Abaloparatide Research Articles

Anti-sclerostin antibodies and abaloparatide have additive effects when used as a countermeasure against disuse osteopenia in female rats.

Prolonged disuse and substantial mechanical unloading are particularly damaging to skeletal integrity. Preclinical studies in rodents and clinical studies have highlighted the need for potent bone anabolic drugs to counteract disuse-induced osteopenia. The aim of present study was to compare the efficacy of romosozumab (Scl-Ab) and abaloparatide (ABL), alone or in combination, to prevent botulinum toxin (BTX) induced bone loss in a rat model. Eighty female Wistar rats were divided into the following six groups: 1. Baseline (n=12); 2. Control (Ctrl) (n=12); 3. BTX (n=12); 4. BTX+Scl-Ab (n=16); 5. BTX+ABL (n=12); and 6. BTX+Scl-Ab + ABL (n=16). Disuse was achieved by injecting 4IU BTX into the hind limb musculature at study start. Scl-Ab (25mg/kg) was injected s.c. twice weekly, while ABL (80μg/kg) was injected s.c. five days a week for four weeks. Hind limb disuse dramatically decreased muscle mass and skeletal integrity and deteriorated the cortical morphology and trabecular microstructure. Treatment with Scl-Ab alone prevented most of the adverse cortical and trabecular effects of disuse, while ABL monotherapy mainly attenuated the disuse-induced loss of femoral areal bone mineral density (aBMD). Moreover, the combination of Scl-Ab and ABL not only counteracted most of the negative skeletal effects of unloading, but also increased aBMD (+10% and +20%), epiphyseal trabecular bone volume fraction (BV/TV) (+25% and +73%), and metaphyseal bone strength (+18% and +30%) significantly above that of Scl-Ab or ABL monotherapy, respectively. The potent and additive osteoanabolic effect of Scl-Ab and ABL, when given in combination, is highly intriguing and underlines that an osteoanabolic bone gain can be maximized by utilizing two pharmaceuticals targeting different cellular signaling pathways. From a clinical perspective, a combination treatment may be warranted in patients where the osteoanabolic effect of either monotherapy is not sufficient, or if a dose-reduction is required due to adverse effects.

Abstract #1164092: Efficacy and Safety of Abaloparatide in Men with Osteoporosis

Osteoporosis in men is an important, but underappreciated, public health problem. In the Phase 3 ACTIVE study in postmenopausal women with osteoporosis, abaloparatide (ABL) significantly increased bone mineral density (BMD), and decreased risk of vertebral, nonvertebral, and clinical fractures vs placebo (PBO), and major osteoporotic fracture vs teriparatide and PBO. The Abaloparatide for the Treatment of Men with Osteoporosis (ATOM) randomized, double-blind, placebo-controlled, phase 3 study evaluated efficacy and safety of ABL vs PBO for osteoporosis treatment in men.

Abaloparatide Improves Rotator Cuff Healing via Anabolic Effects on Bone Remodeling in a Chronic Rotator Cuff Tear Model of Rat With Osteoporosis: A Comparison With Denosumab

Background: Because of poor clinical outcomes, rotator cuff healing in patients with osteoporosis has recently gained attention. Antiresorptive therapy for osteoporosis has been reported to improve healing after repair. However, the comparative effectiveness of anabolic and antiresorptive agents has not been investigated. Hypothesis: Anabolic therapy with abaloparatide (ABL) would outperform antiresorptive therapy with denosumab (Dmab) to improve rotator cuff healing in the osteoporotic status. Study Design: Controlled laboratory study. Methods: A chronic rotator cuff tear model was established in ovariectomy-induced postmenopausal osteoporotic rats. Then, bilateral rotator cuff repairs were conducted in all experimental rats, which were randomly divided into control (CON), Dmab, and ABL groups to receive the corresponding subcutaneous injections. The rats sacrificed at 2 weeks (the early healing period) were used to detect osteoblast and osteoclast activities, related gene expression (osteoclastogenesis, osteogenesis, and chondrogenesis), new bone formation, and mineralization. In the rats sacrificed at 4 and 8 weeks, the bone mineral density and bone architecture at the repaired site were assessed by micro–computed tomography, and rotator cuff healing was evaluated using histological and biomechanical analyses. Results: At 8 weeks, significantly higher failure load and stiffness were observed in the ABL (25.13 ± 3.54 N, P < .001; 21.65 ± 3.08 N/mm, P < .001; respectively), and Dmab (21.21 ± 2.55 N, P < .001; 16.15 ± 2.07 N/mm, P = .008; respectively) groups than in the CON group (13.36 ± 1.70 N; 11.20 ± 2.59 N/mm; respectively), whereas the ABL treatment provided better failure load and stiffness than Dmab (P = .019; P = .003). Although tendon-to-bone healing was improved by Dmab, the most mature tendon insertion at the interface was observed in the ABL group, including a more organized collagen and fibrocartilage and higher bone quality. ABL significantly promoted bone remodeling via coupling between osteoclasts and osteoblasts (osteoblast to osteoclast ratio: 4.80 ± 0.39; P = .022), thereby stimulating more new bone formation and mineralization at the tendon-to-bone healing interface than Dmab (osteoblast to osteoclast ratio: 3.21 ± 0.75) at 2 weeks. Moreover, ABL had significant effects on gene expression [Runt-realted transcription factor 2 (Runx2, collagen type I-alpha 1 (Col1A1]), and sclerostin for osteogenesis; aggrecan and collagen type II (Col2) for chondrogenesis] in mineralized tissues, indicative of enhanced bone and fibrocartilage formation when compared with the CON and Dmab groups. Conclusion: ABL promoted rotator cuff healing in osteoporotic rats by significantly increasing the mineralized tissue quality and collagen maturity at the reattachment site, leading to improved biomechanical properties, and was superior to Dmab in both biomechanical and histological analyses. Clinical Relevance: Anabolic therapy with ABL may outperform antiresorptive therapy with Dmab in improving outcomes after rotator cuff repair in osteoporotic patients.

