Abaloparatide and the Spine: A Narrative Review

Figures & data

Figure 1 Model of parathyroid hormone (PTH)/teriparatide and PTH-related peptide (PTHrP/abaloparatide activation of parathyroid hormone type 1 receptor (PTH1R)).

Table 1 Summary of Study Characteristics

Author	Study Type	Abaloparatide “n” (dosage)	Comparison Group(s)(“n”)	Follow-up (mo)	Female (%)	Age (Mean, SD, Range) (y)
Miller et al.^Citation33	RCT (ACTIVE Trial)	824 (80 µg)	PBO (821) TPTD (818)	18	100%	ABL (68.9 ± 6.5) TPTD (68.8 ± 6.6) PBO 68.7 ± 6.5)
Bone et al.^Citation38	RCT: ACTIVExtend (Extension of ACTIVE trial)	558 (80 µg)	PBO (551)	Addition of 24 months ALN	100%	ABL/ALN (70.2 ± 6.54) PBO/ALN (70.1 ± 6.29)
Leder et al.^Citation45	RCT:ACTIVE & ACTIVExtend post-hoc comparison of ABL vs. ALN	606 (80 µg)	PBO/ALN (from ACTIVExtend) (581)	18	100%	ABL (68.6 ± 6.5) ALN (70.1 ± 6.29)
McCloskey et al.^Citation47	RCT: ACTIVE trial post-hoc analysis in subgroup of women at baseline high risk for fracture based on FRAX probabilities (10-year risk of major osteoporotic fracture > 10% or hip fracture > 5%)	459 (80 µg)	PBO (468) TPTD (473)	18	100%	ABL (69.9 ± 6.67) TPTD (69.9 ± 6.37) PBO (70.0 ± 6.27)
McClung et al.^Citation34	RCT: ACTIVE trial post-hoc analysis in patients age > 80 years	51 (80 µg)	PBO (43)	18	100%	ABL (81.7 ± 1.4) PBO (81.9 ± 1.5)
Bilezikian et al.^Citation6	RCT: post-hoc of ACTIVE trial	24 (80 µg); 25 (40 µg)	PBO (29) TPTD (31)	6	100%	20 µg ABL (68.1 ± 6.3) 40 µg ABL (65.4 ± 6.9) 80 µg ABL (64.3 ± 6.9) TPTD (66.2 ± 7.3) PBO (66.7 ± 7.6)
Cosman et al.^Citation35	RCT: ACTIVE trial post-hoc analysis in varying baseline risk groups	558 (ABL 80 µg /ALN)	PBO/ALN (581) Subgroup analysis of the following groups: Lumbar T-score ≤ - 2.5 vs. > -2.5 Lumbar T-score ≤ -3.0 vs. > -3.0 Total Hip T-score ≤ -2.5 vs. > -2.5 Total Hip ≤ -3.0 vs. > -3.0 Femoral Neck T-score ≤ -2.5 vs. > -2.5 Femoral Neck T-score ≤ -3.0 vs. > -3.0 History of nonvertebral fracture History of vertebral fracture Age < 65 vs. 65 to <75 vs. ≥ 75 years	18	100%	---
Leder et al.^Citation46	RCT: ACTIVExtend post-hoc analysis of fracture risk reduction and BMD changes in specific groups of baseline risk	558 (80 µg)	PBO/ALN (581) Subgroup analysis of the following groups: Lumbar BMD T-score ≤ - 2.5 vs. > -2.5 Lumbar BMD T-score ≤ -3.0 vs. > -3.0 Total Hip BMD T-score ≤ -2.5 vs. > -2.5; Total Hip BMD ≤ -3.0 vs. > -3.0; Femoral Neck BMD T-score ≤ -2.5 vs. > -2.5 Femoral Neck BMD ≤ -3.0 vs. > -3.0 History of nonvertebral fracture History of vertebral fracture Age < 65 vs. 65-75 vs. > 75 years	43	100%	---
Miller et al.^Citation32	RCT: ACTIVE trial post-hoc evaluation of likelihood of response to treatment	824 (80 µg)	PBO (821) TPTD (818)	18	100%	ABL (68.7 ± 6.3) TPTD 68.5 ± 6.3) PBO (68.6 ± 6.3)
Leder et al.^Citation29	RCT	43 (20 µg); 43 (40 µg); 45 (80 µg)	PBO (45) TPTD (45)	6 (Extension to 12 mo)	100%	20 µg ABL(66.3 ± 7.4) 40 µg (64.5 ± 7.2) ABL 80 microgram (64.8 ± 7.2) TPTD (64.5 ± 7.5) PBO 65.0 ± 7.1)

Abbreviations: ABL, abaloparatide; PBO, placebo; TPTD, teriparatide; RR, relative risk; RRR, relative risk reduction; HR, hazzard ratio

