| Sign In to gain access to subscriptions and/or personal tools. |
Review of Postmenopausal Osteoporosis PharmacotherapyBaptist Medical Center–Downtown, Wolfson's Children's Hospital, Jacksonville, Florida Correspondence: Correspondence: Stacey L. Mayes, PharmD, Baptist Medical Center–Downtown, Wolfson's Children's Hospital, 800 Prudential Drive, Jacksonville, FL 32207. Electronic mail may be sent to Stacey.Mayes{at}bmcjax.com. The degradation of bone tissue leading to osteoporosis is often silent and unrecognized until a postmenopausal woman develops a bone fracture. The costs of medical treatment and subsequent changes in the quality of life of a patient are significant, and avoidance via proper nutrition, exercise, and pharmacologic therapy may be the key to decreasing healthcare costs associated with this disease state. A periodic review of current literature is necessary to update the reader of current therapeutic options for the treatment and prevention of osteoporosis. A number of medications exist, and new options are ongoing. Clinicians now have access to antiresorptive and anabolic therapy in addition to lifestyle modification as options for patients. This article consists of a review of established guidelines for screening, diagnosis, and pharmacologic modalities and will provide a comprehensive assessment of therapeutic options. Osteoporosis is a silent progressive disease of porous bone, defined by decreased bone mass and a deterioration of the tissue of the bone, which leads to bone fragility and subsequent fractures. In osteoporosis, the composition of the bone tissue is normal but the quantity is reduced; hence, decreased bone mineral density (BMD). Osteoporotic bone fractures are most commonly located in the spine, hip, and wrist.1,2 The destruction of bone leading to its deterioration is essentially irreversible. The nature of the disease lends itself to vulnerability of any bone within the human body, and it is neither age- nor sex-dependent. The efforts of the clinician must be focused on prevention of further bone loss, treatment of destroyed tissue, and the quest to build new bone. In the progression of bone deterioration from normal to osteoporosis, the bone experiences a phase of osteopenia. Osteopenic bone is soft and weakened and, without further intervention, may lead to a state of osteoporosis. Osteoporosis may be further differentiated into 2 classes: primary or secondary. Primary osteoporosis is a function of the natural aging process in men and women. Primary osteoporosis is most commonly diagnosed in postmenopausal women and may occur late in the life of a man. Secondary osteoporosis is a loss of bone due to nutrition deficiencies, medications, or various chronic medical conditions. Examples of this include hypogonadism, chronic liver disease, alcohol abuse, and glucocorticoid excess. This form of the disease represents 30%–60% of osteoporosis causes in men, whereas the incidence is much lower in women, who more often present with primary osteoporosis.3,4 A fracture of the bone may lead to hospitalization, disability, and a decreased quality of life for many patients. Hip fractures may leave approximately 40% of affected patients with the inability to perform daily activities; 20% are nonambulatory, and >25% may require nursing home placement.5,6 It is the presence of a fracture that often leads to many of the changes in the quality of life and increased costs associated with osteoporosis as described in the literature.7–9 In addition to the confirmation of a fracture, symptoms of weakened bone may present as back pain, kyphosis, and height loss. Gastrointestinal (GI) and respiratory problems due to severe kyphosis may be described by some patients due to compression of the thoracic cavity and intra-abdominal infrastructure. Public health officials describe osteoporosis as a major threat for 55% of people older than age 50. Ten million Americans (80% women) have developed osteoporosis, and 34 million more are estimated to have decreased bone mass, placing them at increased risk for osteoporosis.1 Financial expenditures associated with the direct treatment of osteoporotic fractures are estimated at $18 billion dollars annually in the United States. The estimated cost of a single hip fracture is $40,000 (2001). This cost is expected to triple by 2040.6,10 As an indiscriminate disease, osteoporosis affects men and women of all ages and ethnicities. However, Caucasian postmenopausal women possess the highest incidence of overall fractures, experiencing almost 75% of hip fractures. Twenty-percent of non-Hispanic white and Asian women over the age of 50 are estimated to have osteoporosis. Five percent of non-Hispanic black women over age 50 are estimated to have osteoporosis, and an additional 35% possess low bone mass. The development of decreased bone mass increases the risk of developing osteoporosis.1 As discussed earlier, the incidence of osteoporosis in men is approximately 20%. Seven percent of non-Hispanic white and Asian men over the age of 50 are estimated to have osteoporosis. Four percent of non-Hispanic black men and 3% of Hispanic men over the age of 50 are estimated to develop this clinical condition.1 Fifty percent of all women and 25% of men over the age of 50 will develop an osteoporosis-related fracture. Reports indicate 1.5 million fractures occur annually, including 250,000 wrist fractures, 700,000 vertebral fractures, 300,000 hip fractures, and 300,000 other fractures.6 This silent yet extremely disruptive disease may often lower a patient's quality of life and increase total healthcare costs unexpectedly. The cost of treating osteoporosis is expected to double within the next 30 years due to an increase in the aging population. The development of bone is an ongoing process of continuous remodeling. Growth in the size and strength of bone changes most during childhood. The final stages of bone formation are completed during the third decade of life. Peak bone mass is determined predominantly by human genetics; however, lifestyle characteristics such as diet and exercise are major determinants in the health of the bone. Adequate caloric intake and proper dietary sources of nutrients serve as the foundation for tissue growth and bone health. Vitamins and nutrition supplements as additions to the recommended caloric intake may be necessary to assure appropriate bone growth.
