Bisphosphonates

^ Bisphosphonates are first-line therapy for osteoporosis due to established efficacy in preventing hip and vertebralfractures. They are also the most commonly prescribed therapy for osteoporosis. They decrease bone resorption by binding to the bone matrix and inhibiting osteoclast activity. They remain in the bone for a prolonged period and are released very slowly. These effects increase bone mineral density. Although sever-

al bisphosphonates are currently available, only alendronate, ibandronate, risedronate, and zoledronic acid are currently approved by the FDA for use in osteoporosis. Table 56-7 contains comparative dosing and cost information for these bisphosphonates.

In placebo-controlled clinical trials, bisphosphonates increased bone mineral density by up to 5% to 8% in the lumbar spine, and up to 3% to 6% in the hip.17-20 Additional data with oral bisphosphonates suggest that bone mineral density continues to increase with long-term therapy of 7 to 10 years.21,22 Although increases in bone mineral density have been reported at other sites, most of the clinically significant fractures occur in the hip or spine, and these sites have become clinically important measures in the trials. These increases in bone mineral density at the hip and spine are an important marker of treatment effects and are probably related to the decreases in fracture risk found in larger trials.

Table 56-7 Dosage Regimens and Cost of Prescription Agents for Osteoporosis

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Large, well-designed trials have proven the benefits of bisphosphonate therapy in preventing vertebral and nonvertebral fractures. Several studies have found decreases in vertebral fracture risk by as much as 40% to 50% with oral bisphosphonates and up

117 23

to 70% with zoledronic acid. ' ' Although data suggest a similar reduction on vertebral fractures with ibandronate, only alendronate, risedronate, and zoledronic acid have been shown to decrease the incidence of hip and nonvertebral fractures as well

19 20 23 24

by as much as 25% to 40%. ' ' ' In addition to benefits in fracture reduction, the Horizon Recurrent Fracture Trial found a 28% decrease in mortality associated with

hip fracture in patients treated with IV zoledronic acid.

Several studies have evaluated the long-term efficacy and safety of bisphosphonates in postmenopausal women. One study evaluated the use of alendronate over a 10-year period and found no difference in adverse effects between women who received alendronate for 10 years compared to women who discontinued alendronate after 5 years. Women who discontinued alendronate after 5 years continued to experience sustained increases in bone mineral density compared to baseline values and re-

duction in fracture rates. Another study found sustained increases in bone mineral density after discontinuation of alendronate, albeit less than in those who continued

longer-term alendronate therapy. A 7-year follow-up study with risedronate found continued increases in bone mineral density and no increase in adverse effects in women receiving risedronate for 7 years compared to women receiving risedronate for 2

years.

The safety of long-term bisphosphonates observed in clinical trials has been challenged by a number of case reports. Concern exists over the use of chronic bisphos-

phonate therapy due to reports of nonvertebral atraumatic fractures and osteonecros-

26-28

is of the jaw (ONJ). One report described nonvertebral atraumatic fractures in nine patients and delayed fracture healing in four of those patients while receiving alendronate therapy for 3 to 8 years. Bone biopsies in all patients revealed severely suppressed bone turnover, which may have caused bone weakening due to suppression of osteoclastic activity.26'27 Another report described 63 cases of ONJ resistant

to conservative measures and requiring surgical intervention in most cases. A majority of the cases were reported in cancer patients who had received an IV bisphos-

phonate and only a small number of cases were reported in women who had received

oral bisphosphonates for osteoporosis. Risk factors for development of ONJ include chemotherapy, radiotherapy, corticosteroids, infection or pre-existing dental disease.

The most notable adverse effects associated with the bisphosphonates are GI, ranging from relatively mild nausea, vomiting, and diarrhea to more severe esophageal irritation, and esophagitis. However, the most common adverse reactions reported in clinical trials include dyspepsia, abdominal pain, nausea, and esophageal reflux. Clinically significant adverse events include esophageal ulceration, erosions with bleeding, perforation, stricture, and esophagitis. Upper GI adverse effects can occur in up to 20% of patients taking these medications and are often related to inappropriate administration. Other factors that increase risk for GI adverse events include advanced age, previous upper GI tract disease, and use of nonsteroidal anti-inflammatory drugs. Along with appropriate administration, once-weekly administration of oral bisphosphonates may decrease the risk of adverse GI effects.

In addition to the adverse effects associated with oral bisphosphonates, a number of adverse effects have been noted with injectable bisphosphonates, specifically zole-dronic acid. Patients in osteoporosis clinical trials experienced a higher rate of atrial fibrillation, increases in serum creatinine, and infusion-related reactions. Pretreat-

ment with acetaminophen may alleviate the influenza-like symptoms of headache,

1 20

arthralgia, myalgia, and fever. ' Laboratory monitoring, including serum creatinine, alkaline phosphatase, phosphate, magnesium, and calcium, is recommended prior to administration of each dose.

