We have generated RANK (receptor activator of NF-B) nullizygous mice to determine the molecular genetic interactions between osteoprotegerin, osteoprotegerin ligand, and RANK during bone resorption and remodeling processes. RANK ؊/؊ mice lack osteoclasts and have a profound defect in bone resorption and remodeling and in the development of the cartilaginous growth plates of endochondral bone. The osteopetrosis observed in these mice can be reversed by transplantation of bone marrow from rag1 ؊/؊ (recombinase activating gene 1) mice, indicating that RANK ؊/؊ mice have an intrinsic defect in osteoclast function. Calciotropic hormones and proresorptive cytokines that are known to induce bone resorption in mice and human were administered to RANK ؊/؊ mice without inducing hypercalcemia, although tumor necrosis factor ␣ treatment leads to the rare appearance of osteoclast-like cells near the site of injection. Osteoclastogenesis can be initiated in RANK ؊/؊ mice by transfer of the RANK cDNA back into hematopoietic precursors, suggesting a means to critically evaluate RANK structural features required for bone resorption. Together these data indicate that RANK is the intrinsic cell surface determinant that mediates osteoprotegerin ligand effects on bone resorption and remodeling as well as the physiological and pathological effects of calciotropic hormones and proresorptive cytokines.B one remodeling and homeostasis is an essential function that regulates skeletal integrity throughout adult life in higher vertebrates and mammals. The maintenance of skeletal mass is controlled by the activities of specialized cells within the bone that have seemingly antagonistic activities: bone synthesis and bone resorption. Osteoblastic cells of mesenchymal origin synthesize and deposit bone matrix and increase bone mass. Osteoclastic cells are large, multinucleated phagocytes of hematopoietic origin that resorb both mature and newly synthesized bone upon activation. Bone synthesis and resorption processes are highly coordinated and are regulated by osteotropic and calciotropic hormones during physiological and pathological conditions (1, 2). Increased bone resorption and turnover mediated by activated osteoclasts is known to occur in various crippling diseases, such as osteoporosis and arthritis, and can lead to pathological decreases in bone mass and skeletal integrity.Recently, two critical extracellular regulators of osteoclast differentiation and activation have been identified: osteoprotegerin (OPG) (3) and OPG ligand (OPGL) (4). OPGL is a tumor necrosis factor (TNF)-related cytokine that stimulates osteoclast differentiation from hematopoietic precursor cells and activation of mature osteoclasts in vitro and in vivo. Mice lacking OPGL also lack osteoclasts and have defects in bone remodeling processes that leads to severe osteopetrosis (5). OPG is a secreted TNF receptor (TNFR)-related protein that binds to and neutralizes OPGL bioactivity. Transgenic mice that overexpress OPG also have defects in osteoclastogenesis similar t...

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Objective Acromegaly is associated with increased vertebral fracture (VFs) risk not correlated to bone mineral density (BMD). Trabecular bone score (TBS), related to bone microarchitecture, provides information on bone strength. This cross‐sectional study considered the usefulness of TBS and BMD to assess bone status in long‐term controlled acromegalic patients. Design, patients, measurements 26 acromegaly patients (14 female and 12 males) were included in the study. A further 117 subjects were recruited as controls (58 females and 57 males). BMD was measured using dual‐energy X‐ray absorptiometry (DXA), TBS was obtained applying Medimaps software 2.0. Biochemical parameters were determined by standardized techniques. Results 73% of patients with acromegaly exhibited normal lumbar spine (LS) BMD. TBS was normal in 38% of acromegalic patients and partially degraded or degraded in 31% of patients, respectively. No differences were found in LS BMD between acromegalic patients and controls. TBS values were significantly lower in patients with acromegaly (1.27 ± 0.13 vs. 1.35 ± 0.17, p = .01). Postsurgical remission was associated with higher TBS values (1.35 ± 0.10 vs. 1.23 ± 0.13, p = .02) and pituitary radiotherapy treatment with lower TBS values (1.18 ± 0.12 vs. 1.31 ± 0.12, p = .004). On multivariate analysis, age, BMI and LS BMD were predictors of TBS changes in patients with acromegaly (p < .05). Conclusions Patients with long‐term controlled acromegaly can exhibit deterioration of bone microstructure measured with TBS, despite BMD measurement not showing bone loss. Our study suggests that TBS is useful for monitoring the bone status changes in acromegalic patients.