Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

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.

Effects of active vitamin D on insulin resistance and islet β-cell function in non-diabetic chronic kidney disease patients: a randomized controlled study

Purpose The purpose of the study is to observe the effects of active vitamin D supplementation on insulin resistance and islet β-cell function (HOMA-β) in patients with non-diabetic chronic kidney disease (NDCKD). Methods A total of 134 patients with NDCKD who met the inclusion criteria were enrolled in the prospective controlled study and categorized as such: 60 patients in the non-dialysis (ND) group; 36, hemodialysis (HD) group; and 38, peritoneal dialysis (PD) group. Each group was divided into two equal-numbered subgroups for vitamin D supplementation. Those in the experimental subgroups received calcitriol 0.5 ug/day orally, and were followed-up for 6 months. A total of 117 patients were followed-up, including 57 patients in the ND group; 29, HD group; and 31, PD group. Changes in the insulin resistance index (HOMA-IR) and HOMA-β index were calculated and compared at the time of enrollment and after 1, 3, and 6 months of intervention. Results (1) Mean HOMA-IR value: In the ND group, mean HOMA-IR value of the experimental group significantly decreased compared with that of the control group after 3 months of intervention (P = 0.02). In the HD and PD groups, there was no statistical difference between the experimental and control groups (P > 0.05). (2) Mean HOMA-β index: In the ND group, mean HOMA-β index of the experimental group was higher than that of the control group after 1 month of active vitamin D treatment (P = 0.03), and, with an extended intervention time, the index gradually increased (P < 0.001). In the HD group, mean HOMA-β index of the experimental group was higher than that of the control group after 3 months of active vitamin D treatment (P = 0.01). Among PD patients, mean HOMA-β index of the patients in the experimental group was higher than that of the control group after 6 months of active vitamin D treatment (P = 0.02). Conclusions Active vitamin D supplementation improved insulin resistance and HOMA-β after 6 months in ND patients, but only improved HOMA-β in the dialysis patients, with no significant effect on insulin resistance.

The Combined Beneficial Effects of Postbiotic Butyrate on Active Vitamin D3-Orchestrated Innate Immunity to Salmonella Colitis

Salmonella spp. Remains a major public health problem globally. Biomedicine is the cornerstone of modern health care and could be a solution for antibiotic-resistant Salmonellosis. Although postbiotics seem to be an effective treatment in various clinical conditions, their clinical effects on Salmonella colitis have not been reported. Our previous report revealed that active vitamin D attenuates the severity of Salmonella colitis and invasiveness by reducing inflammation and enhancing the production of antimicrobial peptides. Therefore, we investigated the synergistic effects of butyrate, the most studied postbiotic, and active vitamin D on the severity of Salmonella colitis, invasiveness of Salmonella, and host immune responses, as well as its novel mechanisms, using in vitro and in vivo studies. We demonstrated that a combination of butyrate and active vitamin D (1 alpha, 25-dihydroxyvitamin D3) synergically reduced the severity of Salmonella colitis in C57BL/6 mice and reduced cecal inflammatory mIL-6, mIL-8, mTNF-α, and mIL-1β mRNA expression, but enhanced the antimicrobial peptide mhBD-3 mRNA, compared to a single treatment. Additionally, upregulated vitamin D receptor (VDR) plays a critical role in the synergistic effects. This suggests combined benefits of butyrate and active vitamin D on Salmonella colitis through VDR-mediated antibacterial and anti-inflammatory responses. The combined use of both supplements could be a potential biomedicine for infectious and autoimmune colitis.

Case report: Osteomalacia due to bisphosphonate treatment in a patient on hemodialysis

