High Bone Turnover Research Articles

Digital radiography as an alternative method in the evaluation of bone density in uremic rats.

ABSTRACTIntroduction:Digital radiography (DRx) may provide a suitable alternative to investigate mineral and bone disorder (MBD) and loss of bone density (BD) in rodent models of chronic kidney disease (CKD). The objective of this study was to use DRx to evaluate BD in CKD rats, and to evaluate the correlation between DRx findings and serum MBD markers and bone histomorphometry.Methods:Uremia was induced by feeding Wistar rats an adenine-enriched diet (0.75% for 4 weeks/0.10% for 3 weeks); outcomes were compared to a control group at experimental weeks 3, 4, and 7. The following biochemical markers were measured: creatinine clearance (CrC), phosphate (P), calcium (Ca), fractional excretion of P (FeP), alkaline phosphatase (ALP), fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). DRx imaging was performed and histomorphometry analysis was conducted using the left femur.Results:As expected, at week 7, uremic rats presented with reduced CrC and higher levels of P, FeP, and ALP compared to controls. DRx confirmed the lower BD in uremic animals (0.57±0.07 vs. 0.68 ± 0.06 a.u.; p = 0.016) compared to controls at the end of week 7, when MBD was more prominent. A severe form of high-turnover bone disease accompanied these biochemical changes. BD measured on DRx correlated to P (r=-0.81; p = 0.002), ALP (r = -0.69, p = 0.01), PTH (r = -0.83, p = 0.01), OS/BS (r = -0.70; p = 0.02), and ObS/BS (r = -0.70; p = 0.02).Conclusion:BD quantified by DRx was associated with the typical complications of MBD in CKD and showed to be viable in the evaluation of bone alterations in CKD.

Skeletal impact of 17β-estradiol in T cell-deficient mice: age-dependent bone effects and osteosarcoma formation.

Estrogen (E2)-dependent ER+ breast cancer, the most common breast cancer subtype, is also the most likely to metastasize to bone and form osteolytic lesions. However, ER+ breast cancer bone metastasis human xenograft models in nude mice are rarely studied due to complexities associated with distinguishing possible tumoral vs. bone microenvironmental effects of E2. To address this knowledge gap, we systematically examined bone effects of E2 in developing young (4-week-old) vs. skeletally mature (15-week-old) female Foxn1nu nude mice supplemented with commercial 60-day slow-release E2 pellets and doses commonly used for ER+ xenograft models. E2 pellets (0.05-0.72mg) were implanted subcutaneously and longitudinal changes in hind limb bones (vs. age-matched controls) were determined over 6weeks by dual-energy X-ray absorptiometry (DXA), microCT, radiographic imaging, and histology, concurrent with assessment of serum levels of E2 and bone turnover markers. All E2 doses tested induced significant and identical increases in bone density (BMD) and volume (BV/TV) in 4-week-old mice with high bone turnover, increasing bone mineral content (BMC) while suppressing increases in bone area (BA). E2 supplementation, which caused dose-dependent changes in circulating E2 that were not sustained, also led to more modest increases in BMD and BV/TV in skeletally mature 15-week-old mice. Notably, E2-supplementation induced osteolytic osteosarcomas in a subset of mice independent of age. These results demonstrate that bone effects of E2 supplementation should be accounted for when assessing ER+ human xenograft bone metastases models.

The Association between Fast Increase in Bone Turnover During the Menopause Transition and Subsequent Fracture.

Bone turnover increases rapidly during the menopause transition (MT) and plateaus above premenopausal levels in early postmenopause. It is uncertain whether higher bone turnover is associated with fracture in midlife women with near-normal bone mineral density (BMD). Examine whether faster increases in bone turnover during the MT (2 years before to 2 years after the final menstrual period [FMP]), and greater bone turnover during early postmenopause (≥2 years after the FMP) are risk factors for subsequent fracture, accounting for BMD. The Study of Women's Health Across the Nation, a longitudinal cohort study of the MT. A total of 484 women (initially pre- or early perimenopausal, who transitioned to postmenopause) with bone turnover (urine collagen type I N-telopeptide), BMD, and fracture data. Incident fracture after the MT. Adjusting for age, race/ethnicity, fracture before the MT, cigarette use, body mass index, and study site in Cox proportional hazards regression, each SD increment in the rate of increase in bone turnover during the MT was associated with 24% greater hazard of incident fracture in postmenopause (P = .008). Accounting for the same covariates, each SD increment in bone turnover during early postmenopause was associated with a 27% greater hazard of fracture (P = .01). Associations remained significant after controlling for MT rate of change and early postmenopausal level of BMD. Faster increases in bone turnover during the MT and greater bone turnover in early postmenopause forecast future fractures.