It is important that patients and healthcare providers be educated regarding risk factors that might predispose patients to developing osteoporosis. Patients should be informed that this disease state is both preventable and treatable. Major risk factors associated with the development of osteoporosis in postmenopausal women include previous history of a fracture during adulthood, decreased body weight (<127 pounds), smoking, and use of corticosteroids for 3 or more months. Additional risk factors include estrogen deficiency at an early age (<45), dementia, low calcium intake (<1200 mg elemental calcium daily), decreased physical activity, and alcohol intake of >2 drinks daily1,6,11 (Table 1). Many medical conditions may be associated with an increased risk of osteoporosis. Examples include stroke, inflammatory bowel disease, gastrectomy, amyloidosis, and inadequate dietary intake.12 The most important risk factor for osteoporosis, however, is a previous history of fractures, as these patients may have created a lifestyle that continues to predispose them to fractures if left untreated.13–15 Finally, clinicians should be aware of common medications that are associated with bone mass reduction. Examples of these include anticonvulsants (phenobarbital, phenytoin), cytotoxic therapy, immunosuppressants (cyclosporine, tacrolimus), corticosteroids, tamoxifen, and parenteral nutrition (PN).
Central dual-energy x-ray absorptiometry (DXA) of the hip is the gold standard for the diagnosis of osteoporosis.6,16 This technology may also be used to measure the spine or wrist. This test requires approximately 10 minutes and exposes the patient to less radiation than that of a standard chest x-ray. Other forms of screening include pDXA (peripheral dual x-ray absorptiometry), which is used to measure the forearm or finger, and ultrasound densitometry, which assesses the heel, tibia, patella, or other peripheral sites. Ultrasound measurements are less precise than that of the DXA scan but may be useful screening tools for the prediction of fracture risk. According to the National Osteoporosis Foundation (NOF), BMD testing should be performed on all women age 65 or older, younger women with risk factors, and postmenopausal women presenting with fractures. The National Institutes of Health (NIH) does not recommend routine screening but proposes an individualized approach to screening and diagnosis.6,17,18 Diagnosis of osteoporosis and osteopenia without evidence of fracture was established in 1994 by the World Health Organization (WHO) in postmenopausal white women according to their BMD. This standardization scale provided clinicians with a manner in which to establish a rating scale for the evaluation of bone loss. This method of diagnosis is also used for the diagnosis of osteoporosis in male patients.12 The BMD measurement is used to establish or confirm a diagnosis of osteoporosis and predict the patient's future risk of such an event. The risk of the fracture and the BMD rating have an inverse relationship. These measurements may be taken at any skeletal site; however, measurements at the hip produce the most accurate predictive value. Results of the BMD test are reported as density g/cm2 (g of hydroxyapatite/cm2), T-scores, and Z-scores. The Z-score is most often used to assess bone loss in premenopausal women and men <50 years of age. The Z-score compares the patient's BMD with the average BMD for the patient's age and sex, matched by controlled subjects. A Z-score above –2 is within normal limits; conversely, a score –2 or lower is less than desired.17,19 The T-score is used to differentiate normal bone density, osteopenia, and osteoporosis in men and postmenopausal women age 50 years and older.19 The T-score is the expected BMD for young normal adults (25–30 years old) of the same sex. T-scores decrease proportionally as bone mass decreases, due to increasing age. Differences between the patients' score (Z-score or T-score) and what is considered normal is expressed as standard deviations (SDs) that lie above or below the mean. One SD is usually representative of 10%–20% of the predictive bone density value.6
The definitions of osteopenia and osteoporosis as established by the WHO
BMD scale are as follows. A normal result is represented as a BMD within 1 SD
of a young normal adult (ie, T-score Biochemical markers found in the serum and urine are byproducts of bone formation and resorption. Examples of these markers include osteocalcin, alkaline phosphatase, and procollagen type I propeptides. These markers may not be used for definitive diagnosis, but may be used as supporting data in conjunction with BMD testing.20–22
