INTRODUCTION

A new anabolic or bone-forming drug to treat osteoporosis—abaloparatide—will soon become available in Spain. Once launched, there will be 3 anabolic drugs available for prescription: teriparatide, abaloparatide, and romosozumab, although the latter is actually a dual-action drug, that combines anabolic and antiresorptive mechanisms.

As a clinician, and considering the similarities between abaloparatide and teriparatide, I would ask 3 questions: what is the difference in the mechanism of action compared to teriparatide; what are the differences in clinical impact compared to teriparatide; and finally, what is the patient profile that is suitable for treatment with abaloparatide?

WHAT IS THE DIFFERENCE IN THE MECHNISM OF ACTION COMPARED TO TERIPARATIDE?

Answering the first question, teriparatide is the 1-34 fraction of PTH, while abaloparatide is a synthetic analog of PTHrP (PTH related protein). Both molecules act via the PTH type 1 receptor (PTH1R), which has two high-affinity conformations, R0 and RG. Cell signaling response is more prolonged when ligands bind to R0, while the cell response is more transient when they bind to RG. Abaloparatide selectively binds more to the RG conformation of PTH1R than teriparatide (¹), and as a result of this more transient cell signaling stimulation, it has been hypothesized that abaloparatide may have a more pronounced net anabolic action (bone formation vs bone resorption) than teriparatide. What is the difference in the mechanism of action compared to teriparatide? (¹,²). In this regard, in the ACTIVE trial (Abaloparatide Comparator trial in Vertebral Endpoints), which compared the effects of abaloparatide 80 μg and teriparatide 20 μg, the increase seen in the more robust formation marker, the aminoterminal propeptide of type I procollagen (PINP) was initially similar to that obtained with teriparatide, but after a 3-month administration, this increase was less pronounced compared to teriparatide. At the same time, the resorption marker, the carboxy-terminal telopeptide of type I collagen (CTX), increased more moderately with abaloparatide than with teriparatide across the 18-month study (³).

WHAT ARE THE DIFFERENCES WITH CLINICAL IMPACT COMPARED TO TERIPARATIDE?

When the effects of teriparatide and abaloparatide reducing the risk of fracture and increasing bone mineral density (BMD) are studied in postmenopausal women with osteoporosis, more studies on teriparatide can be found, being particularly prominent here the early trial conducted by Neer et al. (Fracture Prevention trial) and the analyses from the EUROFORS trial (⁴-⁷). Therefore, in the study of the effect of teriparatide on the incidence of fractures in postmenopausal women with prior vertebral fractures, a significant reduction of in new vertebral and non-vertebral fractures compared with placebo was demonstrated over a mean 19 months. Teriparatide 20 μg reduced the risk of vertebral fractures by 65 % and the risk of fragility-related non-vertebral fractures by 53 %, becoming the protective effect of teriparatide vs non-vertebral fractures evident after 9 to 12 months. In this study, a reduced risk of hip fracture was not reported, possibly due to the low number of hip fractures reported in both arms of the trial (⁴). However, a subsequent meta-analysis that included 23 randomized controlled trials on teriparatide 20 μg demonstrated a 56 % reduction in the risk of hip fracture after a mean course of 18 months (⁸).

