High Bone Turnover Research Articles

Abaloparatide Has the Same Catabolic Effects on Bones of Mice When Infused as PTH (1-34).

Abaloparatide is a peptide analog of parathyroid hormone-related protein (PTHrP 1-34) and was approved in 2017 as the second osteoanabolic peptide for treating osteoporosis. We previously showed that intermittent abaloparatide is equally as effective as PTH (1-34). This study was designed to compare the catabolic effects of PTH (1-34) and abaloparatide on bone in young female wild-type mice. Two-month-old C57Bl/6J female mice were continuously infused with human PTH (1-34) or abaloparatide at 80 μg/kg BW/day or vehicle for 2 weeks. At euthanasia, DEXA-PIXImus was performed to assess bone mineral density (BMD) in the whole body, femurs, tibiae, and vertebrae. Bone turnover marker levels were measured in sera, femurs were harvested for micro-computer tomography (μCT) analyses and histomorphometry, and tibiae were separated into cortical and trabecular fractions for gene expression analyses. Our results demonstrated that the infusion of abaloparatide resulted in a similar decrease in BMD as infused PTH (1-34) at all sites. μCT and histomorphometry analyses showed similar decreases in cortical bone thickness and BMD associated with an increase in bone turnover from the increased bone formation rate found by in vivo double labeling and serum P1NP and increased bone resorption as shown by osteoclast numbers and serum cross-linked C-telopeptide. Trabecular bone did not show major changes with either treatment. Osteoblastic gene expression analyses of trabecular and cortical bone revealed that infusion of PTH (1-34) or abaloparatide led to similar and different actions in genes of osteoblast differentiation and activity. As with intermittent and in vitro treatment, both infused PTH (1-34) and abaloparatide similarly regulated downstream genes of the PTHR1/SIK/HDAC4 pathway such as Sost and Mmp13 but differed for those of the PTHR1/SIK/CRTC pathway. Taken together, at the same dose, infused abaloparatide causes the same high bone turnover as infused PTH (1-34) with a net resorption in female wild-type mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Disordered minerals and disease of soft tissue and bones in chronic kidney disease

This article briefly reviews the mineral and bone disorder (MBD) found in patients with chronic kidney disease (CKD) and should provide a useful summary for trainees in nephrology and internal medicine. The storage of minerals is one of the principal roles of our bones, which are alive and are constantly being remodelled under the influence of vitamin D and parathyroid hormone (PTH), aided and abetted by calcium and phosphates. This occurs in a controlled fashion in healthy individuals. In patients with CKD, this control is lost and either an exaggerated, ineffectual remodelling takes place, resulting in the removal (in the case of high-turnover bone disease) or inadequate (in low-turnover bone disease) deposition of minerals. Vascular (and other soft tissue) calcification accompanies MBD, with phosphate and calcium playing major roles in the pathogenesis of the condition.

Denosumab Discontinuation.

To review the pathophysiology, the clinical consequences as well as way of mitigating the effects of denosumab discontinuation. Treatment with denosumab (DMAB) is reversible and upon discontinuation there is a rapid increase in bone turnover and a subsequent bone loss. During this phase of high bone turnover, an increased risk of fractures has been reported. Therefore, treatment with DMAB could be considered life-long. However, side-effects may prompt the need for discontinuation and moreover, treatment with DMAB may have increased BMD to levels where continuing treatment does not provide further fracture risk reduction. Patients stopping DMAB should be offered subsequent antiresorptive treatment with an intense monitoring regimen during the initial year as most of the bone loss occurs within these initial 12 months. In this review, we evaluated the literature published over the past 1 to 3 years investigating DMAB withdrawal with focus on bone turnover markers, bone mineral density, and fracture risk and the transition to other anti-osteoporosis therapies. Furthermore, we summarized the current recommendations of international guidelines. In this review, we evaluated the literature published over the past 1 to 3 years investigating denosumab (DMAB) discontinuation and the transition to other anti-osteoporosis therapies. Additionally, we summarized the current recommendations of international guidelines.