Established guidelines for the initiation of pharmacologic therapy for the prevention and treatment of osteoporosis differ according to organizational standards. The guidelines cited in this manuscript are derived from the NOF, the American Association of Clinical Endocrinology, and the U.S. surgeon general's Pyramid Approach. The NOF recommends treating those patients with a T-score below –2 with no risk factors (see Table 1), a T-score of –1.5 with 1 or more risk factors, or a history of any spine or hip fracture. Nonpharmacologic therapy includes 1200 mg of elemental calcium daily, with 400–800 IU of vitamin D daily and regular weight-bearing exercise. Pharmacologic intervention may include both antiresorptive and anabolic agents.6 The American Association of Clinical Endocrinology recommends treating patients with a T-score less than –2.5, a T-score less than –1.5 with fractures, continued bone loss despite nonpharmacologic intervention, or borderline low BMD with risk factors. The nonpharmacologic and pharmacologic interventions mirror those of the NOF.23 The U.S. Surgeon General's Pyramid Approach suggests no specific recommendations with respect to a patient's T-score. However, 1200 mg of elemental calcium and 600–800 IU of vitamin D daily, with weight-bearing activity (low-impact aerobics, dancing, walking, gardening) for 30 minutes daily, and strength and balance training are suggested. The pharmacologic interventions include antiresorptive and anabolic agents.24 Treatment of osteoporosis involves long-term lifestyle changes and may involve pharmacologic therapy. The risk of fractures decreases by 50% with therapy but does not completely eliminate the risk of a fracture. NOF guidelines recommend that patients be encouraged to exercise regularly, reduce alcohol consumption, and avoid smoking. The NOF recommends regular weight-bearing and muscle-strengthening exercises to reduce the risk of fractures and falls. Exercise improves strength and balance and provides modest increases in bone density.6 Included in the NOF universal recommendations for risk reduction is adequate intake of calcium and vitamin D. The National Academy of Sciences (NAS) recommendation that women age 50 and older consume 1200 mg of elemental calcium daily has been accepted by the NOF. The initiation of pharmacologic therapy in conjunction with proper diet, including calcium and vitamin D supplements, is indicated for patients who have had a low-trauma fracture or are at high risk of developing an osteoporotic fracture according to BMD measurements. The NOF recommends starting therapy in patients with a DXA T-score of –2 or less (regardless of risk factors), women with a DXA T-score of –1.5 with 1 or more risk factors, and patients with a previous vertebral or hip fracture.6
Calcium is an essential mineral necessary for growth and development of bones. In addition to this function, it also plays a role in neuromuscular excitability, hormone secretion, and blood clotting. More than 90% of the body's calcium is stored within the bone.25 Injured or deficient bone structure must be repaired through a process known as bone remodeling. This physiologic process involves bone deposit and bone resorption, which are facilitated by osteoblasts and osteoclasts respectively. The process of bone deposit necessitates adequate amounts of a diet full of proteins, ascorbic acid, cyanocobalamin, vitamin A, and minerals such as calcium, phosphorous, and magnesium. Through a series of processes led by the osteoblasts, calcium and phosphate ions combine to form hydroxyapatite crystals, which form the basic building blocks of the bone matrix.26 Bone resorption is performed by osteoclasts, which are derived from hematopoietic stem cells. These cells release lysosomal enzymes and metabolic acids that digest and phagocytize the bone matrix, releasing calcium and phosphate ions into the interstitial fluid and then into circulation. The fine balance of bone remodeling to maintain the skeleton is regulated by negative-feedback hormonal mechanisms. There is a constant flow of calcium entering the serum via GI absorption and the skeleton, and leaving to enter the bone or exit via urinary excretion. Calcium balance is dependent on GI absorption, bone demineralization, bone mineral formation, and renal calcium clearance. Serum calcium levels are regulated by the parathyroid hormone (PTH), 1,25-dihydroxycholecalciferol (calcitriol), and calcitonin. The average level of total serum calcium is 9.5 mg/dL (approximately 2.5 mmol/L). The body maintains this level within a 10% range.25 Intracellular calcium levels are lower than extracellular levels. It is important to note that serum calcium is available in both bound (40%) and unbound (50%) forms.25 Bound calcium is complexed to various serum calcium binding proteins such as albumin. The remaining 10% forms salt complexes with substances such as citrate. Unbound calcium is that which is available for metabolic functionality. Changes in serum pH may affect the amount of calcium available for these processes. Serum transition to an alkalotic state causes an increase in calcium binding to proteins and a subsequent decrease in unbound calcium. An example of a physical process in which this occurs is neuromuscular hyperexcitability caused by alkalosis.25 Calcitriol, the active metabolite of vitamin D3, increases GI calcium absorption, which is then solubulized in chyme. This absorption occurs most efficiently in the proximal small intestine and least in the distal portion. Increased dietary fat, phosphate, or oxalate levels may decrease calcium absorption. In healthy adults, less than half of dietary calcium is