Selective Androgen Receptor Modulators-Transformative Drugs or Heralds of the Next Drug Epidemic?

This Viewpoint examines whether selective androgen receptor modulators have the potential to be transformative drugs or whether they herald the next drug epidemic.

Inhibition of Lipoxygenases Showed No Benefit for the Musculoskeletal System in Estrogen Deficient Rats.

Background: In previous studies, we reported the beneficial impact of two lipoxygenase-inhibitors, Baicalein and Zileuton, on osteoporotic bone in a postmenopausal rat model. Whereas subcutaneous Baicalein predominantly improved cortical bone, Zileuton enhanced vertebral and femoral trabecular bone. In this study, we aimed to reveal whether the oral administration of Baicalein caused similar effects on bone and whether a combined administration of Baicalein and Zileuton could act synergistically to ameliorate the formerly reported effects in the musculoskeletal system. Methods: We treated ovariectomized (OVX) female Sprague-Dawley rats either with Baicalein (10mg/kg BW), Zileuton (10mg/kg BW) or a combination of both (each 10mg/kg BW) for 13 weeks and compared with untreated OVX and NON-OVX groups (n=12-16 rats per group). Lumbar vertebral bodies and femora were analyzed. Tibiae were osteotomized, plate-stabilized (at week 8 after OVX) and likewise analyzed by biomechanical, histological, micro-computed tomographical and ashing tests. The skeletal muscle structure was analyzed. Results: Oral administration of Baicalein did not confirm the reported favorable cortical effects in neither vertebra nor femur. Zileuton showed a beneficial effect on trabecular vertebra, while the femur was negatively affected. Callus formation was enhanced by all treatments; however, its density and biomechanical properties were unaltered. Lipoxygenase inhibition did not show a beneficial effect on skeletal muscle. The combination therapy did not ameliorate OVX-induced osteoporosis but induced even more bone loss. Conclusions: The preventive anti-osteoporotic treatments with two lipoxygenase inhibitors applied either alone or in combination showed no benefit for the musculoskeletal system in estrogen deficient rats.

Non-Musculoskeletal Benefits of Vitamin D beyond the Musculoskeletal System.

Vitamin D, a fat-soluble prohormone, is endogenously synthesized in response to sunlight or taken from dietary supplements. Since vitamin D receptors are present in most tissues and cells in the body, the mounting understanding of the role of vitamin D in humans indicates that it does not only play an important role in the musculoskeletal system, but has beneficial effects elsewhere as well. This review summarizes the metabolism of vitamin D, the research regarding the possible risk factors leading to vitamin D deficiency, and the relationships between vitamin D deficiency and numerous illnesses, including rickets, osteoporosis and osteomalacia, muscle weakness and falls, autoimmune disorders, infectious diseases, cardiovascular diseases (CVDs), cancers, and neurological disorders. The system-wide effects of vitamin D and the mechanisms of the diseases are also discussed. Although accumulating evidence supports associations of vitamin D deficiency with physical and mental disorders and beneficial effects of vitamin D with health maintenance and disease prevention, there continue to be controversies over the beneficial effects of vitamin D. Thus, more well-designed and statistically powered trials are required to enable the assessment of vitamin D's role in optimizing health and preventing disease.

Maternal use of sedative drugs and its effects on pregnancy outcomes: a Finnish birth cohort study.

Our aim was to evaluate maternal use of sedative drugs before, during, and after pregnancy and to assess the influence of use of these drugs on pregnancy outcomes. The study cohort (N = 6231) consists of all primiparous women, who lived in the city of Vantaa, Finland, and who delivered a singleton between 2009 and 2015. Data were obtained from Finnish national health registers. Of the women, 3.2% (n = 202) purchased at least once sedative drugs within 90 days before conception, during pregnancy and/or within 90 days after delivery. Sedative drug users were older, less likely to cohabitate, more often smokers, had lower educational attainment and had more mental diseases (for all p < 0.001) compared with non-users. Sedative drug users purchased more often antidepressants and drugs for the alimentary tract, musculoskeletal and nervous system than non-users (for all p < 0.001). No adverse birth or pregnancy outcomes were found in the group using sedative drugs compared with the non-users. Studies in larger cohorts are needed to confirm our study findings.

Extracellular Vesicles in Musculoskeletal Regeneration: Modulating the Therapy of the Future.

