These warnings have also resulted in a number of changes to drug labeling and inclusion of new safety information or warnings about risks of the medication. Thousands of Fosamax lawsuits have been filed for similar reasons. Side effects of Fosamax can range from moderate to severe. Patients taking Fosamax commonly experience stomach pains and irritation of the gastrointestinal lining, as well joint, muscle, and bone pains.
In , the FDA released a Drug Safety Communication warning the public of the potential increased risk of sustaining fractures in the femur, or thigh bone, in bisphosphonate patients. Though Fosamax is given to prevent bone loss and fractures, in some cases, Fosamax side effects may contribute to weakened and broken bones. These low-impact fractures have often occurred without extreme stress on the bone. The majority of Fosamax fractures occur in female patients and may occur during routine, non-stressful physical activities.
Reports indicate that Fosamax femur fractures tend to occur spontaneously and may occur during low impact activity. These areas are typically not associated with osteoporosis fractures but are unique to drug side effects. Furthermore, the femur is one of the strongest bones in the body, making Fosamax femur fractures more unusual. In March , the U. Food and Drug Administration FDA conducted an investigation on bisphosphonate drugs like Fosamax and their association with femur fractures.
The research indicated that rare but serious Fosamax femur fractures are associated with long-term use. The study was also published in the Journal of Bone and Mineral Research.
The study examined patients who suffered femur breaks. The results showed that 94 percent of these were caused by Fosamax or other bisphosphonate drugs. Furthermore, the Fosamax femur fractures occurred in patients who had been taking Fosamax for an average of five or more years. The study revealed that a main warning sign of a Fosamax femur fracture is persistent pain in the thigh or groin where the fracture will typically take place. The exact explanation for the incidence of Fosamax femur fractures is currently unknown.
However, it is believed that Fosamax alters the natural process of bone remodeling in the body. When small fractures occur, they accumulate and contribute to severe Fosamax femur fractures. In theory, frozen bone can contribute to the clean fractures that many Fosamax patients experience. Another Fosamax user reported that her femur broke during a commute to work when the subway train she was traveling in came to a routine stop.
Sue Heller of Colorado broke both femur bones during her 10 years of Fosamax treatment. Sandy Potter of New York reported that her femur broke completely in half while jumping rope with neighborhood children.
Also called dead jaw syndrome, Osteonecrosis is a Fosamax side effect which may cause the jawbone to degrade and collapse. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts.
The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about fold higher uptake on osteoclast surfaces than on osteoblast surfaces.
Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active.
Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover i. In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass. Relative to an intravenous IV reference dose, the mean oral bioavailability of alendronate in women was 0. Oral bioavailability of the 10 mg tablet in men 0.
A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast. Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans.
The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Gender: Bioavailability and the fraction of an IV dose excreted in urine were similar in men and women.
Geriatric: Bioavailability and disposition urinary excretion were similar in elderly and younger patients. Renal Insufficiency: Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function.
Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function. Hepatic Insufficiency: As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic insufficiency. No dosage adjustment is necessary. Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2-antagonists is unknown.
Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate. Alendronate is a bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover.
Osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral spinal fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation.
These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in white women increases fold and the risk of vertebral fracture to fold.
Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality. Daily oral doses of alendronate 5, 20, and 40 mg for six weeks in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation such as deoxypyridinoline and cross-linked N-telopeptides of type I collagen.
These biochemical changes tended to return toward baseline values as early as 3 weeks following the discontinuation of therapy with alendronate and did not differ from placebo after 7 months. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with FOSAMAX.
These data indicate that the rate of bone turnover reached a new steady-state, despite the progressive increase in the total amount of alendronate deposited within bone. As a result of inhibition of bone resorption, asymptomatic reductions in serum calcium and phosphate concentrations were also observed following treatment with FOSAMAX.
No further decreases in serum calcium were observed for the five-year duration of treatment; however, serum phosphate returned toward prestudy levels during years three through five.
The reduction in serum phosphate may reflect not only the positive bone mineral balance due to FOSAMAX but also a decrease in renal phosphate reabsorption. Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures especially vertebral, hip, and rib. It occurs both in males and females of all ages. Osteoporosis occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss.