302 Abaloparatide as a novel therapy for posttraumatic osteoarthritis

OBJECTIVES/GOALS: Osteoarthritis (OA) is a cartilage destroying disease. We are investigating abaloparatide (ABL) activation of parathyroid hormone receptor type 1 (PTH1R), which is expressed by articular chondrocytes in OA. We propose ABL treatment is chondroprotective in murine PTOA via stimulation of matrix production and inhibition of chondrocyte maturation. METHODS/STUDY POPULATION: 16-week-old C57BL/6 male mice received destabilization of the medial meniscus (DMM) surgery to induce knee PTOA. Beginning 2 weeks post-DMM, 40 μg/kg of ABL (or saline) was administered daily via subcutaneous injection and tissues were harvested after 6 weeks of daily injections and 8 weeks after DMM surgery. Harvested joint tissues were used for histological and molecular assessment of OA using three 5 μm thick sagittal sections from each joint, 50 μm apart, cut from the medial compartment of injured knees. Safranin O/Fast Green tissue staining and immunohistochemistry-based detection of type 10 collagen (Col10) and lubricin (Prg4) was performed using standard methods. Histomorphometric quantification of tibial cartilage area and larger hypertrophic-like cells was performed using the Osteomeasure system. RESULTS/ANTICIPATED RESULTS: Safranin O/Fast Green stained sections showed a decreased cartilage loss in DMM joints from ABL-treated versus saline-treated mice. Histomorphometric analysis of total tibial cartilage area revealed preservation of cartilage tissue on the tibial surface. Immunohistochemical analyses showed that upregulation of Col10 in DMM joints was mitigated in the cartilage of ABL-treated mice, and chondrocyte expression of Prg4 was increased in uncalcified cartilage areas in ABL-treated group. The Prg4 finding suggests a matrix anabolic effect that may counter OA cartilage loss. Quantification of chondrocytes in uncalcified and calcified tibial cartilage areas revealed a reduction in the number of larger hypertrophic-like cells in ABL treated mice, suggesting deceleration of hypertrophic differentiation. DISCUSSION/SIGNIFICANCE: Cartilage preservation/regeneration therapies would fill a critical unmet need. We demonstrate that an osteoporosis drug targeting PTH1R decelerates PTOA in mice. ABL treatment was associated with preservation of cartilage, decreased Col10, increased Prg4, and decreased number of large hypertrophic-like chondrocytes in the tibial cartilage.

ABALOPARATIDE SUPPORTS CHONDROPROTECTION IN MURINE POSTTRAUMATIC OSTEOARTHRITIS

Purpose: Osteoarthritis (OA) is a painful and disabling disease involving the degeneration of diarthrodial joints, with a hallmark feature of cartilage loss. Currently, there are no approved treatments that can protect or regenerate damaged cartilage. Our lab has investigated activation of the parathyroid hormone receptor type 1 (PTH1R), which is expressed by articular chondrocytes in the setting of OA, with abaloparatide (ABL), a bone anabolic agent FDA-approved for treatment of osteoporosis for postmenopausal women with increased fracture risk.

Proximal Femur Responses to Sequential Therapy With Abaloparatide Followed by Alendronate in Postmenopausal Women With Osteoporosis by 3D Modeling of Hip Dual-Energy X-Ray Absorptiometry (DXA).

