Chronic glucocorticoid (GC) therapy is the most common cause of iatrogenic osteoporosis and represents an important risk factor for osteoporosis and bone fractures. New therapeutic approaches are required in order to treat osteoporosis and reduce the side effects related to the use of anti-osteoporotic drugs. In this context, previous studies reported the efficacy of some isoflavones and carotenoids, such as lycopene and genistein, on the reduction of the risk of fracture related to osteoporosis. The aim of this study was to investigate the effects of a combined oral treatment, consisting of genistein and lycopene, in an experimental model of glucocorticoid-induced osteoporosis (GIO). GIO was induced by subcutaneous injection of methylprednisolone (MP, 30 mg/kg) for 60 days, whereas the control group (Sham) received saline solution only. Following induction, MP animals randomly were assigned to receive alendronate, genistein, lycopene, or the association of genistein and lycopene or saline solution for additional 60 days together with MP. Femurs obtained from the Sham group were used for osteoblasts extraction; they were then incubated with dexamethasone (DEX) for 24 h to be then treated with lycopene or genistein or the association of lycopene and genistein for an additional 24 h. Treatments with lycopene and genistein restored the impaired mineralization of cells observed following DEX treatment and stimulated osteoblast differentiation by increasing the depressed expression of bALP and RUNX2 (p < 0.0001). Wnt5a, β-catenin, and Nrf-2 expression were significantly increased following genistein and lycopene treatment (p < 0.0001), thus confirming their antioxidant activity as well as their ability in stimulating osteoblast function, mostly when genistein and lycopene were used in association. The combined treatment of genistein and lycopene improved the bone damage induced by glucocorticoids and significantly restored the normal architecture of bones as well as adequate interconnectivity of bone trabeculae, thus increasing bone mineral density parameters. The obtained data demonstrated that genistein and lycopene but in particular their association might prevent GC’s adverse effects, thus stimulating bone formation and reducing bone resorption, improving bone structure and microarchitecture, through different molecular pathways, such as the Wnt/β-catenin and the Nrf-2 signaling.

Impaired bone formation is the main characteristics of glucocorticoid (GC)-induced osteoporosis (GIO), which can be ameliorated by tanshinol, an aqueous polyphenol isolated from Salvia miltiorrhiza Bunge. However, the underlying mechanism is still not entirely clear. In the present study, we determined the parameters related to microstructure and function of bone tissue, bone microcirculation, and TXNIP signaling to investigate the beneficial effects of tanshinol on skeleton and its molecular mechanism in GIO rats. Male Sprague-Dawley rats aged 4 months were administrated orally with distilled water (Con), tanshinol (Tan, 25 mg kg-1 d-1), prednisone (GC, 5 mg kg-1 d-1) and GC plus tanshinol (GC + Tan) for 14 weeks. The results demonstrated that tanshinol played a significant preventive role in bone loss, impaired microstructure, dysfunction of bone metabolism and poor bone quality, based on analysis of correlative parameters acquired from the measurement by using Micro-CT, histomorphometry, ELISA and biomechanical assay. Tanshinol also showed a significant protective effect in bone microcirculation according to the evidence of microvascular perfusion imaging of cancellous bone in GIO rats, as well as the migration ability of human endothelial cells (EA.hy926, EA cells). Moreover, tanshinol also attenuated GC-elicited the activation of TXNIP signaling pathway, and simultaneously reversed the down-regulation of Wnt and VEGF pathway as manifested by using Western-blot method in GIO rats, EA cells, and human osteoblast-like MG63 cells (MG cells). Collectively, our data highlighted that tanshinol ameliorated poor bone health mediated by activation of TXNIP signaling via inhibiting microcirculation disturbance and the following impaired bone formation in GIO rats.

Clodronate belongs to Bisphosphonates family and it has been studied especially for osteoporosis treatment, Paget\'s disease, osteolytic metastases, hypercalcemia malignancy and some childhood skeletal diseases. Besides the osteoporosis treatment, it has been successfully used for treating tumoral osteolysis and for bone localization of multiple myeloma, hypercalcemia malignancy, primary hyperparathyroidism, Paget\'s disease and algodystrophy. Filipponi study showed a statistically significant reduction of the incidence of vertebral fractures after 4 years of treatment with clodronate, intravenously administered at a dose of 200 mg every three weeks. Frediani study, published in 2003 on BONE, proved the clodronate efficacy in the prevention of fractures caused by glucocorticoid-induced osteoporosis (GIO). Clodronate doses of 800 mg/day per os and 100 mg i.m./week are substantially equivalent, because the oral absorption is about 1,9%. A higher efficacy on BMD was documented in various works, especially in cohorts of patients with a greater fracture risk, using higher doses (1600 mg per os). This has led to the hypothesis of using clodronate 200 mg i.m. formulation. Clodronate is an osteoporosis drug that can be assumed in different doses (100 mg i.m./week, clodronate 200 mg i.m. every 2 weeks) considering the risk band, identified by algorithms (FRAX o DeFRA), by BMD and by the presence of at least one risk factor. That means that it is possible to envisage a differentiated use of clodronate adapting the doses to the fracture risk and to the severity of pain symptoms, thus promoting a greater adherence to the therapy. To conclude clodronate is helpful in reducing fracture risk, is safe, well tolerated, and has a good rate cost/effectiveness in patients with fracture risk over 7% established with FRAX.

Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures.