Introduction: Osteoporosis is a metabolic bone disease caused by an imbalance in bone resorption and bone remodeling, and characterized by low bone mass and compromised trabecular architecture. Menopause, ovarian failure, ovariectomy and estrogen or testosterone deficiency can speed up skeletal catabolism and lead to osteoblast malfunction, increased osteoclastogenesis and osteoporosis. The treatment of estrogen deficiency-induced osteoporosis is still a challenge and most of the current therapeutics come with many side-effects. More therapeutic strategies are needed for the prevention of osteoporosis caused by estrogen deficiency, ovariectomy and menopause.
Methods: In this review article, the therapeutic effects of anti-RANKL and anti-Sclerostin antibodies were studied. Keywords such as “Osteoporosis”, “estrogen-deficiency”, “bone loss”, “monoclonal antibodies” and “ovariectomy” from 2018-2021 were searched in PubMed, Elsevier and google scholar, and review articles were excluded. One hundred and seventy-four articles were found. One hundred and twenty-nine of them were eliminated upon reading the title or abstract.
Results: Two major monoclonal antibodies made for the treatment of estrogen deficiency-induced bone loss are denosumab (anti-RANKL) and romosozumab (anti-Sclerostin). RANKL/RANK plays a significant role in osteoclastogenesis. RANK is expressed on osteoclast precursors and is activated by RANKL which leads to osteoclast maturation and bone resorption. Sclerostin is a secreted glycoprotein, mainly expressed by osteocytes that inhibits osteoblast differentiation and bone formation by inhibiting Wnt/β-catenin signaling pathway. Thus blocking the RANK/RANKL interaction or blocking sclerostin activity may be promising strategies for preventing osteoporosis. Studies on animals such as rodents, rabbits and monkeys showed a decreased number of active osteoclasts, increased bone mineral density and bone formation. Several short-term and long-term clinical trials on postmenopausal women or elderly men reported denosumab to be effective. It increased bone mineral density, decreased bone resorption and significantly decreased the risk of bone fracture. Many studies showed a combination of denosumab and teriparatide, or zoledronate to be equally effective. One study showed denosumab to be more effective than bisphosphate at improving bone mineral density, especially at lumbar spine, total hip and femoral neck. A recent study on ovariectomized rabbits showed that using the combination of pulsed electromagnetic field (PEMF) technique along with the administration of sclerostin monoclonal antibodies leads to better results than single-drug therapy. One of the biggest disadvantages of denosumab and romosozumab is the reversibility of their therapeutic effects. In one study, romosozumab decreased bone resorption marker (β-CTX). However, its levels increased again upon discontinuation. Similar results have been noted in denosumab clinical trials. Many studies have reported that treatment effects of denosumab and romosozumab are reversible upon discontinuation, and patients who decide to discontinue them should rapidly transition to alternative treatments in order to prevent bone loss.
Conclusion: Overall, both anti-RANKL and anti-Sclerostin appear to enhance bone mineral density and have beneficial effects on both cortical and trabecular bone mass.