Evaluation of Lifestyle and Some Biochemical Parameters Involved in Bone Health in Pre and Postmenopausal Cameroonian Women

Aims: A healthy skeletal system with strong bones is essential to overall health. This study aimed to assess lifestyle and bone’s biomarkers of women.
 Study Design: This was a cross-sectional study.
 Place and Duration of Study: The enrollment took place at the Yaounde Military Hospital from November 2016 to July 2017.
 Methodology: A set of 105 postmenopausal and 127 premenopausal participants were enrolled from November 2016 to July 2017 in Yaounde. Their physical activities level was evaluated using a questionnaire. Sunlight exposure between 10:00AM and 4:00PM was assessed. Colorimetric methods were used to evaluate calcium, albumin, and alkaline phosphatase activity in plasma. These parameters were then compared within year since menopause (YSM) and osteoporosis risk assessment instrument (ORAI) sub-groups.
 Results: 13.4% participants were moderately active. Only 22.8% participants had at least 30 minutes sun exposure daily. A multivariable analysis of demographic, lifestyle, biochemical characteristic revealed age, BMI, albumin and calcium were the main factors that influenced bone health among our participants. A significant difference of calcium concentration was found between the two groups whereas albumin was significantly higher in premenopausal than postmenopausal. Albumin was the only variable with a significant difference in the YSM sub-groups while only calcium was non-significantly higher among the ORAI sub-groups.
 Conclusion: Elevated plasma level of calcium, albumin and alkaline phosphatase could be indicators of high bone turnover.

Treatment of hyperphosphatemia: the dangers of aiming for normal PTH levels.

Secondary hyperparathyroidism is part of the complex of chronic kidney disease-associated mineral and bone disorders (CKD-MBD) and is linked with high bone turnover, ectopic calcification, and increased cardiovascular mortality. Therefore, measures for CKD-MBD aim at lowering PTH levels, but there is no general consensus on optimal PTH target values. This manuscript is part of a pros and cons debate for keeping PTH levels within the normal range in children with CKD, focusing on the cons. We conclude that a modest increase in PTH most likely represents an appropriate adaptive response to declining kidney function in patients with CKD stages 2-5D, due to phosphaturic effects and increasing bone resistance. There is no evidence for strictly keeping PTH levels within the normal range in CKD patients with respect to bone health and cardiovascular outcome. In addition, the potentially adverse effects of PTH-lowering measures, such as active vitamin D and calcimimetics, must be taken into account. We suggest that PTH values of 1-2 times the upper normal limit (ULN) may be acceptable in children with CKD stage 2-3, and that PTH levels of 1.7-5 times UNL may be optimal in patients with CKD stage 4-5D. However, standard care of CKD-MBD in children relies on a combination of different measures in which the observation of PTH levels is only a small part of, and trends in PTH levels rather than absolute target values should determine treatment decisions in patients with CKD as recommended by the 2017 KDIGO guidelines.

Low Bone Mineral Density and High Bone Turnover in Patients With Non-Hodgkin's Lymphoma (NHL) Who Receive Frontline Therapy: Results of a Multicenter Prospective Study.