absorbed. Serum calcium is obtained from the GI tract as a result of dietary intake. The absorption of calcium from the bone is a continuous process.25 Increased serum levels cause calcium to diffuse from the serum and into bone. Decreased serum calcium levels increase calcium flux out of the bone. This calcium bone efflux is controlled by the PTH, calcitonin, and calcitriol. The kidneys filter unbound calcium, reabsorbing 98% of its calcium filtrates. This process predominantly takes place in the proximal tubule and the loop of Henle.25 Adequate amounts of calcium intake are necessary for bone health because deficiencies are a risk factor for osteoporosis. Calcium supplements may be taken for patients unable to attain adequate amounts from food. These supplements are available in the following salt forms (percent elemental calcium): carbonate (40%), citrate (21%), phosphate (23%–39%), lactate (18%), and gluconate (9%; see Table 2). Calcium phosphate and carbonate salts require an acidic environment for proper absorption; ingestion with meals enhances absorption. It is recommended that patients with achlorhydria (such as those receiving proton-pump inhibitors or histamine-2 antagonists) take citrate, lactate, or gluconate salt forms, which are not dependent on an acidic environment for absorption. Oyster shell and bonemeal (a calcium phosphate matrix) products require an acidic environment for absorption.27–29
The body best absorbs 500 mg of elemental calcium at once. Doses of calcium supplements or dietary sources needed to reach daily goals should be divided throughout the day. This absorption may be inhibited by dietary fiber and antacids.30 The recommended daily calcium intake for adults is 1000 mg for those 19–50 years of age; 1200 mg for adults >50; and a recommended maximum of 2500 mg daily. The intake of recommended doses has been proven to reduce bone loss and increase lumbar spine BMD but will not prevent estrogen-related bone loss.30 The ingestion of surplus calcium may lead to milk-alkali syndrome, kidney stones, or interference with iron absorption. Patients at risk for kidney stones should be instructed to take calcium citrate as a source. The simultaneous administration of calcium citrate with potassium citrate was found to reduce the risk of uric acid and calcium oxalate stones.27 The most common side effects of calcium intake are cramps, bloating, and flatulence. Calcium supplementation is contraindicated in patients experiencing digitalis toxicity and hypercalcemia secondary to thiazide diuretic administration. Individual factors that may precipitate increasing or uncontrolled serum levels of calcium should be assessed on a per-patient basis. Vitamin D is critical in the prevention of osteoporosis because it maximizes intestinal calcium absorption. Vitamin D deficiency leads to osteomalacia, a weakness of the bones that could lead to fractures, bone pain, and eventually osteoporosis. It is derived from a variety of food sources and is produced by the skin on exposure to light.31 Exposure to the sun 10–15 minutes twice weekly usually provides adequate amounts. The initial activation occurs in the skin through the conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) by ultraviolet light. Subsequent activation occurs through the kidneys and liver. A deficiency in vitamin D usually occurs in elderly adults as a result of a decreased ability to perform the aforementioned conversion to vitamin D3, decreased GI absorption, and decreased exposure to sunlight. Adults up to age 50 require 200 IU (international units) of vitamin D daily. The recommended intake of additional vitamin D as needed for adults 51–70 years of age is 400 IU and 600 IU for adults over the age of 70. Dietary sources of vitamin D include fortified milk (400 IU per quart) and cereals (40–50 IU per serving), egg yolks, liver, and salt-water fish.31 Patients with documented vitamin D deficiency require substantially higher amounts of vitamin D. Vitamin D3 is the preferred replacement product for deficient patients due to better absorption and ease of measurement. The recommended dose is 50,000 IU orally once weekly. Treatment should last no longer than 3 months. Clinicians should retest the serum 25-hydroxy vitamin D level after treatment to determine the success of such treatment. Successful treatment should be supplemented with 800 IU daily as maintenance treatment. Treatment failure may indicated a malabsorptive state.18