Alendronate decreases bone resorption without directly inhibiting bone formation. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.
In clinical trials, FOSAMAX 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, FOSAMAX induced generally mild, transient, and asymptomatic decreases in serum calcium and phosphate.
These included two three-year, multicenter studies of virtually identical design, one performed in the United States U. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites.
Increases in BMD were evident as early as three months and continued throughout the three years of treatment. See figures below for lumbar spine results. BMD at the femoral neck, forearm and total body were maintained. FOSAMAX was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied at least 2 standard deviations below the premenopausal mean.
Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.
The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers. To assess the effects of FOSAMAX on the incidence of vertebral fractures detected by digitized radiography; approximately one third of these were clinically symptomatic , the U. There was a statistically significant reduction in the proportion of patients treated with FOSAMAX experiencing one or more new vertebral fractures relative to those treated with placebo 3.
A reduction in the total number of new vertebral fractures 4. In the pooled analysis, patients who received FOSAMAX had a loss in stature that was statistically significantly less than was observed in those who received placebo The Fracture Intervention Trial FIT consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture.
Fracture Intervention Trial: Three-Year Study patients with at least one baseline radiographic vertebral fracture. Furthermore, in this population of patients with baseline vertebral fracture, treatment with FOSAMAX significantly reduced the incidence of hospitalizations The figure below displays the cumulative incidence of hip fractures in this study.
Fracture Intervention Trial: Four-Year Study patients with low bone mass but without a baseline radiographic vertebral fracture. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women.
The results are shown in the table below for the patients with osteoporosis. Thus, FOSAMAX reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture.
FOSAMAX, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. At the end of the FIT studies the between-treatment group differences were 3. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with FOSAMAX is of normal quality.
A two-year, double-blind, placebo-controlled, multicenter study of FOSAMAX 10 mg once daily enrolled a total of men between the ages of 31 and 87 mean, A one-year, double-blind, placebo-controlled, multicenter study of once weekly FOSAMAX 70 mg enrolled a total of men between the ages of 38 and 91 mean, These increases in BMD were similar to those seen at one year in the 10 mg once-daily study. Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women years of age.
In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 2. At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination 8.
HRT alone 1. In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD. Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture.
These studies enrolled and patients, respectively, between the ages of 17 and 83 with a variety of glucocorticoid-requiring diseases. Patients received supplemental calcium and vitamin D. In the placebo-treated patients, a significant decrease in BMD occurred at the femoral neck Of the original patients in these studies, patients who remained on at least 7.
After two years of treatment, spine BMD increased by 3. Significant increases in BMD relative to placebo were also observed at the femoral neck, trochanter, and total body. After one year, 2.
The following figure shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment. At six months the suppression in alkaline phosphatase in patients treated with FOSAMAX was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients.
FOSAMAX was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied at least twice the upper limit of normal. As in patients treated for osteoporosis see Clinical Studies, Treatment of osteoporosis in postmenopausal women, Bone histology , FOSAMAX did not impair mineralization, and the expected decrease in the rate of bone turnover was observed.
The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats.
In this assay, the lowest dose of alendronate that interfered with bone mineralization leading to osteomalacia was fold the antiresorptive dose. The corresponding ratio for etidronate was one to one. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia. Osteoporosis may be confirmed by the finding of low bone mass for example, at least 2 standard deviations below the premenopausal mean or by the presence or history of osteoporotic fracture.
Risk factors often associated with the development of postmenopausal osteoporosis include early menopause; moderately low bone mass for example, at least 1 standard deviation below the mean for healthy young adult women ; thin body build; Caucasian or Asian race; and family history of osteoporosis. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. The optimal duration of use has not been determined. As a class, BPs share properties in common.
However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs. Even though many of the well-established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come.
Furthermore in many areas, e. New 'designer' BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled. The adventure that began in Davos more than 40 years ago is not yet over.
Abstract The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in , so it is timely after 40years to review the history of their development and their impact on clinical medicine. Publication types Review.
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