Daphnetin Alleviates Senile and Disuse Osteoporosis by Distinct Modulations of Bone Formation and Resorption.

Senile and disuse osteoporosis have distinct bone turnover status and lack effective treatments. In this study, senescence-accelerated mouse prone 8 (SAMP8) and hindlimb unloading mouse models were used to explore the protective effects of daphnetin on these two types of osteoporosis, and primary osteoblasts and bone marrow monocyte-derived osteoclasts, as well as pre-osteoblast MC3T3-E1, and osteoclast precursor RAW264.7 cells were used to investigate the underlying mechanisms. The results showed that daphnetin administration effectively improved bone remodeling in both senile and disuse osteoporosis, but with different mechanisms. In senile osteoporosis with low bone turnover, daphnetin inhibited NOX2-mediated ROS production in osteoblasts, resulting in accelerated osteogenic differentiation and bone formation, while in disuse osteoporosis with high bone turnover, daphnetin restored SIRT3 expression, maintained mitochondrial homeostasis, and additionally upregulated SOD2 to eliminate ROS in osteoclasts, resulting in attenuation of osteoclast differentiation and bone resorption. These findings illuminated that daphnetin has promising potential for the prevention and treatment of senile and disuse osteoporosis. The different mechanisms may provide clues and basis for targeted prevention and treatment of osteoporosis according to distinct bone turnover status.

ODP595 Case Series Of Idiopathic Hypercalciuria And Secondary Osteoporosis

Abstract Background Secondary causes for low bone density may be present in 30% of women and up to 50% of men with low bone density and osteoporosis. Idiopathic hypercalciuria is associated with lower bone density and higher bone turnover, and an increased risk of fractures. Thiazide diuretics have been used often for treatment for idiopathic hypercalciuriaCase Series: We present a case series of 9 patients who presented for low or declining bone density. They underwent workup for secondary causes of osteoporosis and were noted to have idiopathic hypercalciuria with high bone turnover on initial evaluation. They were started on thiazide diuretics or amiloride and the dose titrated up daily based on their blood pressure tolerance. They were monitored for hypokalemia and hyponatremia. Several of these patients exhibited a > 30% decrease in bone resorption, as measured by urine N-telopeptide on a second fasting specimen. Follow-up bone density at 1 year and 3-year after starting diuretic therapy showed stability or significant increase in bone density. Some of these patients were able to maintain bone density in the osteopenic range on follow up for > 6 years. Conclusion Some patients with idiopathic hypercalciuria may have a more robust response to thiazide diuretics compared to others even in the absence of anti-resorptive therapy. Significant reduction of > 30% in bone resorption markers may identify patients who are more likely to have a robust response in the bone density after starting thiazide medications. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP083 Burosumab Treatment for Fibrous dysplasia/McCune-Albright Syndrome with Severe Spine Deformity

Abstract Introduction Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS) is a rare multi-endocrine disorder with bone abnormalities called polyostonic fibrous dysplasia, presumably related to fibrous growth factor 23 (FGF23). We present a case of a patient with FD/MAS who successfully underwent spinal fusion surgery after efficacious anti-FGF23 treatment using its monoclonal antibody (burosumab). Clinical Case A late teenage boy, clinically diagnosed with FD/MAS, was referred to our hospital for possible treatment of burosumab, because he desperately needed promising medical intervention for bisphosphonate-resistant severe polyostonic fibrous dysplasia with enormously high turnover bone disease. On presentation, he had severe scoliosis (>80 degree-thoracic spine curve) with mild hypophosphatemia (2.5 mg/dL), low 25-hydroxyvitamin D (7.3 ng/mL), normal corrected calcium (9.6mg/dL) and high intact PTH (95.7 pg/mL). His FGF23 level was 90.4pg/mL, which was inappropriately high. He had a history of previous bilateral hip fractures with partially removed Café au macules on the back. Baseline laboratory findings revealed no remarkable signs of endocrinopathies, whereas serum bone markers were remarkably high (tartrate-resistant acid phosphatase 5b, >1500 mU/dL; procollagen type 1 N-propeptide, >1200 ng/mL, alkaline phosphatase, 2638 U/L). He was started on monthly 50mg of burosumab therapy subcutaneously. Interestingly enough, his alkaline phosphatase levels gradually decreased down to 1619 U/L at month 6 post-anti-FGF23 treatment. Subsequent spine fusion surgery was successfully underwent with his thoracic curve corrected by instrumentation. Discussion This is, to our knowledge, the first case with FD/MAS, who was given monthly burosumab, followed by orthopedic spinal instrumentation to straighten the spine curve. Burosumab treatment for FD/MAS may enhance bone flexibility by blocking abnormal FGF23-related signaling, enabling safer approach to promising orthopedic surgeries. Presentation: No date and time listed