Drug therapy used to treat osteoporosis may be divided into 2 categories: antiresorptive and anabolic agents. Antiresorptive agents inhibit bone resorption. Anabolic agents stimulate bone growth and formation. The antiresorptive agents consist of 7 U.S. Food and Drug Administration (FDA)-approved medications for the treatment of osteoporosis: the bisphosphonates (alendronate, risedronate, and ibandronate), the selective estrogen receptor modulator (SERM) raloxifene, estrogen, and calcitonin. There is currently 1 FDA-approved anabolic agent, teriparatide.12,18,28 The mechanism of action of antiresorptive agents involves a decrease in osteoclastic bone resorption, with no effect on osteoblast function and, hence, the development of new bone. These agents decrease the rate of the remodeling process and reduce the number and severity of resorption sites. The increase in BMD as a result of this therapy is due to the ability of bone formation to occur at a quicker rate than bone resorption due to the presence of such agents. The oral bisphosphonates are the most widely prescribed agents of the antiresorptive therapies and are considered first-line therapy for the treatment of postmenopausal osteoporosis. The currently marketed products are second- and third-generation bisphosphonates. Etidronate and clodronate are first-generation bisphosphonates that are not approved for treatment of osteoporosis in the United States but are available in Europe. The bisphosphonates (alendronate sodium, risedronate sodium, and ibandronate sodium) are structural analogs of pyrophosphate, a naturally occurring inhibitor of bone resorption. Using a targeting-carrier system, the bisphosphonate prodrug rapidly delivers the compound to the surface of the bone.32 These agents bind hydroxyapatite crystals of the bone with high affinity and inhibit bone resorption by decreasing osteoclast activity and growth. After the inhibition of resorption, these agents may be eliminated renally or become affixed to the bone matrix, where they reside until remodeling begins again. It is this mechanism that is responsible for the long half-lives of these agents. Alendronate (Fosamax or Fosamax Plus D; Merck, Whitehouse Station, NJ) is approved by the FDA for prevention and treatment of osteoporosis in postmenopausal women. It reduces the incidence of hip, spine, and wrist fractures by 50% over a 3-year period in patients with a previous spine fracture. Alendronate reduces the risk of spine fractures by 48% over a 3-year period in patients with no history of a spine fracture. The dosing of alendronate for these indications is 5 mg daily or 35 mg weekly for prevention of fractures and 10 mg daily or 70 mg weekly (with or without 2800 IU of vitamin D3) for treatment of fractures. This product is available as a 70-mg once-weekly oral solution. The alendronate tablet should be administered with a full glass of water (6–8 oz) after waking. Patients should be instructed to drink 1 entire bottle of the alendronate oral solution, followed by 2 oz of plain water. Neither formulation should be taken at bedtime. Patients should be instructed to remain upright and refrain from ingestion of other foods or medications for at least 30 minutes after medication consumption. Alendronate is not metabolized systemically. No dosage adjustment is necessary for patients with mild to moderate renal insufficiency (creatinine clearance [CrCl] 35–60 mL/min). Alendronate is not recommended for patients with severe renal insufficiency.6,33 The Fracture Intervention Trial (FIT) examined the effect of alendronate on the rate of vertebral and nonvertebral fractures in postmenopausal women.34 This trial was randomized, double-blinded, placebo-controlled, and took place at 11 community-based centers. Women ages 54–81 with femoral neck BMD of 0.68 g/cm2 or less but no vertebral fractures were enrolled. The total enrollment was 4432 women, with 4272 completing the study. Subjects received calcium and vitamin D supplementation during the study period and were assigned to placebo or 5 mg of alendronate for the initial 2 years, then 10 mg of alendronate daily or placebo for the final 2 years. Results determined that alendronate increased BMD at all sites (p < .001) and reduced clinical fractures from 312 in the placebo group to 272 in the treatment group, but results were not statistically significant (14% reduction; 95% confidence interval [CI] 0.73–1.01). The rate of clinically identified fractures was decreased by 36% in women with osteoporosis at the femoral neck (>2.5 SDs below normal young adult mean; 95% CI, 0.50–0.82; number needed to treat [NNT] 15), but there was no significant reduction among patients with high BMD. Alendronate decreased the rate of vertebral fractures by 44% overall (RR, 0.56; 95% CI, 0.39–0.80; NNT, 60), but it did not increase the risk of adverse effects compared with placebo. Alendronate increased BMD in patients with initially low BMD of –2.5 or less. Patients with higher BMD levels were unaffected by 4 years of therapy. There was an overall reduction in the risk of clinical fractures among women with osteoporosis and with hip or spine T-scores of –2 or more. Risedronate (Actonel and Actonel with calcium; Proctor & Gamble, Cincinnati, OH) reduces the risk of spine fractures up to 49% and non-spine fractures by 36% over a 3-year period in patients with a prior spine fracture. The manufacturer recommended dosing for risedronate is 5 mg daily or 35 mg weekly for both prevention and treatment of bone fractures. Risedronate is absorbed in the upper GI tract and reaches maximum absorption within 60 minutes. Serum steady-state levels are achieved in approximately 56 days. Risedronate is not systemically metabolized. There is no dosage adjustment necessary for patients with renal insufficiency.6,35 The efficacy, safety, and fracture risk reduction of risedronate therapy in