Oral bisphosphonates are poorly absorbed (less than 5%). Taking them in the presence of food or calcium supplementation further reduces absorption. After absorption, bisphosphonate uptake to the primary site of action is rapid and sustained. Once attached to bone tissue, bisphosphonates are released very slowly. They are not recom mended for use in patients with renal insufficiency as they are renally excreted and not metabolized.

Proper drug administration is important for optimal absorption and prevention of adverse effects. Oral bisphosphonates should be taken 30 to 60 minutes prior to the first meal or food in the morning after an overnight fast with 6 to 8 ounces (about 180-240 mL) of water (or 2 ounces [60 mL] with the oral solution). Patients should remain upright and refrain from lying down for 30 to 60 minutes after administration. The tablets should be swallowed whole without chewing or sucking. Administration should be with water only and not combined with other fluids. Bisphosphon-ates should not be taken with other medications or dietary supplements. Bisphosphon-ates are not recommended for use in patients with esophageal abnormalities, hypocal-cemia, renal insufficiency or failure (creatinine clearance less than 30-35 mL/min). For patients unable to tolerate oral bisphosphonates, options exist for IV administration with ibandronate or zoledronic acid.

Selective Estrogen Receptor Modulators

Raloxifene is a selective estrogen receptor modulator (SERM) that has estrogen-like activity on bones and cholesterol metabolism and estrogen antagonist activity in breast and endometrium. These drugs reduce bone resorption and decrease overall bone turnover. The related SERMs tamoxifen and toremifene have partial agonist and antagonist activity at various estrogen receptors. However, the latter agents are limited to the treatment of breast cancer; potential adverse effects preclude further study for long-term use in osteoporosis.

Raloxifene increases bone mineral density and reduces fracture rates. In trials of 1 to 3 years, raloxifene increased vertebral and hip bone mineral density by 2% to 3%

and 1% to 2%, respectively. In the Multiple Outcomes for Raloxifene Evaluation (MORE) trial, raloxifene decreased the risk of vertebral fractures by 30% in postmen-

opausal women with at least one prior fracture. No significant reduction in nonver-tebral fractures was reported.

Additional beneficial effects of raloxifene relate to its antagonistic activity in breast tissue. The Raloxifene Use for the Heart (RUTH) study found a significant decrease in estrogen receptor positive invasive breast cancers in postmenopausal women who took raloxifene for more than 5 years.30 Raloxifene's beneficial effects on the lipid profile prompted the RUTH trial, which sought to determine raloxifene's impact on cardiovascular disease. This study did not find a difference in cardiovascular events but did reveal an increased risk of fatal stroke in women treated with ralox-ifene.30

Adverse effects of raloxifene include hot flushes, leg cramps, and increased risk of venous thromboembolism. Hot flushes are very common and may be intolerable in postmenopausal women who are already predisposed to experiencing them. A more serious adverse effect is the significantly increased risk of venous thromboembolism that has been found in clinical trials.30 A previous history of venous thromboembolism is a contraindication to therapy.

Hormone Therapy

Estrogen, either alone or in combination with a progestin as hormone replacement therapy (HRT), has a long history as an effective treatment of osteoporosis. The Women's Health Initiative (WHI) trial found a 33% reduction in both vertebral and hip fractures and a 23% reduction in other fractures in postmenopausal women receiving conjugated estrogen and medroxyprogesterone.31 However, data from the WHI and another well-designed trial, the Hormone and Estrogen/progestin Replacement Study (HERS), found significant risks associated with HRT, including a higher incidence of breast cancer and venous thromboembolism.31,32 For these reasons, the AACE no longer recommends estrogen or hormone replacement therapy for the treatment of osteoporosis.

Calcitonin

Calcitonin is a naturally occurring mammalian hormone that plays a major role in regulation of calcium levels. It inhibits bone resorption by binding to osteoclast receptors. Compared to mammalian calcitonin, salmon calcitonin has high potency and extended duration of action. Although commercial formulations of calcitonin-salmon are actually synthetic and not derived from salmon, they contain the same amino acid sequence as calcitonin of salmon origin.

Calcitonin salmon is available in injectable and intranasal formulations. It cannot be administered orally due to inactivation by gastric fluids. The parenteral formulation must be administered either subcutaneously or intramuscularly every other day. It is associated with significant adverse effects including flushing, urinary frequency, nausea, vomiting, abdominal cramping, and irritation at the injection site. Additionally, the benefits of the parenteral formulation on bone may diminish over time due to the formation of neutralizing antibodies.

The intranasal formulation is the preferred route of administration due to ease of administration and fewer adverse effects, which are mainly local in nature. Adverse effects associated with the intranasal formulation include rhinitis, nasal irritation, and dryness. Hypersensitivity can develop with either formulation and should be considered before administering to patients with suspected risk of hypersensitivity.

Perhaps the most benefit of calcitonin salmon is in patients with or at risk for vertebral fractures. Nasal calcitonin increases vertebral bone mineral density by 1% to 33 33

3%. One 5-year study found a 30% decrease in the risk of vertebral fractures.