PSAT189 Severe Hypocalcemia and Hypophosphatemia Associated with Denosumab use in a Chronic Myeloid Leukemia Patient on Imatinib

Abstract Background Hypocalcemia and hypophosphatemia are known side effects of Denosumab, especially in presence of risk factors including underlying chronic kidney disease, osteoblastic metastasis, high bone turnover states, vitamin D deficiency and preexisting hypocalcemia. We report a unique case of prolonged severe hypocalcemia and hypophosphatemia in a patient with CML on Imatinib, treated with Denosumab for osteoporosis. Clinical case A 73-year-old lady with history of CML, on Imatinib for 4 years and osteoporosis with a chronic L1 compression fracture treated with her second dose of Denosumab 3-months back, presented with complaints of numbness and tingling involving the entire body. Labs revealed severe hypocalcemia (calcium 5.6 mg/dL, ionized calcium 2.93 mg/dL), severe hypophosphatemia, (phosphorus of 0.5mg/dL) and a low normal magnesium level of 1.5mg/dL, with normal ALP, liver and kidney function parameters. Of note she had normal calcium, phosphorus and vitamin D levels before receiving denosumab. Further work-up revealed an elevated PTH level of 241 pg/mL, normal 25 hydroxy vitamin D level of 26.0 ng/ml, slightly low 1,25 (OH) vitamin D of 16pg/ml and an elevated FGF 23 of 299RU/mL (normal <180RU/mL). Her calcium and phosphorus levels remained suboptimal despite treatment with up to 24 grams of calcium carbonate supplementation daily, K-phos 1 packet QID and calcitriol 0.25 mcg TID. 24-hour urine calcium and phosphorus levels were low at 4mg/day and 0.2mg/day respectively. Fractional excretion of phosphate was 13.63%, suggesting renal phosphorus wasting, likely from an elevated FGF23. Bone scan showed no metastatic lesion. After discussion with oncology, Imatinib was held inpatient and she was started on intravenous calcium gluconate infusion, and continued on Calcitriol, vitamin D3 and K-phos supplementation. After receiving almost 18gm of calcium gluconate intravenously over 2 days, her hypocalcemia and hypophosphatemia resolved with improvement in symptoms. Conclusion Hypocalcemia is a recognized adverse effect of Denosumab that is seen in patients with underlying risk factors. Emerging data now suggests the deregulatory effect of long term Imatinib therapy on bone formation by inhibition of osteoclastic activity along with transient increase in osteoblastic activity leading to retention and sequestration of calcium and phosphate in bone, resulting in hypocalcemia and hypophosphatemia. Ours is the first reported case of severe hypocalcemia and hypophosphatemia observed in a CML patient on Imatinib after receiving Denosumab, with resistance to high dose oral calcium and phosphate supplementation, requiring intravenous supplementation and transient discontinuation Imatinib. The elevated FGF 23 likely played a key role in severe hypophosphatemia. This unique case addresses the prospect of occurrence of severe hypocalcemia and hypophosphatemia in patients on Imatinib receiving Denosumab, while questioning the possibility of potentiation of the osteoclast inhibitory effect of this medication when used in patients on long term Imatinib therapy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Aberrant activation of TGF-β1 induces high bone turnover via Rho GTPases-mediated cytoskeletal remodeling in Camurati-Engelmann disease.