Tissue regeneration is a hot topic in health sciences, particularly because effective therapies promoting the healing of several cell types are lacking, specifically those of the musculoskeletal system. Mesenchymal Stem/Stromal Cells (MSCs) have been identified as crucial players in bone homeostasis, and are considered a promising therapy for diseases such as osteoarthritis (OA) and Rheumatoid Arthritis (RA). However, some known drawbacks limit their use, particularly ethical issues and immunological rejections. Thus, MSCs byproducts, namely Extracellular Vesicles (EVs), are emerging as potential solutions to overcome some of the issues of the original cells. EVs can be modulated by either cellular preconditioning or vesicle engineering, and thus represent a plastic tool to be implemented in regenerative medicine. Further, the use of biomaterials is important to improve EV delivery and indirectly to modulate their content and secretion. This review aims to connect the dots among MSCs, EVs, and biomaterials, in the context of musculoskeletal diseases.

The molecular mechanisms of probiotic strains in improving ageing bone and muscle of d-galactose-induced ageing rats.

AIM: The aim of this study was to evaluate the molecular mechanisms of Lactobacillus strains in improving ageing of the musculoskeletal system. METHODS AND RESULTS: The anti-ageing mechanism of three probiotics strains Lactobacillus fermentum DR9, Lactobacillus paracasei OFS 0291 and L. helveticus OFS 1515 were evaluated on gastrocnemius muscle and tibia of d-galactose-induced ageing rats. Upon senescence induction, aged rats demonstrated reduced antioxidative genes CAT and SOD expression in both bone and muscle compared to the young rats (P < 0·05). Strain L. fermentum DR9 demonstrated improved expression of SOD in bone and muscle compared to the aged rats (P < 0·05). In the evaluation of myogenesis-related genes, L. paracasei OFS 0291 and L. fermentum DR9 increased the mRNA expression of IGF-1; L. helveticus OFS 1515 and L. fermentum DR9 reduced the expression of MyoD, in contrast to the aged controls (P < 0·05). Protective effects of L. fermentum DR9 on ageing muscle were believed to be contributed by increased AMPK-α2 expression. Among the osteoclastogenesis genes studied, TNF-α expression was highly elevated in tibia of aged rats, while all three probiotics strains ameliorated the expression. Lactobacillus fermentum DR9 also reduced the expression of IL-6 and TRAP in tibia when compared to the aged rats (P < 0·05). All probiotics treatment resulted in declined proinflammatory cytokines IL-1ß in muscle and bone. CONCLUSIONS: Lactobacillus fermentum DR9 appeared to be the strongest strain in modulation of musculoskeletal health during ageing. SIGNIFICANCE AND IMPACT OF THE STUDY: The study demonstrated the protective effects of the bacteria on muscle and bone through antioxidative and anti-inflammatory actions. Therefore, L. fermentum DR9 may serve as a promising targeted anti-ageing therapy.

Tissue selective effects of bazedoxifene on the musculoskeletal system in female mice.

The actions of selective estrogen receptor modulators are tissue dependent. The primary objective of the current study was to determine the tissue selective effects of bazedoxifene (BZA) on the musculoskeletal system of ovariectomized (OVX) female mice, focusing on the strengths of muscle-bone pairs in the lower hindlimb. Treatment with BZA after ovariectomy (OVX+BZA) did not prevent body or fat mass gains (P < 0.05). In vivo plantarflexor muscle isometric torque was not affected by treatment with BZA (P = 0.522). Soleus muscle peak isometric, concentric and eccentric tetanic force production were greater in OVX+BZA mice compared to OVX+E2 mice (P ≤ 0.048) with no effect on maximal isometric specific force (P = 0.228). Tibia from OVX+BZA mice had greater cortical cross-sectional area and moment of inertia than OVX mice treated with placebo (P < 0.001), but there was no impact of BZA treatment on cortical bone mineral density, cortical thickness, tibial bone ultimate load or stiffness (P ≥ 0.086). Overall, these results indicate that BZA may be an estrogen receptor agonist in skeletal muscle, as it has previously been shown in bone, providing minor benefits to the musculoskeletal system.

Assessment of the risk of musculoskeletal adverse events associated with fluoroquinolone use in children: A meta-analysis.

BACKGROUND: The use of fluoroquinolone antibiotics has been restricted in children because of their potential to cause adverse musculoskeletal events. This study was performed to systematically evaluate whether there is a difference between fluoroquinolone and non-fluoroquinolone antibiotics in terms of their associated risk of adverse musculoskeletal events in children. METHODS: Cochrane Library, Embase, and PubMed databases were used to retrieve studies related to fluoroquinolone and non-fluoroquinolone-induced musculoskeletal adverse events in children. A meta-analysis was performed using Stata 11. RESULTS: A total of 10 studies were included in the analysis. The combined results showed that there was no statistical difference between fluoroquinolone and non-fluoroquinolone groups in terms of musculoskeletal adverse events in children (risk ratio = 1.145, 95% confidence interval = 0.974 - 1.345, P = .101). Subgroup analysis was performed using a random-effects model. Here, the effects on the trovafloxacin and levofloxacin groups were significantly different from that of the control group. However, musculoskeletal adverse events due to either drug was not reported after long-term follow-up. CONCLUSIONS: The results showed that fluoroquinolone and non-fluoroquinolone antibiotics were not different in terms of their ability to cause musculoskeletal adverse events in children. For this reason, fluoroquinolone antibiotics can be used in children as appropriate. PROSPERO REGISTRATION NUMBER: CRD42019133900.

