Early Effects of Abaloparatide on Bone Formation and Resorption Indices in Postmenopausal Women With Osteoporosis

David W Dempster, Hua Zhou, Sudhaker D Rao, Chris Recknor, Paul D Miller, Benjamin Z Leder, Miriam Annett, Michael S Ominsky, Bruce H Mitlak, David W Dempster, Hua Zhou, Sudhaker D Rao, Chris Recknor, Paul D Miller, Benjamin Z Leder, Miriam Annett, Michael S Ominsky, Bruce H Mitlak

Abstract

Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Trial registration: ClinicalTrials.gov NCT03710889.

Keywords: ANABOLICS; BONE HISTOMORPHOMETRY; BONE MODELING AND REMODELING; CLINICAL TRIAL; OSTEOPOROSIS.

© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Figures

Fig 1
Fig 1
Study design. DEM = demeclocycline; SC = subcutaneous; TET = tetracycline.
Fig 2
Fig 2
Bone formation at baseline and 3 months. (A) Median mineralizing surface per unit of bone surface at baseline and 3 months for the four bone envelopes. (B) Median bone formation at baseline and 3 months. Shown are remodeling‐based formation (RBF), modeling‐based formation (MBF), and overflow modeling‐based formation (oMBF) as a percentage of bone surface in the cancellous, endocortical, and periosteal envelopes. ***p < .001 within‐group changes from baseline to 3 months by paired t test (or Wilcoxon signed‐rank test instead, if the normality assumption of the data is not satisfied). MBF = modeling‐based formation; MS/BS = mineralizing surface/bone surface; oMBF = overflow modeling‐based formation; RBF = remodeling‐based formation.
Fig 3
Fig 3
Increase in MS/BS and oMBF with abaloparatide treatment. ABL = abaloparatide; MS/BS = mineralizing surface/bone surface; oMBF = overflow modeling‐based formation.
Fig 4
Fig 4
Percent bone formation at baseline and 3 months (median). Shown are remodeling‐based formation (RBF), modeling‐based formation (MBF), and overflow modeling‐based formation (oMBF) as a percentage of bone surface at 3 months by bone envelope. BS = bone surface; ES = eroded surface; MBF = modeling‐based formation; oMBF = overflow modeling‐based formation; QS = quiescent surface; RBF = remodeling‐based formation.
Fig 5
Fig 5
Correlations between changes in s‐PINP/s‐CTX and changes in cancellous/intracortical MS/BS. (A) Scatter plots of change in mineralizing surface per unit of bone surface (MS/BS) at 3 months by changes in s‐PINP at 1 month and 3 months. (B) Scatter plots of change in intracortical mineralizing surface (MS/BS) at 3 months by changes in s‐CTX at month 1 and month 3. ET = end of treatment; MS/BS = mineralizing surface/bone surface; s‐CTX = serum carboxy‐terminal cross‐linking telopeptide for type I collagen; s‐PINP = serum procollagen type I N‐terminal propeptide.