postmenopausal women with osteoporosis was tested by Harris et al36 and published in 1999. This study was randomized and placebo-controlled with 2458 participants, with at least 1 vertebral fracture in each group. Patients were enrolled in 1 of 110 centers throughout North America from 1993 to 1998. Study treatment required the administration of placebo, 2.5 or 5 mg of risedronate. All patients received calcium and vitamin D supplementation. Patients assigned to 2.5 mg daily of risedronate therapy were discontinued after 1 year, whereas the 5-mg and placebo treatment groups completed 3 years of treatment. Researchers discovered that 5 mg of risedronate daily resulted in a 41% reduction in the risk of new radiographically identified vertebral fractures (95% confidence interval [CI]; 18%–58% over 3 years; 11.3% incidence of fractures in risedronate group vs 16.3% in placebo group; p = .003). The rates of nonvertebral fractures was reduced by 39% (95% CI; 6%–61%; 5.2% incidence of fractures in risedronate group vs 8.4% in placebo group; p = .02) BMD increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1%), femoral neck (1.6% vs 1.2%), femoral trochanter (3.3% vs 0.7%), and mid-shaft radius (0.2% vs –1.4%). The safety profile of risedronate was similar to placebo. Ibandronate (Boniva; Roche, Research Triangle Park, NC) is the newest agent in this class, a once-monthly tablet of 150 mg, or 2.5 mg daily, approved by the FDA for prevention and treatment of postmenopausal osteoporosis. Ibandronate may reduce the risk of fractures by 50%. The absorption of ibandronate occurs in the upper GI tract. The oral bioavailability is reduced by 90% when administered concomitantly with a standard breakfast. This product is not metabolized in humans. Approximately 50%–60% of the dose is not absorbed by the bone and is eliminated via renal excretion. Ibandronate is not recommended in patients with severe renal impairment (CrCl <30 mL/min).6,37 The administration of oral bisphosphonates requires that patients take them after waking with 8 oz of plain water before any other food or drink of the day and remain sitting upright for 30 minutes (60 minutes if ibandronate is administered).37 Sitting upright reduces the potential of a possible esophageal injury. Patients should also be instructed to not eat or drink anything for at least 30 minutes after ingesting the drug. These instructions are based on the product bioavailability and tolerability. The oral bioavailability of risedronate and alendronate is <1% in the fasting state. The absorption of these medications is reduced by the introduction of other food, drink, or medications. The most common side effect is GI upset. Inappropriate administration of alendronate led to a number of postmarketing reports of esophagitis, esophageal ulcers, and erosions. Consider the discontinuance of bisphosphonates if patients experience symptoms of esophageal disease or injury, musculoskeletal pain, eye inflammation, or jaw necrosis. There are a number of published case reports (>2000) describing jaw necrosis associated with bisphosphonate therapy. Woo and colleagues38 conducted a recent systematic review to evaluate the incidence of jaw necrosis in patients receiving bisphosphonate therapy.39 Among 368 published reports, the researchers discovered 94% of cases occurred in patients with metastatic carcinoma to the skeleton or multiple myeloma who were taking intravenous bisphosphonates (zolendronic acid, pamidronate). Sixty percent of these cases included patients with a recent dental surgical procedure. The incidence of osteonecrosis in cancer patients is <10%; the prevalence of this necrosis in those patients taking oral bisphosphonates is unknown. The mechanism of necrosis is believed to be due to an oversuppression of osteoclastic activity. Current FDA recommendations suggest that cancer patients receiving chemotherapy or corticosteroids and those with poor oral hygiene receive a dental examination before initiating bisphosphonate therapy. Recommendations from the American Dental Association also suggest that the incidence of bone necrosis associated with oral bisphosphonate therapy is low (0.7 cases per 100,000 person-years' exposure). Patients should receive a comprehensive dental examination before the initiation of oral therapy. Conservative dental surgical procedures should be used, if needed.40 After initiating, patients should avoid dental procedures if possible. Specific information regarding jaw recovery after discontinuance of these agents is unclear. Bisphosphonates are contraindicated in patients with hypersensitivity to the components of the drug, renal insufficiency (CrCl <35 mL/min), hypocalcemia, or esophageal irritation. Intravenous pamidronate (Aredia; Novartis, East Hanover, NJ) has been used to treat osteoporosis as off-label use. It is an option for women that cannot tolerate or absorb oral bisphosphonates. A loading dose of 90 mg is usually administered, followed by 30 mg every 3 months. The efficacy of pamidronate in the reduction of fractures has not been established.18 Intravenous zoledronic acid (Zometa; Novartis) is approved for the treatment of malignant hypercalcemia