In the adult skeleton, the bone remodeling process involves a dynamic coordination between osteoblasts and osteoclasts, which is disrupted in diseases with high bone turnover rates and dysregulated transforming growth factor beta 1 (TGF-β1). However, little is known about how TGF-β1 signaling mediates bone resorption. Here, we described a pedigree with a heterozygous variant in TGF-β1 (R218C) that resulted in aberrant activation of TGF-β1 through an activating mechanism that caused Camurati-Engelmann disease (CED). We showed that CED patients have high levels of active Rho GTPases and the migration-related proteins Integrin β1 and Integrin β3 in their peripheral blood. HEK293T cells transfected with a plasmid encoding this mutant expressed high levels of TGF-β1 and active Rho GTPases. Furthermore, activation of Rho by TGF-β1 increased osteoclast formation and bone resorption, with increased migration of pre-osteoclasts, as well as cytoskeletal remodeling of pre-osteoclasts and mature osteoclasts. Importantly, pharmacological inhibition of Rho GTPases effectively rescued hyperactive TGF-β1-induced osteoclastogenesis in vitro. Overall, we propose that Rho GTPases mediate TGF-β1-induced osteoclastogenesis and suggest that Rho-TGF-β1 crosstalk is associated with high bone turnover in CED.

Roxadustat improves renal osteodystrophy by dual regulation of bone remodeling.

Renal osteodystrophy (ROD), a component of chronic kidney disease-mineral and bone disorder (CKD-MBD) can lead to bone loss increasing fracture risks in CKD patients. Therefore, it is important to prevent and treat ROD. Activation of hypoxia-inducible factor-1α (HIF-1α) signaling was reported to prevent osteoporotic bone loss. Roxadustat, which is used to treat renal anemia in the clinic, is a novel HIF stabilizer. In our study, we aimed to investigate the effects of roxadustat on ROD. We established an adenine-induced CKD rat model. Roxadustat was administered intragastrically to normal and CKD rats for 4 weeks. Hemoglobin concentrations and serum biochemical parameters were tested, and bone histomorphometric analysis was performed. CKD rats exhibited impaired renal function with anemia, secondary hyperparathyroidism and high-turnover ROD-induced significant bone loss. Roxadustat ameliorated renal anemia and attenuated the extreme increase in intact parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) in CKD rats. Bone histomorphometric analysis showed that roxadustat significantly alleviated bone loss and bone microarchitecture deterioration in CKD rats by increasing osteoblast activity and inhibiting osteoclast activity. We did not find that roxadustat had significant effects on bone metabolism in normal rats. Roxadustat can improve ROD via dual regulation of bone remodeling. The use of roxadustat may be a promising strategy to treat osteoporotic bone disorders, such as ROD.

High-salt diet accelerates bone loss accompanied by activation of ion channels related to kidney and bone tissue in ovariectomized rats.

Excessive salt intake can induce a variety of diseases, such as hypertension, cardiovascular disease, kidney disease and so on，it is also one of the factors promoting bone resorption. The mechanism of osteoporosis-induced exacerbations of high salt diet is not well-defined. In this study, we used ovariectomized 6-month-old Sprague Dawley rats to construct a high bone turnover model, and then administrated with high sodium chloride diet (2.0% w/w NaCl, 8.0% w/w NaCl) for 12 weeks to observe the effect of high salt diet on bone metabolism. The results showed that high salt diet could lead to the destruction of bone microstructure, promote the excretion of urinary calcium and phosphorus and accelerate the bone turnover, as well as cause the pathologic structural abnormalities in renal tubular. At the same time, it was accompanied by the up-regulated expression of the epithelial sodium channel (ENaCα), voltage-gated chloride channels (ClC)-3 and the down-regulated expression of Na-Cl cotransporter (NCC), sodium calcium exchanger (NCX1) in femoral tissue and renal tubules. These findings confirm that high salt diet can destroy the microstructure of bone by increasing bone resorption and affect some ion channels of bone tissue and renal tubule in ovariectomized rats.