References

    1. Rizzoli R, Bonjour JP, Ferrari SL. Osteoporosis, genetics and hormones. J Mol Endocrinol. 2001;26(2):79–94.
    1. Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis. 2016;8(6):225–35.
    1. Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 2007;357(9):905–16.
    1. Dempster DW, Zhou H, Recker RR, et al. Ruff, remodeling‐ and modeling‐based bone formation with teriparatide versus denosumab: a longitudinal analysis from baseline to 3 months in the AVA study. J Bone Miner Res. 2018;33(2):298–306.
    1. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the diagnosis and treatment of postmenopausal osteoporosis—2020 update executive summary. Endocr Pract. 2020;26(5):564–70.
    1. Pavone V, Testa G, Giardina SMC, Vescio A, Restivo DA, Sessa G. Pharmacological therapy of osteoporosis: a systematic current review of literature. Front Pharmacol. 2017;8:803.
    1. Lindsay R, Cosman F, Zhou H, et al. A novel tetracycline labeling schedule for longitudinal evaluation of the short‐term effects of anabolic therapy with a single iliac crest bone biopsy: early actions of teriparatide. J Bone Miner Res. 2006;21(3):366–73.
    1. Ma YL, Zeng Q, Donley DW, et al. Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF‐II immunoreactivity in postmenopausal women with osteoporosis. J Bone Miner Res. 2006;21(6):855–64.
    1. 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):722–33.
    1. Moreira CA, Fitzpatrick LA, Wang Y, Recker RR. Effects of abaloparatide‐SC (BA058) on bone histology and histomorphometry: the ACTIVE phase 3 trial. Bone. 2017;97:314–9.
    1. Chavassieux P, Chapurlat R, Portero‐Muzy N, et al. Bone‐forming and antiresorptive effects of romosozumab in postmenopausal women with osteoporosis: bone histomorphometry and microcomputed tomography analysis after 2 and 12 months of treatment. J Bone Miner Res. 2019;34(9):1597–608.
    1. Dempster DW, Zhou H, Recker RR, et al. Differential effects of teriparatide and denosumab on intact PTH and bone formation indices: AVA osteoporosis study. J Clin Endocrinol Metab. 2016;101(4):1353–63.
    1. Rubin MR, Dempster DW, Sliney J Jr, et al. PTH(1‐84) administration reverses abnormal bone‐remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res. 2011;26(11):2727–36.
    1. Dempster DW, Zhou H, Krege J, Alam J, Taylor K, Ruff V. Correlations between longitudinal changes in the bone turnover marker P1NP and bone formation at the tissue level across 3 envelopes with teriparatide in the AVA osteoporosis study. J Bone Miner Res. 2017;32(Suppl 1):S268–9.
    1. Eastell R, Mitlak BH, Wang Y, Hu M, Fitzpatrick LA, Black DM. Bone turnover markers to explain changes in lumbar spine BMD with abaloparatide and teriparatide: results from ACTIVE. Osteoporos Int. 2019;30(3):667–73.
    1. Dempster DW, Zhou H, Recker RR, et al. Skeletal histomorphometry in subjects on teriparatide or zoledronic acid therapy (SHOTZ) study: a randomized controlled trial. J Clin Endocrinol Metab. 2012;97(8):2799–808.
    1. Dempster DW, Cosman F, Kurland ES, et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res. 2001;16(10):1846–53.
    1. Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28(1):2–17.
    1. Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF. Recombinant human parathyroid hormone (1‐34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res. 2003;18(11):1932–41.
    1. Lindsay R, Zhou H, Cosman F, Nieves J, Dempster DW, Hodsman AB. Effects of a one‐month treatment with PTH(1‐34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res. 2007;22(4):495–502.
    1. Varela A, Chouinard L, Lesage E, Smith SY, Hattersley G. One year of abaloparatide, a selective activator of the PTH1 receptor, increased bone formation and bone mass in osteopenic ovariectomized rats without increasing bone resorption. J Bone Miner Res. 2017;32(1):24–33.
    1. Arlt H, Mullarkey T, Hu D, et al. Effects of abaloparatide and teriparatide on bone resorption and bone formation in female mice. Bone. 2020;13:100291.
    1. Besschetnova T, Brooks DJ, Hu D, et al. Abaloparatide improves cortical geometry and trabecular microarchitecture and increases vertebral and femoral neck strength in a rat model of male osteoporosis. Bone. 2019;124:148–57.
    1. Doyle N, Varela A, Haile S, et al. Abaloparatide, a novel PTH receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption. Osteoporos Int. 2018;29(3):685–97.
    1. 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.
    1. Deal CL, Mitlak BH, Wang Y, Fitzpatrick LA, Miller PD. Response rates for hip, femoral neck, and lumbar spine bone mineral density in patients treated with abaloparatide followed by alendronate: results from phase 3 ACTIVExtend. Bone Rep. 2019;11:100230.
    1. Eriksen EF, Chapurlat R, Boyce RW, et al. Extensive modeling‐based bone formation after 2 months of romosozumab treatment: results from the FRAME clinical trial. J Bone Miner Res. 2019;34(Suppl 1):17.
    1. Boyce RW, Paddock CL, Franks AF, Jankowsky ML, Eriksen EF. Effects of intermittent hPTH(1‐34) alone and in combination with 1,25(OH)(2)D(3) or risedronate on endosteal bone remodeling in canine cancellous and cortical bone. J Bone Miner Res. 1996;11(5):600–13.
    1. Winzenrieth R, Ominsky MS, Wang Y, Humbert L, Weiss RJ. Differential effects of abaloparatide and teriparatide on hip cortical volumetric BMD by DXA‐based 3D modeling. Osteoporos Int. 2021:(manuscript in preparation).
    1. Hauge EM, Mosekilde L, Melsen F, Frydenberg M. How many patients are needed? Variation and design considerations in bone histomorphometry. Bone. 2001;28(5):556–62.
    1. Cosman F, Dempster DW, Nieves JW, et al. Effect of teriparatide on bone formation in the human femoral neck. J Clin Endocrinol Metab. 2016;101(4):1498–505.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться