Hip Pads and Other Assistive Devices. Hip protectors have been shown to prevent hip fractures in compliant subjects at significant risk of falling. An observational study in nursing homes using hip protectors showed a 60% reduction in hip fractures. Assistive devices such as canes, walkers, and other gait stabilizers are useful.
Hormone Replacement Therapy. In postmenopausal women, bone turnover increases, the rate of bone resorption exceeds the rate of bone formation, and bone density decreases. In the Women’s Health Initiative (WHI) trial of women unselected for osteoporosis on estrogen plus progesterone, there was a reduction of all fractures by 24% and a reduction of hip fractures by 33% compared with placebo. In the WHI trial of unopposed estrogen in postmenopausal women with a prior hysterectomy, the patients taking unopposed estrogen demonstrated a reduction in hip fracture of 39% and of vertebral fracture by 38%. Unopposed estrogen therapy is associated with an increased risk of endometrial cancer, and combined estrogenprogesterone hormone therapy is associated with increased risk of breast cancer.
Estrogen Agonist-Antagonists. Estrogen agonistantagonists possess tissue specificity and bind to estrogen receptors. Depending on the target organ, these compounds may demonstrate estrogen antagonist or agonist effects. These agents inhibit bone resorption through mechanisms similar to estrogens without stimulating breast or uterine tissue. Raloxifene decreases bone turnover and increases bone density and has been shown to reduce vertebral fracture by 30% in subjects with a prevalent fracture and by 55% in subjects without a prevalent fracture. Raloxifene does not reduce the risk of nonvertebral fracture. Women receiving raloxifene have a higher risk of venous thromboembolism, leg cramps, and hot flashes. After 8 years of therapy with raloxifene the risk of invasive breast cancer was reduced by 66%.
Calcitonin. Calcitonin, a naturally occurring 32-amino acid polypeptide hormone, is secreted in response to high plasma calcium levels. Salmon calcitonin, administered both parenterally or as a nasal spray, is used as therapy for the treatment of postmenopausal osteoporosis. Nasal calcitonin, 200 IU/day, reduced vertebral compression fractures by 33%; no reduction in hip fracture or other nonvertebral fractures was seen. Calcitonin may have analgesic effects on bone pain in patients with osteoporosis.
Introduction and Mechanism of Action. Bisphosphonates are synthetic analogs of pyrophosphate. They suppress osteoclast-mediated bone resorption. They bind avidly to bone, a property that is primarily related to the R1 side chain (an OH group for nitrogen-containing bisphosphonates) that functions as a “bone hook.” The R2 side chain determines the compound’s potency and contains the nitrogen group common to all potent bisphosphonate compounds. The nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, pamidronate, and zoledronate) interfere with the mevalonate pathway by inhibiting the enzyme farnesyl pyrophosphate. This prevents protein prenylation, the attachment of a lipid anchor in the membrane, which inhibits osteoclast recruitment and differentiation, formation of the ruffled border, and acid production and induces apoptosis.
Pharmacologic Properties. Bisphosphonates are poorly absorbed; less than 0.7% is absorbed into the bloodstream. Food and liquids (except plain water) inhibit the absorption within the first 120 minutes after dosing. Approximately 50% of the dose is retained in the skeleton, and the remainder is excreted in the urine. Patients with impaired renal function, creatinine clearance less than 30 mL/min, retain a greater amount of the dose in the skeleton.
Bisphosphonates decrease fracture risk in patients at high risk for fracture, including those with prevalent vertebral fractures and/or low BMD.
1. Alendronate. Alendronate was approved for prevention and treatment of osteoporosis in 1995. In postmenopausal women with low BMD (femoral neck T-score < −1.6) and prevalent vertebral fracture (Fracture Intervention Trial Vertebral Fracture Arm (FIT 1) treated for 3 years, alendronate reduced vertebral, hip, and wrist fractures by 50% and multiple vertebral fractures by 89%; all nonvertebral fractures were reduced by 19%.
2. Risedronate. Risedronate was approved for prevention and treatment of osteoporosis in 2000. In clinical trials in postmenopausal women with previous fractures treated for 3 years, vertebral fractures were reduced by 41% and 49% and nonvertebral fractures were reduced by 33% and 39%, respectively (VERT-NA and VERT-MN). Multiple vertebral fractures also were reduced by 77% and 96%, respectively. A trial with hip fracture as a primary end point showed a reduction in hip fracture of 30% (P = .02).
