Paget's disease of bone

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Paget’s disease of bone: an osteoimmunological disorder?

Paget’s disease of bone: an osteoimmunological disorder?

Abstract: Osteoimmunology represents a large area of research resulting from the cross talk between bone and immune systems. Many cytokines and signaling cascades are involved in the field of osteoimmunology, originating from various cell types. The RANK/receptor activator of nuclear factor Kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling has a pivotal role in osteoimmunology, in addition to proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17. Clinically, osteoimmunological disorders, such as rheuma- toid arthritis, osteoporosis, and periodontitis, should be classified according to their pattern of osteoimmunological serum biomarkers. Paget’s disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation. With the exception of the cellular responses to measles virus nucleocapsid protein and the interferon-gamma signature, the exact role of the immune system in Paget’s disease of bone is not well understood. The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders. As a potential osteoimmunological disorder, the treatment of Paget’s disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition. Keywords: Paget’s disease of bone, SQSTM1/p62, osteoimmunology, osteoclast, RANKL
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Current options for the treatment of Paget’s disease of the bone

Current options for the treatment of Paget’s disease of the bone

Abstract: Paget’s disease of bone (PDB) is a chronic bone remodelling disorder characterized by increased osteoclast-mediated bone resorption, with subsequent compensatory increases in new bone formation, resulting in a disorganized mosaic of woven and lamellar bone at affected skeletal sites. This disease is most often asymptomatic but can be associated with bone pain or deformity, fractures, secondary arthritis, neurological complications, deafness, contributing to substantial morbidity and reduced quality of life. Neoplastic degeneration of pagetic bone is a relatively rare event, occurring with an incidence of less than 1%, but has a grave prognosis. Specific therapy for PDB is aimed at decreasing the abnormal bone turnover and bisphospho- nates are currently considered the treatment of choice. These treatments are associated with a reduction in plasma alkaline phosphatase (ALP) activity and an improvement in radiological and scintigraphic appearance and with a reduction in bone pain and bone deformity, Recently, the availability of newer, more potent nitrogen-containing bisphosphonates has improved treatment outcomes, allowing a more effective and convenient management of this debilitating disorder.
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Current perspectives on bisphosphonate treatment in Paget’s disease of bone

Current perspectives on bisphosphonate treatment in Paget’s disease of bone

In spite of that, there were no significant differences identified in quality of life, overall bodily pain, or in pagetic bone pain between the groups. Similarly, hearing thresholds, as assessed by audiometry, did not change significantly and did not differ between the treatment groups. Furthermore, there was no significant difference both in the incidence of clinical fractures and in the number of orthopedic surgery required between the two groups. Clinical fractures occurred in 46 of 661 patients (7.0%) in the intensive treatment group as compared with 49 of 663 patients (7.4%) in the symptomatic treatment group, and orthopedic surgery was required in 50 of 661 patients (7.3%) in the former and in 55 of 663 patients (8.3%) in the latter. It was concluded by the investigators that aiming to maintain normal ALP levels with intensive bisphosphonate therapy conferred no clinical advantage over symptom-driven management in patients with established Paget’s disease of bone.
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Emerging strategies and therapies for treatment of Paget’s disease of bone

Emerging strategies and therapies for treatment of Paget’s disease of bone

Figure 2 Pathogenesis of Paget’s disease of bone: viral and genetic interactions, unifying hypothesis. Schematic models of cytoplasmic autophagy in A) normal hematopoietic progenitors with adequate clearance of the autolysosome by the proteasome, B) hematopoietic progenitors carrying a germline SQSTM1/p62 mutation leading to defective p62-mediated autophagy, accumulation of p62, further amplifying the process, and p62 aggregates, C) hematopoietic progenitors with persistent measles virus infection and replication leading to impaired autophagy with accumulation of MvNP/p62 aggregates, D) persistent measles virus infection of hematopoietic progenitors carrying a germline SQSTM1/p62 mutation further amplifies the genetically-induced defective p62-mediated autophagy. B–D) These abnormalities in the autophagy process are perpetuated in cells differentiated from the hematopoietic cells with specific functional consequences on mature osteoclasts (see text).
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<p>Response to Pyrotinib in a Chinese Patient with Bone-Metastatic Scrotal Paget&rsquo;s Disease Harboring Triple Uncommon HER2 Mutation: A Case Report</p>

<p>Response to Pyrotinib in a Chinese Patient with Bone-Metastatic Scrotal Paget&rsquo;s Disease Harboring Triple Uncommon HER2 Mutation: A Case Report</p>