ABSTRACTPrevious subgroup analyses from the ACTIVE trial in women with postmenopausal osteoporosis (NCT01343004) using three‐dimensional (3D)‐processing of dual X‐ray absorptiometry (DXA) scans indicated greater increases in total hip cortical volumetric bone mineral density (Ct.vBMD) and estimated indices of hip strength following 18 months of abaloparatide (ABL) versus placebo or teriparatide. The current post hoc analyses describe hip 3D‐DXA data for ACTIVExtend (NCT01657162), in which 18 months of ABL followed by 24 months of alendronate (ABL/ALN) increased hip and spine areal BMD (aBMD) and reduced fracture risk versus placebo (PBO) followed by ALN (PBO/ALN). In an ACTIVExtend subgroup (ABL/ALN, n = 204; PBO/ALN, n = 202), hip DXA scans retrospectively underwent 3D modeling via 3D‐Shaper software. Changes from baseline in cortical and trabecular compartments were calculated for total hip and hip subregions (femoral neck, trochanter, and shaft). Estimated strength indices comprising cross‐sectional moment of inertia, section modulus, and buckling ratio were calculated for each hip subregion. Correlations between bone turnover marker levels at the time of alendronate initiation and subsequent BMD gains with alendronate were also investigated within each group. Total hip trabecular and cortical 3D‐DXA parameters increased from baseline in both groups (all p < 0.001), with greater average increases for ABL/ALN versus PBO/ALN (trabecular vBMD: 10.87% versus 4.3%; cortical thickness: 2.32% versus 1.14%; Ct.vBMD: 3.41% versus 1.86%; cortical surface BMD: 5.82% versus 3.0%; all p < 0.001). Strength indices in the ABL/ALN group improved in all subregions versus baseline (all p < 0.0001) and versus PBO/ALN (all p < 0.02). In the ABL/ALN group, collagen type I N‐terminal propeptide (P1NP) levels at the time of alendronate initiation correlated with subsequent percent changes in all 3D‐DXA parameters with 24 months of alendronate therapy. In conclusion, sequential ABL/ALN or PBO/ALN treatment improves trabecular and cortical 3D‐DXA parameters at the hip, as well as strength indices of hip subregions, with greater increases with ABL/ALN versus PBO/ALN. © 2022 Radius Health, Inc. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Importance of Time Point–Specific Indirect Treatment Comparisons of Osteoporosis Treatments: A Systematic Literature Review and Network Meta-Analyses

PurposeThe efficacy comparison of osteoporosis treatments can be hindered by the absence of head-to-head trials; instead, network meta-analyses (NMAs) have been used to determine comparative effectiveness. This study was the first to investigate the impact of time point–specific NMAs of osteoporosis treatments on variability in treatments’ onset of action caused by their different mechanisms of actions and trial designs. MethodsA systematic literature review was conducted to identify randomized controlled trials (RCTs) of treatments for postmenopausal women with osteoporosis, including romosozumab (ROMO), teriparatide (TPTD), abaloparatide (ABL), alendronate (ALN), risedronate (RIS), ibandronate (IB), zoledronic acid/zoledronate (ZOL), denosumab (DEN), and raloxifene (RLX), on at least 1 fracture or bone mineral density (BMD) outcome. Of 100 RCTs identified in 5 databases, 27 RCTs were included for NMAs of new vertebral, nonvertebral, and hip fracture outcomes at 12, 24, and 36 months, and 47 RCTs were included for NMAs of BMD outcomes at lumbar spine, total hip, and femoral neck to compare the relative efficacy of osteoporosis treatments. Quality of included studies was assessed using the Cochrane Risk of Bias tool. FindingsFor vertebral fractures, TPTD (83.63%), ABL (69.11%), and ROMO/ALN (78.70%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO/ALN had the highest probability (54.4%, 64.69%, and 90.29%, respectively) to be the most effective treatment for nonvertebral fractures at 12, 24, and 36 months. For hip fractures, ROMO/ALN (46.31%), ABL (61.1%), and DEN (55.21%) had the highest probability to be the most effective treatment at 12, 24, and 36 months, respectively. ROMO had the highest probability (76.06%, 44.19%, and 51.78%, respectively) to be the most effective treatment for BMD outcomes at lumbar spine, total hip, and femoral neck. ImplicationsThe importance of indirectly comparing available osteoporosis treatments using time point–specific NMAs was confirmed because indirect comparison results differed substantially across time points.

Short-term glucocorticoid excess blunts abaloparatide-induced increase in femoral bone mass and strength in mice

Glucocorticoids (GCs), such as prednisolone, are widely used to treat inflammatory diseases. Continuously long-term or high dose treatment with GCs is one of the most common causes of secondary osteoporosis and is associated with sarcopenia and increased risk of debilitating osteoporotic fragility fractures. Abaloparatide (ABL) is a potent parathyroid hormone-related peptide analog, which can increase bone mineral density (aBMD), improve trabecular microarchitecture, and increase bone strength. The present study aimed to investigate whether GC excess blunts the osteoanabolic effect of ABL. Sixty 12–13-week-old female RjOrl:SWISS mice were allocated to the following groups: Baseline, Control, ABL, GC, and GC + ABL. ABL was administered as subcutaneous injections (100 μg/kg), while GC was delivered by subcutaneous implantation of a 60-days slow-release prednisolone-pellet (10 mg). The study lasted four weeks. GC induced a substantial reduction in muscle mass, trabecular mineral apposition rate (MAR) and bone formation rate (BFR/BS), and endocortical MAR compared with Control, but did not alter the trabecular microarchitecture or bone strength. In mice not receiving GC, ABL increased aBMD, bone mineral content (BMC), cortical and trabecular microarchitecture, mineralizing surface (MS/BS), MAR, BFR/BS, and bone strength compared with Control. However, when administered concomitantly with GC, the osteoanabolic effect of ABL on BMC, cortical morphology, and cortical bone strength was blunted. In conclusion, at cortical bone sites, the osteoanabolic effect of ABL is generally blunted by short-term GC excess.