Background No publications have reported on osteomalacia in patients receiving intermittent cyclical therapy with etidronate (a bisphosphonate) and undergoing long-term hemodialysis (HD). Case presentation We report on a 46-year-old Japanese man admitted to our hospital for further examination of left forearm pain. Maintenance HD was started at age 24 years, and the man had been on HD since then. At age 38 years, surgical parathyroidectomy was performed for secondary hyperparathyroidism; iliac crest bone biopsy performed at the same time showed osteitis fibrosa. The active vitamin D3 preparation calcitriol was started, and intermittent cyclical etidronate therapy was introduced 2 years later for osteoporosis. At age 45 years, the patient stopped taking calcitriol because of hypercalcemia but continued with etidronate. At age 46 years, a pseudofracture with a Looser zone occurred in the left ulna, and left femur bone biopsy revealed osteomalacia. Etidronate was discontinued, and calcitriol was restarted; open reduction and internal fixation with an angular stability plate were performed. Union of the bone was achieved 10 months after the operation. At age 49 years, a lumber bone biopsy confirmed improved bone morphometry. Conclusions We believe that intermittent cyclical etidronate therapy without administration of active vitamin D3 during long-term HD might have induced osteomalacia, resulting in the ulna insufficiency fracture. Therefore, we propose that administration of active vitamin D3 is essential to prevent osteomalacia in patients on long-term HD who are receiving bisphosphonates and have potential vitamin D3 deficiency.

Inflammation- and Gut-Homing Macrophages, Engineered to De Novo Overexpress Active Vitamin D, Promoted the Regenerative Function of Intestinal Stem Cells

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients’ quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells’ regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)2D, was necessary to maintain Lgr5+ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)2D in intestinal stem cells’ regenerative function. First, to avoid the side effects of systemic high 1,25(OH)2D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)2D concentrations specifically to inflamed intestines. Second, because of the Lgr5+ intestinal stem cells’ active cycling status, we used a pulse-and-chase strategy via 5-bromo-2′-deoxyuridine (BrdU) labeling to trace the Lgr5+ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)2D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)2D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.

PaTH Forward: A randomized, double-blind, placebo-controlled phase 2 trial of TransCon PTH in adult hypoparathyroidism

Context Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. Objective Investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. Design Phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension. Patients Enrolled 59 subjects with hypoparathyroidism. Interventions TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 26-week extension where TransCon PTH dose was titrated (6–60 µg PTH[1-34]/day). Results By Week 26, 91% of subjects treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 mcg/day and calcium (Ca) ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n=44) while normal serum Ca (sCa) was maintained and serum phosphate (sP) and Ca x P fell within the normal range. By Week 26, mean scores on SF-36 domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale Symptom and Impact scores improved through 26 weeks. TransCon PTH was well-tolerated with no treatment-related serious or severe adverse events. Conclusions TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most subjects, achieving normal sCa, sP, uCa, CaxP, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Mortality in Hemodialysis Patients with COVID-19, the Effect of Paricalcitol or Calcimimetics

Background. In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD) patients, there is VD deficiency and markedly reduced calcitriol levels, which may predispose them to worse outcomes of COVID-19 infection. Some hemodialysis patients receive treatment with drugs for secondary hyperparathyroidism, which have well known pleiotropic effects beyond mineral metabolism. The aim of this study was to evaluate the impact of VD status and the administration of active vitamin D medications, used to treat secondary hyperparathyroidism, on survival in a cohort of COVID-19 positive HD patients. Methods. A cross-sectional retrospective observational study was conducted from 12 March to 21 May 2020 in 288 HD patients with positive PCR for SARS-CoV2. Patients were from 52 different centers in Spain. Results. The percent of HD patients with COVID-19 was 6.1% (288 out of 4743). Mortality rate was 28.4% (81/285). Three patients were lost to follow-up. Serum 25(OH)D (calcidiol) level was 17.1 [10.6–27.5] ng/mL and was not significantly associated to mortality (OR 0.99 (0.97–1.01), p = 0.4). Patients receiving active vitamin D medications (16/94 (17%) vs. 65/191(34%), p = 0.003), including calcimimetics (4/49 (8.2%) vs. 77/236 (32.6%), p = 0.001), paricalcitol or calcimimetics (19/117 (16.2%) vs. 62/168 (36.9%); p < 0.001), and also those on both paricalcitol and calcimimetics, to treat secondary hyperparathyroidism (SHPTH) (1/26 (3.8%) vs. 80/259 (30.9%), p < 0.001) showed a lower mortality rate than patients receiving no treatment with either drug. Multivariate Cox regression analysis confirmed this increased survival. Conclusions. Our findings suggest that the use of paricalcitol, calcimimetics or the combination of both, seem to be associated with the improvement of survival in HD patients with COVID-19. No correlation was found between serum VD levels and prognosis or outcomes in HD patients with COVID-19. Prospective studies and clinical trials are needed to support these findings.