Cholecalciferol or Calcifediol in the Management of Vitamin D Deficiency.

Vitamin D deficiency is a global health problem due to its high prevalence and its negative consequences on musculoskeletal and extra-skeletal health. In our comparative review of the two exogenous vitamin D supplementation options most used in our care setting, we found that cholecalciferol has more scientific evidence with positive results than calcifediol in musculoskeletal diseases and that it is the form of vitamin D of choice in the most accepted and internationally recognized clinical guidelines on the management of osteoporosis. Cholecalciferol, unlike calcifediol, guarantees an exact dosage in IU (International Units) of vitamin D and has pharmacokinetic properties that allow either daily or even weekly, fortnightly, or monthly administration in its equivalent doses, which can facilitate adherence to treatment. Regardless of the pattern of administration, cholecalciferol may be more likely to achieve serum levels of 25(OH)D (25-hydroxy-vitamin D) of 30-50 ng/mL, an interval considered optimal for maximum benefit at the lowest risk. In summary, the form of vitamin D of choice for exogenous supplementation should be cholecalciferol, with calcifediol reserved for patients with liver failure or severe intestinal malabsorption syndromes.

Bilateral Sub-deltoid Bursitis in a Patient Receiving Infliximab for Crohn's Disease.

BACKGROUND: Infiximab has been shown to be effective in inducing and maintaining remission of intestinal bowel diseases. Infiximab has been associated with many adverse events. Articular manifestations are commonly reported, but they are of variable clinical expression and aetiology. Among them, inflammatory bursitis has rarely been described. OBJECTIVE: Herein a case of inflammatory bursitis in a patient with Crohn's disease after switching to biosimilar infliximab is reported. CASE REPORT: A 41-year-old man with Crohn's disease evolving from 3 years was referred to infliximab therapy at a dose of 5mg/kg because of an aggressive resistant perineal fistula. After 14 infusions of infliximab, the treatment was switched to infliximab biosimilar using the same dose and frequency of administration. Forty-eight hours after the second infusion, he developed an acute onset of muscle pain and stiffness on both of his shoulders. A musculoskeletal ultrasound was performed and revealed a hypoechoic widening of both subacromial bursae. It was more severe on the left side. DISCUSSION: The diagnosis of non-infective sub-acromial bursitis secondary to infliximab infusion was made as the patient's symptoms resolved rapidly without any antibiotics. Infliximab was definitively stopped and adalimumab was introduced. CONCLUSION: Musculoskeletal side effects of infliximab infusion are uncommonly reported. Among them, bursitis has been reported in only a few cases. Ultrasonography can help early diagnosis of bursitis. The time of occurring of this reaction regarding infliximab infusion, screening of Antibodies to Infliximab (ATI) and clinical outcome after drug discontinuation are the main helpful arguments.

Effects of loratadine, a histamine H1 receptor antagonist, on the skeletal system of young male rats.

BACKGROUND: Histamine H1 receptor antagonists are widely used in the treatment of allergic diseases. H1 receptors are expressed on bone cells and histamine takes part in regulation of bone metabolism. Loratadine is often prescribed to children. PURPOSE: The aim of the present study was to investigate the effects of loratadine on the skeletal system of young rats. MATERIAL AND METHODS: Loratadine (0.5, 5, and 50 mg/kg p.o. daily) was administered for 4 weeks to male Wistar rats, 6-week-old at the start of the experiment. Bone mass, mass of bone mineral, calcium, and phosphorus content in the bone mineral of the tibia, femur, and L-4 vertebra, histomorphometric parameters of the femur, mechanical properties of the proximal tibial metaphysis, femoral diaphysis and femoral neck, and serum levels of bone turnover markers were examined. RESULTS: Loratadine at 0.5 and 5 mg/kg did not significantly affect the skeletal system of young rats. At 50 mg/kg, loratadine decreased the femoral length, increased content of calcium and phosphorus in the bone mineral of the vertebra, and tended to improve mechanical properties of the tibial metaphysis. CONCLUSION: High-dose loratadine slightly but significantly affected development of the skeletal system in rapidly growing rats.