Case Presentation: We present a case of a Chinese patient with bone-metastatic scrotal Pagets disease harboring triple uncommon HER2 mutations (R678Q/S310Y/S310F). Due to poor conditions (severe anemia, thrombocytopenia, ECOG PS3), this patient could not tolerate traditional chemotherapy and radiotherapy. Then, the patient participated in a registered clinical trial (NCT03239015) about basket trial for intractable cancer. The patient received pyrotinib (400 mg po qd) and achieved a partial response for 4.0 months. Conclusion: This is the fi rst report describing a patient with scrotal Pagets disease harbor- ing triple uncommon HER2 mutation who responds well to pyrotinib. This case suggested that HER2 mutation is also a potential biomarker for treatment in extramammary Pagets disease and pyrotinib may be an ideal choice for these patients.
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Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant

Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant

Valosin-containing protein (VCP) is a ubiquitous member of the AAA-ATPase supergene family. VCP is known to play an important role in cellular activities including ubi- quitin (Ub) -dependent protein degradation [1], chromatin- associated protein degradation [2], messenger ribonucleic acid (mRNA) metabolism [3], autophagy [4], anti-apoptotic function [5], and post-mitotic Golgi apparatus reassembly [6]. Mutations in the VCP gene were first found to cause inclusion-body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) [7,8]. IBMPFD is an autosomal dominantly inherited disorder with variable penetrance of 3 predominant phenotypic features, i.e., my- opathy, Paget disease of bone, and frontotemporal demen- tia (FTD) [9]. The penetrance of the gene is 82% for myopathy, 49% for Paget’s disease, and 30% for FTD [10]. IBMPFD patients with VCP mutations can develop disor- ders in other organ systems including sphincters [11], car- diac muscles [12], auditory system [13], and liver [14], as well as in visuoconstructive ability [14]. Neurodegenerative diseases associated with a VCP mutation encompass scapu- loperoneal muscular dystrophy and dropped head syn- drome [15], Parkinson’s disease [16-18], hereditary spastic paraplegia [19], and cerebellar ataxia [20]. In addition to mutations in VCP [7,8], mutations in Heterogeneous Nu- clear Ribonucleoprotein A2B1 (HNRNPA2B1) and Heteroge- neous Nuclear Ribonucleoprotein A1 (HNRNPA1) [21] have been identified in families with IBMPFD. Given these ob- servations, the name of multisystem proteinopathy (MSP) has been proposed, using the nomenclature of MSP1 for IBMPFD caused by a VCP mutation, MSP2 for IBMPFD related to an HNRNPA2B1 mutation, MSP3 for IBMPFD related to an HNRNPA1 mutation, and MSP4 for IBMPFD due to some unidentified gene [22]. Clinically, 37.7% pa- tients of IBMPFD with a VCP mutation (MSP1) develop FTD [9]. FTD cases with a VCP mutation (MSP1) present with TAR DNA-binding protein 43 kDa (TDP-43) and ubiquitin-positive short dystrophic neurites and frequently lentiform neuronal intranuclear inclusions in their neocor- tex [23-25]. On the other hand, only rare VCP-positive neuronal intranuclear inclusions are detected, and those that are detected lack the characteristic lentiform morph- ology [23]. This finding suggests that TDP-43 and ubiquitin positive-inclusions do not contain VCP and supports the idea that VCP gene mutations in IBMPFD produce a dominant-negative loss of VCP function [23,25].
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Clinical Reasoning: Progressive proximal weakness in a 56-year-old man with bone pain

Clinical Reasoning: Progressive proximal weakness in a 56-year-old man with bone pain

Rimmed vacuoles are a nonspecific finding in many myo- pathies, including sporadic IBM (sIBM) and myofibrillar myopathy (MFM). As noted previously, the patient’s pattern of muscle involvement was not typical for sIBM. There was no amorphous or granular material on muscle histology and EM did not show myofibrillar degeneration to support MFM. Interestingly, rimmed vacuoles can also be found in a rare inherited spectrum of disorders known as inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). Knowing our patient was recently di- agnosed with PDB, there was thus high clinical suspicion for this disorder. 3–5
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Paget disease of bone

