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      Bioequivalence of generic alendronate sodium tablets (70 mg) to Fosamax ® tablets (70 mg) in fasting, healthy volunteers: a randomized, open-label, three-way, reference-replicated crossover study

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          Abstract

          Purpose

          The aim of this study was to evaluate the bioequivalence of a generic product 70 mg alendronate sodium tablets with the reference product Fosamax ® 70 mg tablet.

          Materials and methods

          A single-center, open-label, randomized, three-period, three-sequence, reference-replicated crossover study was performed in 36 healthy Chinese male volunteers under fasting conditions. In each study period, the volunteers received a single oral dose of the generic or reference product (70 mg). Blood samples were collected at pre-dose and up to 8 h after administration. The bioequivalence of the generic product to the reference product was assessed using the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reference-scaled average bioequivalence (RSABE) methods.

          Results

          The average maximum concentrations ( C max) of alendronic acid were 64.78±43.76, 56.62±31.95, and 60.15±37.12 ng/mL after the single dose of the generic product and the first and second doses of the reference product, respectively. The areas under the plasma concentration–time curves from time 0 to the last timepoint (AUC 0– t ) were 150.36±82.90, 148.15±85.97, and 167.11±110.87 h⋅ng/mL, respectively. Reference scaling was used because the within-subject standard deviations of the reference product ( s WR ) for C max and AUC 0– t were all higher than the cutoff value of 0.294. The 95% upper confidence bounds were −0.16 and −0.17 for C max and AUC 0– t , respectively, and the point estimates for the generic/reference product ratio were 1.08 and 1.00, which satisfied the RSABE acceptance criteria of the FDA. The 90% CIs for C max and AUC 0– t were 90.35%–129.04% and 85.31%–117.15%, respectively, which were within the limits of the EMA for the bioequivalence of 69.84%–143.19% and 80.00%–125.00%.

          Conclusion

          The generic product was bioequivalent to the reference product in terms of the rate and extent of alendronate absorption after a single 70 mg oral dose under fasting conditions.

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          Most cited references 23

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          Bisphosphonates: from the laboratory to the clinic and back again.

          Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates are therefore stable analogues of naturally occuring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains. Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget's disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. In addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of new bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures. The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs. oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid-associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradual
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            Effects of teriparatide, alendronate, or both in women with postmenopausal osteoporosis.

            Teriparatide increases both bone formation and bone resorption. We sought to determine whether combining teriparatide with an antiresorptive agent would alter its anabolic action. This was a randomized controlled trial conducted in a single university hospital. We randomized 93 postmenopausal women with low bone mineral density (BMD) to alendronate 10 mg daily (group 1), teriparatide 40 microg sc daily (group 2), or both (group 3) for 30 months. Teriparatide was begun at month 6. BMD of the lumbar spine, proximal femur, proximal radius, and total body was measured by dual-energy x-ray absorptiometry (DXA) every 6 months. Lumbar spine trabecular BMD was measured at baseline and month 30 by quantitative computed tomography. Serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide levels were assessed frequently. Women who had at least one repeat DXA scan on therapy were included in the analyses (n = 69). DXA spine BMD increased more in women treated with teriparatide alone than with alendronate alone (18 +/- 11 vs. 7 +/- 4%; P < 0.001) or both (18+/-11 vs. 12 +/- 9%; P = 0.045). Similarly, femoral neck BMD increased more in women treated with teriparatide alone than with alendronate alone (11 +/- 5 vs. 4 +/- 4%; P < 0.001) or both (11 +/- 5 vs. 3 +/- 5%; P < 0.001). Quantitative computed tomography spine BMD increased 1 +/- 7, 61 +/- 31, and 24 +/- 24% in groups 1, 2, and 3 (P < 0.001 for all comparisons). Serum osteocalcin, N-terminal propeptide of type 1 collagen, and cross-linked N-telopeptides of type I collagen increased more with teriparatide alone than with both (P < 0.001 for each marker). Alendronate reduces the ability of teriparatide to increase BMD and bone turnover in women.
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              Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group.

              Estrogen-replacement therapy prevents osteoporosis in postmenopausal women by inhibiting bone resorption, but the balance between its long-term risks and benefits remains unclear. Whether other antiresorptive therapies can prevent osteoporosis in these women is also not clear. We studied the effect of 2.5 mg or 5 mg of alendronate per day or placebo on bone mineral density in 1174 postmenopausal women under 60 years of age. An additional 435 women who were prepared to receive a combination of estrogen and progestin were randomly assigned to one of the above treatments or open-label estrogen-progestin. The main outcome measure was the change in bone mineral density of the lumbar spine, hip, distal forearm, and total body measured annually for two years by dual-energy x-ray absorptiometry. The women who received placebo lost bone mineral density at all measured sites, whereas the women treated with 5 mg of alendronate daily had a mean (+/-SE) increase in bone mineral density of 3.5+/-0.2 percent at the lumbar spine, 1.9+/-0.1 percent at the hip, and 0.7+/-0.1 percent for the total body (all P<0.001). Women treated with 2.5 mg of alendronate daily had smaller increases in bone mineral density. Alendronate did not increase bone mineral density of the forearm, but it slowed the loss. The responses to estrogen-progestin were 1 to 2 percentage points greater than those to the 5-mg dose of alendronate. Alendronate was well tolerated, with a safety profile similar to that of placebo or estrogen-progestin. Alendronate prevents bone loss in postmenopausal women under 60 years of age to nearly the same extent as estrogen-progestin.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                11 July 2017
                : 11
                : 2109-2119
                Affiliations
                [1 ]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai
                [2 ]Department of Pharmacy, The General Hospital of Shenyang Military Region, Shenyang, People’s Republic of China
                Author notes
                Correspondence: Dafang Zhong, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201210, People’s Republic of China, Tel/fax +86 21 5080 0738, Email dfzhong@ 123456simm.ac.cn
                Article
                dddt-11-2109
                10.2147/DDDT.S138286
                5513855
                © 2017 Zhang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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