Table 2 Summary of Study Findings

Author	Lumbar BMD Outcomes	Vertebral Fracture Outcomes	Bone Turnover Markers	Other
Miller et al^Citation33	6.58% increase in lumbar spine BMD in ABL group vs 5.25% with TPTD and 0.60% with PBO at 6 months (p < 0.001) 9.77% increase in lumbar spine BMD with ABL vs 8.28% with TPTD and 0.45% in PBO groups at 12 months (p < 0.001) 11.2% in lumbar spine BMD with ABL group vs.10.49% in TPTD and 0.63% in PBO groups at 18 months (p = 0.17)	New vertebral fracture in 0.58% of ABL group vs 0.84% in TPTD and 4.22% in PBO groups (Risk difference −3.64 (RR 0.14 (0.05, 0.39) (p < 0.001))	S-P1NP (bone formation marker effects: Initial increases in month #1 were similar, but s-PINP began to decrease in the ABL group compared to the TPTD group after month #1. s-CTX (bone resorption marker) effects: Lower magnitude of increases in the ABL group than in TPTD	—
Bone et al^Citation38	Absolute increase 0.265 ± 0.0451 with ABL/ALN Absolute increase 0.0479 ± 0.0378 PBO/ALN (p < 0.001)	0.9% of patients with new vertebral fracture (ABL/ALN) vs 5.6% (PBO/ALN) RRR 84% (p < 0.001)	—	—
Cosman et al^Citation35	Percent increase in lumbar spine BMD treated with ABL/ALN vs PBO/ALN in the following subgroups: Lumbar spine BMD T-score ≤ −2.5 (8.90%) vs > −2.5 (8.28%) (p = 0. 361) Lumbar spine BMD T-score ≤ −3.0 (8.95%) vs > −3.0 (8.56%) (p = 0.534) Total hip BMD T-score ≤ −2.5 (9.88%) vs > −2.5 (8.42%) (p = 0.036) Total hip BMD T-score ≤ −3.0 (8.94%) vs > −3.0 (8.75%) (p = 0.864) Femoral neck BMD T-score ≤ −2.5 (9.62%) vs > −2.5 (8.41%) (p = 0.063) Femoral neck BMD T-score ≤ −3.0 (9.53%) vs > −3.0 (8.68%) (p = 0.404) History of vertebral fracture (8.35%) vs No history of vertebral fracture (8.86%) (p = 0.49) Presence of any prior nonvertebral fracture (8.23%) vs No history of any prior nonvertebral fracture (9.26%) (p = 0.075) Age < 65 years (7.62%) vs age 65 to <75 years (8.86%) vs age > 75 years (9.53%) (p = 0.170)	Relative risk of fracture in patients treated with ABL/ALN vs PBO/ALN in the following subgroups: Lumbar spine T-score ≤ −2.5 (RR = 0.14) vs > −2.5 (RR = 0.13) (p = 0.960) Lumbar spine T-score ≤ −3.0 (RR = 0.18) vs > −3.0 (RR = 0.08) (p = 0.493) Total hip T-score ≤ −2.5 (RR = 0.10) vs > −2.5 (RR = 0.16) (p = 0.699) Total hip T-score ≤ −3.0 (RR = 0.37) vs > −3.0 (RR = 0.11) (p = 0.356) Femoral neck T-score ≤ −2.5 (RR = 0.19) vs > −2.5 (RR = 0.11) (p = 0.588) Femoral neck T-score ≤ −3.0 (RR = NA) vs > −3.0 (RR = 0.16) (p = 0.403) History of vertebral fracture (RR = 0.07) vs No history of vertebral fracture (RR = 0.20) (p= 0.371) History of any prior nonvertebral fracture (RR = 0.14) vs No history of any prior nonvertebral fracture (RR = 0.13) (p= 0.984) Age < 65 (RR = 0.13) vs age 65–75 (RR = 0.06) vs age > 75 (RR = 0.48) (p = 0.209)	—	Hazard ratio of fracture in patients in patients treated with ABL/ALN vs PBO/ALN in the following subgroups: Lumbar spine BMD T-score ≤ −2.5 (HR = 0.58) vs > −2.5 (HR = 0.53) (p = 0.879) Lumbar spine BMD T-score ≤ −3.0 (HR = 0.34) vs > −3.0 (HR = 0.98) (p = 0.082) Total hip BMD T-score ≤ −2.5 (HR = 0.56) vs > −2.5 (HR = 0.58) (p = 0.951) Total hip BMD T-score ≤ −3.0 (HR = 0.58) vs > −3.0 (HR = 0.56) (p = 0.968); Femoral neck BMD T-score < −2.5 (HR = 0.48) vs > −2.5 (HR = 0.61) (p = 0.707) Femoral neck BMD T-score ≤ −3.0 (HR = 86) vs > −3.0 (HR = 0.53) (p = 0.567) History of vertebral fracture (HR = 0.44) vs No history of vertebral fracture (HR = 0.62) (p= 0.622) History of any prior nonvertebral fracture (HR = 0.60) vs No history of any prior nonvertebral fracture (HR = 05213) (p= 0.790) Age < 65 (HR = 0.35) vs age 65–75 (HR = 0.90) vs age > 75 (HR = 0.29) (p = 0.230)
Leder et al^Citation45		Rate of new vertebral fracture 0.47 per 100 patient-years with ABL vs 1.66 per 100 patient-years with ALN (p = 0.027)	—	—