Paget disease of bone

Several observations suggest that environmental factors may also contribute to the pathogenesis of PD. The variable penetrance of PD within families with a genetic predisposition to PD, the obser- vation that the disease remains highly localized to a particular bone or bones rather than affecting the entire skeleton, and the fact that the incidence and severity of the disease has been chang- ing over the last 25 years (83, 84) all support the hypothesis that additional, nongenetic factors are involved in the development of PD. PD affected approximately 2–8% of the population in the United Kingdom and New Zealand 20 years ago, but recent studies of the prevalence of PD in subjects of European origin in 2 New Zealand cities found that the prevalence of PD was about half of what had been estimated 25 years ago (84). Similarly, Van Staa and coworkers recently conducted a radiologic survey in 10 British cit- ies and found a decrease in the incidence of PD compared with the findings of the original studies performed some 20 years earlier (83). These reports suggest that an additional, nongenetic factor(s) Biochemical markers of bone remodeling
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				A CASE STUDY ABOUT THE EFFECT OF ASTHISHRIKLA GHRIT MATRA VASTI IN THE MANAGEMENT OF ASTHIKSHAYA W.S.R.TO. OSTEOPOROSIS

← Return to Article Details A CASE STUDY ABOUT THE EFFECT OF ASTHISHRIKLA GHRIT MATRA VASTI IN THE MANAGEMENT OF ASTHIKSHAYA W.S.R.TO. OSTEOPOROSIS

hyperparathyroidism. PTH is secreted in response to low serum calcium levels. It increases calcium re-absorption from bone, decreases renal calcium excretion, and increases renal production of 1,25- dihydroxyvitamin D (1,25[OH]2 D)-an active hormonal form of vitaminD that optimizes calcium and phosphorus absorption, inhibits PTH synthesis, and plays a minor role in bone re-absorption. Around the world herbs are in use for thousands of years to treat several health conditions.One of the herbs that have shown significant beneficial effects on bone healing belong to the Cissus family of plants. Cissus quadrangularisis a medicinal herb used as a general analgesic tonic it’s also known as ASTHISHRINKHALA. It is used especially for bone fracture healing, in Ayurvedic medicine since ancient times. ASTHISHRINKHALA contains a high amount of Vitamin C, carotene A, anabolic steroidal substance and calcium. To give effective relief to the patient, Ayurvedic science is a boon for such cases through Shodhana and Shamana formulations. ASTHISHRIKLA GHRIT MATRA vasti is among such preparations. In this study, we will found the incredible effect of Vasti in osteoarthritis. ASTHISHRIKLA has strengthening effects on bones, joint, ligaments, and muscles. It is primarily used for treating the diseases related to these structures. It increases mineralization in the bone and promotes the formation of the mineral nodules. It promotes osteoblastic proliferation and differentiation. It increases bone mineral density (BMD) and reduces the susceptibility to bone fracture. (3)
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Original Article Expression of vascular endothelial growth factor and basic fibroblast growth factor in extramammary Paget disease

Original Article Expression of vascular endothelial growth factor and basic fibroblast growth factor in extramammary Paget disease

Abstract: Extramammary Paget’s disease (EMPD) is a special type of cancers. The etiology of the disease is still unclear. We aimed to study the expression differences of vascular endothelial growth factor (VEGF) and basic fibro- blast growth factor (bFGF) in EMPD tissues and corresponding adjacent normal tissues. The mRNA expression was detected by RT-PCR and the protein expression was explored by immunohistochemistry. Higher immunostaining signal scores of bFGF and VEGF in EMPD tissues had been found (z = -3.827, P < 0.001, z = -3.729, P < 0.001, respectively). In addition, the mRNA expression of bFGF and VEGF was higher in EMPD tissues, which had been validated by RT-PCR (t = 5.771, P < 0.001, t = 3.304, P = 0.004, respectively). The VEGF and bFGF might be the key signaling proteins in angiogenesis of EMPD. How to block the VEGF and bFGF in EMPD and to destroy the blood supply of the tumor cells becomes the focus of our future research.
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Ex vivo exposure of bone marrow from chronic kidney disease donor rats to pravastatin limits renal damage in recipient rats with chronic kidney disease

Ex vivo exposure of bone marrow from chronic kidney disease donor rats to pravastatin limits renal damage in recipient rats with chronic kidney disease