Roles of Follicle-Stimulating Hormone on Bone Metabolism in Late Postmenopausal Women.

BackgroundThe effects of elevated follicle-stimulating hormone (FSH) levels on physiological changes in the bone remain unclear. This study aimed to clarify the association between FSH concentrations and bone mineral density (BMD) and bone turnover markers (BTM) in late postmenopausal women.MethodsA total of 169 Korean women were enrolled. The participants’ ages ranged from 60 to 84 years (mean age, 69.0±5.1) and reported a mean duration of 19.4±6.6 years since menopause (YSM). The participants showed an average body mass index (BMI) of 24.4±2.8 kg/m2. Age, YSM, estradiol, testosterone, and BMI were confounders in the Pearson’s partial correlation. A test for trends across the quartiles of FSH levels was performed for each variable.ResultsThe mean FSH and estradiol concentrations were 61.5 IU/L and 2.9 pg/mL, respectively. Serum FSH concentration was not significantly associated with BMD (lumbar, r=0.09, P=0.30; total hip, r=0.00, P=0.96; and femoral neck, r=0.05, P=0.62). BTM across the FSH quartiles did not show any trend association (bone-specific alkaline phosphate, P=0.31; cross-linked C-terminal telopeptide of type I collagen, P=0.90). Instead, FSH levels were negatively correlated with BMI (r=−0.34, P=0.00). In the multivariate regression model adjusted for age, testosterone, and estradiol, only BMI showed a negative value across the FSH quartiles (β coefficient −0.11, P=0.00).ConclusionsThis study identified that high FSH concentrations were not associated with bone loss or high bone turnover in women in the late postmenopausal period.

Prognostic value of preoperative serum alkaline phosphatase for predicting 3-year mortality in patients undergoing kidney transplantation: A retrospective study.

Serum alkaline phosphatase (ALP) levels are related to high-turnover bone disease and reflect vascular calcification and inflammation. ALP has been reported to have a prognostic impact in various cohorts including chronic kidney disease. This study investigated whether preoperative serum ALP level could be used for predicting mortality in patients undergoing kidney transplantation. We retrospectively reviewed 1,718 patients who underwent kidney transplantation between November 2005 and June 2017. Finally, 1,533 patients who met the inclusion criteria were classified into tertiles based on preoperative serum ALP level (< 51, 51–72, > 72 IU/L). The incidence of mortality was compared among the three tertiles, and a stepwise logistic regression analysis was performed to evaluate the predictors for mortality. The incidence of 3-year mortality was the highest in the third tertile (1.0% vs. 2.5% vs. 4.4% in the first, second, and third tertile, respectively, p = 0.003). The third tertile of ALP level (odds ratio [OR] 1.855, 95% CI 1.192–2.886, p = 0.006), age (OR 1.052, 95% CI 1.022–1.082, p = 0.011), and history of hypertension (OR 0.401, 95% CI 0.210–0.765, p = 0.006) remained as independent predictors of mortality. Preoperative serum ALP level was significantly higher in the non-survivor group than in the survivor group (58.00 [44.00–76.00] vs. 75.00 [56.25–113.00], p = 0.003). The optimal cut-off value of serum ALP to predict 3-year mortality was 71 IU/L (area under the curve 0.636, 95% CI 0.554–0.719, p = 0.003). Therefore, preoperative serum ALP level was an independent predictor of 3-year mortality in patients undergoing kidney transplantation.

Prevalence of Bone Mineral Disorder in Hemodialysis patients: A Single Centered Study of Local Population