Abaloparatide Real-World Patient Experience Study.

ABSTRACTDespite the availability of various osteoporosis treatments, adherence remains suboptimal. One contributing factor may be patient experience with therapy. This US, multicenter, combined retrospective chart review and patient questionnaire study included postmenopausal women at high risk for fracture and is the first study to describe real‐world patient experience with abaloparatide (ABL) injection. Eight geographically diverse secondary care sites in the United States participated (n = 193). Mean ± SD age was 67.4 ±8.62 years. Most patients (86%) were satisfied with the ABL regimen, especially with ease of preparation (82%), ease of storage (87%), and storage convenience (89%), an attribute 83% of the patients thought was important. The majority of patients reported complete satisfaction with the ABL regimen allowing for their ability to conduct daily activities (85%) and convenience to fit into their daily schedule (84%). All reported taking ABL as directed, by injection in the lower abdomen, and 83% of patients reported medium or high adherence. Patients were satisfied with the needle size (76% completely satisfied), and 93% reported never deliberately missing a dose. Although injecting medication (18%) and higher out‐of‐pocket costs (17%) were deemed the most bothersome attributes, the majority (69%) noted their healthcare team understands how osteoporosis impacts their lives. In multivariable analyses, ease of preparation (OR = 2.62; 95% CI, 1.01–6.81; p = 0.048) and fracture history (OR = 1.72; 95% CI, 1.03–2.86; p = 0.037) were significantly associated with overall satisfaction. Ease of preparation was a predictor of higher satisfaction with treatment convenience (coefficient = 13.60; 95% CI, 8.08–19.12; p = 0.00). Remembering to take the medication was a significant predictor of self‐reported adherence (OR = 16.66; 95% CI, 3.30–84.24; p = 0.001). In conclusion, the majority of patients were satisfied with ABL and found it convenient/easy to prepare and store. High self‐reported adherence may be associated with positive patient experience including ease of use and adequate support from healthcare providers. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Differential effects of abaloparatide and teriparatide on hip cortical volumetric BMD by DXA-based 3D modeling

SummaryIn postmenopausal osteoporotic women in ACTIVE, abaloparatide reduced fracture risk and increased areal bone mineral density (BMD) more than teriparatide at the hip and wrist. DXA-based 3D modeling showed significantly greater increases in hip cortical volumetric BMD with abaloparatide versus teriparatide. This may explain differences reported in aBMD by DXA.IntroductionIn ACTIVE, abaloparatide (ABL) increased bone mineral density (BMD) shown by dual-energy X-ray absorptiometry (DXA) while reducing fracture incidence in postmenopausal osteoporotic women. Changes in DXA BMD with ABL, 80 μg, were significantly greater than with open-label teriparatide (TPTD), 20 μg, at cortical sites including total hip, femoral neck, and 1/3 distal radius. The purpose of this study was to better understand the relative effects of ABL and TPTD on cortical and cancellous compartments in the proximal femur.MethodsHip DXA images from a subset of randomly selected patients in the ACTIVE trial (n = 250/arm) were retrospectively analyzed using three-dimensional modeling methods (3D-SHAPER software) to evaluate changes from baseline at months 6 and 18.ResultsSimilar significant increases in trabecular volumetric BMD (vBMD, + 9%) and cortical thickness (+ 1.5%) were observed with ABL and TPTD by 3D-DXA at 18 months. In contrast, only ABL significantly increased cortical vBMD versus baseline (+ 1.3%), and changes in both cortical vBMD and cortical surface BMD were significantly greater with ABL versus TPTD. In the TPTD group, changes in cortical vBMD were inversely correlated with changes in serum CTX (carboxy-terminal telopeptide of type I collagen) and PINP (procollagen type I N-terminal propeptide), suggesting that higher bone turnover may have attenuated cortical gains.ConclusionThese results suggest previously reported differences in areal BMD increases between ABL and TPTD may be due to differential effects on cortical vBMD. Further studies are warranted to investigate how these differences affect therapeutic impact on hip strength in postmenopausal women with osteoporosis.

Abaloparatide treatment increases bone formation, bone density and bone strength without increasing bone resorption in a rat model of hindlimb unloading.

