Significant medical need exists for new therapy that will increase bone strength beyond what is achieved with anticatabolic bone agents such as bisphosphonates. PTH has shown its ability to increase cancellous bone mass and has a positive impact in reducing the incidence of vertebral fractures. However, its high cost and mode of administration marginalize its widespread usage across the world. An orally delivered drug that would restore bone mass and strength of the skeleton to prevent vertebral and non-vertebral fractures would have significant benefit to large numbers of people at elevated risk of suffering a debilitating skeletal fracture. Androgens have long been suggested to have anabolic effects on the skeleton. It is clear that androgens contribute to significant bone gain during adolescence in boys and in hypogonadal adult males. However, it has not been proven that androgens can increase bone mass in adults who are androgen replete or in elderly males with age-related reductions in androgens. Significant progress has been achieved in our understanding how nuclear receptors act as transactivation factors in gene expression and of how these effects are translated at the tissue level. Selective estrogen receptor modulators including raloxifene have been approved for the prevention and treatment of osteoporosis. Other more efficacious SERMs are in development and should offer therapeutic advantages over current SERMs including tamoxifen and raloxifene. Knowledge and understanding of drug discovery efforts acquired in the discovery of SERMs could transfer to other nuclear receptors to identify selective receptor modulators including androgen, termed selective androgen receptor modulators (SARMs). We sought to identify selective androgen receptor modulators to test the hypothesis that a SARM could have beneficial effects on the skeleton and be devoid of the adverse side effects of testosterone administration including prostate hypertrophy and HDL reduction. Highly selective androgen receptor modulators were identified. These agents selectively bound with high affinity to the androgen receptor comparable to testosterone. Further these SARMs acted as agonists in AR-dependent cell proliferation assays. In vivo assays suggest that SARMs were identified that showed the ability to significantly increase the weight of the levator ani muscle, while having minimal effects on the prostate weight. This suggested that the ability to obtain tissue selective action with androgen receptor agonists, a first step in identifying SARMs. Additionally, compounds showed the ability to prevent the loss of muscle mass in a model of casting immobilization. Finally, SARMs were tested in orchidectomized and aged male rats to evaluate their effects on bone parameters. SARMs were shown to increase periosteal apposition and decrease endocortical and trabecular bone turnover. These effects suggest that SARMs produce increased bone mass by improving cortical bone and preventing loss of cancellous bone. Together, these apparent opposite activities on different bone surfaces may have positive long-term consequences in the treatment of osteoporosis.
Purpose: Low back pain (LBP) and its association with disability has emerged as an area of concern. This study aimed to investigate the influence of demographic, low back pain on disability to provide insights for informed interventions enhancing students’ inclusive health and wellbeing. Materials & Methods: A cross-sectional study was conducted among 351 students of all genders, aged 17 to 30. Nordic questionnaire was used to check the prevalence of low back pain. Oswestry disability index was employed to assess the back pain induced disability. Logistic regression analysis was used to analyse the association between risk factors and LBP. Results: Among students, the total prevalence of LBP was 81.5%. Adjusted odds ratio and standardized coefficient, variables such as year of study (OR = 2.526, CI = 1.629–3.923), mode of study (OR = 4.725, CI = 1.767–12.630), and duration of electronic gadgets usage (OR = 2.912, CI = 1.544–5.490) were found to be independent risk factors and predictors for the occurrence of LBP among university students. Conclusion: The study results demonstrate a substantial association between the use of computers, year of study, and use of electronic gadgets with prevalence of low back discomfort. Future investigations should focus on strategies to emphasize the significance of ergonomic guidance about computer usage and managing study workload throughout different academic years among university students.
The morbidity and mortality associated with impaired/delayed fracture healing remain high. Our objective was to identify a small nonpeptidyl molecule with the ability to promote fracture healing and prevent malunions. Prostaglandin E2 (PGE2) causes significant increases in bone mass and bone strength when administered systemically or locally to the skeleton. However, due to side effects, PGE2 is an unacceptable therapeutic option for fracture healing. PGE2 mediates its tissue-specific pharmacological activity via four different G protein-coupled receptor subtypes, EP1, -2, -3, and -4. The anabolic action of PGE2 in bone has been linked to an elevated level of cAMP, thereby implicating the EP2 and/or EP4 receptor subtypes in bone formation. We identified an EP2 selective agonist, CP-533,536, which has the ability to heal canine long bone segmental and fracture model defects without the objectionable side effects of PGE2, suggesting that the EP2 receptor subtype is a major contributor to PGE2's local bone anabolic activity. The potent bone anabolic activity of CP-533,536 offers a therapeutic alternative for the treatment of fractures and bone defects in patients.
