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.

Living-donor fresh parathyroid tissue allotransplantation as treatment for permanent hypoparathyroidism: case report

Introduction: the standard hypoparathyroidism treatment consists of replacing calcium and active vitamin D (calcitriol), but it does not correct the underlying abnormality, parathyroid hormone (PTH) deficiency. Both the disease and its treatment are responsible for many morbidities that affect multiple organs and systems. Therefore, parathyroid allotransplantation has been described as an alternative treatment option, especially in refractory cases. Objectives: to verify if parathyroid allotransplantation is effective as a treatment for permanent hypoparathyroidism. Methodology: fresh parathyroid tissue was obtained from a 36-year-old male with a past medical history of hyperparathyroidism secondary to end-stage renal disease and immediately implanted in the recipient’s non-dominant forearm, a 57-year-old female with refractory hypoparathyroidism, despite high doses of calcium and calcitriol replacement. Corticosteroid immunosuppression was performed for 10 days. Results: the allograft showed no evidence of functionality eleven months after transplant. The procedure was considered safe. Conclusion: more studies are required to validate this technique and improve its results.

Vitamin D Serum Levels in Subjects Tested for SARS-CoV-2: What Are the Differences among Acute, Healed, and Negative COVID-19 Patients? A Multicenter Real-Practice Study

Vitamin D might play a role in counteracting COVID-19, albeit strong evidence is still lacking in the literature. The present multicenter real-practice study aimed to evaluate the differences of 25(OH)D3 serum levels in adults tested for SARS-CoV-2 (acute COVID-19 patients, subjects healed from COVID-19, and non-infected ones) recruited over a 6-month period (March–September 2021). In a sample of 117 subjects, a statistically significant difference was found, with acute COVID-19 patients demonstrating the lowest levels of serum 25(OH)D3 (9.63 ± 8.70 ng/mL), significantly lower than values reported by no-COVID-19 patients (15.96 ± 5.99 ng/mL, p = 0.0091) and healed COVID-19 patients (11.52 ± 4.90 ng/mL, p > 0.05). Male gender across the three groups displayed unfluctuating 25(OH)D3 levels, hinting at an inability to ensure adequate levels of the active vitamin D3 form (1α,25(OH)2D3). As a secondary endpoint, we assessed the correlation between serum 25(OH)D3 levels and pro-inflammatory cytokine interleukin-6 (IL-6) in patients with extremely low serum 25(OH)D3 levels (<1 ng/mL) and in a subset supplemented with 1α,25(OH)2D3. Although patients with severe hypovitaminosis-D showed no significant increase in IL-6 levels, acute COVID-19 patients manifested high circulating IL-6 at admission (females = 127.64 ± 22.24 pg/mL, males = 139.28 ± 48.95 ng/mL) which dropped drastically after the administration of 1α,25(OH)2D3 (1.84 ± 0.77 pg/mL and 2.65 ± 0.92 ng/mL, respectively). Taken together, these findings suggest that an administration of 1α,25(OH)2D3 might be helpful for treating male patients with an acute COVID-19 infection. Further studies on rapid correction of vitamin D deficiency with fast acting metabolites are warranted in COVID-19 patients.

Assessment of Calcium and Vitamin D Medications Adherence in Patients with Hypoparathyroidism After Thyroidectomy

Summary: In this study, we found that patients with hypoparathyroidism had a problem with calcium medication compliance, and this problem increased with the duration of the disease. We also showed that patients are concerned about the possible side effects of drugs.Introduction: In this study, we aimed to evaluate adherence to avtive vitamin D and calcium replacement in patients with post surgical hypoparathyroidism.Methods: To elucidate the medication adherence, we performed a questionnaire survey using the six item “Medication adherence questionnaire’’(MAQ). The first, second and sixth questions reflect the motivation status of the patients whereas the third, forth and sixth questions reflect the knowledge about the medication that is received. The responses are scored and patients are classified regarding their motivation to and knowledge about the particular drug.Results: Totally 64 patients (Male:12/Female:52; mean age 48.6±11.6 years) who had postoperative hypoparathyroidism were included in our study. Median disease durance was 60 months (min-max; 12-295 months). We found that motivation score of calcium usage was significantly lower compared to vitamin D usage (p<0.001). The calcium motivation score was reversely correlated with disease duration (r= -0.256 and p=0.046). The most common worry about calcium usage was nephrotoxicity, and the most common worries about calcitriol treatment were kidney damage and polyuria. One third of the patients were taking oral calcium and calcitriol less than the recommended dose.Conclusion: One third of patients lack motivation to use calcium whereas half of the patients’ experiences anxiety about drug related side effects. This is a preliminary study showing that vital calcium and active vitamin D intake may be interrupted due to side effect anxiety and motivation can be increased by frequent visits and acknowledging the patient about the deleterious effects of drug withdrawal.

