The recently published results of the sequential treatment of postmenopausal osteoporotic women with subcutaneous abaloparatide (80 µg/day) (ABL) for 18 months followed by 6 months of oral alendronate (70 mg/week) (ALN) support the administration of an anti-resorptive agent after completion of a treatment course with an osteoanabolic agent. The ABL/ALN sequence resulted in greater bone mineral density gains at all skeletal sites and in a reduction of vertebral, non-vertebral, major and clinical fractures compared to what is observed after 18 months of placebo followed by 6 months of ALN. Whereas questions remained unanswered about the ideal anti-resorptive agent to be used after ABL, the optimal duration of the administration of the anti-resorptive drug or the potential interest of re-initiating a course of ABL after a limited administration of ALN, these results support the use of the ABL/ALN sequence in the management of postmenopausal osteoporosis. 相似文献
Introduction: Osteoporosis is a common skeletal disease with serious consequences due to osteoporotic fractures and high costs to society for post-fracture care. Most patients at high risk for fracture are not receiving care to reduce fracture risk. The osteoporosis treatment gap has reached crisis proportions. Strategies to reduce the treatment gap include systematic methods for identifying and treating high risk patients, better education of patients and healthcare providers, better use of currently available drugs, and development of new drugs to treat osteoporosis.
Areas covered: Two osteoanabolic agents with novel mechanisms of action have recently completed phase 3 clinical trials. The efficacy and safety findings of these studies are reviewed. Abaloparatide, a synthetic analog of parathyroid hormone-related protein, has received regulatory approval for the treatment of postmenopausal women with osteoporosis at high risk for fracture. Romosozumab, a humanized monoclonal antibody to sclerostin, an endogenous inhibitor of bone formation, is under regulatory review.
Expert opinion: Osteoanabolic therapy for osteoporosis can restore, at least in part, the degradation of bone microarchitecture that is a hallmark of this disease. The emergence of new osteoanabolic compounds expands the treatment options for patients at high risk for fracture. 相似文献
The recently published Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) assessed the efficacy and safety of abaloparatide (80 µg daily subcutaneous) (ABL) vs placebo during 18 months, in postmenopausal osteoporosis. Teriparatide (20 µg daily subcutaneous) (TPD) was used as an open label active comparator. The results of the study suggest that ABL increases bone mineral density more than TPD and reduces major osteoporotic fractures to a greater extent than TPD with a more rapid onset of action. These outcomes combined with a positive safety profile make ABL an interesting addition to the armamentarium against postmenopausal osteoporosis. 相似文献
Introduction: Osteoporosis is a skeletal disorder characterized by loss of bone mass and strength affecting up to 30–50% of postmenopausal women worldwide. Current therapeutic options include antiresorptives such as aminobisphosphonates or denosumab and osteoanabolic compounds such as teriparatide.
Areas covered: In this review, the authors summarize the clinical development, safety and efficacy profile of abaloparatide, a new osteoanabolic agent recently marketed in the US for the treatment of postmenopausal osteoporosis in women who are at high risk for fracture or who fail antiresorptive therapy.
Expert opinion: Abaloparatide is a 1-34 PTH related peptide-like molecule that has been modified in order to potentiate the osteoanabolic effect. In its pivotal phase 3 trial in postmenopausal women with osteoporosis, subcutaneous abaloparatide 80 mcg/day reduced the risk of vertebral, nonvertebral, major osteoporotic, and clinical fractures compared with placebo and reduced the risk of major osteoporotic fractures compared with teriparatide. These results, together with a reduced prevalence of hypercalcemia and a lower cost of the marketed compound, point toward improved cost effectiveness with abaloparatide versus teriparatide. However, some concerns have been raised due to a somewhat higher occurrence of adverse effects (particularly with palpitations and increased heart rate) or the resultant discontinuation due to these adverse effects when compared to teriparatide. 相似文献
To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis).
Patients and Methods
ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients.
Results
Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95%?CI, 0.04-0.41; P<.001). Kaplan-Meier estimated rates of nonvertebral fractures were PBO/ALN, 5.6% vs ABL-SC/ALN, 2.7%; risk reduction, 52% (hazard ratio [HR], 0.48; 95%?CI, 0.26-0.89; log-rank P=.02). There was also a 58% risk reduction of major osteoporotic fractures (HR, 0.42; 95%?CI, 0.21-0.85; log-rank P=.01) and a 45% risk reduction of clinical fractures (HR, 0.55; 95%?CI, 0.33-0.92; log-rank P=.02) in the ABL-SC/ALN group vs the PBO/ALN group. At 25 months, bone mineral density percentage change from ACTIVE baseline for ABL-SC/ALN vs PBO/ALN was as follows: lumbar spine, 12.8%; total hip, 5.5%; femoral neck, 4.5% vs 3.5%, 1.4%, 0.5%, respectively (group differences at all sites P<.001).
Conclusion
Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis.
Introduction: Teriparatide, a PTH analogue, was the first anabolic agent to be approved for the treatment of osteoporosis in 2002. Abaloparatide was also recently approved by the FDA. The need for other anabolic agents is still unmet.
Areas covered: In this review, we discuss target molecules and recent advances in the field of anabolic therapy for osteoporosis. PTH and PTHrP analogues binding to the PTH receptor and different routes of administration of teriparatide to avoid the burden of daily subcutaneous injections are discussed. We also review antibodies targeting suppressors of the Wnt pathway such as sclerostin and Dickopff-1.
Expert opinion: The development of alternative ways of administering PTH receptor ligands is a promising field, especially via the transdermal route. Other more promising molecules are still at very early stages of development. FDA recently requested more data on Romosozumab. 相似文献
Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1–34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1–34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1–34) treated rats. Comparing the effects of abaloparatide and hPTH(1–34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1–34) at similar exposure. 相似文献