Interestingly, 6 weeks of systemic in vivo treatment with pravastatin did not influence CKD progression or renal fibrosis in our model of established CKD. Although cholesterol-lowering effects of statins do not occur in ro- dents, pleiotropic effects have been reported [40] such as reduced inflammation and oxidative stress, enhanced endothelial function and increased mobilization and function of EPCs. Some older studies showed beneficial effects of statins on renal function and morphology in experimental CKD, although others reported harmful ef- fects such as induction of renal fibrosis [41,42]. Recently, Geng and colleagues performed a meta-analysis on the effect of statins on renal function (estimated GFR and proteinuria) in patients with CKD. The analysis showed that the beneficial effect of statins on renal function may be dose and time dependent and that statins are well tolerated in patients with National Kidney Foundation Kidney Disease Outcomes Quality Initiative stages 1 to 3. However, the effect of statins on renal function in National Kidney Foundation Kidney Disease Outcomes Quality Initiative stages 4 and 5 remains controversial [43]. The lack of effect of statin treatment in our in vivo study cannot be explained by insufficient dosing of prav- astatin. Similar statin doses have previously been shown to increase EPC mobilization in mice [44]. Furthermore, we observed a significant decrease in triglycerides and an increase in HMGCR mRNA expression after sys- temic pravastatin treatment, which indicates that the dose was sufficient to affect the mevalonate pathway, and is in agreement with Zager and colleagues [45].
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Fibroblast growth factor 23 contributes to diminished bone mineral density in childhood inflammatory bowel disease

Fibroblast growth factor 23 contributes to diminished bone mineral density in childhood inflammatory bowel disease

Controversy exists about the relation between decreased BMD and fracture risk among children with IBD [53]. However, low BMD during childhood is associated with increased fracture risk later in life [54]. Bone metabolism in children is characterized by predominant bone modeling with simultaneous activity of both osteoblasts and osteoclasts on different parts of the bone. Therefore, the principles of bone loss observed in adult patients with chronic inflammation are not directly applicable to children [55]. Understanding the specific underlying mechanisms for decreased BMD among children with IBD may help to implement more effective therapies for this complication.
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Mineral bone disorders (MBD) in patients on peritoneal dialysis

Mineral bone disorders (MBD) in patients on peritoneal dialysis

may influence the grade of vascular calcification and osteoporosis. In addition, high-glucose PD solution may lead to low-turnover bone, and further studies are needed to explore whether it is true or not. Moreover, continuous renal replacement therapy may be associated with a change in bone metabolism or vascular calcification. While a loss of circadian rhythm is a characteristic of sec- ondary hyperparathyroidism, a continuous replacement therapy will affect the PTH level. Updated clinical practice guideline for the management of CKD-MBD in Japanese dialysis patients will be published in the near future.
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Sclerostin : a key regulator of bone metabolism

Sclerostin : a key regulator of bone metabolism

Bone loss following the exogenous administration of glucocorticoids is biphasic with an initial rapid phase occurring during the first months of treatment followed by a prolonged phase of much slower bone loss. It has been postulated that during the initial phase an imbalance between bone resorption and bone formation, in favor of resorption, is the predominant pathogenetic factor for bone loss while during the second, chronic, phase reduced bone formation and osteocyte apoptosis are the main determinants of bone strength (17). Our findings in patients with chronic endogenous hypercortisolism are consistent with this sequence of events. Thus, in the presence of chronic glucocorticoid excess sclerostin does not seem to affect bone formation but its values in blood may be a measure of the function and/or number of osteocytes. However, sclerostin may very well be directly involved in the initial phase of bone loss induced by glucocorticoids. This could not be studied in our patients but we previously showed that treatment of a patient with sclerostin deficiency with prednisone reduced both resorption and formation markers and we suggested that sclerostin plays an important role in the modulation of bone resorption by glucocorticoids while it does not affect their action on bone formation (18). Furthermore, mice treated with dexamethasone were protected from glucocorticoid-induced bone loss, when they were simultaneously treated with a neutralizing antibody against sclerostin (7). In these mice the protective effect of the sclerostin antibody was mainly due to the stabilization of bone resorption, with no evident effect on bone formation. Sclerostin is thought to act predominantly as an inhibitor of bone formation but a recent study has shown that sclerostin can also stimulate osteoclast differentiation and function, by a RANKL-mediated mechanism in osteocytes (19). In addition, inhibition of RANKL by OPG reduces the rate of osteocyte apoptosis in glucocorticoid-treated mice (20). Thus, although we found no evidence for a role of sclerostin in glucocorticoid-induced suppression of bone formation during long-standing endogenous hypercortisolism, sclerostin may play a role in the early phase of glucocorticoid-induced bone loss. Further studies are needed to address these questions.
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Mandibular bone mineral density in patients with Beh&ccedil;et&rsquo;s disease

Mandibular bone mineral density in patients with Beh&ccedil;et&rsquo;s disease

The study included 45 adults with BD (male/female: 24/21) and 30 volunteer healthy adults (male/female: 15/15) as a control group. All patients gave informed written con- sent. A questionnaire was used to collect information on age, sex, disease history, drug status, menopausal status, weight, and height. The control group was randomly chosen from patients in the Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Afyon Kocatepe University. All BD patients were receiving 1–1.5 mg/day of colchicines therapy.

