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PurposeIn women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO).MethodsWomen who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only.ResultsFive hundred fifty-eight women from ACTIVE’s ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan–Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group.ConclusionsEighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures.

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The oral bioavailabilities of the human immunodeficiency virus (HIV) protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) are low and/or variable, with limited penetration into the central nervous system (CNS) (18). Saquinavir mesylate was the first drug approved in this class. The two marketed saquinavir capsule formulations have mean oral bioavailabilities that range from 4 to 16% and are highly variable, as indicated by area under the concentrationtime curve (AUC) coefficients of variation that are Ն30% (11). Saquinavir's low and variable bioavailability is primarily attributed to metabolism by cytochrome P-450 3A4 (27). However, there is increasing understanding that membrane transporters contribute significantly to the biopharmaceutic characteristics of saquinavir and this entire class of drugs.To relate bioavailability to molecular transport characteristics, we, like many others, speculated that an efflux (countertransport) mechanism might contribute to the low and variable bioavailability of saquinavir and other HIV protease inhibitors. Saquinavir efflux (basolateral to apical [BL3AP] permeability Ͼ AP3BL permeability) and the inhibition of saquinavir efflux with verapamil hydrochloride, a substrate for multiple transporters and a nonspecific efflux inhibitor, were demonstrated with a Caco-2 cell model (3). In preliminary work, we demonstrated that saquinavir efflux from rat intestinal tissue is an active process (27). However, these studies did not specifically identify the transporter or transporters involved within these complex tissues. Since Caco-2 cells and rat intestinal tissue are known to express multiple transporters, the observed saquinavir transport behavior may be related to multiple transporters with multiple affinities.Recent studies have shown that the HIV protease inhibitors are substrates for the P glycoprotein (Pgp [ABCB1]) efflux pump and have demonstrated reduced saquinavir cytotoxicity due to saquinavir transport by Pgp (17). Saquinavir transport by Pgp has also been correlated with reduced bioavailability and CNS penetration (18). However, saquinavir transport by Pgp does not rule out saquinavir being a substrate for other putative membrane transporters. To this end, other investigators have demonstrated that saquinavir inhibits multidrug resistance-associated protein (MRP) family (MRP1 and MRP2)-mediated transport (15,20,24) and that a fluorescent saquinavir derivative is transported by MRP2 (14). Additionally, intracellular saquinavir concentrations were shown to be reduced in MRP1-expressing human lymphocytes relative to those in control cells (15,16).To determine if unmodified saquinavir is a substrate of human MRP1 (hMRP1 [ABCC1]) or the human canalicular multispecific organic anion transporter hMRP2 (cMOAT, or

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Abaloparatide-SC is a novel 34-amino acid peptide created to be a potent and selective activator of the parathyroid hormone receptor type 1 (PTHR1) signaling pathway. In the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) Phase 3 trial (NCT01343004), abaloparatide reduced new morphometric vertebral fractures by 86% compared with placebo (p < 0.001) and nonvertebral fractures by 43% (p ¼ 0.049) in postmenopausal women with osteoporosis. Abaloparatide-SC increased bone mineral density (BMD) 3.4% at the total hip, 2.9% at the femoral neck, and 9.2% at the lumbar spine at 18 months (all p < 0.001 versus placebo). The analysis reported here was designed to evaluate whether fracture risk reductions and BMD accrual were consistent across different levels of baseline risk. Risk factor subgroups were predefined categorically for BMD T-score of the lumbar spine, total hip, and femoral neck ( -2.5 versus >-2.5 and -3.0 versus >-3.0), history of nonvertebral fracture (yes versus no), prevalent vertebral fracture (yes versus no), and age (<65 versus 65 to <75 versus !75 years) at baseline. Forest plots show that there were no clinically meaningful interactions between any of the baseline risk factors and the treatment effect of abaloparatide-SC on new morphometric vertebral fractures, nonvertebral fractures, or BMD increases. Abaloparatide provides protection against fractures consistently across a wide variety of ages and baseline risks, including those with and without prior fractures, and it has potential utility for a broad group of postmenopausal women with osteoporosis.

clinicaltrials.gov Identifier: NCT01657162.

Background: Intracerebral hemorrhage (ICH) causes 10-15% of primary strokes, with mortality related to hematoma volume. Blood pressure (BP) reduction may attenuate hematoma expansion. ACCELERATE (the Evaluation of Patients with Acute Hypertension and Intracerebral Hemorrhage with Intravenous Clevidipine Treatment) is a pilot study representing the first evaluation of safety and efficacy of intravenous clevidipine for the rapid treatment of hypertension in ICH patients. Methods: ICH patients with a systolic BP (SBP) >160 mm Hg who present within 6 h (n = 27) or 12 h (n = 10) of symptoms were prospectively enrolled, treated with open-label clevidipine until SBP ≤160 mm Hg was achieved and then titrated to keep target SBP between 140-160 mm Hg. Results: A total of 35 patients with baseline median Glasgow Coma Scale score of 12, median NIH Stroke Scale score of 14, mean SBP of 186 mm Hg and a mean time from onset of symptoms of 5.5 h received clevidipine. Median time to achieve SBP target range was 5.5 min. All patients achieved target SBP within 30 min; 96.9% achieved target SBP with clevidipine monotherapy. CT scans showed minimal hematoma volume change for the overall population (median change 0.01 ml, -2.9%). Mild/moderate hypotension was reported in 3 patients and resolved with dose reduction or drug discontinuation. Conclusion: Clevidipine monotherapy was effective and safe for rapid BP reduction in this cohort of critically ill ICH patients. Overall, patients showed minimal hematoma expansion with BP reduction, suggesting that rapid BP control with clevidipine may have a beneficial impact on hematoma expansion and warrants further investigation.