Disuse osteoporosis can result from prolonged bed rest, paralysis, casts, braces, fractures and other conditions. Abaloparatide (ABL) is a PTHrP analog that increases bone density and strength by stimulating osteogenesis with limited effects on bone resorption. We examined skeletal responses to abaloparatide in young adult male rats with normal weight-bearing and with hindlimb unloading via a pelvic harness. Rats were allocated to four groups (10-12 per group): normal weight-bearing plus vehicle treatment (CON-VEH), normal weight-bearing plus ABL treatment (CON-ABL), hindlimb-unloading plus vehicle (HLU-VEH), or hindlimb-unloading plus ABL (HLU-ABL). Rats received ABL (25μg/kg/day, s.c.) or vehicle throughout the 28-day unloading period and were then sacrificed, at which time HLU-VEH rats exhibited reduced bone formation and significant deficits in tibial, femoral, and vertebral bone mass compared with CON-VEH. ABL treatment increased serum osteocalcin in CON and HLU animals while having no effect on the osteoclast marker TRACP-5b. Longitudinal peripheral quantitative computed tomography (pQCT) indicated that ABL increased trabecular and cortical bone mass in the tibia. ABL was also associated with improved trabecular and cortical bone mass and architectural parameters at the femur, tibia, and vertebrae by μCT. Tibial histomorphometry indicated increased trabecular and endocortical bone formation with HLU-ABL versus HLU-VEH and with CON-ABL versus CON-VEH, and ABL was also associated with lower trabecular and endocortical osteoclast surfaces. Vertebral finite element analysis indicated higher ultimate load and stiffness for CON-ABL versus CON-VEH and for HLU-ABL versus HLU-VEH. In summary, ABL was associated with improved trabecular and cortical bone density and architecture in normal weight-bearing and hindlimb-unloaded rats, with higher bone formation and no difference in bone resorption. ABL was also associated with improved bone biomechanical parameters. These results provide rationale for investigating the ability of abaloparatide to prevent or treat disuse osteoporosis in humans.

Frequent administration of abaloparatide shows greater gains in bone anabolic window and bone mineral density in mice: A comparison with teriparatide.

Abaloparatide (ABL) is a novel 34-amino acid peptide analog of parathyroid hormone-related protein. In clinical studies, although ABL showed a greater bone mineral density (BMD) increase than teriparatide (TPTD, human parathyroid hormone 1-34), the responses of ABL to bone formation and resorption markers were weaker, making it difficult to understand the relationship between the bone anabolic window (increase in bone formation versus resorption) and bone mass. In the present study, the effects of ABL and TPTD were compared in mice. Given that the rate of bone turnover is higher in rodents than in humans, the comparison was made with several administration regimens providing equivalent daily dosages: once daily (QD, 30μg/kg every 24h), twice daily (BID, 15μg/kg every 12h), or three times a day (TID, 10μg/kg every 8h). Frequent administration of ABL showed higher BMD with enhancement of trabecular and cortical bone mass and structures than that of TPTD, consistent with the clinical results seen with once daily administration. ABL increased bone formation marker levels more than TPTD with more frequent regimens, while bone resorption marker levels were not different between ABL and TPTD in all regimens. Analysis of bone histomorphometry and gene expression also suggested that ABL increased bone formation more than TPTD, while the effect on bone resorption was almost comparable between ABL and TPTD. The bone anabolic windows calculated from bone turnover markers indicated that ABL enhanced the anabolic windows more than TPTD, leading to a robust increase in BMD. The mechanism by which ABL showed a better balance of bone turnover was suggested to be partly due to the enhanced remodeling-based bone formation involved in Ephb4. Taken together, our findings would help elucidate the mechanism by which ABL shows excellent BMD gain and reduction of fractures in patients with osteoporosis.

Characterizing patients initiating abaloparatide, teriparatide, or denosumab in a real-world setting: a US linked claims and EMR database analysis

SummaryWe characterized patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) in a real-world clinical setting from a large medical and pharmacy claims database. Differences were noted in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use for patients initiating ABL and TPTD compared with those receiving DMAB.IntroductionTo characterize patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) treatment in a real-world clinical setting.MethodsPatients aged ≥ 18 years initiating ABL, TPTD, or DMAB between May 1, 2017, and September 24, 2018 (without receiving the same drug in the previous 12 months), were identified using the OM1 Data Cloud, which contains medical and pharmacy claims from approximately 200 million US patients. The index date was the date of initial prescription or dispensing for ABL, TPTD, or DMAB during the study period.ResultsDuring the study period, 2666 patients initiated ABL, 9210 TPTD, and 116,718 DMAB. Mean age (standard deviation) was 69.2 (10.6) years for the ABL cohort, 68.6 (11.3) for TPTD, and 72.1 (10.2) for DMAB (P < 0.001; ABL vs DMAB). Proportionally more patients initiating ABL were female (95.2% ABL, 86.9% TPTD, and 91.3% DMAB, P < 0.001 ABL vs TPTD or DMAB). Nearly twice as many patients initiating ABL (19.1%) and TPTD (18.8%) had a previous pathologic/fragility fracture vs DMAB (9.6%; P < 0.001 ABL vs DMAB). Fewer patients initiating ABL (36.3%) or TPTD (39.7%) had Charlson comorbidity index of ≥ 2 vs DMAB (48.4%; P < 0.001 ABL vs DMAB). Before initiating ABL, TPTD, or DMAB, 44.3%, 33.8%, and 33.9% of patients had prior osteoporosis treatment, respectively. Bisphosphonate use was more common before initiating ABL (19.2%) or TPTD (19.6%), than before initiating DMAB (16.6%; P < 0.001 ABL vs DMAB).ConclusionsPatients initiating ABL and TPTD differed in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use compared with those initiating DMAB.