Chemotherapy associated osteoporosis is a severe problem in patients with malignant diseases as it increases the risk for fractures and deteriorates quality of life. There are very limited data in the literature for the effect of chemotherapy on bone metabolism of adult patients with Non-Hodgkin Lymphoma (NHL). We prospectively evaluated bone remodeling pre- and post-chemotherapy in 61 patients with newly diagnosed NHL. First-line chemotherapy resulted in high bone turnover, which led to increased bone loss and reduced bone mineral density (BMD) of lumbar spine (L1-L4) and femur neck (FN). The reduction of L1-L4 and FN BMD post-chemo was more profound in males and in older patients (>55 years). Patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 and FN BMD as compared to 6 cycles. The administration of chemotherapy also resulted in a dramatic increase of bone resorption markers (CTX and TRACP-5b), bone formation markers, (bALP and Osteocalcin) and of osteoblast regulator Dickkopf-1. During study period, one patient had a pathological fracture in his right FN.

Fatal Hypocalcaemia Due to Hungry Bone Syndrome with Secondary Refractory HyperParathyroidism after Parathyroidectomy: A Case Report

IntroductionHungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphatemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. [1]Case reportThis report concerns a dialysed patient who underwent surgical treatment for secondary refractory hyperparathyroidism. Haemodialysis was carried out pre-operatively, and subsequently, a total parathyroidectomy with auto-transplantation of parathyroid tissue in the sternocleidomastoid muscle (SCM) was performed. Rapid and progressive hypocalcaemia symptoms developed during the second day postoperatively. Acute cardiac symptoms with tachyarrhythmia, haemodynamic instability and finally asystole occurred, which required cardiopulmonary resuscitation (CPR). The ionic calcium level was 2.2 mg/dL being consistent with a diagnosis of HBS. A second cardiac arrest unresponsive to CPR followed an initial period of normal sinus rhythm. Death ensued shortly after. Before death, the ionic calcium was 3.1 mg/dL.ConclusionHBS, after parathyroidectomy in patients with secondary hyperparathyroidism (SHPT), may be severe, prolonged and sometimes fatal. Generally, HBS symptomatology is that of a mild hypocalcaemia. It can, however, include heart rhythm disturbances with haemodynamic alterations requiring intensive care measurements and even cardiopulmonary resuscitation. A close clinical and laboratory post-parathyroidectomy monitoring of dialysed patients is of the utmost importance.

Bone Loss and High Bone Turnover in Patients with Non-Hodgkin's Lymphoma Who Receive Frontline Chemotherapy: Final Results of a Multicenter Prospective Study

Bone Loss and High Bone Turnover in Patients with Non-Hodgkin's Lymphoma Who Receive Frontline Chemotherapy: Final Results of a Multicenter Prospective Study

A meta-analysis of serum osteocalcin level in postmenopausal osteoporotic women compared to controls

BackgroundCirculatory osteocalcin (OC) has been widely used as a biomarker to indicate bone turnover status in postmenopausal osteoporosis (PMO). However, the change of serum OC (sOC) level in PMO cases compared to postmenopausal controls remains controversial.MethodsWe searched the online database of PubMed and Cochrane Library. A meta-analysis of case-control studies was performed to compare the pooled sOC level between PMO patients and postmenopausal controls. Subgroup analysis according to potential confounding factors (different OC molecules and regions of the study population) was also performed.ResultsTen case-control studies with 1577 postmenopausal women were included in this meta analysis. We found no significant difference in the pooled sOC level [mean difference (MD) = 1.84, 95% confidence interval (CI): (− 1.49, 5.16), p = 0.28] between PMO patients and controls. Subgroup analysis also revealed no significant difference in intact OC [MD = 1.76, 95%CI: (− 1.71, 5.23), p = 0.32] or N-terminal mid-fragment of the OC molecule [MD = 0.67, 95%(− 5.83, 7.18), p = 0.84] between groups. For different regions, no significant difference in sOC was found in Asian population between cases and controls [MD = -0.06, 95%(− 6.02, 5.89), p = 0.98], while the pooled sOC level was significantly higher in European PMO cases than controls [MD = 3.15, 95%(0.90, 5.39), p = 0.006].ConclusionsOur analysis revealed no significant difference in sOC level between PMO cases and controls according to all the current eligible studies. OC molecules are quite heterogeneous in the circulation and can be influenced by glucose metabolism. Therefore, sOC is currently not a good indicator for the high bone turnover status in PMO. More trials with standardized methodologies for the evaluation of circulatory OC are awaited to update our current findings.

