Drugs Used for

Osteoporosis
◦ Osteoporosis and osteomalacia are disorders of the
bone.
◦ Osteoporosis is characterized by progressive loss of
bone mass and skeletal fragility. Patients with
osteoporosis have an increased risk of fractures, which
can cause significant morbidity.
◦ Osteoporosis occurs most frequently in postmenopausal
women. It can also occur in older men and in patients
who take medications that induce bone loss, such as
glucocorticoids.
◦ Osteomalacia is softening of the bones that is most often
attributed to vitamin D deficiency.{Note: Osteomalacia in
children is referred to as rickets}. Signs and symptoms of
osteomalacia may include bone pain fractures, and leg
weakness.
◦ PREVENTION OF OSTEOPOROSIS
◦ Strategies to prevent bone loss in postmenopausal women include ade-
quate dietary intake of calcium and vitamin D, weight-bearing exercise,
smoking cessation, and avoidance of excessive alcohol intake.
◦ Patients with inadequate dietary intake of calcium should receive calcium
supplementation. Calcium carbonate is an inexpensive and commonly
used calcium supplement. It contains 40% elemental calcium and should
be taken with meals for best absorption. Calcium citrate (21% elemental
calcium)is better tolerated and maybe taken with or without food. Adverse
effects of calcium supplementation include gas, bloating, and
constipation. Calcium may interfere with absorption of iron preparations,
thyroid replacement, and fluoroquinolone and tetracycline antibiotics;
therefore, administration of these drugs should be separated by several
hours.
◦ Vitamin D is essential for absorption of calcium and bone health, and
older patients are often at risk for vitamin D deficiency. Supplementation
with vitamin D2, (ergocalciferol) or vitamin D3, (cholecalciferol) is used
for treatment. In addition, patients at risk for osteoporosis should avoid
drugs that increase bone loss such as glucocorticoids ,if possible.
◦ TREATMENT OF OSTEOPOROSIS
◦ Pharmacologic therapy for osteoporosis is warranted in postmenopausal
women and men aged 50 years or over who have a previous osteoporotic
fracture, a bone mineral density that is 2.5 standard deviations or more below
that of a healthy young adult, or a low bone mass (osteopenia) with a high
probability of future fractures.

◦ A. Bisphosphonates
◦ Bisphosphonates including alendronate , risedronate and zoledronic acid
are preferred agents for the treatment of postmenopausal osteoporosis.
These bisphosphonates, along with etidronate , ibandronate, and
pamidronate , comprise an important drug group used for the treatment of
bone disorders such as osteoporosis (includes postmenopausal osteopo-
rosis, osteoporosis in men, and glucocorticoid-induced osteoporosis)

◦ Mechanism of action: Bisphosphonates bind to hydroxyapatite crystals in

the bone and decrease osteoclastic bone resorption, resulting in a small
increase in bone mass and a decreased risk of fractures in patients with
osteoporosis. The beneficial effects of alendronate persist over several years
of therapy , but discontinuation results in a gradual loss of effects. Zoledronic
acid has a very high affinity for mineralized bone, and it decreases bone
resorption for up to 1 year after a single intravenous infusion of the drug.
◦ Pharmacokinetics: The oral bisphosphonates alendronate, risedronate, and
ibandronate are dosed on a daily, weekly, or monthly basis depending on the drug .
Absorption after oral administration is poor, with less than 10% of the dose
absorbed. Food and other medications significantly interfere with absorption of oral
bisphosphonates.
◦ Bisphosphonates are rapidly cleared from the plasma, primarily because they bind
to hydroxyapatite in the bone. Once bound to bone, they are cleared over a period
of hours to years depending on the rate of bone turnover.
◦ Elimination is predominantly 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.