3. Ibandronate. Ibandronate was approved for the prevention and treatment of osteoporosis in 2003. After 3 years, new morphometric vertebral fractures were reduced by 62%. Nonvertebral fractures were not reduced. The drug is also approved for use as an intravenous medication given every 3 months.
4. Zoledronate. Intravenous zoledronate was approved for the prevention and treatment of osteoporosis in 2007 and is given as a once-yearly intravenous infusion. After 3 years, new morphometric fractures were reduced by 70%, nonvertebral fractures by 25%, and hip fractures by 41%. All-cause mortality was reduced by 28% in a post–hip fracture population.
Side Effects with Bisphosphonates. Gastrointestinal side effects include nausea, esophageal erosions, and stricture. Patients with esophageal motility disorders and esophageal stricture are at greater risk for toxicity.
Intravenous administration of bisphosphonate associated with an influenza-like illness may be seen for 24 to 48 hours after infusion and is characterized by fever, myalgia, arthralgia, and nausea. Some patients have severe bone pain with bisphosphonates. Osteonecrosis of the jaw with bisphosphonates was first reported in 2003, usually in cancer patients treated with high doses of intravenous bisphosphonates. The incidence of this disorder with oral bisphosphonates is about 1 per 100,000 patients treated. Before bisphosphonate therapy, if teeth need to be pulled, a delay in treatment initiation is appropriate. Atypical fractures occurring in the femur shaft have been reported in patients on long-term bisphosphonate therapy.
Receptor activation for nuclear factor-kB ligand (RANKL), a member of the tumor necrosis factor (TNF) family, is a mediator of bone remodeling. RANKL binds to RANK, a receptor on osteoclast membranes, and induces differentiation, activation, and survival of osteoclasts. A regulator of RANK-RANKL is the soluble cytokine osteoprotegerin (OPG). OPG is a naturally occurring member of the TNF receptor family that functions as a decoy receptor by competing for binding to RANK.
Denosumab is a fully human monoclonal IgG2 antibody that binds selectively to RANKL. It was approved for the treatment of postmenopausal women at high risk for fracture in 2010. Patients given denosumab as a subcutaneous injection every 6 months had a 68% reduction in spine fractures, a 40% reduction in hip fractures, and a 20% reduction in nonvertebral fractures. Denosumab differs from the bisphosphonates: bone turnover markers decline rapidly, as soon as 12 hours after an injection, and have a more rapid recovery after discontinuation, and there is no accumulation in bone as with bisphosphonates. Cellulitis was reported in the trial.
Anabolic therapy with teriparatide (rhPTH 1-34) was approved in the United States in 2002 and is available in the European Union, as is rhPTH 1-84 ([1-34]PTH and [1-84]PTH).
Teriparatide is indicated for postmenopausal women and men who are at high risk for fracture. Recombinant hPTH (1-34) treatment in postmenopausal women for 19 months increased BMD by 9.7% in the lumbar spine and reduced vertebral fractures by 65% and nonvertebral fractures by 53%. A comparison of BMD response of teriparatide and alendronate at 18 months showed an areal BMD (DXA) increase of 10.3% with teriparatide and 5.5% with alendronate. Volumetric density (QCT) increased 19.0% with teriparatide and 3.8% with alendronate.
PTH and alendronate were compared as single agents or in combination. Alendronate with PTH blunted the BMD increase of PTH. The effects of teriparatide after 18 to 36 months of therapy with either raloxifene or alendronate showed patients previously treated with raloxifene had a greater increase in lumbar spine BMD in response to teriparatide than patients previously treated with alendronate (10.2% vs. 4.1%, respectively). A study comparing previous risedronate and alendronate on PTH response showed that previous alendronate therapy blunted both bone density and bone marker response to PTH significantly more than prior risedronate. After 12 months of therapy with teriparatide, subjects who received prior risedronate showed a 76% greater increase in QCT of trabecular bone at the spine compared with those who previously received alendronate.
Side Effects. Adverse effects from the use of rhPTH (1-34) include dizziness and leg cramps. Mild hypercalcemia is common (11%), but treatment was discontinued only very rarely. In a toxicology study, rats treated with high doses for long duration developed osteosarcoma. There has been no signal of an increased risk of osteosarcoma in humans treated with teriparatide.
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