SUN-335 Abaloparatide Prevents Unloading-Induced Bone Loss in Adult Rats

Disuse osteoporosis (bone loss resulted from a reduction in mechanical loading) occurs in patients due to prolonged bed rest, paralysis and application of braces. Abaloparatide (ABL) is a synthetic peptide analog of PTHrP that has been shown to promote bone formation with limited bone resorption. ABL was approved by the FDA in 2017 to treat osteoporosis in postmenopausal women at high fracture risk. Yet, the ability of ABL to prevent bone loss in disuse is unknown. We hypothesized that ABL would prevent bone loss in the hindlimb unloading (HLU) rat model of disuse osteoporosis.Adult male Wistar rats, 13–14 weeks of age, were assigned to 1 of 4 groups (10 rats/group): ambulatory + vehicle (CON-VEH), ambulatory + ABL (CON-ABL), HLU + vehicle (HLU-VEH) or HLU + ABL (HLU-ABL). The rats received a daily subcutaneous injection of ABL (25µg/kg/day) or vehicle for 28 days. Blood serum was collected on day 0, 7, 14 and 28 to examine the expression of bone markers such as osteocalcin (OCN) and TRAcP5b. pQCT scans were acquired at the proximal tibia at day 0 and 28 to measure changes in the total and trabecular vBMD. Following euthanasia, trabecular (Tb) and cortical (Ct) bone microarchitecture from femurs, tibias and L4 vertebrae were assessed using µCT. Femurs were mechanically tested to failure in 3-point bending to determine ultimate load (N) and stiffness (N/mm). Treatment effects were evaluated using 2-way ANOVA. Effects were considered significant at p < 0.05. Data reported as mean±SD.HLU led to loss of bone density and structure that were prevented by ABL. Longitudinal pQCT revealed significant increases in total vBMD in ABL-CON (52±17%) vs. VEH-CON (20±5%); and in HLU-ABL (24±6%) vs. HLU-VEH (-2±3%) (p<0.001 for both). Significant differences were observed in the µCT analysis of the distal femur: Tb.BV/TV, thickness and BMD were 43.7%, 12.9% and 27.4% lower, respectively, in HLU-VEH compared to CON-VEH (p<0.05 for all). ABL prevented these negative effects, such that Tb.BV/TV, thickness and BMD were 66.5%, 39% and 50.3% higher in HLU-ABL compared to HLU-VEH (p<0.01 for all). A positive impact of ABL on bone morphology was also seen in the CON-VEH rats. CON-ABL had greater femoral stiffness (+22.9%, p=0.03) and ultimate load (+20.5%, p=0.01) than CON-VEH. Vertebral and tibial trabecular parameters mimicked the distal femur parameters. Serum TRAcP5b did not differ among groups, yet both ABL groups had higher OCN levels than the VEH-treated control groups (+63%, p<0.05).We demonstrated positive effects of ABL on BMD, trabecular bone mass and structure in both ambulating and unloaded rats. These results are consistent with prior studies showing positive effects of ABL on bone mass, structure and strength in OVX and ORX rats. Limits include only male rats and 1 dose of ABL. However, the results observed in this study provide a strong rationale for investigating the ability of ABL to prevent disuse bone loss in humans.

PMS89 A REAL-WORLD STUDY OF THE PATIENT EXPERIENCE WITH ABALOPARATIDE

In addition to clinical outcomes reported in randomized controlled trials, real-world patient experience with osteoporosis (OP) is critical for evaluating disease management. Herein we describe the experience of patients who have initiated treatment with abaloparatide (ABL) injection.

Cost-effectiveness of sequential treatment with abaloparatide followed by alendronate vs. alendronate monotherapy in women at increased risk of fracture: A US payer perspective

ObjectivesEmerging evidence supports sequential therapy with anabolic followed by antiresorptive in patients at high-risk of fragility fractures. This study assessed the cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) [(ABL/ALN)] compared to ALN monotherapy and to sequential treatment starting with antiresorptive therapy (ALN/ABL/ALN). MethodsA previously validated Markov microsimulation model was used to estimate the cost-effectiveness of sequential ABL/ALN compared to ALN monotherapy and to sequential ALN/ABL/ALN from a lifetime US payer perspective. In line with practice guidelines, patients were assumed to receive ABL for 18 months followed by 5 years of ALN, or ALN monotherapy for 5 years, or a sequence of ALN for 2 years followed by 18 months of ABL and then by 3 years ALN. Evaluation was conducted for patients aged 50–80 years old with a BMD T-score ≤-3.5 and without a history of prior fracture, or with a T-score between -2.5 and -3.5 and a history of ≥ 1 osteoporotic fracture. ResultsSequential ABL/ALN was cost-effective (threshold of US$150,000 per QALY) vs generic ALN monotherapy in women ≥60 years with a BMD T-score ≤−3.5 and in women with BMD T-score between −2.5 and −3.5 and history of osteoporotic fracture. In all simulated populations, sequential ABL/ALN therapy was dominant (lower costs, more QALYs) compared with sequential ALN/ABL/ALN, resulting from limited effect of ABL in patients previously treated with an antiresorptive agent. ConclusionsSequential ABL/ALN therapy is cost-effective vs ALN monotherapy for US postmenopausal women aged ≥60 years at increased risk of fractures.