Treatment of hyperphosphatemia: the dangers of high PTH levels.

The control of secondary hyperparathyroidism (SHPT) in pediatric chronic kidney disease is of utmost importance. Even though parathyroid hormone (PTH) is an important biomarker of mineral and bone disorders associated to CKD (CKD-MBD), calcium, phosphate, alkaline phosphatase, and vitamin D are also crucial and should be assessed together. In pediatric dialysis, high PTH levels have been associated with impaired longitudinal growth, bone disease, cardiovascular comorbidities, left ventricular hypertrophy, anemia, and even mortality (when PTH levels were above 500 pg/mL, i.e., 8.3-fold the upper normal limit (UNL)). As such, high PTH levels are for sure deleterious, but too low PTH levels have also been shown to impair growth and to promote vascular calcifications because of the underlying adynamic bone. This manuscript is part of a pros and cons debate for keeping PTH levels within the normal range in pediatric CKD, focusing on the pros. High bone turnover lesions can occur at lower PTH levels than "current" guidelines would suggest; thus, PTH alone is not a good predictor of the underlying osteodystrophy. PTH results can vary locally depending on the assay. Existing guidelines for PTH targets are conflicting and based on a very little evidence. However, the 120-180 pg/mL (2- to 3-fold the UNL) range is common to most of the guidelines; it seems to be a reasonable target in children undergoing dialysis, even though it does not correspond to "normal" PTH levels. As always, the philosophy of PTH levels in pediatric dialysis may be balanced, i.e., "not too low, not too high, and keep phosphate under control."

Pathophysiological characteristics and gene transcriptional profiling of bone microstructure in a low calcium diet fed laying hens

Calcium depletion is a valuable non-invasive tool for studying skeletal system disorders. A low calcium diet (LCD) was used to examine the pathophysiological characteristics and molecular mechanisms of osteoporotic damage in caged laying hens. Sixty 64-wk-old laying hens were randomly housed in single-bird cages, and the cages were divided into 2 treatments: fed a regular calcium diet (RCD, 3.69%) or a LCD (1.56%) for 8 wk. The diet-induced changes of serum bone remodeling indicators, bone strength, microstructure of the distal femur, and the gene expression profiling of keel bone were measured. Compared to RCD hens, LCD hens had higher activity of serum alkaline phosphatase and tartrate resistant acid phosphatase but lower serum calcium concentrations with reduced tibial and femoral mass, width, and strength (P < 0.05). In addition, LCD hens had greater densities of osteoclasts, osteoblasts, connective tissue cells, and osteoid in the trabecular bone (P < 0.05). The transcriptome analysis revealed that 563 unigenes were differentially expressed in keel bone between LCD and RCD hens. The Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed genes were mainly associated with the osteoporosis-related signaling pathways involved in the biological functions of the bone cellular and extracellular structural modulations. The real-time PCR analysis further confirmed that the LCD enhanced the mRNA expression of collagen type 1 alpha 2, integrin-binding sialoprotein and periostin, but inhibited sclerostin expression. These findings indicate that LCD hens have a higher bone turnover and micro-architectural damage compared to RCD hens. The results further evidence dietary supplement of calcium is a critical nutrient strategy for improving hen skeletal health.

Clinical evidence of the effect of bisphosphonates on pregnancy and the infant.

Bisphosphonates (BPs) are potent inhibitors of osteoclast mediated bone resorption. These drugs are widely used in the management of osteoporosis and other diseases, characterized by high bone turnover. The effect of BPs on gestation and lactation, when they are used as therapeutic agents in premenopausal women, is yet unknown. We conducted a detailed literature review and identified the cases of BPs use in young women, as well as, the effects of this therapy on the gestation and the embryo. The published data, regarding the use of BPs in premenopausal women and their effects on the pregnancy outcome, are limited. However, we could identify the outcomes of 40 pregnant women, who had received BPs prior to or during pregnancy, that have been documented in the literature. All women had valid indications to receive BPs for serious bone metabolism conditions. We could not identify any prospective trials, which focus on pregnancy outcomes following after the in-utero exposure to BPs. In total, no serious adverse effects were reported. Problems related to the offspring, such as hypocalcemia and a tendency for low body weight (LBW), were self-resolving. In addition, no serious adverse outcomes were reported for women having completed pregnancy. Nevertheless, follow-up was limited for both outcomes suggesting the necessity of national and international registries.

