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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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