PMS26 COST-EFFECTIVENESS OF SEQUENTIAL TREATMENT WITH ABALOPARATIDE FOLLOWED BY ALENDRONATE VS ALENDRONATE MONOTHERAPY FOR THE PREVENTION OF FRACTURES IN POSTMENOPAUSAL US WOMEN AT INCREASED RISK OF FRACTURE

Emerging evidence supports sequential therapy with osteoanabolic followed by antiresorptive in patients at high-risk of fragility fractures. Further cost-effectiveness evaluation of sequential abaloparatide (ABL) followed by alendronate (ALN) vs ALN monotherapy is needed to inform prescribers about the economic value of anabolic first for those at high risk of fracture. This study aims to assess the cost-effectiveness of sequential ABL followed by ALN (ABL/ALN) vs ALN monotherapy for postmenopausal osteoporosis, from the US payer perspective. A Markov microsimulation model was developed to estimate the cost-effectiveness of sequential ABL/ALN vs ALN with a lifetime horizon from the US payer perspective. Patients were assumed to receive 18 months ABL followed by 5 years ALN. The effects of ABL on fracture risk were derived from the ACTIVExtend trial and were assumed to be maintained during subsequent ALN treatment, consistent with ACTIVExtend. Evaluation was completed for high-risk patients 50-80 years old with a BMD T-score ≤-3.5 or BMD T-score between -2.5 and -3.5 and a history of ≥1 osteoporotic fracture. Sensitivity analyses were performed to test the robustness of the model results. In simulated populations, sequential ABL/ALN was cost-effective (threshold of $150,000/QALYs) vs generic ALN monotherapy, in women ≥60 years with a BMD T-score ≤-3.5 without a history of prior fracture and in women with BMD T-score between -2.5 and -3.5 and history of osteoporotic fracture. In patients aged 70 years with BMD T-score ≤-3.5, sequential ABL/ALN reduced the expected number of fractures per patient by 0.340 and increased lifetime QALY gained by 0.163 over a patient’s lifetime. Probabilistic sensitivity analyses suggested ABL/ALN was cost-effective in 65.5%, 96% and 92.5% of simulations at the ages of 60, 70 and 80 years, respectively. Sequential ABL/ALN therapy is cost-effective vs ALN monotherapy for US postmenopausal women at increased risk of fractures.

SAT-519 Effect of Abaloparatide on Bone Mineral Density and Fracture Incidence in a Subset of Younger Postmenopausal Women with Osteoporosis at High Risk for Fracture Representative of Covered Commercial Insurance Enrollees

Abaloparatide (ABL) is a novel, selective activator of the PTH1 receptor signaling pathway. In the 18-month Phase 3 ACTIVE study in women with postmenopausal osteoporosis (NCT01343004), ABL significantly increased bone mineral density (BMD), and decreased the risk of vertebral (VF), nonvertebral (NVF), and clinical fractures vs placebo (PBO), and major osteoporotic fractures vs PBO and teriparatide (TPTD). The objective of this post hoc analysis was to evaluate the efficacy of ABL in a subset of women representative of commercial insurance enrollees considered to be at high risk for fracture and meeting potential criteria for coverage. In ACTIVE, 2,463 postmenopausal women with osteoporosis were randomized 1:1:1 to double-blind daily ABL 80 µg SC or PBO, or open-label TPTD 20 µg SC for 18 months. This post hoc analysis included women <65 years of age who met the defined utilization management (UM) criteria (baseline T-score at any site of ≤-2.5 and a prevalent VF and/or at least one prior clinical fracture within 5 years of randomization). New VF incidence was evaluated using the modified intent-to-treat (mITT) population, other endpoints were evaluated using the ITT population. Percentage change at 18 months from baseline in BMD at the total hip (TH), femoral neck (FN), and lumbar spine (LS) were calculated. A total of 296 women were identified in the three treatment groups; ABL (n=94), PBO (n=103), and TPTD (n=99) [overall median age: 60 years; range: 49-64 years; mean LS T-score: -2.97]. At baseline, 92 (31%) had a prevalent VF, 234 (79%) reported ≥1 prior NVF in the past 5 years. Percent experiencing any new VF were 1.3%, 7.1%, and 2.3% in ABL, PBO, and TPTD groups, respectively (P=NS). Kaplan-Meier estimated cumulative incidence were 1.3%, 5.7%, and 3.1% for NVF, 2.6%, 8.9%, and 7.6% for clinical fracture, 2.6%, 6.9%, and 3.2% for major osteoporotic fracture, and 1.3%, 4.5%, and 1.0% for wrist fracture in ABL, PBO, and TPTD groups, respectively (all, P=NS). At 18 months, significant increases (P<0.0001) in BMD from baseline were observed for ABL vs PBO at the TH (mean change 3.20% vs -0.12%), FN (2.71% vs -0.67%), and LS (7.81% vs -0.17%), consistent with the overall ACTIVE population results. Results were similar for TPTD vs PBO. BMD improvements with ABL vs PBO were consistent across age subgroups (≤60 vs >60). Among a subgroup of postmenopausal women with osteoporosis representative of commercial insurance enrollees meeting most payers established UM criteria for coverage, ABL resulted in a numerical risk reduction for VF and NVF as well as significant improvements in BMD, compared with PBO. Results from this post hoc analysis suggest ABL may provide a valuable treatment option for a younger population of women who are at risk for fracture whose coverage is through commercial insurance. Funding: Radius Health, Inc.

