See all CNNMoney. Merck's osteoporosis blockbuster loses patent protection Wednesday and generic drug makers line up cheaper versions. Play video. More drug news The FDA's higher bar on new drugs. Drugmakers offer weak '08 outlook. Further details were not disclosed. Also yesterday, Teva Pharmaceuticals and Barr Labs becamethe first two generics companies to receive FDA approval to make and sellalendronate.
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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. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. FOSAMAX, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa.
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including FOSAMAX. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue FOSAMAX and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
In patients who cannot comply with dosing instructions due to mental disability, therapy with FOSAMAX should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. Causes of osteoporosis other than estrogen deficiency, aging, and glucocorticoid use should be considered. Other disorders affecting mineral metabolism such as vitamin D deficiency should also be effectively treated.
Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop.
Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Known risk factors for osteonecrosis of the jaw include invasive dental procedures e. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon.
In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients.
These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area.
They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids e. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture.
Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Before initiating treatment, the hormonal status of both men and women should be ascertained and appropriate replacement considered. A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined FOSAMAX and glucocorticoid treatment.
The efficacy of FOSAMAX for the treatment of glucocorticoid-induced osteoporosis has been shown in patients with a median bone mineral density which was 1.
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