Bisphosphonate Therapy in America: A Literature Review
Osteoporosis is a disease that is characterized by low bone mass and due to deterioration in the micro architecture of bone which increases its susceptibility to fracture. Normal bone mineral density (BMD) is measured by using dual x-ray absorptiometry (DEXA scan) and is rated with a numeric value, or T-score, that falls within 1 standard deviation (SD) of the mean value for healthy, young white women. Based on epidemiologic studies, the World Health Organization (WHO) defines osteoporosis as a BMD (spine, hip, or wrist) that is 2.5 SDs or more below the standard mean for healthy, young Caucasian women (corresponding to a T-score below −2.5) and osteopenia as a BMD that is between 1 and 2.5 SDs below the reference standard (Nall, Miller. 2001).
Osteoporosis is more than twice as common in Caucasian and Hispanic women than in African American women (WHO, 1994). In Causasian women over the age of 50, the overall risk of osteoporotic fractures reaches 40 percent and more than 90 percent of hip fractures in the elderly can be attributed to osteoporosis. Osteoporosis is responsible for almost 2 million hip and vertebral fractures annually. In 2003, osteoporotic fractures prompted more than 2.5 million physician visits, 532,000 hospitalizations, and 210,000 nursing home admissions. In the United States alone, the annual medical expenditures for the treatment of osteoporotic fractures may be as high as $17 billion (Fliesch, 1997).
There are many misnomers when defining hip fractures and their overall relatedness. The orthopeadic definition of a hip fracture is readily accepted as “… a fracture of the femur above a point 5 cm below the distal part of the less trochanter” (BMJ). This definition encompasses both intra and extra capsular anatomic structures, along with the neck of the femur. In developed countries, the overall risk of sustaining a hip fracture is about 21% in women and 7% in men (Pouilles, et. al, 2003). In those patients who sustain a hip fracture, one in four will die within the first year, and one in three will require long term care as the result of a hip fracture (Heard, Balena, Blake, Fogleman, 2007).
One study out of Armenia attempted to quantify to loss of life after a hip fracture. The results showed a substantial loss of years with the largest segment in the male population over the age of 80. On average, men aged 51-60 years lost 18% of their expected years, with men over the age of 80 loosing as much as 58%. The results were not as pronounced in women but still just as staggering. Women less who were than 50 years old could expect a loss of 27% versus 38% in women over the age of 80 (Wimalawansa , 2005). This shows the significant need to prevent or at least mitigate the propensity of hip fractures. Although the patient's co morbidities can be at least in part a contributing factor to their demise, it can be thoroughly concluded that a hip fracture might very well be the beginning of the end for many patients. Various modalities have shown to be effective to varying degrees in the prevention of hip fractures. Yet none have shown to be as effective as the incorporation of bisphosphonates and their subsidiaries zoledronic acid (Zometa), alendronate (Fosamax), pamidronate (Aredia), ibandronate (Boniva) , into the patients regiment.
Bisphosphonates are a class of pharmokinetics that employ a phosphate-carbon-phosphate core and has a strong affinity to the calcium molecule. In the past several decades, these medications have taken on an important role in the treatment of osteoporosis due to their overall efficacy and the lagley ease of use. Despite the exact mechanism of action not being completely understood, we know that these medications strongly inhibit osteoclast-mediated bone resorption (Mclung, et. al, 1998). As the bone remodeling phase is decelerated, both development and re-absorption are decreased, yet the re-absorption is inhibited slightly more so than formation. This practice allows for a modest increase in bone mineral density (BMD) (Hosking, et al, 2008). The ossification action of bisphosphonates and their overall loss of affinity outside the skeleton structure have led to the increased use of these drugs in the treatment and prevention of osteoporosis.
Cyclical etidronate was the first of the bisphosphonate class to be evaluated for the treatment of established postmenopausal osteoporosis (Lindsay, 1999). During the eight years of treatment, BMD in the spine increased by approximately 7 percent in women taking cyclical etidronate, and BMD of the hip increased 1 to 2 percent respectively over baseline values. Continuous treatment with cyclical etidronate notably decreased the vertebral fracture rate, but only in patients who had the highest risk for fracture. Due to this discrepancy, the FDA has not labeled etidronate (Didronel) for the treatment of osteoporosis (Mortensen, Bekker, Digenarro, Johnston, 2004).