Teriparatide Administration By The Omnipod Pump: A Self-Managed Therapeutic Option for Refractory Hypoparathyroidism

Context : Hypoparathyroidism (hypoPTH) in adults is mainly due to total thyroidectomy. Conventional therapies (calcium, active vitamin D) can fail to normalize calcemia, expose the patient to hypercalciuria and impact quality-of-life. Human parathormone (hPTH) replacement therapy is a suitable option in these cases, although few clinical reports have been published so far. Methods we describe two cases of refractory postsurgical hypoPTH for which subcutaneous infusion of recombinant parathormone (teriparatide) through the Omnipod® pump was started after failure of all other therapeutic options. Besides, we performed a review of literature of hypoPTH cases treated by continuous infusion of teriparatide. Results two women aged 46 and 61yo failed to normalize calcemia either with conventional treatments (calcium 8g/d + calcitriol 9µg/d and calcium 5g/d + calcitriol 12µg/d) or with thrice-daily subcutaneous injections of teriparatide. As a last resort, teriparatide infusion via Omnipod® device normalized their calcemia and allowed calcium/vitamin D withdrawal, with average teriparatide dose of 23 and 32 µg/day, respectively. Notably, a dedicated protocol currently allow each patient to be autonomous with its pump without adverse dyscalcemia until now. In the literature, 15 adult cases (13 women, mean age 44.5 ± 5.2 yo) are reported. HypoPTH was consecutive to surgery in all of them. Mean dose of teriparatide administered was 25 ± 6 µg/d with improvement of calcemia level and quality-of-life in all patients. Conclusion Continuous administration of teriparatide through Omnipod® is a safe and efficient therapeutic option in refractory hypoPTH, which can, furthermore, be safely self-managed by the patient.

Extended-release calcifediol in stage 3–4 chronic kidney disease: a new therapy for the treatment of secondary hyperparathyroidism associated with hypovitaminosis D

A high percentage of patients with chronic kidney disease have hypovitaminosis D, which is a driver of secondary hyperparathyroidism and an important factor in chronic kidney disease-mineral and bone disorder. Vitamin D deficiency (serum total 25-OH vitamin D levels < 30 ng/mL) occurs early in the course of chronic kidney disease and treatment guidelines recommend early intervention to restore 25-OH vitamin D levels as a first step to prevent/delay the onset/progression of secondary hyperparathyroidism. The vitamin D forms administered to replace 25-OH vitamin D include cholecalciferol, ergocalciferol, and immediate- or extended-release formulations of calcifediol. Most patients with intermediate-stage chronic kidney disease will develop secondary hyperparathyroidism before dialysis is required. Control of parathyroid hormone levels becomes a major focus of therapy in these patients. This article focuses on the position of extended-release calcifediol in the treatment of patients with stage 3–4 chronic kidney disease and secondary hyperparathyroidism with hypovitaminosis D. Several characteristics of extended-release calcifediol support its use in the intermediate stages of chronic kidney disease. The pharmacokinetics of extended-release calcifediol make it effective for replenishing 25-OH vitamin D levels, with minimal impact on vitamin D catabolism from fibroblast-growth factor-23 and CYP24A1 upregulation. Extended-release calcifediol increases circulating 25-OH vitamin D levels in a dose-dependent manner and lowers parathyroid hormone levels by a clinically relevant extent, comparable to what can be achieved by administering active vitamin D analogues, though with a lower risk of hypercalcaemia and hyperphosphataemia. Active vitamin D analogues are reserved for patients undergoing dialysis or pre-dialysis patients with severe progressive secondary hyperparathyroidism. Graphic abstract