Bone and body composition response to testosterone therapy vary according to polymorphisms in the CYP19A1 gene.

PURPOSE: To evaluate the influence of single nucleotide polymorphisms (SNPs) of CYP19A1 on the response and susceptibility to side effects from testosterone therapy. This is a prospective, single-arm study of men with low-morning serum testosterone (<10.68 nmol/l) administered testosterone cypionate 200 mg intramuscularly every 2 weeks for 18 months. METHODS: We measured areal bone mineral density (aBMD) and body composition by dual energy X-ray absorptiometry, tibial volumetric BMD and geometry by peripheral quantitative computer tomography, bone turnover markers by enzyme-linked immunosorbent assay, testosterone, and estradiol by liquid-chromatography/mass-spectroscopy, genotyping by microarray, CYP19A1 expression by quantitative polymerase chain reaction, hematocrit and prostate-specific antigen (PSA). RESULTS: We enrolled 105 men (40-74-years-old). SNPs rs1062033 and rs700518 were associated with significant differences in outcomes at 18 months. The GG genotype in rs1062033 had significant increase in whole body aBMD, but had significant decrease in tibial bone size compared to the CG and CC genotypes. Body composition analysis showed that the CC genotype of rs1062033, and the AA genotype of rs700518, had significant increase in total lean and appendicular lean mass compared to CG and GG, and AG and GG, respectively. The GG genotype of rs700518 had significant increase in PSA (GG = 105.8 ± 23.3% vs. AG + AA = 53.4 ± 11.3%, p = 0.046) while hematocrit changes were comparable among genotypes. CYP19A1 expression was highest in GG genotype in both SNPs. CONCLUSIONS: For the first time, we demonstrated that CYP19A1 SNPs influence response to testosterone therapy in hypogonadal men, highlighting the importance of genetic profiling in therapeutics even for common clinical conditions.

Vitamin D and Metabolic Supplementation in Orthopedic Trauma.

Active assessment and management of hypovitaminosis D among orthopedic patients is low-risk and low-cost while retaining significant potential to improve patient care. Vitamin D has an established role in musculoskeletal development and calcium homeostasis, and vitamin D deficiency is pervasive in orthopedic trauma populations. Clinical guidelines for screening and supplementation for hypovitaminosis D are lacking. Literature on the effects of vitamin K on bone health is limited. Anabolic hormone analogues may have a future role in delayed union or nonunion treatment. Vitamin D deficiency and other endocrine abnormalities should be considered in orthopedic trauma patients presenting with fracture nonunion of uncertain cause.

Diabetes pharmacotherapy and effects on the musculoskeletal system.

Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age-matched persons without diabetes, attributed to disease-specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin-based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall-related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo-anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium-dependent glucose co-transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes-related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

The Effect of Tobacco Smoking on Musculoskeletal Health: A Systematic Review.

This systematic review explored associations between smoking and health outcomes involving the musculoskeletal system. AMSTAR criteria were followed. A comprehensive search of PubMed, Web of Science, and Science Direct returned 243 articles meeting inclusion criteria. A majority of studies found smoking has negative effects on the musculoskeletal system. In research on bones, smoking was associated with lower BMD, increased fracture risk, periodontitis, alveolar bone loss, and dental implant failure. In research on joints, smoking was associated with increased joint disease activity, poor functional outcomes, and poor therapeutic response. There was also evidence of adverse effects on muscles, tendons, cartilage, and ligaments. There were few studies on the musculoskeletal health outcomes of secondhand smoke, smoking cessation, or other modes of smoking, such as waterpipes or electronic cigarettes. This review found evidence that suggests tobacco smoking has negative effects on the health outcomes of the musculoskeletal system. There is a need for further research to understand mechanisms of action for the effects of smoking on the musculoskeletal system and to increase awareness of healthcare providers and community members of the adverse effects of smoking on the musculoskeletal system.

Musculoskeletal senescence: a moving target ready to be eliminated.

Aging is the prime risk factor for the broad-based development of diseases. Frailty is a phenotypical hallmark of aging and is often used to assess whether the predicted benefits of a therapy outweigh the risks for older patients. Senescent cells form as a consequence of unresolved molecular damage and persistently secrete molecules that can impair tissue function. Recent evidence shows senescent cells can chronically interfere with stem cell function and drive aging of the musculoskeletal system. In addition, targeted apoptosis of senescent cells can restore tissue homeostasis in aged animals. Thus, targeting cellular senescence provides new therapeutic opportunities for the intervention of frailty-associated pathologies and could have pleiotropic health benefits.