Role of Vitamin K in CKD: Is Its Supplementation Advisable in CKD Patients?

<b><i>Background:</i></b> Patients with CKD are at an increased risk of developing vascular calcification (VC) and bone complications which translate into a higher morbidity and mortality. The dephosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP) is considered to be an indicator of vitamin K2 status and correlates with markers of VC. It is activated by γ-glutamyl carboxylase that converts inactive MGP into an active form, and vitamin K2 is a cofactor of this reaction. The active form of MGP is a known inhibitor of arterial wall calcification and plays an important role in bone turnover. Recent studies show poor vitamin K2 status in CKD patients. We aimed to review the literature for the association between vitamin K2 status and calcification and bone disease risk and the efficacy of vitamin K2 supplementation in CKD population. <b><i>Summary:</i></b> Most CKD patients, including those on renal replacement therapy, have vitamin K2 deficiency. The dp-ucMGP level, a marker of vitamin K2 status, is decreased by vitamin K2 supplementation in CKD patients, but there is no unequivocal proof that it influences arterial calcification progression and bone complications. <b><i>Key Messages:</i></b> CKD population are at risk of vitamin K deficiency. Supplementation of vitamin K2 is safe and improves the serum markers of its deficiency. There is lack of strong evidence that vitamin K2 supplementation slows progression of calcification or reduces the frequency of bone complications. More prospective studies are needed.

Giant cell tumor of bone: Effect of longer dosing intervals of denosumab on tumor control and bone related complications.

11525 Background: Giant cell tumor of bone (GCTB) is a benign but locally aggressive bone neoplasm characterized by osteoclast activation causing destructive osteolysis. Denosumab, a human monoclonal antibody against RANK ligand, has emerged as an effective treatment option when surgery is not recommended, but can cause significant bone toxicity. Current standard dosing is every 4 weeks after 3 weekly loading doses. As patients (pts) with GCTB are often young adults, frequent denosumab administration long-term may be burdensome and associated with increased risk of complications. We assessed whether alternative, longer dosing intervals are associated with differences in efficacy or bone toxicity. Methods: Retrospective chart review was conducted on GCTB pts over 18 years old at University of Michigan who received at least 1 year of standard denosumab treatment. Pts were identified using a free-text medical record search engine with keywords “giant cell tumor” and “denosumab” until August 2020. We compared bone-related adverse effects and tumor control in pts who continued denosumab every 4 weeks versus longer treatment intervals. Decision to increase interval between doses was based on provider and pt discussion and preference as part of routine medical care. Results: 37 GCTB pts were identified; 51% female and 49% male. Average age was 41 years (range 22-73). Most common primary location was lower extremity (38%), followed by pelvis (35%), upper extremity (14%), spine (8%), and head/neck (5%). Metastasis were present at start of treatment in 14% of pts, involving lung (n = 4) and spine (n = 1). Pts received median of 71 (range 15-139) total doses of denosumab. Dosing interval was increased in 38% (n = 14). With the first interval change, 43% changed to every 6 weeks, 29% every 8 weeks, and 29% every 12 weeks dosing. Most common final dosing interval was 12 weeks (n = 8). 6 pts (16%) had bone complications after mean of 56 doses. This included osteonecrosis of the jaw (n = 4), atypical fracture (n = 1), and non-healing dental wounds (n = 2). All pts with bone complications were treated on the monthly dosing schedule, but there was no statistically significant difference compared to longer intervals (p = 0.22). Pts with GCT progression (n = 10) were either no longer receiving therapy or had missed denosumab doses. There was no statistically significant difference in PFS with standard vs. interval increased dosing (p = 0.97). However, 5-year PFS was superior with interval increased vs standard dosing (p = 0.036). Conclusions: Increasing the interval of denosumab dosing for GCTB provided similar tumor control as compared to standard dosing and is potentially associated with less bone toxicity and more convenience for afflicted pts. Further larger scale studies are needed to better define the optimal interval of denosumab administration in GCTB and the effect on efficacy, toxicity, and associated health care expense.

