Estradiol replacement attenuates alendronate-associated adverse effects on alveolar bone repair in ovariectomized rats

Abstract

Background: Sodium alendronate (ALN) is widely used to treat postmenopausal osteoporosis, but both estrogen deficiency and antiresorptive therapy may impair alveolar bone repair after tooth extraction. A clinically relevant but insufficiently explored scenario involves estrogen-deficient individuals receiving hormone replacement therapy (HRT) who subsequently initiate ALN treatment. This study investigated whether estradiol valerate (E) replacement attenuates ALN-associated disturbances in alveolar bone repair in ovariectomized (OVX) rats. Methods: Sixty-three female Wistar rats were divided into sham-operated (SHAM) or OVX groups and treated with ALN (5 or 10 mg/kg) or 0.9% sodium chloride saline solution (SAL), with or without E replacement (0.8 mg/kg). The left first molar was extracted, and alveolar repair was evaluated 28 days later through clinical, radiographic, histological, and immunohistochemical (tumor necrosis factor alpha [TNF-α], receptor activator of nuclear factor kappa-B ligand [RANKL], osteoprotegerin [OPG], and tartrate-resistant acid phosphatase [TRAP]) analyses. Results: OVX increased body mass and reduced uterine wet mass (p < 0.001). Radiographically, ALN-treated groups exhibited increased socket radiolucency, particularly at the higher dose (p = 0.040). Microscopic analysis revealed more empty osteocyte lacunae (p = 0.012) and connective tissue (p = 0.010), particularly in ALN-treated OVX groups. OVX and ALN increased TNF-α, RANKL, and TRAP expression and reduced OPG levels (p = 0.004; = 0.002; = 0.030; < 0.001). E replacement mitigated these effects and reduced type III collagen deposition (p < 0.001). Conclusions: Chronic ALN impaired alveolar bone repair, exacerbated by estrogen deficiency. HRT with E partially attenuated these effects without fully restoring healing. The persistent remodeling disturbances highlight the relevance of hormonal status for dental risk assessment in patients receiving bisphosphonates. Plain Language Summary: Osteoporosis is common in postmenopausal women due to reduced estrogen levels and leads to weaker bones. Alendronate is widely prescribed to lower fracture risk, but it may interfere with bone healing after dental procedures such as tooth extraction. Using a rat model that mimics postmenopausal bone loss, this study examined how estrogen deficiency, alendronate treatment, and estrogen replacement together influence healing of the tooth socket, a process highly relevant to periodontal and oral surgical care. The results showed that estrogen deficiency alone already compromised bone repair, and this effect became more pronounced when alendronate was used. Estrogen replacement with estradiol valerate did not fully restore normal healing, but it reduced several harmful changes in bone structure and local inflammatory activity associated with alendronate. Importantly, no bone necrosis was observed under the conditions studied, although persistent disturbances in bone remodeling were evident. These findings help clarify how systemic bone conditions and osteoporosis treatments can influence periodontal wound healing and support more informed risk assessment and interdisciplinary planning when dental extractions are required in patients with osteoporosis.