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Lung function and associations with multiple dimensions of dental health: a prospective observational cross sectional study

Lung function and associations with multiple dimensions of dental health: a prospective observational cross sectional study

Only few authors have considered radiologic abnormal- ities assessed by orthopantomogramms with regard to lung function; these studies addressed alveolar bone loss with regard to the presence of COPD. In the investigation by Wang and co-workers [22], the higher alveolar bone loss in COPD marginally failed statistical significance in univariate analysis, whereas in another study [12] it was very well associated with COPD. Similarly, Leukfeld and colleagues [14] observed that a mean marginal bone level  ≥4  mm was associated with COPD independent of other risk factors for periodontitis. We found radio- logic abnormalities in 47.9 % of subjects but no signifi- cant associations with lung function. Similar results were obtained when including patients with alveolar bone loss of  ≥1 only (41.3  %). Possibly, radiologic abnormalities only occur in very advanced respiratory disease [14], but not in a general population as studied by us.
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Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn’s disease

Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn’s disease

When considering HSCT, the question remains whether its risk to benefit ratio justifies it. Observations of case re- ports published to date suggest that sustained clinical re- mission with HSCT is initially likely to result from lymph ablation by drugs used in the conditioning regimen; altered immune reconstitution may be a later effect. Temporarily disrupting the immunological memory and ceasing the chronic inflammatory burden using non-ablative HSCT has been shown to be effective in non-controlled study de- signs [9]. However, the recent ASTIC trial [13] failed to demonstrate a statistically significant improvement in sus- tained disease remission at 1-year of HSCT. According to our study, the pooled rate of clinical remission was 73% (95% CI 36 – 93) for patients who underwent autologous HSCT, which was higher than 23% (95% CI 7 – 54) for patients who received ASC. Based on these trial findings, further study of HSCT in patients with refractory CD may be warranted.
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Cross Sectional study on Metabolic Bone disease in non cholestatic chronic liver disease.

Cross Sectional study on Metabolic Bone disease in non cholestatic chronic liver disease.

Cirrhosis (chronic liver disease) represents a disorder which causes progressive hepatic fibrosis characterized by distorted liver architecture and the formation of nodules which are regenerative. Cirrhosis of any cause is usually not reversible when it is in the advanced stages at which the only option available may be liver transplantation. However, in recent times reversal of cirrhosis has been reported in several forms of liver disease following treatment of the underlying cause if detected in its early stages. Patients with cirrhosis are prone to a variety of complications.
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Radiographic features of osteogenesis imperfecta

Radiographic features of osteogenesis imperfecta

normal children who suffer trauma and usually consoli- date within the normally expected times. Some children may have few or no fractures, whereas others experience numerous fractures throughout their lives, especially when they start walking. The most common fractures occur in the long bone diaphyses, the spine and the apophyses. Diaphyseal fractures may be complete (Fig. 6) or incomplete (Fig. 7), and more or less displaced. In the spine, multiple thoracolumbar compres- sion fractures may be seen (Fig. 8). Spondylolysis of L5, with or without consecutive spondylolisthesis, is also common in children with OI due to a fracture (Fig. 9) or an elongation of the pars interarticularis of L5, all of which are fostered by bone fragility and/or hyperlordosis [13, 14]. Apophyseal avulsion fractures are less common; they are often displaced and sometimes bilateral [15, 16]. They classically involve the olecranon or the tibial tuber- cle, and usually require internal fixation [15, 16].
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Bone resorption predicts for skeletal complications in metastatic bone disease

Bone resorption predicts for skeletal complications in metastatic bone disease

Although urinary Ntx has proved to be one of the most responsive bone markers in metastatic bone disease and results from the present study are encouraging, it would be desirable to study the relationship between skeletal events and other urine and serum bone markers. Serum markers are especially convenient as blood is often being taken for other purposes (though diurnal variation is a problem for serum) and serum measurement avoids complex urine collection and creatinine correction. A recent study of ibandronate in multiple myeloma (Menssen et al, 2002) demonstrated that patients experienced significantly fewer skele- tal-related events per patient year when the ibandronate dose selected effectively suppressed the bone turnover markers serum osteocalcin and urinary Ctx. This study also found that patients experiencing a defined reduction in both bone markers suffered fewer events than in those with reduction in only one marker, raising the possibility that an index comprising more than one bone marker may add further predictive value.
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