and multiple myeloma and has the ability to increase BMD and suppress bone resorption in postmenopausal women for 1 year after a single 4-mg dose. The safety and efficacy of this therapy for osteoporosis is being evaluated by the FDA.12,41 Selective estrogen receptor modulator raloxifene (Evista; Eli Lilly and Co, Indianapolis, IN) slows bone decomposition by blocking cytokine signaling to the osteoclast. Raloxifene has both agonist and antagonistic activity exhibited by its ability to interact in an agonistic fashion with estrogen receptors in the bone while interacting antagonistically in the breast and uterus. Raloxifene is FDA approved for the prevention and treatment of postmenopausal osteoporosis, at a dose of 60 mg daily. This product decreases vertebral fractures by 40% in as early as 1 year while increasing BMD. Raloxifene reduces the risk of spine fractures by 30% in patients with and by 55% in patients without a spine fracture over a 3-year period. The risk of breast cancer and coronary heart disease in patients taking raloxifene is under investigation. Clinicians should be aware of an increased risk of venous thromboembolism (VTE) present with raloxifene administration. The most common adverse effects of raloxifene include hot flashes and leg cramps. Raloxifene is contraindicated in patients with a history of VTE.12,41 Clinical trial information to assess the use of raloxifene in postmenopausal women for the treatment of osteoporosis is supplied by the MORE (Multiple Outcomes of Raloxifene Evaluation) trial.42 Results of this trial indicate that over a 36-month period, administration of raloxifene (60 mg daily) reduced the risk of vertebral fractures by 30% (relative risk [RR], 0.7; 95% CI, 0.5–0.8), reduced the frequency in both men and women without prevalent fractures, and increased BMD at all studied sites (p < .001). The risk of nonvertebral fractures was not reduced significantly compared with placebo with the administration of raloxifene. Calcitonin (Miacalcin; Novartis), a polypeptide hormone derived from salmon, partially inhibits osteoclast activity and has FDA approval for the treatment of osteoporosis in women who are >5 years past menopause. It is available as a daily intranasal spray (200 IU) or subcutaneous injection. Chesnut and colleagues43 conducted the PROOF trial (Prevent Recurrence of Osteoporotic Fractures) over a 5-year period in a randomized, double-blind, placebo-controlled fashion. Researchers discovered that 200 IU of salmon calcitonin administered via nasal passages reduced the risk of new vertebral fractures by 33% (p = .03) in postmenopausal women with previous osteoporosis. There were no significant results with respect to an increase in BMD or a reduction in nonvertebral fractures. One of the clinical applications of this product is the reduction of pain associated with acute compression fractures. The mechanism for analgesia is unexplained. Side effects include nausea and nasal congestion. Adverse effects associated with nasal administration include dryness, itching, and epistaxis. Injectable administration may cause local reactions, flushing, and rashes.12,41 Estrogen hormone therapy is FDA approved for the prevention of osteoporosis associated with menopause. Estrogen blocks cytokine signaling the osteoclast, which decreases bone resorption. Women who have an intact uterus require progestin to protect the endometrium from cancer. Results of the Women's Health Initiative (WHI) revealed that after 5 years of hormone therapy using Prempro (conjugated equine estrogens/medroxyprogesterone), the risk of vertebral fractures and hip fractures was reduced by 34%.44 This trial randomized 16,608 healthy postmenopausal women between the ages of 50 and 79 with an intact uterus, to receive conjugated equine estrogen-medroxyprogesterone or placebo for 8.5 years. The primary endpoint was an evaluation of cardiovascular events. This was established to examine the relationship between estrogen therapy and cardiovascular complications. The primary adverse endpoint was the frequency of breast cancer. Secondary endpoints included fractures, VTE, stroke, and colon and endometrial cancer. This trial was halted after 5 years due to an increase in participant adverse affects. The relative increase in risk was 41% for stroke, 29% for cardiovascular disease (CVD) events, and 26% for invasive breast cancer. Positive results obtained from the trial included 37% risk reduction in colorectal cancer and 34% risk reduction in hip and clinical vertebral fractures. A number of limitations were established due to clinical trial results. Patients electing to seek osteoporosis therapy using hormone therapy should weigh the benefits vs risk profile. The FDA does not recommend estrogen hormone therapy as a first-line option for osteoporosis prevention. The ability of estrogen to increase BMD has been demonstrated in women of early and late menopausal phases. The administration of low-dose (0.3–0.45 mg) conjugated equine estrogen in combination with calcium and vitamin D produces an increase in BMD and a reduction in bone resorption. Results of WHI have led to concerns regarding an increased risk