NCLEX: Drugs for Bone Disorders

Osteoporosis, Paget disease, 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 in older men and women but is most pronounced in postmenopausal women. Paget disease is a disorder of bone remodeling that results in disorganized bone formation and enlarged or misshapen bones. Unlike osteoporosis, Paget disease is usually limited to one or a few bones. Patients may experience bone pain, bone deformities, or fractures. Osteomalacia is softening of the bones that is most often attributed to vitamin D deficiency. [Note: Osteomalacia in children is referred to as rickets].

Drugs for Bone Disorders

Drugs for Bone Disorders: BONE REMODELING

Focus topic: Drugs for Bone Disorders

Throughout life, bone is continuously remodeled, with about 10% of the adult skeleton replaced each year. The purpose of bone remodeling is tore move and replace damaged bone and to maintain calcium homeostasis. Osteoclasts are cells that break down bone, a process known as bone resorption. Following bone resorption, osteoblasts or bone-building cells synthesize new bone. Crystals of calcium phosphate known as hydroxyapatite are deposited in the new bone matrix during the process of bone mineralization. Bone mineralization is essential for bone strength. Lastly, bone enters a resting phase until the cycle of remodeling begins again. Bone loss occurs when bone resorption exceeds bone formation during the remodeling process.

Drugs for Bone Disorders

Drugs for Bone Disorders: TREATMENT OF OSTEOPOROSIS

Focus topic: Drugs for Bone Disorders

Nondrug strategies to reduce bone loss in postmenopausal women include adequate dietary intake of calcium and vitamin D, weight-bearing exercise, and smoking cessation. In addition, patients at risk for osteoporosis should avoid drugs that increase bone loss such as glucocorticoids. [Note: Use of glucocorticoids (for example, prednisone 5 mg/day or equivalent) for 3 months or more is a significant risk factor for 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 young adult, or a low bone mass with a high probability of future fractures.

Drugs for Bone Disorders

A. Bisphosphonates

Focus topic: Drugs for Bone Disorders

Bisphosphonates including alendronate [a-LEND-row-nate], ibandronate [eye-BAN-dro-nate], risedronate [rih-SED-row-nate], and zoledronic [zole-DROE-nick] acid are preferred agents for prevention and treatment 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 apoptosis (programmed cell death) and inhibition of the cholesterol biosynthetic 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 osteoporosis. The beneficial effects of alendronate persist over several years of therapy, but discontinuation results in a gradual loss of effects.

2. 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 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. 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 minimize 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 associated 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- term, continuous administration.

Drugs for Bone Disorders

Drugs for Bone Disorders

Drugs for Bone Disorders

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B. Selective estrogen receptor modulators

Focus topic: Drugs for Bone Disorders

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 recommended as a primary preventive therapy for osteoporosis. Raloxifene [rah-LOX-ih-feen] is a selective 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 intolerant 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.

C. Calcitonin

Focus topic: Drugs for Bone Disorders

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 bisphosphonates. 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 treatment of osteoporosis. Common adverse effects of intranasal administration 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.

D. Denosumab

Focus topic: Drugs for Bone Disorders

Denosumab [den-OH-sue-mab] is a monoclonal antibody that targets 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.

E. Teriparatide

Focus topic: Drugs for Bone Disorders

Teriparatide [ter-ih-PAR-a-tide] is a recombinant form of human parathyroid 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 osteoporosis 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.

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