Adipokines and Chronic Rheumatic Diseases: from Inflammation to Bone Involvement

Besides its well-known role as energy storage tissue, adipose tissue is a biologically active tissue that can also be considered as an endocrine organ, as it is able to secrete adipokines. These bioactive factors, similar in structure to cytokines, are involved in several physiological and pathological conditions, such as glucose homeostasis, angiogenesis, blood pressure regulation, control of food intake, and also inflammation and bone homeostasis via endocrine, paracrine, and autocrine mechanisms. Given their pleiotropic functions, the role of adipokines has been evaluated in chronic rheumatic osteoarticular inflammatory diseases, particularly focusing on their effects on inflammatory and immune response and on bone alterations. Indeed, these diseases are characterized by different bone complications, such as local and systemic bone loss and new bone formation. The aim of this review is to summarize the role of adipokines in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, osteoarthritis, and osteoporosis, especially considering their role in the pathogenesis of bone complications typical of these conditions.

Childhood‐onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report

Background Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X. Case presentation A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin. Conclusions An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.

Quality of life and pain in patients with metastatic bone disease from solid tumors treated with bone-targeted agents– a real-world cross-sectional study from Switzerland (SAKK 95/16)

Background Bone-targeted agents (BTAs) are widely used in the management of patients with bone metastases from solid tumors. Knowledge of the impact of their routine care use on patient-reported pain and bone pain-related quality of life (QoL) is limited. Methods This real world, cross-sectional study enrolled patients over a 3-month period through oncologists across Switzerland. Patients were ≥ 18 years, had solid tumors and at least one bone metastasis, and received routine care for bone metastases. Physicians provided data on BTA-related practices, risk of bone complications and BTA regimen. Patients completed questionnaires about pain (BPI-SF), general and bone pain-related QoL (FACT-G, FACT-BP) and treatment satisfaction (FACIT-TS-G). Results Eighteen sites recruited 417 patients. Based on the FACT-BP, 42% of the patients indicated not having bone pain. According to the BPI-SF, 28% reported no, 43% mild, 14% moderate, and 15% severe pain, respectively. Patients not treated with a BTA had better overall QoL (FACT-G: p = 0.031) and bone pain-related QoL (FACT-BP, p = 0.007) than those treated with a BTA. All pain and other QoL scales did not differ between groups. Patients perceived at ‘low risk of bone complications’ by their physician not receiving a BTA reported less pain and better QoL than those considered at ‘low risk’ but receiving BTA treatment or those considered at ‘high risk’ regardless of BTA treatment. Overall satisfaction with the treatment was good; almost 50% of patients reporting that they were completely satisfied. Conclusions Overall, pain and QoL did not differ according to BTA treatment or physicians’ risk perception. Patient with low risks not receiving BTA treatment reported least pain and highest QoL scores. These results may suggest that treating physicians assess bone complication risk appropriately and treat patients accordingly, but they need to be confirmed by objective determination of longitudinal skeletal complication risk.

Mechanisms of Bone Impairment in Sickle Bone Disease

Sickle bone disease (SBD) is a chronic and invalidating complication of Sickle cell disease (SCD), a multisystem autosomal recessive genetic disorder affecting millions of people worldwide. Mechanisms involved in SBD are not completely known, especially in pediatric age. Among the hypothesized pathogenetic mechanisms underlying SBD are bone marrow compensatory hyperplasia and bone ischemic damage, both secondary to vaso-occlusive crisis (VOC), which leads to cell sickling, thus worsening local hypoxia with a negative impact on osteoblast recruitment. Furthermore, the hypoxia is a strong activator of erythropoietin, which in turn stimulates osteoclast precursors and induces bone loss. Hemolysis and iron overload due to a chronic transfusion regimen could also contribute to the onset of bone complications. Vitamin D deficiency, which is frequently seen in SCD subjects, may worsen SBD by increasing the resorptive state that is responsible for low bone mineral density, acute/chronic bone pain, and high fracture risk. An imbalance between osteoblasts and osteoclasts, with a relative decrease of osteoblast recruitment and activity, is a further possible mechanism responsible for the impairment of bone health in SCD. Moreover, delayed pubertal growth spurt and low peak bone mass may explain the high incidence of fracture in SCD adolescents. The aim of this review was to focus on the pathogenesis of SBD, updating the studies on biochemical, instrumental, and biological markers of bone metabolism. We also evaluated the growth development and endocrine complications in subjects affected with SCD.

Childhood-onset Systemic Lupus Erythematosus With Trisomy X and the Increased Risk for Bone Complications: A Case Report

Background: Childhood-onset systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease mediated by immune complexes with the age of onset before 18 years. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.Case presentation: A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening over the course of the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further deterioration and osteoporosis. High plasma levels of factor VIII were detected by additional tests for coagulation functions. Conclusions: An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X are at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.

Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

Persistent Hypophosphatemia after Ferric Carboxymaltose Is Associated with Persistent Changes in Biomarkers of Bone Metabolism

Introduction High-dose intravenous (IV) iron formulations are used to correct iron-deficiency anemia in patients when there is a clinical need to deliver iron rapidly or to treat patients who do not tolerate or fail to respond to oral iron. Hypophosphatemia is an important adverse effect of some IV iron formulations. Persistent hypophosphatemia is associated with bone complications, including osteomalacia. In two recent head-to-head trials, ferric carboxymaltose (FCM) induced marked increases in the phosphaturic hormone fibroblast growth factor 23 (FGF23), which led to significantly higher rates of incident and persistent hypophosphatemia than in patients treated with ferric derisomaltose (FDI) (Wolf et al. JAMA. 2020;323:432-43). Here, we present a post hoc analysis of patients with incident hypophosphatemia in which we investigated predictors of persistent hypophosphatemia and tested whether persistent hypophosphatemia was associated with persistent changes in biomarkers of bone metabolism, which could help explain bone complications that have been linked to FCM in numerous case reports. Methods We analyzed pooled data from two open-label, randomized clinical trials that compared the US dosing of FCM (2 doses of 750mg administered 1 week apart; N=117) to FDI (1 dose of 1000mg; N=125). In this analysis only patients who developed incident hypophosphatemia (serum phosphate &lt;2.0 mg/dL) after treatment were included. This subgroup was then classified according to their serum phosphate at the end of the trials' observation period on day 35 as either 'recovered' (≥2.0 mg/dL) or 'persistent' (&lt;2.0 mg/dL). We used multivariate logistic regression analyses with forward stepwise selection to identify baseline predictors of persistent hypophosphatemia. To better understand the effects of persistent hypophosphatemia on bone health, we compared changes in biomarkers of bone metabolism in patients who developed persistent hypophosphatemia with those who recovered from hypophosphatemia. Results Overall, 90 patients (FDI, n=8; FCM, n=82) who developed incident hypophosphatemia were classified as 'recovered' or 'persistent'. All 8 patients who developed hypophosphatemia after FDI recovered. In the FCM group, hypophosphatemia recovered in 43% of patients (n=35) and persisted in 57% (n=47). Besides FCM use, no baseline predictor could independently distinguish patients who developed hypophosphatemia and recovered from patients who experienced persistent hypophosphatemia. Within the FCM group, patients who developed persistent hypophosphatemia had greater increases in intact FGF23 on day 8 compared to patients who recovered (mean change from baseline to day 8 [95% CI]: 471.3 pg/mL [402.7 to 539.9] vs 228.3 pg/mL [186.8 to 269.9]). Compared to patients who recovered from hypophosphatemia, patients in whom hypophosphatemia persisted also had significant and persistent differences in multiple biomarkers at study end on day 35 (mean change from baseline to day 35 [95% CI]): increased intact FGF23 (58.7 pg/mL [40.8 to 76.5] vs -0.1 pg/mL [-6.7 to 6.5); increased parathyroid hormone (38.6 pg/mL [26.6 to 50.5] vs 14.5 pg/mL [4.5 to 24.5]); decreased 1,25-(OH)2-vitamin D (-35.1 pg/mL [-39.1 to -30.9] vs -3.4 pg/mL [-8.5 to 1.7]); and decreased N-terminal pro-peptide of type 1 collagen (-22.5 ng/mL [-26.3 to -18.6] vs -6.1 ng/mL [-11.1 to -1.1]). Conclusion Persistent hypophosphatemia developed only in patients who received FCM. Baseline characteristics could not discern whether patients with incident hypophosphatemia would remain persistently hypophosphatemic or go on to recover by study end. Persistent hypophosphatemia resulted in similarly persistent changes in biomarkers of bone metabolism. These findings suggest that treatment with FCM may affect bone health, especially in patients with persistent hypophosphatemia, and may help explain the association of FCM with osteomalacia and fractures that has been described in several case reports. Disclosures Wolf: Akebia: Consultancy, Honoraria; Amag: Consultancy, Honoraria; Ardelyx: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pharmacosmos: Consultancy, Honoraria; Bayer: Consultancy. Schaefer:Vifor Pharma: Honoraria; Pharmacosmos A/S: Honoraria, Research Funding. Zoller:Pharmacosmos A/S: Consultancy, Honoraria, Research Funding; Vifor Pharma: Consultancy, Honoraria.