Background: Mineral homeostasis deteriorates when kidney function diminishes, manifesting as variations in blood and tissue levels of calcium and phosphate, followed by the change in circulating parathyroid hormone (PTH). Mineral bone disorders (MBD) are a clinical illness caused by chronic renal disease that expresses as a systemic impairment of mineral and bone metabolism. Aim: To find out prevalence of bone mineral disorders in hemodialysis patients presenting in Nephrology Ward, SIMS. Lahore Methodology: This observational analysis included a total of 88 patients, who were on dialysis at the nephrology department of SHL for the period of more than six months. The study was conducted from 17 September 2021 to 10 March 2022 after the approval of the ethical review board of the Department. According to their blood PTH levels, the patients were split into three groups: those with PTH levels less than 150 pg/ml (low bone turnover), those with PTH levels between 150 and 300 pg/ml (normal bone turnover), and those with PTH levels greater than 300 pg/ml (high bone turnover). Results: The prevalence of bone mineral disorder was 87.5% in hemodialysis patients presenting at the nephrology department, in which prevalence of high turnover bone disorder was 73.9% whereas the prevalence of low turnover bone disorder was 13.6%. In the early dialysis period (0.5-5 years) the prevalence of bone mineral disorders was more prominent as compared to the patients on dialysis for more than 5 years. Conclusion: There was a high prevalence of bone mineral disorders, in which patients with high turnover were found to be more prevalent. Similarly, patients in the early years of dialysis are more prone to develop bone mineral disorders. Thus, we should keep these findings in mind while doing the follow up and adjust the medication accordingly. Keywords: Bone Mineral Disorders, Low Turnover Bone Disorders, Hyper Para Thyroid Disorder, Prevalence of Disease

Bone Specific Alkaline Phosphatase and Serum Calcification Propensity Are Not Influenced by Etelcalcetide vs. Alfacalcidol Treatment, and Only Bone Specific Alkaline Phosphatase Is Correlated With Fibroblast Growth Factor 23: Sub-Analysis Results of the ETACAR-HD Study

Secondary hyperparathyroidism in chronic kidney disease poses a major risk factor for vascular calcification and high bone turnover, leading to mineralization defects. The aim was to analyze the effect of active vitamin D and calcimimetic treatment on fibroblast growth factor 23 (FGF23), serum calcification propensity (T50), a surrogate marker of calcification stress and bone specific alkaline phosphatase (BAP) in hemodialysis. This is a subanalysis of a randomized trial comparing etelcalcetide vs. alfacalcidol in 62 hemodialysis patients for 1 year. We compared the change of BAP and serum calcification propensity between the two medications and assessed the influence of FGF23 change over time. We found no significant differences in the change of BAP or serum calcification propensity (T50) levels from baseline to study end between treatment arms (difference in change of marker between treatment with etelcalcetide vs. alfacalcidol: BAP : 2.0 ng/ml [95% CI-1.5,5.4], p = 0.3; T50: –15 min [95% CI –49,19], p = 0.4). Using FGF23 change over time, we could show that BAP levels at study end were associated with FGF23 change (–0.14 [95% CI –0.21, –0.08], p < 0.001). We did not observe the same association between FGF23 change and T50 (effect of FGF23 change on T50: 3.7 [95% CI –5.1, 12], p = 0.4; R2 = 0.07 vs. R2 = 0.06). No significant difference was found in serum calcification propensity (T50) values between treatment arms. FGF23 was not associated with serum calcification propensity (T50), but was negatively correlated with BAP underlying its role in the bone metabolism.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT03182699].

Effect of vitamin D sterols on bone histology in pre-dialysis patients: Aprospective controlled study.

Abnormalities related to mineral and bone metabolism are a common finding in chronic kidney disease (CKD). Vitamin D compounds are often prescribed to CKD patients with the purpose to control secondary hyperparathyroidism and reduce the risk of high-turnover bone disease. However, data on the effect of vitamin D sterols on bone histology in non-dialysis CKD is limited. A prospective controlled study was conducted on a cohort of 56 patients with CKD stages 3 and 4. 19 patients on calcitriol and 12 patients on cholecalciferol were compared to a group of 25 age- and sex-matched controls. Participants underwent a tetracycline double-labelled transiliac bone biopsy before starting therapy and again 12 months later. Changes from baseline in circulating biomarkers and bone histomorphometric parameters were analyzed. Low-turnover bone disease was the most common pattern of renal osteodystrophy on the initial biopsy. There was no difference in biochemical or histomorphometric values between the three study groups at baseline. Serum intact parathormone (iPTH) and bone formation rate decreased significantly in calcitriol-treated patients, with prevalence of low-turnover bone disease doubling from baseline. In contrast, no significant changes were noted in cholecalciferol-treated and control subjects. Calcitriol was effective in preventing secondary hyperparathyroidism and high-turnover bone disease. However, it was associated with an increased risk of developing or aggravating low-turnover bone disease. In the absence of a bone biopsy, calcitriol use in pre-dialysis CKD should be reserved for patients with a progressive rise in iPTH levels, in whom high-turnover bone disease is suspected.

