Modeling-based bone formation after 2 months of romosozumab treatment:​ results from the FRAME clinical trial

Eriksen, Erik F.<sup>1,2</sup>; Chapurlat, Roland<sup>3</sup>; Boyce, Rogely Waite<sup>4</sup>; Shi, Yifei<sup>4</sup>; Brown, Jacques P.<sup>5</sup>; Horlait, Stéphane<sup>6</sup>; Betah, Donald<sup>4</sup>; Libanati, Cesar<sup>7</sup>; Chavassieux, Pascale<sup>3</sup>

Affiliations

¹Institute of Clinical Dentistry, University of Oslo, Oslo, Norway

²Spesialistsenteret Pilestredet Park, Oslo, Norway

³INSERM UMR 1033, Université de Lyon, Hospices Civils de Lyon, Lyon, France

⁴Amgen Inc, Thousand Oaks, CA, USA

⁵CHU de Québec Research Centre and Laval University, Quebec City, Canada

⁶Amgen, Boulogne-Billancourt, France

⁷UCB Pharma, Brussels, Belgium

Abstract and keywords

The bone-forming agent romosozumab is a monoclonal antibody that inhibits sclerostin, leading to increased bone formation and decreased resorption. The highest levels of bone formation markers in human patients are observed in the first 2 months of treatment. Histomorphometric analysis of bone biopsies from the phase 3 FRAME trial (NCT01575834) showed an early significant increase in bone formation with concomitant decreased resorption. Preclinical studies demonstrated that most new bone formation after romosozumab treatment was modeling-based bone formation (MBBF). Here we analyzed bone biopsies from FRAME to assess the effect of 2 months of romosozumab versus placebo on the surface extent of MBBF and remodeling-based bone formation (RBBF). In FRAME, postmenopausal women aged ≥55 years with osteoporosis were randomized 1:1 to 210 mg romosozumab or placebo sc every month for 12 months, followed by 60 mg denosumab sc every 6 months for 12 months. Participants in the bone biopsy substudy received quadruple tetracycline labeling and underwent transiliac biopsies at month 2. A total of 29 biopsies were suitable for histomorphometry. Using fluorescence microscopy, bone formation at cancellous, endocortical, and periosteal envelopes was classified based on the appearance of underlying cement lines as modeling (smooth) or remodeling (scalloped). Data were compared using the Wilcoxon rank-sum test, without multiplicity adjustment. After 2 months, the median percentage of MBBF referent to the total bone surface was significantly increased with romosozumab versus placebo on cancellous (18.0% versus 3.8%; p = 0.005) and endocortical (36.7% versus 3.0%; p = 0.001), but not on periosteal (5.0% versus 2.0%; p = 0.37) surfaces, with no significant difference in the surface extent of RBBF on all three bone surfaces. These data show that stimulation of bone formation in the first 2 months of romosozumab treatment in postmenopausal women with osteoporosis is predominately due to increased MBBF on endocortical and cancellous surfaces.

Keywords: BONE HISTOMORPHOMETRY; BONE MODELING AND REMODELING; OSTEOPOROSIS; THERAPEUTICS; Wnt/β-CATENIN/LRPs CELL/TISSUE SIGNALING

Links

DOI: 10.1002/jbmr.4457

PubMed: 34633116

WoS: 000720244200001

History

Received: 2021-03-17

Revised: 2021-09-20

Accepted: 2021-10-03

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Cited By (1)

Year	Entry
2023	Sano H, Whitmarsh T, Skingle L, Shimakura T, Yamamoto N, Compston JE, Takahashi HE, Poole KES. Buds of new bone formation within the femoral head of hip fracture patients coincide with zones of low osteocyte sclerostin. J Bone Miner Res. November 2023;38(11):1603-1611.