Leder et al.^Citation46	Percent increase in lumbar spine BMD treated with ABL/ALN vs PBO/ALN in the following subgroups: Lumbar spine BMD T-score ≤ −2.5 (3.72%) vs > −2.5 (3.68%) (p = 0.952) Lumbar spine BMD T-score ≤ −3.0 (3.73%) vs > −3.0 (3.68%) (p = 0.938) Total hip BMD T-score ≤ −2.5 (3.88%) vs > −2.5 (3.65%) (p = 0.680) Total hip BMD T-score ≤ −3.0 (4.19%) vs > −3.0 (3.66%) (p = 0.588) Femoral neck BMD T-score ≤ −2.5 (4.24%) vs > −2.5 (3.48%) (p = 0.173) Femoral neck BMD T-score ≤ −3.0 (4.81) vs > −3.0 (3.57%) (p = 0.113) History of vertebral fracture (3.94%) vs No history of vertebral fracture (3.62%) (p = 0.552) History of any prior nonvertebral fracture (3.72%) vs No history of any prior nonvertebral fracture (3.70%) (p = 0.950) Age < 65 years (3.72%) vs age 65 to <75 years (3.68%) vs age > 75 years (3.91%) (p = 0.976)	Relative risk of fracture in patients treated with ABL/ALN vs PBO/ALN in the following subgroups: Lumbar spine BMD T-score ≤ −2.5 (RR = 0.16) vs > −2.5 (RR = 0.18) (p = 0.896) Lumbar spine BMD T-score ≤ −3.0 (RR = 0.14) vs > −3.0 (RR = 0.21) (p = 0.686) Total hip BMD T-score ≤ −2.5 (RR = 0.12) vs > −2.5 (RR = 0.18) (p = 0.682) Total hip BMD T-score ≤ −3.0 (RR = 0.56) vs > −3.0 (RR = 0.14) (p = 0.277) Femoral neck BMD T-score ≤ −2.5 (RR = 0.24) vs > −2.5 (RR = 0.14) (p = 0.574) Femoral neck BMD T-score ≤ −3.0 (RR = 0.017) vs > −3.0 (p = 0.592) History of vertebral fracture (RR = 0.06) vs No history of vertebral fracture (RR = 0.30) (p= 0.115) History of any prior nonvertebral fracture (RR = 0.10) vs No history of any prior nonvertebral fracture (RR = 0.26) (p= 0.320) Age < 65 (RR = 0.13) vs age 65 to <75 (RR = 0.06) vs age > 75 (RR = 0.42) (p = 0.222)	—	—
McCloskey et al^Citation47	—	0.5% with new vertebral fracture in ABL group vs 1.4% in TPTD group and 5.6% in PBO group RRR 91% vs placebo. “Not statistically significant” vs TPTD (p value not given)	—	—
McClung et al^Citation34	12.1% increase in lumbar spine BMD with ABL (p < 0.001)	0% fractures in ABL vs 5.9% fractures in PBO “not statistically significant”(p value not given)	—	—
Miller et al^Citation32	—	—	—	Percentage of patients with >3% increase in BMD at all anatomic sites: 19.1% of patients in ABL vs 6.5% in TPTD and 0.9% in placebo groups at 6 months (p<0.001) 33.2% of patients in ABL group vs 19.8% in TPTD and 1.5% in placebo groups at 12 months (p<0.001) 44.5% of patients in ABL group vs 32% in TPTD and 1.8% in placebo groups at 18 months (p<0.001) Percentage of patients with >6% increase in BMD at all anatomic sites: 33.2% of patients in ABL vs 19.8% in TPTD and 1.5% in placebo groups at 12 months (p<0.001)2.3% of patients in ABL group vs 0.3% in TPTD and 0% in placebo groups at 12 months (p<0.002) 8.5% of patients in ABL vs 2.9% in TPTD and 0% in placebo groups at 12 months (p<0.002) 13.4% of patients in ABL vs 7.0% in TPTD and 0.2% in placebo groups at 18 months (p<0.002)
Bilezikian et al^Citation6	Trabecular Bone Score (TBS) changes at 24 weeks: TBS Increased 2.27% in ABL 20 µg (P = 0.91) Increased 3.14% in ABL 40 µg group (p = 0.42) Increased 4.21% in ABL 80 µg groups at 24 weeks (p < 0.03) TBS Increased 2.21% in TPTD group at 24 weeks TBS decreased by 1.08% in PBO group at 24 weeks (p < 0.0001 vs all groups)	—	—	—
Leder et al^Citation29	BMD increased +1.6 ±3.4% in PBO group; TPTD +5.5 ± 4.1%; 20µg +2.9 ± 4.5%; 40µ 5.2 ±4.5%; (p < 0.001); 80mircrogram 6.7 ±4.2%; (p < 0.001).	At 48 weeks, lumbar spine BMD increased by 0.7 in PBO vs 5.1 in ABL (20 µg), 9.8 in ABL (40µg), 12.9 in ABL (80 µg), and 8.6% in TPTD groups. Not statistically significant given small numbers of the extension study.	P1NP (bone formation) increased by week 1. Increased by median 55% at 24 weeks in ABL 40 and 52% in ABL 80, and 98% in TPTD group. Decreased by 20% in PBO group (all groups p < 0.001 when compared to placebo); CTX (bone resorption) not apparent increased until week 12. Increased by 33% at 24 weeks in ABL40 group, 23% in ABL80 group, but 76% in the TPTD group and 7% in the PBO group. (P < 0.003 in all ABL groups compared to TPTD.)	—

Abbreviations: ABL, abaloparatide; PBO, placebo; TPTD, teriparatide; RR, relative risk; RRR, relative risk reduction; HR, hazard ratio.

Miller PD, Hattersley G, Riis BJ, et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA. 2016;316(7):722–733. doi:10.1001/jama.2016.1113627533157

 PubMed Web of Science ®Google Scholar

Bone HG, Cosman F, Miller PD, et al. ACTIVExtend: 24 months of alendronate after 18 months of abaloparatide or placebo for postmenopausal osteoporosis. J Clin Endocrinol Metab. 2018;103(8):2949–2957. doi:10.1210/jc.2018-0016329800372

 PubMed Web of Science ®Google Scholar

Leder BZ, Mitlak B, Hu MY, Hattersley G, Bockman RS. Effect of abaloparatide versus alendronate on fracture risk reduction in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2019;105(3):938–43.

 Web of Science ®Google Scholar

McCloskey EV, Fitzpatrick LA, Hu MY, Williams G, Kanis JA. Effect of abaloparatide on vertebral, nonvertebral, major osteoporotic, and clinical fractures in a subset of postmenopausal women at increased risk of fracture by FRAX probability. Arch Osteoporos. 2019;14(1):15. doi:10.1007/s11657-019-0564-730719589

 PubMed Web of Science ®Google Scholar

McClung MR, Harvey NC, Fitzpatrick LA, et al. Effects of abaloparatide on bone mineral density and risk of fracture in postmenopausal women aged 80 years or older with osteoporosis. Menopause. 2018;25(7):767–771. doi:10.1097/GME.000000000000108029462094

 PubMed Web of Science ®Google Scholar

Bilezikian JP, Hattersley G, Fitzpatrick LA, et al. Abaloparatide-SC improves trabecular microarchitecture as assessed by trabecular bone score (TBS): a 24-week randomized clinical trial. Osteoporos Int. 2018;29(2):323–328. doi:10.1007/s00198-017-4304-929167971

 PubMed Web of Science ®Google Scholar

Cosman F, Hattersley G, Hu MY, Williams GC, Fitzpatrick LA, Black DM. Effects of abaloparatide-SC on fractures and bone mineral density in subgroups of postmenopausal women with osteoporosis and varying baseline risk factors. J Bone Miner Res. 2017;32(1):17–23. doi:10.1002/jbmr.299127612281

 PubMed Web of Science ®Google Scholar

Leder BZ, Zapalowski C, Hu MY, et al. Fracture and bone mineral density response by baseline risk in patients treated with abaloparatide followed by alendronate: results from the phase 3 ACTIVExtend trial. J Bone Miner Res. 2019;34(12):2213–2219. doi:10.1002/jbmr.384831411768

 PubMed Web of Science ®Google Scholar

Miller PD, Hattersley G, Lau E, et al. Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: results from the ACTIVE Phase 3 trial. Bone. 2019;120:137–140. doi:10.1016/j.bone.2018.10.01530359763

 PubMed Web of Science ®Google Scholar

Leder BZ, O’Dea LS, Zanchetta JR, et al. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2015;100(2):697–706. doi:10.1210/jc.2014-371825393645

 PubMed Web of Science ®Google Scholar