The ACTIVE trial aimed to primarily assess the effect of abaloparatide 80 μg on the reduction of new vertebral fractures compared with placebo. Additionally, its impact on reducing non-vertebral, clinical, and major osteoporotic fractures was analyzed. Teriparatide was also included as a comparator (open-label). Abaloparatide significantly reduced the development of vertebral, non-vertebral, and major osteoporotic fractures compared with placebo over the 18-month study period. The risk of vertebral fractures was reduced by 86 %, while the risk of non-vertebral fractures was reduced by 43 % with abaloparatide vs placebo. When its effects were compared with teriparatide in reducing new fractures, abaloparatide was similar to teriparatide in reducing the risk of vertebral fracture and superior to teriparatide in reducing major osteoporotic fractures. An interesting result to highlight from the study was that abaloparatide showed an earlier reduction in the risk of non-vertebral and major osteoporotic fractures vs placebo than teriparatide. While abaloparatide significantly reduced non-vertebral fractures vs placebo, this reduction was not significant for teriparatide vs placebo in the ACTIVE trial; however, there were not significant differences when abaloparatide and teriparatide were compared. In this regard, the authors comment that the populations of the pivotal studies of both drugs were different, as in the teriparatide trial all patients had, at least, one prevalent vertebral fracture, whereas in the ACTIVE trial only about 25%, which is why these results should be interpreted with caution (³). In fact, a real-world evidence study that compared the efficacy profile of abaloparatide with teriparatide in women with osteoporosis proved that after 18-month of treatment, both anabolic drugs were similar preventing non-vertebral fractures, with abaloparatide also being associated with a significant 22 % reduction in the risk of hip fracture (⁹). Considering the hip fractures sustained during treatment with abaloparatide and teriparatide in the ACTIVE trial, we should mention that only two cases were found, both in the placebo group (³). A meta-analysis that examined the efficacy profile of all drugs approved to treat postmenopausal osteoporosis in reducing fractures highlighted the effectiveness of both anabolic drugs in preventing vertebral and non-vertebral fractures, with no evidence for hip fracture reduction (¹⁰).

When analyzing changes in BMD induced by teriparatide and abaloparatide in the two pivotal studies, the Fracture prevention trial and the ACTIVE trial, with different populations, reported a significant and similar increase in BMD in the lumbar spine of 9 % and 10.4 % for teriparatide and abaloparatide, respectively, compared with placebo (³,⁴). At the femoral neck increases compared with placebo were 3 % for teriparatide and 4 % for abaloparatide. When the changes in BMD induced by teriparatide and abaloparatide were compared in the ACTIVE trial at 18 months of the study, the increased BMD in the lumbar spine was practically identical for both drugs. However, the femoral neck and total hip BMD increase was significantly higher for abaloparatide at 6, 12, and 18 months (³). Volumetric hip density measurement using 3D-DXA in a post-hoc analysis of the ACTIVE trial showed that only abaloparatide increased cortical density, while both abaloparatide and teriparatide increased trabecular density at 18 months (¹¹).

The ACTIVE trial analyzed the safety profile, and adverse events of abaloparatide and teriparatide. Discontinuation of the study due to adverse events was more common in the abaloparatide group (9.9 %) than in the teriparatide group (6.8 %). Abaloparatide induced hypercalcemia less frequently, particularly when the sample was obtained 4 hours after the injection. Perhaps an adverse event we should mention associated with abaloparatide was a higher frequency of palpitations, with other adverse events being balanced between both treatment groups (³). It is worth noting that abaloparatide has the same administration contraindications as teriparatide.

Sequential therapy was also included in the development of abaloparatide with an extension of the ACTIVE trial, in which alendronate was administered for 24 months after 18 months of abaloparatide or placebo. With the abaloparatide/alendronate sequence, the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures was reduced, along with greater gains in BMD compared to placebo/alendronate (¹²).

Overall, and trying to answer the question of what are the differences between abaloparatide and teriparatide with clinical impact, both anabolic agents are effective in reducing vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. Perhaps abaloparatide has a faster action in reducing non-vertebral and major osteoporotic fractures and a more favourable effect on the cortical bone of the hip, which could translate into a reduction in fractures at this level, although this aspect needs to be confirmed.

