Non-classical Vitamin D Actions for Renal Protection

Chronic Kidney Disease (CKD), a disorder that affects 11% of the world's population, is characterized by an acceleration in skeletal, immune, renal, and cardiovascular aging that increases the risk of cardiovascular mortality by 10- to 20-fold, compared to that in individuals with normal renal function. For more than two decades, the progressive impairment in renal capacity to maintain normal circulating levels of the hormonal form of vitamin D (1,25-dihydroxyvitamin D or calcitriol) was considered the main contributor to the reduced survival of CKD patients. Accordingly, calcitriol administration was the treatment of choice to attenuate the progression of secondary hyperparathyroidism (SHPT) and its adverse impact on bone health and vascular calcification. The development of calcitriol analogs, designed to mitigate the resistance to calcitriol suppression of PTH associated with CKD progression, demonstrated survival benefits unrelated to the control of SHPT or skeletal health. The exhaustive search for the pathophysiology behind survival benefits associated with active vitamin D analogs has identified novel anti-inflammatory, anti-hypertensive, anti-aging actions of the vitamin D endocrine system. A major paradigm shift regarding the use of calcitriol or active vitamin D analogs to improve survival in CKD patients emerged upon demonstration of a high prevalence of vitamin D (not calcitriol) deficiency at all stages of CKD and, more significantly, that maintaining serum levels of the calcitriol precursor, 25(OH)vitamin D, above 23 ng/ml delayed CKD progression. The cause of vitamin D deficiency in CKD, however, is unclear since vitamin D bioactivation to 25(OH)D occurs mostly at the liver. Importantly, neither calcitriol nor its analogs can correct vitamin D deficiency. The goals of this chapter are to present our current understanding of the pathogenesis of vitamin D deficiency in CKD and of the causal link between defective vitamin D bioactivation to calcitriol and the onset of molecular pathways that promote CKD progression independently of the degree of SHPT. An understanding of these mechanisms will highlight the need for identification of novel sensitive biomarkers to assess the efficacy of interventions with vitamin D and/or calcitriol(analogs) to ameliorate CKD progression in a PTH-independent manner.

The Long-Term Residual Effects of Low-Magnitude Mechanical Stimulation On Murine Femoral Mechanics

As an alternative to drug treatments, low-magnitude mechanical stimulation (LMMS) may improve skeletal health without potential side effects from drugs. LMMS has been shown to increase bone health short term in both animal and clinical studies. Long term changes to the mechanical properties of bone from LMMS are currently unknown, so the objective of this research is to investigate the long-term effects of whole body vibration therapy on the elastic and viscoelastic properties of bone. In this study 10-week old female BALB/cByJ mice were given LMMS (15 min/day, 5 days/week, 0.3 g, 90 Hz) for 8 weeks; SHAM did not receive LMMS. Two sets of groups remained on study for an additional 8 or 16 weeks post LMMS (N=17). MicroCT and histomorphology of these femurs were studied and results were published by Bodnyk et al. [1]. Femoral quasi-static bending stiffness trended 4.2% increase in stiffness after 8-weeks of LMMS and 1.3% increase 8-weeks post LMMS compared to SHAM. Damping, tan delta, and loss stiffness, significantly increased by 17.6%, 16.3%, and 16.6% respectively at 8 weeks LMMS compared to SHAM. Finite element models of applied LMMS signal showed decreased stress in the mid-diaphyseal region at both 8-week LMMS and 8-week post LMMS compared to SHAM. Residual mechanical changes in bone during and post-LMMS indicates that LMMS could be used to increase long-term mechanical integrity of bone.

The Role of Cannabinoids in Bone Metabolism: A New Perspective for Bone Disorders

Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous remodeling process needs to occur involving the coordinated action of different types of bone cells: osteoblasts (OBs), which have the capacity to produce newly formed bone, and osteoclasts (OCs), which can remove old bone. Bone remodeling is a highly regulated process that requires many hormones and messenger molecules, both at the systemic and the local level. The whole picture is still not fully understood, and the role of novel actors, such as the components of the endocannabinoids system (ECS), including endogenous cannabinoid ligands (ECs), cannabinoid receptors (CBRs), and the enzymes responsible for endogenous ligand synthesis and breakdown, is extremely intriguing. This article reviews the connection between the ECS and skeletal health, supporting the potential use of cannabinoid receptor ligands for the treatment of bone diseases associated with accelerated osteoclastic bone resorption, including osteoporosis and bone metastasis.

Effect of adrenocorticotropic hormone infusion on circulating sclerostin levels

Glucocorticoid use is the most common cause of secondary osteoporosis. Poor skeletal health related to glucocorticoid use is thought to involve inhibition of the Wnt/β-catenin signaling pathway, a key pathway in osteoblastogenesis. Sclerostin, a peptide produced primarily by osteocytes, is an antagonist of the Wnt/β-catenin signaling pathway, raising the possibility that sclerostin is involved in glucocorticoids’ adverse effects on bone. The aim of this study was to determine whether an acute infusion of cosyntropin (i.e., ACTH [1-24]), which increases endogenous cortisol, increases serum sclerostin levels as compared to a placebo infusion. This study was performed using blood samples obtained from a previously published, double-blind, placebo-controlled, randomized, cross-over study among healthy men and women who received infusions of placebo or cosyntropin after being supine and fasted overnight (ClinicalTrials.gov NCT02339506). A total of seventeen participants were analyzed. There was a strong correlation (R2 = 0.65, p < 0.0001) between the two baseline sclerostin measurements measured at the start of each visit, and men had a significantly higher average baseline sclerostin compared to women. As anticipated, cosyntropin significantly increased serum cortisol levels, whereas cortisol levels fell during placebo infusion, consistent with the diurnal variation in cortisol. There was no significant effect of cosyntropin as compared to placebo infusions on serum sclerostin over 6-24 hours (p = 0.10). In conclusion, this randomized, placebo-controlled study was unable to detect a significant effect of a cosyntropin infusion on serum sclerostin levels in healthy men and women.

Effects of Bisphenol A and its Alternatives, Bisphenol F and Tetramethyl Bisphenol F on Osteoclast Differentiation

Bisphenol A (BPA) is a typical environmental endocrine disruptor that exhibits estrogen-mimicking, hormone-like properties and can cause the collapse of bone homeostasis by an imbalance between osteoblasts and osteoclasts. Various BPA substitutes, structurally similar to BPA, have been used to manufacture ‘BPA-free’ products; however, the regulatory role of BPA alternatives in osteoclast differentiation still remains unelucidated. This study aimed to investigate the effects of these chemicals on osteoclast differentiation using the mouse osteoclast precursor cell line RAW 264.7. Results confirmed that both BPA and its alternatives, bisphenol F and tetramethyl bisphenol F (TMBPF), were nontoxic to RAW 264.7 cells. In particular, tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell staining and activity calculation assays revealed that TMBPF enhanced osteoclast differentiation upon stimulation of the receptor activator of nuclear factor-kappa B ligand (RANKL). Additionally, TMBPF activated the mRNA expression of osteoclast-related target genes, such as the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CtsK). Western blotting analysis indicated activation of the mitogen-activated protein kinase signaling pathway, including phosphorylation of c-Jun N-terminal kinase and p38. Together, the results suggest that TMBPF enhances osteoclast differentiation, and it is critical for bone homeostasis and skeletal health.

Diagnosis and Treatment of Adult Growth Hormone Deficiency

Adult growth hormone (GH) deficiency is associated with insulin resistance, elevated cardiovascular risk profile, increased fat mass, reduced muscle mass, skeletal fragility, and impaired quality of life. GH replacement therapy improves body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life, while reducing mortality. Prior to initiation of GH replacement therapy, it is essential to diagnose GH deficiency via a GH stimulation test in adults suspicious of such deficiency. Therapy should be started using (individualized) low dose of GH, followed by titration to the normal range of insulin-like growth factor-1. Clinical improvements should be monitored and side effects should be minimized.

Application of Ultraviolet Light for Poultry Production: A Review of Impacts on Behavior, Physiology, and Production

The application of ultraviolet (UV) light in poultry production is garnering increased interest with the drive toward improved poultry welfare and optimized production. Poultry can see in the UV spectrum (UVA wavelengths: 320–400 nm) thus inclusion of these shorter wavelengths may be viewed as more natural but are typically excluded in conventional artificial lights. Furthermore, UVB wavelengths (280–315) have physiological impact through stimulation of vitamin D pathways that can then improve skeletal health. However, better understanding of the effects of UV supplementation must occur before implementation practically. This non-systematic literature review aimed to summarize the impacts of UV supplementation on the behavior, welfare, and production of laying hens, meat chickens (breeders and growers), and other domestic poultry species including directions for future research. The literature demonstrated that UVA light has positive impacts on reducing fear and stress responses but in some research, it significantly increases feather pecking over age during the production phase. UVB light will significantly improve skeletal health, but an optimum duration of exposure is necessary to get this benefit. Supplementation with UVB light may have more distinct impacts on egg production and eggshell quality when hens are experiencing a dietary vitamin D3 deficiency, or if they are at the terminal end of production. The relative benefits of UVB supplementation across different ages needs to be further verified along with commercial trials to confirm beneficial or detrimental impacts of adding UVA wavelengths. Further research is warranted to determine whether adding natural light wavelengths to indoor poultry production is indeed a positive step toward optimizing commercial housing systems.

A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype

Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up.