Denosumab to Prevent High-Turnover Bone Loss After Bariatric Surgery

Denosumab to Prevent High-Turnover Bone Loss After Bariatric Surgery

Commercial Laboratory Reproducibility of Serum CTX in Clinical Practice.

ABSTRACTIn 2011, the International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine selected serum collagen type‐I crosslinked C‐peptide (s‐CTX) as the reference standard for bone resorption. This study aimed to determine the within and between laboratory reproducibility for s‐CTX assays. To create standardized pools, serum was collected from 10 premenopausal and 10 postmenopausal women. Premenopausal sera were pooled to approximate a population with normal bone turnover; postmenopausal sera were pooled to approximate a population with high bone turnover; and a third pool was created from an equal proportion of the pre‐ and postmenopausal pools. Multiple identical aliquots from each pool were created and frozen; all were labeled as routine clinical specimens. To evaluate longitudinal laboratory reproducibility, an identical aliquot from each of the three pools was sent to four US commercial laboratories on five dates over a 6‐month period. To evaluate within‐run reproducibility, each lab received five identical aliquots from each pool on the fifth date. Three labs (Mayo, ARUP, and Quest) used the Roche Diagnostics Elecsys assay, and one (Esoterix/LabCorp) used the IDS‐iSYS assay. Reproducibility was assessed using the coefficient of variation (CV) with 95% confidence intervals (CIs). Labs were unaware of the investigation. Across labs, mean s‐CTX values were 423, 533, and 480 pg/mL for the premenopausal, postmenopausal, and mixed pools, respectively, but the means differed between labs (p < 0.001). The premenopausal pool longitudinal CVs ranged from 5.0% to 14.9%; the postmenopausal pool CVs ranged from 3.4% to 19.3%; and the mixed pool CVs ranged from 3.3% to 16.0%. The longitudinal reproducibility for Esoterix/LabCorp was higher (CV 13.9%; 95% CI, 10.1% to 22.2%) than for the other labs. Within‐run CVs were also higher for Esoterix/LabCorp (CV 8.6%; 95% CI, 6.3% to 13.6%) compared with the other labs (CVs 2.1% to 6.2%). In conclusion, the reproducibility of s‐CTX varied across US commercial labs, and was poorer for Esoterix/LabCorp, which used the IDS assay, compared with the other three labs, which used the Roche assay. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Permian metabolic bone disease revealed by microCT: Paget's disease-like pathology in vertebrae of an early amniote.

Bone remodeling is an essential physiological process in growth and healing. In modern systems deviations from normal bone physiology in the form of pathologies aid in the understanding of normal bone metabolism. Here we use external morphology and X-ray microtomography to diagnose and describe a metabolic bone disease in an amniote from the early Permian. The specimen consists of two fused tail vertebrae of a small varanopid from early Permian (289 million years old) cave deposits near Richards Spur, Oklahoma, USA. Inspection of the outer morphology reveals that the fusion encompasses the vertebral centra, zygopophyses and haemal arches, with the fusion zones distinctly swollen on the left side of the specimen. With visualization of its internal structure by microCT, this specimen is diagnosed as a complex metabolic bone disease. The radiological imaging suggests a pathologically high bone turnover rate, as shown by abnormal bone formation in some areas and increased bone resorption in others. This supports that the varanopid suffered from a metabolic bone disease similar to Paget’s disease of bone as seen in humans today, which is linked to both genetic and viral factors. This finding extends the occurrence of Paget-like disease to the early Permian, and–provided a viral component was present–would also be by far the oldest evidence of viral infection in the fossil record.

Long-term outcomes and management considerations after parathyroidectomy in the dialysis patient.