PROFILE OF PATIENTS ELIGIBLE FOR ABALOPARATIDE

The profile of patients who would be suitable for treatment with abaloparatide should be based on the recommendations for the administration of anabolic drugs in postmenopausal osteoporosis according to the clinical practice guidelines (¹³,¹⁴). The indication for abaloparatide would therefore be in women at very high risk of fracture. González-Macías et al, in their thoughtful special article in this volume of Journal of Osteoporosis and Mineral Metabolism (Revista de Osteoporosis y Metabolismo Mineral) (¹⁵), highlight the lack of homogeneity of this concept. There is a significant variability in the factors included in the classification of very high risk of fracture: T-score ranging from ≤ -2.5 to ≤ -3.5; a history of either a single vertebral fracture or multiple vertebral fractures and/or major osteoporotic fractures and/or hip fractures; a very high fracture probability according to FRAX; and in numerous guidelines, the time elapsed after the fracture, which ranges from 12 months to 3 years. Therefore, I will focus on the indication for anabolic drugs based on the SEIOMM guidelines: “very high risk corresponds to women with a) two or more vertebral fractures or an equivalent situation (such as vertebral and hip fracture); b) very low BMD (T < -3.5), or c) vertebral or hip fracture, along with a T-score < -3.0” (¹⁶). While it is true that under this definition of very high risk, teriparatide and romosozumab are recommended in all recent guidelines, including that of SEIOMM, abaloparatide is also included at the same level in guidelines from countries where abaloparatide was available, such as the United States (¹³,¹⁴). We should mention that abaloparatide was not available in European countries when most of the latest clinical guidelines were published (¹⁶,¹⁷).

Some clinical practice guidelines, such as those published by the Endocrine Society recommend teriparatide or abaloparatide for postmenopausal women at a very high risk of fracture “such as those with severe or multiple vertebral fractures,” differentiating their indication from romosozumab, which is recommended “in women with a low T-score < -2.5 and fractures, or multiple vertebral fractures” (¹⁴). Similarly, the Swiss Association against Osteoporosis guidelines from 2020 recommend teriparatide for postmenopausal women with prevalent vertebral fractures and a very high risk of fracture (¹⁷). Cosman et al., in an article on the selection of the most ideal anabolic agent according to the characteristics of the patient, highlight the suitability of abaloparatide, closely followed by teriparatide, in patients with a very high risk of vertebral fracture on the basis of prevalent vertebral fract (particularly multiple, severe, or recent), or very low BMD in the spine and/or a severely degraded trabecular bone score (TBS). For patients with a very high risk of non-vertebral fractures, especially those with hip fractures or other major osteoporotic fractures and/or very low BMD at the hip, Cosman favors romosozumab as the first-line therapy, abaloparatide as the second option, and teriparatide as the third option in this scenario (¹⁸).

Specifically, the patient profile that would benefit from treatment with abaloparatide would include postmenopausal women at very high risk of fracture, particularly vertebral fracture, where reducing the risk of vertebral and non-vertebral fracture is required. In addition, abaloparatide could be effective in reducing the risk of hip fracture and may be superior to teriparatide when very rapid action is desired to reduce the risk of major osteoporotic fractures. These aspects, particularly its possible effect on reducing the risk of hip fracture, require further detailed analy

CONCLUSION

Abaloparatide is a new anabolic option for postmenopausal women at very high risk of fracture, particularly vertebral fracture. Abaloparatide binds more selectively to the RG conformation of PTH1R than teriparatide, resulting in a more transient cell signalling response and a greater net anabolic effect. The ACTIVE trial and its extension are the most relevant studies of abaloparatide, complemented by a study with real-life data. Together, they show similar efficacy of abaloparatide to teriparatide in reducing the risk of vertebral and non-vertebral fractures compared with placebo, with greater increases in BMD at the femoral neck and total hip at the expense of cortical bone. Based on the available data, the profile of the patient who would benefit from treatment with abaloparatide would be a postmenopausal woman at very high risk of fracture, particularly vertebral fracture. Possibly, abaloparatide reduces the risk of major osteoporotic fractures more rapidly than teriparatide and perhaps shows efficacy in reducing hip fractures due to its effect on cortical bone, but these features need to be further analysed.