Cholecalciferol supplementation effectively improved tertiary hyperparathyroidism, FGF23 resistance and lowered coronary calcification score: a prospective study.

IntroductionTertiary hyperparathyroidism (THPT) and vitamin D deficiency are commonly seen in kidney transplant recipients, which may result in persistently elevated fibroblast growth factor 23 (FGF23) level after transplantation and decreased graft survival. The aim of this study is to evaluate the effect of vitamin D supplementation on THPT, FGF23-alpha Klotho (KLA) axis and cardiovascular complications after transplantation.Materials and methodsTwo hundred nine kidney transplant recipients were included and further divided into treated and untreated groups depending on whether they received vitamin D supplementation. We tracked the state of THPT, bone metabolism and FGF23–KLA axis within 12 months posttransplant and explored the predictors and risk factors for intact FGF23 levels, KLA levels, THPT and cardiovascular complications in recipients.ResultsVitamin D supplementation significantly improved FGF23 resistance, THPT and high bone turnover status, preserved better graft function and prevented coronary calcification in the treated group compared to the untreated group at month 12. The absence of vitamin D supplementation was an independent risk factor for THPT and a predictor for intact FGF23 and KLA levels at month 12. Age and vitamin D deficiency were independent risk factors for coronary calcification in recipients at month 12.ConclusionVitamin D supplementation effectively improved THPT, FGF23 resistance and bone metabolism, preserved graft function and prevented coronary calcification after transplantation.

Radium-223 for Metastatic Castrate-Resistant Prostate Cancer

Prostate cancer is a significant cause of morbidity and mortality among men worldwide. Although most patients present with localized or regional disease and experience excellent outcomes with treatment, approximately 10% to 20% of patients develop castrate-resistant prostate cancer (CRPC) within 5 years of diagnosis. Bone metastases, which can cause pain and adversely affect quality of life, are common among this population.Radium-223 has a relatively short half-life and decays via α-decay. Its daughter products, α−particles, have a short path length in tissue and exhibit high linear energy transfer. Together, these properties allow radium-223 to achieve relatively high cell kill in its target tissue while sparing the surrounding normal tissues. Administered in the clinic as radium-223 dichloride (Xofigo), radium-223 acts as a calcium mimetic in the human body, forming complexes with hydroxyapatite. In areas of high bone turnover, such as the osteoblastic bone metastases that are common in patients with CRPC, radium-223 is preferentially incorporated into the bone matrix, where it can exert an antitumor effect.In May 2013, the U.S. Food and Drug Administration approved Xofigo for use in patients with CRPC who have symptomatic bone metastases and no visceral metastases. In this topic discussion, we review the mechanism of action and clinical efficacy of radium-223 in patients with metastatic CRPC. We also discuss its administration and handling, distribution and elimination, and associated toxicities.

Hypocalcemia After the Administration of Denosumab in a Patient With Osteoporotic Fracture and Vitamin D Deficiency

Denosumab is a potent antiresorptive agent used for the treatment of osteoporosis and the prevention of skeletal-related events in patients with multiple myeloma or bone metastasis from solid tumors. Although denosumab generally seems to be safe and well tolerated, denosumab-associated hypocalcemia may occur, and the majority of cases are asymptomatic or mild. Underlying malignancy, renal failure, calcium or vitamin D deficiency, and high bone turnover have been reported as risk factors for hypocalcemia. Here, the author reports a case of hypocalcemia and hypophosphatemia following the administration of denosumab for the treatment of osteoporotic fracture in a patient with underlying but unrecognized severe vitamin D deficiency. Following the supplementation of calcium, vitamin D, and phosphorus, serum calcium and phosphorus levels returned to normal levels after about 2 weeks. To avoid denosumab-associated hypocalcemia, calcium and vitamin D status, as well as renal function should be assessed and corrected if appropriate. J Endocrinol Metab. 2022;12(3):111-115 doi: https://doi.org/10.14740/jem810