OR03-1 The Effect of Abaloparatide on Bone Mineral Density and Fracture Incidence in Postmenopausal Women with Osteoporosis and Osteoarthritis

Abaloparatide (ABL) is a novel, selective activator of the PTH1 receptor signaling pathway. In the 18-month Phase 3 ACTIVE study in women with postmenopausal osteoporosis (OP) (NCT01343004), ABL significantly increased bone mineral density (BMD), and decreased the risk of new vertebral (VF), nonvertebral (NVF), and clinical fractures vs placebo (PBO), and major OP fractures vs teriparatide (TPTD) and PBO. The relationship between osteoarthritis (OA) and OP is unclear. However, increased risk of fragility fracture has been associated with OA despite those patients having higher than average BMD. The objective of this post hoc analysis was to evaluate the efficacy and safety of ABL in patients with OA enrolled in ACTIVE. In ACTIVE, 2,463 postmenopausal women with OP were randomized 1:1:1 to double-blind daily ABL 80 µg or PBO, or open-label TPTD 20 µg, SC for 18 months. Patients were identified as those with medical history of ongoing “osteoarthritis”, “spinal osteoarthritis”, “nodal osteoarthritis”, or “intervertebral disc degeneration.” New VF incidence was evaluated using the modified intent-to-treat (mITT) population, other efficacy endpoints were evaluated using the ITT population. The percent mean changes in BMD from baseline to 18 months were calculated for the total hip (TH), femoral neck (FN), and lumbar spine (LS). A total of 888 patients with ongoing OA were identified in three treatment groups; ABL (n=291), PBO (n=303), and TPTD (n=294) [overall median age: 70 years; range: 50-85 years; mean FN T-score: -2.10]. Most common sites of OA were at the spine (n=336, 38%) and knee (n=328, 37%). At baseline, 196 (22%) patients had a prevalent VF, 208 (23%) reported ≥1 prior NVF within the last 5 years, and 369 (42%) had no prior fractures. Percent experiencing any new VF were 0%, 5.1%, and 0.4% in ABL, PBO, and TPTD, respectively (ABL vs PBO, P<0.001). Kaplan-Meier estimated cumulative incidence for other fracture endpoints was similar across treatment groups. At 18 months, significant increases (P<0.0001) in BMD from baseline were observed for ABL vs PBO at the TH (mean change 3.17% vs -0.35%), FN (2.81% vs -0.36%), and LS (8.78% vs 0.86%), consistent with the overall ACTIVE population results. Most common TEAEs were hypercalciuria (11% vs 10.2%), dizziness (10.7% vs 6.6%), increased creatinine clearance (8.9% vs 10.6%), upper respiratory tract infection (8.6% vs 6.9%), and back pain (7.9% vs 11.6%) for ABL vs PBO groups, respectively. Among postmenopausal women with OP enrolled in ACTIVE, in a subpopulation with prevalent OA, ABL resulted in significant reduction in risk of new VF as well as significant improvements in BMD, vs PBO. Results suggest ABL may be useful in the treatment of women with postmenopausal OP and concurrent OA, at high risk for fracture. Funding: Radius Health, Inc.

Osteoanabolic and dual action drugs.

Teriparatide (TPTD) and abaloparatide (ABL) are the only osteoanabolic drugs available, at this time, for treatment of osteoporosis. TPTD is a 34-amino acid fragment that is identical in its primary sequence to the 34 amino acids of full-length human parathyroid hormone [hPTH(1-84)]. ABL is identical to parathyroid hormone-related peptide (PTHrP) through the first 22 residues with significantly different amino acids inserted thereafter, between residues 22 and 34. The osteoanabolic actions of PTH are due directly to its effects on cells of the osteoblast lineage and indirectly by stimulating IGF-I synthesis and suppressing sclerostin and associated enhancement of Wnt signalling. Both TPTD and ABL are ligands that bind to and activate the PTH receptor type 1 (PTHR1) receptor but they appear to do so differently: ABL favours the transient, more anabolic configuration of the receptor. Both TPTD and ABL reduce the risk of vertebral fractures and non-vertebral fractures. Both drugs are administered for a maximum of 24 months, and should be followed by an antiresorptive agent to maintain gains in bone mineral density (BMD). Romosozumab, a monoclonal antibody that binds to and inhibits sclerostin, appears to have dual actions by stimulating bone formation and reducing bone resorption. In the pivotal clinical trial, romosozumab, administered as a 210mg monthly subcutaneous dose, significantly reduced new vertebral fractures and in a subsequent study reduced both vertebral and non-vertebral fractures.