Abaloparatide-Zoledronate combination protects against 4-vinylcyclohexene diepoxide-induced postmenopausal osteoporosis in mice: an osteoanabolic-antiresorptive approach.

Abaloparatide, a 34-amino acid synthetic peptide analog of parathyroid hormone-related protein (PTHrP), was approved for treating postmenopausal osteoporosis in high-risk individuals or those resistant to existing drugs. This study aimed to investigate the impact of abaloparatide (20 µg/kg/d; s.c.), an osteoanabolic drug with an antiresorptive drug zoledronate (125 µg/kg i.v.) twice weekly for a month against 4-vinylcyclohexene diepoxide (VCD)-induced postmenopausal osteoporosis in mice. Female Swiss albino mice were made ovotoxic by treatment with VCD (160 mg/kg/d) for 15 days to mimic a postmenopausal state, confirmed by primordial follicle destruction in histopathological assessment. Microarchitectural analysis of distal femoral epiphysis and cortical mid-diaphysis was carried out using micro-computed tomography. Histopathological evaluation of bone, along with bone markers such as N-terminal propeptide of type 1 procollagen (P1NP) levels, C-terminal cross-linking telopeptide of type 1 collagen (CTX-1), soluble receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG) were assessed. The VCD-treated mice exhibited bone loss as evidenced through micro CT and histopathology. Treatment with abaloparatide and zoledronate combination for 30 days reversed VCD-induced alterations of BV/TV, BMD, Tb.N, and Tb.Sp, while the individual treatments were only partially effective. Serum analysis indicated reduced bone turnover in VCD-treated mice. The abaloparatide individually and in combination reversed the VCD-induced alterations in P1NP, CTX-1, and RANKL. The combination therapy also lowered the RANKL/OPG ratio. These findings suggest that the combined approach of osteoanabolic and antiresorptive treatment may offer superior protection compared to individual therapies, holding promise for postmenopausal osteoporosis treatment.