Parathyroidectomy (PTX) remains an important intervention for dialysis patients with poorly controlled secondary hyperparathyroidism (SHPT), though there are only retrospective and observational data that show a mortality benefit to this procedure. Potential consequences that we seek to avoid after PTX include persistent or recurrent hyperparathyroidism, and parathyroid insufficiency. There is considerable subjectivity in defining and diagnosing these conditions, given that we poorly understand the optimal PTH targets (particularly post PTX) needed to maintain bone and vascular health. While lowering PTH after PTX decreases bone turnover, long-term changes in bone activity have been poorly explored. High turnover bone disease, usually present at the time a PTX is considered, often swings to a state of low turnover in the setting of sufficiently low PTH levels. It remains unclear if all low bone turnover equate with disease. However, such changes in bone turnover appear to predispose to vascular calcification, with positive calcium balance after PTX being a potential contributor. We know little of how the post-PTX state resets calcium balance, how calcium and VDRA requirements change or what kind of adjustments are needed to avoid calcium loading. The current consensus cautions against excessive reduction of PTH although there is insufficient evidence-based guidance regarding the management of chronic kidney disease - mineral bone disease (CKD-MBD) parameters in the post-PTX state. This article aims to compile existing research, provide an overview of current practice with regard to PTX and post-PTX chronic management. It highlights gaps and controversies and aims to re-orient the focus to clinically relevant contemporary priorities in CKD-MBD management after PTX.

Calcitriol loading before total parathyroidectomy with autotransplant in patients with end-stage kidney disease: does it prevent postoperative hypocalcaemia?

Hungry bone syndrome (HBS) is one of the most serious complications following parathyroidectomy for severe hyperparathyroidism. There is a lack of literature informing the treatment and risk factors for this condition and the ideal pre-operative strategy for prevention. The primary aims were to examine the incidence of HBS with pre-operative calcitriol loading for 10 days and to determine the risk factors for HBS. The secondary aims were to determine the rate of intravenous calcium replacement in those with HBS and to assess whether cinacalcet removal has increased rates of parathyroidectomy in the end-stage kidney disease population. We performed a retrospective study from 2011 to 2018 on 45 patients with end-stage kidney disease undergoing total parathyroidectomy with autotransplantation for severe hyperparathyroidism. This was based at the John Hunter and Newcastle Private Hospitals in New South Wales. 28.3% of patients with calcitriol loading undergoing parathyroidectomy fulfilled criteria for HBS. Pre-operative variables that were associated with HBS were elevated parathyroid hormone (P = 0.028) and longer duration of renal replacement therapy (P = 0.033). Rates of total parathyroidectomy were higher after the removal of calcimimetics from the Pharmaceutical Benefits Scheme (P = 0.0024). HBS remains a common complication of parathyroidectomy, even with prolonged high-dose calcitriol loading. This emphasises the need for further trials investigating other targeted therapies, such as bisphosphonates, to prevent HBS. Those most at risk of HBS are patients with high bone turnover and prolonged renal replacement therapy.

Abstract 3936: Efficacy of single agent radium-223 in the syngeneic MBT-2 bladder cancer bone growth model in mice