◦ Adverse effects: Common side effects include diarrhea, abdominal pain, and
musculoskeletal pain.
◦ Oral bisphosphonates can cause esophagitis and esophageal ulcers, which can be
minimized by remaining upright after taking drug for at least 30 minutes.
◦ Rare but serious side effects include osteonecrosis of the jaw (ONJ) and atypical
femur fractures, particularly with long-term use. Guidelines suggest considering a
“drug holiday” after 5 years of oral or 3 years of IV therapy for some patients,
except those at high risk of fractures.
◦ RANKL inhibitor
◦ Denosumab is a monoclonal antibody that targets receptor activator of
nuclear factor kappa-B ligand (RANKL). By binding to RANKL, denosumab
prevents activation of RANK receptors on osteoclasts, thereby inhibiting
osteoclast formation and function and reducing bone resorption.
◦ Denosumab is approved for the treatment of postmenopausal osteoporosis
in women at high risk of fracture, as well as osteoporosis in men and
glucocorticoid-induced osteoporosis. It is administered via subcutaneous
injection every 6 months. Denosumab is considered an alternative first-line
agent for postmenopausal osteoporosis, particularly in patients at higher
risk of fractures.
◦ The drug has been associated with gastrointestinal upset, bone pain,
increased risk of infections , dermatologic reactions, hypocalcemia, and
rarely, ONJ, and atypical fractures.
◦ If therapy with denosumab is discontinued, patients should be started on an
alternative agent such as a bisphosphonate to prevent a rebound increase
in bone resorption.
◦ Parathyroid agents
◦ Teriparatide is a recombinant form of human parathyroid hormone and
abaloparatide is an analog of parathyroid hormone-related peptide. These
drugs act as agonists at the parathyroid hormone receptor, and once-daily
subcutaneous administration results in stimulation of osteoblastic activity
and increased bone formation and bone strength.
◦ The parathyroid agents should be reserved for patients at high risk of
fractures and those who have failed or cannot tolerate other osteoporosis
therapies.
◦ Adverse effects include injection site reactions, hypercalcemia, and
orthostatic hypotension. In addition, hyperuricemia may occur with
abaloparatide. Both drugs have been associated with an increased risk of
osteosarcoma in rats, and these agents are contraindicated in patients at
risk for osteosarcoma. Cumulative lifetime use of either agent for more
than 2 years is not recommended. Following completion of therapy with
teriparatide or abaloparatide, another antiresorptive agent for osteoporosis
should be initiated to maintain bone mineral density and prevent future
bone loss.
◦ Sclerostin inhibitor
◦ Romosozumab is a monoclonal antibody and an inhibitor of sclerostin.
Sclerostin is an important regulatory factor in bone remodeling, where it
inhibits bone formation. Romosozumab binds to sclerostin and inhibits its
action, thereby promoting osteoblast activity and bone formation. A
secondary and lesser mechanism of action is a decrease in bone
resorption .
◦ Romosozumab is indicated in women with postmenopausal osteoporosis
who have a high risk of fractures.
◦ It is administered as a once monthly subcutaneous injection for 12 months.
◦ Adverse effects include arthralgias , headache, and injection site
reactions. The drug should be avoided in patients with a history of
myocardial infarction or stroke, as a small but significant increase in these
events occurred in clinical trials.
◦ After 12 months of therapy with romosozumab is completed, therapy with
other antiresorptive agents should be initiated.
◦ 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 endometrial cancer (when used without a progestin in women
with an intact uterus), breast cancer, stroke, venous thromboembolism, and
coronary events, it is no longer routinely recommended as a therapy for
osteoporosis. [Note: Estrogen therapy for osteoporosis may be considered for
women with severe symptoms of menopause and contraindications or intolerance
to first-line agents for osteoporosis.]
◦ Raloxifene is a selective estrogen receptor modulator (SERM) approved for the
prevention and treatment of osteoporosis in postmenopausal women. It has
estrogen-like effects on bone and estrogen antagonist effects on breast and
endometrial tissue. Therefore, raloxifene increases bone density without increasing
the risk of endometrial cancer. It also decreases the risk of invasive breast cancer.
◦ Adverse effects include hot flashes, leg cramps, and increased risk of venous
thromboembolism. Raloxifene should be avoided in patients with a history of
thromboembolic disease (pulmonary embolism or deep venous thrombosis).
◦ Calcitonin
◦ Calcitonin, a peptide hormone secreted by the thyroid gland,
decreases serum calcium and phosphate by binding to osteo-
clasts inhibiting bone resorption and inhibiting renal
reabsorption of these minerals
◦ Salmon calcitonin has a greater potency and a longer duration
of action than human calcitonin. It 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 other agents.
◦ It is also associated with a higher risk of new malignancy with
long term administration. Therefore, calcitonin should only be
used for the treatment of osteoporosis if other agents are
inappropriate or not tolerated.
◦ Calcitonin is used more frequently for the management of
hypercalcemia (injectable formulation) than the treatment of
osteoporosis.