However, increases in hip bone mineral density and reductions in nonvertebral frac-

tures have not been demonstrated. Calcitonin may have analgesic effects in women with back pain from vertebral fractures. However, enthusiasm for using calcitonin in this setting has waned in favor of managing fracture risk and pain separately.12

Anabolic Agents

Teriparatide, recombinant human parathyroid hormone (1-34), is the first anabolic agent approved by the FDA for treatment of osteoporosis. It is generally reserved for patients with moderate to severe osteoporosis. This agent differs from antiresorptive therapies in that it stimulates osteoblastic activity to form new bone when administered once daily. Teriparatide also has many actions that are similar to endogenous parathyroid hormone, and continuous infusions actually stimulate osteoclastic activity and increase bone resorption. In one study, its bone-forming properties increased bone mineral density in the spine and hip by 9% and 3%, respectively. After 21 months of therapy, these increases led to 65% and 35% reductions in vertebral and nonvertebral fractures, respectively.34

The dose of teriparatide is 20 mcg given by subcutaneous injection once daily. It is available in a prefilled multiple-dose pen delivery system. Common adverse effects include nausea, headache, leg cramps, dizziness, injection site discomfort, and hyper-calcemia. Patients may also experience orthostatic hypotension. For this reason, patients should be seated after the first several doses until drug response is predictable. Osteosarcoma has been observed in animal studies, but no cases have been reported in humans. However, this potential concern has led to the inclusion of a "black-box warning" in the product labeling. The warning states that teriparatide should not be used in patients at increased risk for osteosarcoma, including patients with Paget's disease of bone, unexplained elevations of alkaline phosphatase, prior radiation therapy involving the skeleton, and/or children and young adults with open epiphyses. Additionally, teriparatide should not be used in patients with pre-existing hypercal-

cemia. Patient-related concerns regarding the use of teriparatide include cost of therapy and need for subcutaneous injections. The labeling recommends treatment for a maximum of 2 years because it has not been studied for longer periods.

Combination and Sequential Therapy

Interest in combination antiresorptive therapies developed from the hope that using two agents with differing mechanisms for inhibiting bone resorption would result in greater increases in bone mineral density and reductions in fracture rates. Studies have evaluated the combination of bisphosphonates plus estrogen or raloxifene, or estrogen plus calcitonin. Combination therapy produced greater increases in bone mineral density than single agents in some trials, but there was no further reduction in fracture risk. Combination therapy is also more expensive, and concern has been raised

that significant reductions in bone turnover may promote bone that is more brittle. The AACE does not recommend combination antiresorptive therapy for treating osteoporosis.

The combination of a bisphosphonate with anabolic therapy (teriparatide) should not be used because a well-controlled trial showed that women receiving the combination actually had smaller increases in bone mineral density than women receiving teriparatide alone.36 However, sequential therapy with these agents may be more promising. In one study, women who received parathyroid hormone for 1 year followed by alendronate for 1 year had greater increases in bone mineral density than those receiving combination alendronate plus parathyroid hormone, alendronate monotherapy, or parathyroid hormone for one year followed by placebo for 1 year.

Additionally, patients who received no therapy after 1 year of parathyroid hormone

experienced decreases in bone mineral density. Whether sequential therapy leads to reductions in fracture risk remains to be seen.

Other Therapies

Investigational Agents

Several agents, including anabolic and antiresorptive therapies, are currently under investigation for treatment of osteoporosis. A number of SERMs (ospemifene, lasofox-ifene, bazedoxifene, and arzoxifene) are undergoing phase 2 and 3 clinical trials for

treatment of osteoporosis.

Strontium ranelate is an oral agent possessing bone-forming and antiresorptive

properties. Some data suggest significant reductions in vertebral fractures. However, the benefit in nonvertebral fractures is unclear.

Denosumab is a human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL) action. The resultant antiresorptive effects are fully reversible, which may be advantageous in patients who experience adverse events. In clinical trials, denosumab was administered subcutaneously at 3- and 6-month intervals.40

PTH (1-84) is an injectable parathyroid hormone that is currently being investigated for use in osteoporosis. It is an 84 amino acid peptide and is known as full-length parathyroid hormone. This is in contrast to teriparatide (PTH 1-34), which is an N-ter-minal parathyroid hormone analog. It is thought that the full-length parathyroid hormone has additional biologic functions on the bone.41 PTH (1-84) has shown mixed

results in vertebral and hip fracture reduction. Alternative Therapies

Several studies have evaluated dietary supplements such as isoflavones, which are found in soy products and red clover. A well-controlled trial in more than 400 postmenopausal women evaluating a specific isoflavone, ipriflavone, found no benefits on bone mineral density or fracture rates after 3 years.4 Nevertheless, because these therapies are available without prescription and are not regulated by the FDA, patients may choose to self medicate with isoflavones. Lymphocytopenia appeared in several patients treated with ipriflavone in clinical trials. Additionally, ipriflavone should be used with caution in immunocompromised patients or those with renal disease. It may inhibit CYP 1A2 and 2C9 and may interact with drugs metabolized by those pathways, such as warfarin.

Herbal Remedies For Acid Reflux

Herbal Remedies For Acid Reflux

Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.

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