIS

Answer 6

Alendronate FOSAMAX, BINOSTO
Calcitonin FORTICAL, MIACALCIN
Denosumab PROLIA
Ibandronate BONIVA
Risedronate ACTONEL, ATELVIA
Raloxifene EVISTA
Teriparatide FORTEO
Zoledronic acid RECLAST, ZOMETA

Question 7

DRUGS FOR DISORDERS OF BONE
REMODELING

Answer 7

Etidronate
Pamidronate
Tiludronate SKELID