Abaloparatide: A review of preclinical and clinical studies.

Osteoporosis is a debilitating disease characterized by reduced bone mineral density and an increased risk of fractures. This review aims to provide a comprehensive overview of, and map current knowledge, obtained from preclinical and clinical studies of the osteoanabolic agent abaloparatide. PubMed and Embase were meticulously searched from inception to May 4, 2021.178 titles and abstracts were screened, and 57 full-text articles were assessed for inclusion. A total of 55 articles were included; 5 (9%) in vitro studies, 21 (38%) in vivo studies, and 29 (53%) clinical studies. Preclinical in vitro studies have demonstrated receptor conformation preferability, structural insights into the receptor-agonist complex, and proliferative effects of abaloparatide on osteoblasts. Preclinical studies have shown abaloparatide to be similarly effective to teriparatide using comparable doses in both ambulating mice and rats challenged by disuse. Other animal studies have reported that abaloparatide effectively mitigates or prevents bone loss from ovariectomy, orchiectomy, and glucocorticoids and improves fracture healing. The pivotal clinical study ACTIVE demonstrated 18 months of treatment with abaloparatide substantially increase bone mineral density and reduce fracture risk in post-menopausal women compared with placebo. The extension study ACTIVExtend highlighted that subsequent treatment with alendronate sustained the bone gained by abaloparatide treatment and the reduced fracture risk for up to two years. Post-hoc sub-group analyses have also supported the efficacy and safety of abaloparatide treatment independent of various baseline risk factors. In conclusion, mounting evidence from preclinical and clinical studies has uniformly reported that abaloparatide increases bone mineral density and reduces fracture risk.

Short-term glucocorticoid excess blunts abaloparatide-induced increase in femoral bone mass and strength in mice.

Glucocorticoids (GCs), such as prednisolone, are widely used to treat inflammatory diseases. Continuously long-term or high dose treatment with GCs is one of the most common causes of secondary osteoporosis and is associated with sarcopenia and increased risk of debilitating osteoporotic fragility fractures. Abaloparatide (ABL) is a potent parathyroid hormone-related peptide analog, which can increase bone mineral density (aBMD), improve trabecular microarchitecture, and increase bone strength. The present study aimed to investigate whether GC excess blunts the osteoanabolic effect of ABL. Sixty 12-13-week-old female RjOrl:SWISS mice were allocated to the following groups: Baseline, Control, ABL, GC, and GC + ABL. ABL was administered as subcutaneous injections (100 µg/kg), while GC was delivered by subcutaneous implantation of a 60-days slow-release prednisolone-pellet (10 mg). The study lasted four weeks. GC induced a substantial reduction in muscle mass, trabecular mineral apposition rate (MAR) and bone formation rate (BFR/BS), and endocortical MAR compared with Control, but did not alter the trabecular microarchitecture or bone strength. In mice not receiving GC, ABL increased aBMD, bone mineral content (BMC), cortical and trabecular microarchitecture, mineralizing surface (MS/BS), MAR, BFR/BS, and bone strength compared with Control. However, when administered concomitantly with GC, the osteoanabolic effect of ABL on BMC, cortical morphology, and cortical bone strength was blunted. In conclusion, at cortical bone sites, the osteoanabolic effect of ABL is generally blunted by short-term GC excess.

The effect of oral dabigatran etexilate on bone density, strength, and microstructure in healthy mice.

Thrombin is a key component in the coagulation cascade where it converts factor V, VIII, XI, and fibrinogen. In addition to the abundant production of thrombin in the liver, osteoclasts synthesize and secrete thrombin as well. Osteoblasts express thrombin receptors, and it has been reported that thrombin stimulates the expression of RANKL relatively to OPG, resulting in greater osteoclast activation and bone degradation. Pradaxa (dabigatran etexilate, DE) is a new anticoagulant, which has recently been approved for clinical use. DE is a direct thrombin inhibitor with potential to modulate the RANKL/OPG ratio and thereby limit osteoclast activation and bone degradation. The purpose of the study was to investigate whether DE can increase bone density, bone strength, and bone microstructure in healthy male and female mice and to investigate whether the effect of DE is sex-dependent. Twenty-eight 14-week-old male C57BL/6 mice were stratified by weight into 4 groups: 1. Control 3 weeks; 2. DE 3 weeks; 3. Control 6 weeks; 4. DE 6 weeks. An identical study design was applied to twenty-four 14-week-old female C57BL/6 mice. Chow mixed with DE was offered ad libitum, resulting in a dose of 1.70 mg DE/g body weight and 1.52 mg DE/g body weight, to female and male mice, respectively. The animals were euthanized after 3 or 6 weeks. Bone mineral density (aBMD) and bone mineral content (BMC) were evaluated with DEXA, 3D microstructural properties were determined with µCT, bone strength was determined with mechanical testing, and bone formation and resorption was evaluated with bone histomorphometry. In female mice, DE resulted in significant higher tibial aBMD values after 6 weeks of intervention. Furthermore, DE significantly increased tibial diaphyseal cortical bone area and tissue area, which was accompanied by significantly increased strength of the tibial shaft. DE had no effect on femoral cortical bone or on femoral and vertebral trabecular 3D microstructure. Finally, bone histomorphometry showed that DE had no effect on MS/BS or Oc.S/BS. In male mice, no bone positive effects of DE were found in any of the parameters investigated. In conclusion, intervention with DE may result in a weak positive site specific effect at tibial cortical bone in female mice, and importantly, no major deleterious effects of DE on bone tissue were seen in either female or male mice despite the relatively high dose of DE used.