The newer bisphosphonates have changed our understanding of the management of osteoporosis because of their improved effectiveness. Alendronate (Fosamax) is the first of these latest bisphosphonates to be allowed by the FDA to be marketed for treatment and prevention of osteoporosis. In early trials, treatment with alendronate (10 mg daily) over a three-year period increased spine BMD by approximately 8 to 9 percent and BMD of the hip by 7 to 9 percent over baseline values (Ravn, Clemmessen, Riis, Christensen, 2006). More recently, a landmark study was published entitled the Fracture Intervention Trial (FIT) (Filipponi, et. al, 1995) in which postmenopausal women with low femoral BMD were randomized to receive placebo or alendronate (5 mg per day). In the second year of the study, the daily alendronate dosage was increased to 10 mg per day. The use of alendronate over three years increased spinal BMD to 10 percent over baseline, and there was a 55 percent decrease in the risk of new hip, wrist, and vertebral fractures in women with at least one preexisting fracture at baseline. In the second part of the FIT trial, women who did not display a preexisting fracture at baseline yet still had a low hip BMD (T-scores lower than -1.0), alendronate showed to reduce the risk of clinical fractures by 46 percent in patients who had the lowest baseline femoral BMD (T-scores lower than -2.5). There was no reduction in fracture efficacy noted in women taking alendronate who had higher baseline BMD values in the osteopenic range (Heikkinen, Selander, Laitinen, Arnala, Vaananen, 2003).
Changes in BMD establish the overall success of an osteoporosis prevention trial. In prevention studies, women with average or slightly sub-average bone mass (osteopenia: T-scores of 1.0 or higher) are included. There have been numerous studies over the past 15 years that have shown that bisphosphonate therapy does conserve bone mass in healthy postmenopausal women (Adachi, 1997). Results of several studies using intravenous bisphosphonates given every three months, have shown to increase the boney matrix in the hip and spine equally as effective as oral management (Geusens, 2008). Overall, both oral and intravenous bisphosphonates are equally as efficient in the prevention of bone demineralization in early to late-postmenopausal women. The amount of increase in BMD is dosage-dependent and more pronounced at the spine versus the hips or radius. This increase in BMD is also greater in older women.
Results of one study (Pitt, Todd, Webber, Pack, Moniz, 2006) showed that, in women taking 5 mg per day of alendronate for one year, a corresponding increase in BMD of 4 to 6 percent over baseline values was noted at the femoral neck and medial cortices of the trochanter, while women taking placebo had a decrease in BMD of 4 to 5 percent at those same sites. In another study (Strues, Snelder, Mulder, 2001) alendronate was compared with hormone replacement therapy (HRT) in 1,284 postmenopausal women less than 60 years of age. Women treated with 5 mg of alendronate daily showed a 4.2 percent increase over baseline in hip BMD and a 2.1 percent increase in BMD of the vertebrae. Women in the estrogen-progestin arm displayed a 2 percent increase over baseline values in spine BMD and a 2.1to 3.1 percent increase in areas of the hip after two years of treatment.
Risedronate (Actonel) was the second bisphosphonate to be labeled by the FDA for the treatment of osteoporosis. Results of several large studies (Liberman, 1995) show the efficacy of risedronate therapy in increasing BMD and along with decreasing fracture risk in women with postmenopausal osteoporosis and previous fractures. In each study, patients were treated with supplemental calcium, vitamin D if needed, and risedronate or matching placebo for three years. In the North American arm of the trial, 2,458 subjects who were treated with 5 mg of risedronate daily, displayed an increased spine BMD over baseline of approximately 6 percent along with a reduction in overall incidence of nonvertebral fractures by 32 percent. In the multinational arm of the same study that enrolled 12,596 women, their treatment regiment of 5 mg of risedronate daily for three years reduced the risk of new vertebral fractures by 52 percent and the risk of nonvertebral fractures by 35 percent. Risedronate (Actonel) was compared with placebo in young postmenopausal women. The women in the placebo group had a 4.1 percent decrease in spine BMD, compared with a 1.6 percent increase over baseline values in spine BMD in patients taking risedronate (Devogelaer, Broll, Correa-Rotter, Cumming, Deuxchaisnes, 2006).
Postmenopausal osteoporosis is a serious chronic medical condition that warrants long-term treatment. Due to their overall safety, bisphosphonates have been FDA approved for the treatment of metabolic bone derangements such as Paget's disease, for over 20 years. The newer generation of bisphosphonates tend to not have an effect on bone mineralization, such as osteomalacia, increase bone fragility, or reduce the quality of boney matrix (Black, et. al, 1996). This is due to the mechanism of action in which bisphosphonates reduce activation frequency yet does not impede micro fracture remodeling. The activation frequency of remodeling does not diminish with continual usage, thus allowing for new bone formation while inhibiting bone re-absorption.
Bisphosphonates have minimal skeletal toxicity since they bind only to the skeletal structures and are not taken up by other organs or tissues. The decline in renal function that has been reported in rodent models associated with high-dosage oral bisphosphonate has not been reported in clinical practice. Conversely, since bisphosphonates are excreted via glomerular filtration, IV administration of large doses of pamidronate (Aredia) in patients with severe to chronic renal failure or patients on dialysis could be at greater predisposition to both hypocalcemia and/or hypophosphatemia with related tetany (Heilberg, 2006).
Bisphosphonates are also noted to have potential GI side effects in some segments of the patient population. In clinical trials, the degree and regularity of severe upper GI complications are comparable to those with placebo (Harris, et. al, 2005) yet, in clinical practice, GI side effects are frequently noted. The exact reasons for this variance are not fully appreciated. Oral bisphosphonates appear to provoke potentially serious esophagitis in certain patients, which could result in gastritis and cause diarrhea. When used as prescribed, serious esophageal complications are mitigated. Yet in patients with established esophageal disease (e.g., Barrett's esophagus , severe reflux , achalasia, stricture, and scleroderma) should be advised to avoid taking oral bisphosphonates. Patients who complain of GI symptoms should stop taking the medication immediately. They may potentially begin therapy at lower dosages or intermittent dosing once the upper GI symptoms disappear (Reginster, 2001). Etidronate (Didronel) is noted to have fewer upper GI side effects but several reports point to a higher propensity for lower GI side effects than alendronate. Pamidronate (Aredia) should be considered in populations with marked osteoporosis who have also demonstrated fractures and who would not be able to tolerate oral regiments otherwise, as it is administer intravenously. In several ongoing studies, the newer oral bisphosphonates have shown great potential in patient compliance, yet more research needs to be performed in this area (Strues, 2001).
Although osteoporosis is more commonly seen in women versus men, osteoporotic induced fractures do occur in the male population. To date, there has been very little research concerning therapeutic or prevention for men. As of date, there have been no pharmacological agents that have approved by the FDA for the prevention or treatment of osteoporosis in older men. Nonetheless, it is quite probable that bisphosphonates are equally as efficient in men as they are in women. Preliminary data from a large scale, prospective, randomized placebo-controlled trial (Miller, 2006) of alendronate in men with osteoporosis has also eluded to a positive effect on bone density. Even though the actual number of studies is modest, there is has been some evidence presented for the efficacy of bisphosphonates in particular groups of men with low bone mass in the presence of fractures.
Osteoporosis is a major medical problem that can potentially affect all sects of America. Through both direct and indirect measurements, we are able to quantify it effects on our citizens by reduction in quality of life, loss of production, and increased medical costs that are shifted to insurers. To date, there is not one regiment that can prevent osteoporosis in all facets of the population. Each of the bisphosphonates discussed have potential benefits and drawback that can be associated with its usage. Yet all have been shown to help reduce the potential side effects of osteoporosis, with varying degrees. As newer medications emerge from the FDA process, further studies will be warranted to monitor their efficacy and overall effectiveness.
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