of cardiovascular events and breast cancer, which have caused a decline in the use of estrogen as an optimal therapy for osteoporosis prevention. There are no published trials with adequate power to verify the superiority of combination therapy using antiresorptive agents vs monotherapy and the outcome on fractures. Bisphosphonate and estrogen combination therapy may increase BMD.45 Likewise, combination therapy of antiresorptive agents and anabolic agents has not been proven to be superior to monotherapy in the reduction of osteoporotic fractures.46–48 In 2002, recombinant human parathyroid hormone (1–34), [rh PTH (1–34)], teriparatide (Forteo; Eli Lilly and Co.) was approved by the FDA for the treatment of osteoporosis in postmenopausal women at high risk for fracture (T-score <–3.5). It was manufactured by using a strain of Escherichia coli modified by recombinant DNA technology. This parenteral product is supplied as a cartridge that is preassembled in a multidose pen that delivers 20 µg daily for up to 28 days. The pen should be stored under refrigeration at 2°C–8°C.49,50 The medication should be injected into the subcutaneous tissue of the abdomen or thigh. Contents of the pen are not to be transferred to a syringe. The compound is the first anabolic (bone-building) agent approved for osteoporosis treatment. PTH stimulates bone remodeling by increasing bone building. Physiologically, PTH regulates bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. Daily administration stimulates new bone formation of trabecular and cortical bone surfaces by preferentially activating osteoblasts vs osteoclasts. The absolute bioavailability is 95% after subcutaneous administration. The half-life of teriparatide is 60 minutes if given subcutaneously. No metabolism or excretion studies have been performed. After administration, serum calcium levels begin to increase within 2 hours and reach maximum at approximately 5 hours postdosing. These levels will decline and return to baseline within 24 hours. The dose of PTH (1,34) is 20 µg subcutaneously daily, and it has been proven to decrease the risk of spine fractures by 65% and nonspine fractures by 53% in patients with osteoporosis up to 18 months after therapy has been discontinued. The possibility that this product may be used in conjunction with antiresorptive agents is being explored; however, no definitive recommendations have been published. The maximum duration of therapy is 2 years due to limited safety data. Adverse events include dizziness (<10%), nausea (<10%), arthralgias (10%), leg cramps (<10%), and postinjection hypercalcemia (<10%). Teriparatide should be avoided in patients with Paget's disease of the bone, those being exposed to radiation therapy, and patients with skeletal malignancies.
Osteoporosis is preventable and treatable. Proper use of available therapies by clinicians may enhance the lives of patients, thereby improving their quality of life. Early detection and administration of essential vitamins and supplements, in addition to proper diet and exercise, may greatly decrease possible catastrophic events that seem to debilitate so many postmenopausal women. The use of oral bisphosphonates as first-line antiresorptive therapy is both effective and safe when used in combination with calcium and vitamin D. The appropriateness of the bisphosphonate of choice is a clinical decision that may be individualized per patient, according to the patient's current clinical status, such as renal function or swallowing capability, and other confounding factors (patient compliance, concurrent medication regimen). Calcium and vitamin D supplementation are critical to bone formation and bone remodeling homeostasis. A number of products are available, including tablets, liquid, and soft chewable forms, which should aid in administration efforts. Anabolic pharmacologic intervention for patients with severe bone loss has proven to be extremely promising. Clinicians must be vigilant in encouraging patients to be screened and treated as per guidelines. Such actions will decrease overall healthcare costs and improve the long-term quality of life of our patients. 1 National Osteoporosis Foundation. Osteoporosis disease statistics: "fast facts." Available at: http://www.nof.org/osteoporosis/diseasefacts.htm. Accessed November 25, 2006. 2 Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res.1994; 9:1137 –1141.[Web of Science][Medline] [Order article via Infotrieve]3 Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc. 2002;77:453 –468.
Nutrition in Clinical Practice, Vol. 22, No. 3,
276-285 (2007) This article has been cited by other articles:
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
|
 |
|
Sign In to gain access to subscriptions and/or personal tools.
Top
Risk Factors for Osteoporosis
Diagnosis
–1). Low bone mass (osteopenia)
is defined as a hip BMD between 1 and 2.5 SDs below that of a "young
normal" adult (ie, T-score between –1 and –2.5).
Osteoporosis is defined as a BMD 2.5 SDs or more below that a "young
normal" adult (ie, T-score 
–2.5). Patients presenting with
osteoporosis with a previous fracture are described as having severe
osteoporosis. 
