Abaloparatide: a new anabolic therapy on the horizon.

Teriparatide administered by daily subcutaneous injection, was approved in the United States in 2002, and has been the only anabolic medication available in the United States for almost 13 years. Outside the US, teriparatide is joined only by intact PTH (1–84) as anabolic therapy for osteoporosis treatment. Although both anabolic and antiresorptive medications improve bone density and strength, their mechanisms of action are distinctly different. Because anabolic agents stimulate new bone formation, they have the potential to repair disordered bone architecture and increase bone mass to a greater extent than antiresorptive therapies. Some of the anabolic action of teriparatide is through modeling on the quiescent bone surface owing to activation of resting lining cells and/or recruitment of newly formed/differentiated osteoblasts to the bone surface. Some of the anabolic action is remodeling based, with stimulation of osteoblast activity within existing or new remodeling units, leading to overfilling of resorption cavities and, thereby, thicker packets of new bone. Larger packets of new bone growth are also seen because of the formation overspilling the already filled resorption cavities and/or stimulation of modeling–based bone formation adjacent to the remodeling cavities. The balance between the amount of modeling versus remodeling-based bone formation might change with time on teriparatide treatment. One of the challenges with teriparatide has been the lack of appreciable difference in nonvertebral fracture incidence before at least 9 months of teriparatide treatment. Ultimately, within 18 months, teriparatide does produce a 35–50% reduction in nonvertebral fractures (range based on different definitions of nonvertebral fractures). However, it is unclear if this effect is truly better than potent antiresorptive therapy in skeletal sites that are primarily cortical bone. Teriparatide does improve cortical thickness at 18–36 months, however, BMD of the hip does not increase more with teriparatide than with alendronate. Furthermore, hip strength increases modestly and not significantly more than with alendronate. In the few small studies where teriparatide was compared head-to-head with bisphosphonates, whereas teriparatide reduced the risk of vertebral fractures more than alendronate or risedronate, nonvertebral fracture incidence did not differ between teriparatide and oral bisphosphonates. Of course, these studies were not designed or powered to assess the fracture outcomes for either vertebral or nonvertebral sites. Lastly, in patients who have already been treated with prior oral bisphosphonates or denosumab, the benefit of subsequent teriparatide treatment is diminished, particularly with respect to hip BMD and hip strength, perhaps in part because of excessive bone resorption when the stimulation of remodeling by teriparatide is coincident with the withdrawal of a potent antiresorptive agent. A number of potential anabolic therapies have failed in various stages of development because of lack of efficacy, including several calcilytic agents designed to stimulate endogenous PTH production and transdermal patches containing teriparatide. Abaloparatide is a synthetic analog of PTHrP that retains anabolic activity with less bone resorption, compared with PTHrP. Leder et al. recently published results from a short term phase 2 trial of three doses of Abaloparatide (20, 40 and 80 mcg by daily subcutaneous injection), compared with daily placebo and teriparatide over 24 weeks. A small subset, 55 of the original 222 subjects, received extended treatment to 48 weeks. Enrolled subjects were largely treatment naive with no prior use of teriparatide or denosumab and no bisphoshphonate use within the previous 5 years. At 24 weeks, BMD increases above placebo were seen in the spine, total hip and femoral neck, and were for the most part dose dependent. Spine BMD increases with the two higher abaloparatide doses (40 and 80 mcg) were similar to that seen with teriparatide (5.2, 6.7 and 5.5%, respectively). In the total hip, BMD increases with the 40 and 80 mcg doses were greater than that seen with teriparatide (2.0, 2.6 and 0.5%, respectively). There were no BMD data presented for the radius. The increases in biochemical markers of bone formation (PINP and osteocalcin) stimulated by abaloparatide and teriparatide were similar, whereas the effect of abaloparatide on a marker of bone resorption (CTX) was of lesser magnitude than that seen with teriparatide. In the small group of women who completed the extension study, spine BMD increased further from 24–48 weeks, reaching a mean increment of 12.9% with the 80 mcg abaloparatide dose. Citation: BoneKEy Reports 4, Article number: 661 (2015) | doi:10.1038/bonekey.2015.28 & 2015 International Bone & Mineral Society All rights reserved 2047-6396/15 www.nature.com/bonekey