Zoledronic Acid use and Adverse Drug Reaction (ADR)

Bone is the part of body that most common for metastasis solid tumors. Bisphosphonates are an effective treatment for preventing bone damage events and improve quality of life patients. Zoledronic acid (ZOL) is the third generation of nitrogen-containing bisphosphonates (NBPs) that can inhibit osteoclasts in the process of bone resorption. Mechanism action of this drug related to affinity with hydroxyapatite crystals of bone, through a high bone turnover result in reducing speed of bone remodeling. This drug has higher affinity compared with other bisphosphonates for bonding hydroxyapatite . Zoledronic acid internalizes into osteoclasts, which disrupts the metabolic process and function of osteoclast cells and accelerates the occurrence of apoptosis. In the other hand it has adverse drug reactions mild to moderate which have reported but the mechanism still unclear such as hypocalcaemia and secondary hypophosphatemia, acute phase response (APR), renal toxicity, and osteonecrosis of the jaw (ONJ). Adverse drug reaction can cause harm to patient indeed arise death, highly recommended to offer monitoring for patients.

MO807: Tenascin-C is a Promising Marker of High-Turnover Bone Disease and Vascular Calcification in Prevalent Haemodialysis Patients

Abstract BACKGROUND AND AIMS Tenascin-C is an extracellular matrix glycoprotein associated with high cell turnover, vascular calcification and atherosclerosis. This study determines the frequency of tenascin-C in uncontrolled intact parathyroid hormone (iPTH) and its relation to vascular calcification in prevalent haemodialysis patients. METHOD A cross-sectional study included 90 prevalent haemodialysis patients divided into two equal groups: uncontrolled iPTH level &amp;gt;300 pg/mL and controlled iPTH (150–300 pg/mL) groups. Serum tenascin-C was measured by ELISA and vascular calcification was assessed by the Adragao score, by plain X-ray on hands, pelvis and vascular access for all patients. RESULTS The prevalence of tenascin-C was 84.4% (38 patients), and vascular calcification was 46.7% (21 patients) in patients with uncontrolled iPTH. Serum tenascin-C can predict high-turnover bone disease (uncontrolled iPTH) at a cutoff value of 7377 ng/mL with AUC 0.794, sensitivity 84.4% and specificity 60%, while predict vascular calcification at a cutoff value of &amp;gt;8859 ng/mL AUC 0.745, sensitivity 72.7%, specificity 72.1%. Tenascin-C was high in patients with uncontrolled iPTH [median (IQR) 637 (4245) ng/mL] compared with patients with controlled iPTH [median (IQR) 211 (143) ng/mL; P-value &amp;lt; .0001]. According to Adragao calcification score, in uncontrolled iPTH, 31.1% (14 patients) had a score 1 and 15.6% (7 patients) had a score 2. All patients with controlled iPTH had a score 0. Patients with vascular calcification had high tenascin-C [median (IQR) 10 697 (53 974) ng/mL] compared with patients without vascular calcification [median (IQR) 7697 (18 000) ng/mL; P-value &amp;lt; .001]. Patients have elevated tenascin-C had 10.3, 3.7 risk to have high-turnover bone disease and vascular calcification [odds ratio (95% confidence interval) 10.3 (3–34.7), 3.7 (1.2–11.1), respectively]. Tenascin-C was positively correlated with iPTH level (r = 0.494; P &amp;lt; .001) in patients with uncontrolled iPTH. CONCLUSION Tenascin-C appears to be a sensitive marker for assessment of high-turnover bone disease and vascular calcification in prevalent haemodialysis patients.