Abstract Radium-223 dichloride (Ra-223, Xofigo®) is a targeted alpha therapy which prolongs the survival of castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. As a calcium-mimetic, Ra-223 selectively binds to hydroxyapatite and targets areas of high bone turnover such as bone metastases. Here, we report the effects of Ra-223 on development and progression of osteolytic bone lesions and on survival in the syngeneic intratibial MBT-2 murine bladder cancer model in immunocompetent mice. Female 5-7-week-old C3H/HeNHsd mice were injected intratibially with 5x105 MBT-2 cells on day 0. The mice were stratified based on body weight (n=40 per group) on day 5 and Ra-223 (300 kBq/kg, i.v.) or vehicle control was administered on days 5, 33, and 61. The tumor-induced osteolytic lesion area was imaged using radiography on days 10, 18, 25, 76, and at sacrifice. The mice were sacrificed when they met the pre-defined sacrifice criteria (&amp;gt; 20% body weight loss, palpable tumor outgrowth from the bone or general deterioration of health status). The study was terminated on day 158. In this study, the first mice met the sacrifice criteria on study day 24 and the survival curves plateaued at 52% after 84 days in the control group and at 68% after 112 days in the Ra-223 treatment group. Survival on day 40 was significantly improved in the Ra-223 treatment group compared to the vehicle control (p&amp;lt; 0.001), but the effect was not statistically significant at the end of the study. Based on X-ray imaging 25 days after cancer cell inoculation, Ra-223 treatment also significantly decreased the bone lesion area compared to the vehicle treatment (p=0.0041). After initially sacrificing the mice with extensive bone lesions, tumor growth in bone was stabilized around day 25. The main reason for sacrifice at a later stage was breathing difficulties due to lung metastases, and in the Ra-223-treated mice only one mouse was sacrificed due to bone metastases. Ra-223 treatment was well-tolerated; no body weight loss was observed. In summary, radium-223 dichloride (Xofigo®) demonstrates moderate single agent in vivo efficacy in the intratibial MBT-2 murine bladder cancer model of osteolytic bone metastasis. Retaining a functional immune system in syngeneic mouse models is particularly relevant for the characterization of potential immune-stimulatory effects of Ra-223. The promising results obtained in this model warrant further investigation of Ra-223 in combination with immuno-oncological treatments like checkpoint inhibitors. Citation Format: Tiina E. Kähkönen, Mari I. Suominen, Jenni H. Mäki-Jouppila, Birgitta Sjöholm, Ilmari Ahonen, Dominik Mumberg, Karl Ziegelbauer, Jussi M. Halleen, Sanna-Maria Käkönen, Arne Scholz. Efficacy of single agent radium-223 in the syngeneic MBT-2 bladder cancer bone growth model in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3936.

Bone metabolism markers and hungry bone syndrome after parathyroidectomy in dialysis patients with secondary hyperparathyroidism.

To explore the short-term variation in bone metabolic markers and the characteristics of hungry bone syndrome (HBS) after parathyroidectomy (PTX) with forearm autotransplantation in uremic patients with secondary hyperparathyroidism (SHPT) and to provide a basis for the pathogenesis, diagnosis and treatment of metabolic bone disease in SHPT. A total of 115 patients with SHPT receiving PTX from July 2015 to December 2017, hospitalized at the First Affiliated Hospital of Nanjing Medical University, were enrolled in our study. We retrospectively analyzed the baseline clinical data, the levels of bone metabolism markers before and on the third day after PTX, and the risk factors predicting HBS. Preoperative baseline data showed that the levels of bone metabolic markers such as bone metabolism-regulating hormones: iPTH, calcitonin (CT); bone formation markers: phosphatase (ALP), osteocalcin (OC); bone resorption markers: type I collagen cross-linked N-telopeptides (NTX), type I collagen cross-linked C-telopeptides (CTX), tartrate-resistant acid phosphatase 5b (TRAP-5b) were all increased compared to normal levels. The levels of postoperative serum iPTH, CT, CTX and TRAP-5b decreased significantly compared to preoperative levels, while the levels of OC and ALP increased significantly. Of the 115 patients, 101 (87.8%) developed HBS after PTX. High preoperative serum ALP and low preoperative serum calcium level independently predicted the occurrence of HBS. Younger preoperative age, high preoperative serum ALP and iPTH level independently predicted the severity of HBS. In severe SHPT, both bone formation and resorption were active, which suggested the presence of high-turnover bone diseases characterized by up-regulation of osteoclasts-osteoblasts functionally coupling activation in the patients. PTX could promote osteoblast activity and reduce osteoclast activity. HBS was common after PTX. Preoperative higher serum ALP and lower calcium were independent predictors of the occurrence of HBS. Younger patients with higher preoperative ALP and PTH may need to closely monitor serum calcium levels and intensive calcium supplementation after PTX.

Osteoclast-Released Wnt-10b Underlies Cinacalcet Related Bone Improvement in Chronic Kidney Disease.

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/β-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.