Burden of bone disease in chronic pancreatitis:A systematic review and meta-analysis

BACKGROUND Bone disease is an under-recognized cause of morbidity in chronic pancreatitis(CP).Over the past decade,publications of original studies on bone disease in CP has warranted synthesis of the evidence to ascertain the true burden of the problem.AIM To quantify the prevalence of osteopenia,osteoporosis,and fragility fractures in CP patients and investigate the associated clinical features and outcomes.METHODS A systematic search identified studies investigating bone disease in CP patients from Cochrane Library,Embase,Google Scholar,Ovid Medline,PubMed,Scopus,and Web of Science,from inception until October 2022.The outcomes included prevalence of osteopenia,osteoporosis,and fragility fractures,which were metaanalyzed using a random-effects model and underwent metaregression to delineate association with baseline clinical features.RESULTS Twenty-one studies were included for systematic review and 18 studies were included for meta-analysis.The pooled prevalence of osteopenia and osteoporosis in CP patients was 41.2%(95%CI:35.2%-47.3%)and 20.9%(95%CI:14.9%-27.6%),respectively.The pooled prevalence of fragility fractures described among CP was 5.9%(95%CI:3.9%-8.4%).Metaregression revealed significant association of pancreatic enzyme replacement therapy(PERT)use with prevalence of osteoporosis[coefficient:1.7(95%CI:0.6-2.8);P<0.0001].We observed no associations with mean age,sex distribution,body mass index,alcohol or smoking exposure,diabetes with prevalence of osteopenia,osteoporosis or fragility fractures.Paucity of data on systemic inflammation,CP severity,and bone mineralization parameters precluded a formal metaanalysis.CONCLUSION This meta-analysis confirms significant bone disease in patients with CP.Other than PERT use,we observed no patient or study-specific factor to be significantly associated with CP-related bone disease.Further studies are needed to identify confounders,at-risk population,and to understand the mechanisms of CP-related bone disease and the implications of treatment response.

Assessment of bone turnover and bone quality in type 2 diabetic bone disease： current concepts and future directions

Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes （T2D） and may be predictive of fractures independently of bone mineral density （BMD）. Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score （TBS） and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT （HRpQCT） imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct （AGE） accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.

Epigenetic regulation by long noncoding RNAs in osteo-/adipogenic differentiation of mesenchymal stromal cells and degenerative bone diseases

Bone is a complex tissue that undergoes constant remodeling to maintain homeostasis,which requires coordinated multilineage differentiation and proper proliferation of mesenchymal stromal cells(MSCs).Mounting evidence indicates that a disturbance of bone homeostasis can trigger degenerative bone diseases,including osteoporosis and osteoarthritis.In addition to conventional genetic modifications,epigenetic modifications(i.e.,DNA methylation,histone modifications,and the expression of noncoding RNAs)are considered to be contributing factors that affect bone homeostasis.Long noncoding RNAs(lncRNAs)were previously regarded as‘transcriptional noise’with no biological functions.However,substantial evidence suggests that lncRNAs have roles in the epigenetic regulation of biological processes in MSCs and related diseases.In this review,we summarized the interactions between lncRNAs and epigenetic modifiers associated with osteo-/adipogenic differentiation of MSCs and the pathogenesis of degenerative bone diseases and highlighted promising lncRNA-based diagnostic and therapeutic targets for bone diseases.

Surgical treatment of metastatic bone disease of the distal extremities

Metastatic bone disease of the distal extremities,also known as acrometastasis,is very rare.Thus,there is very limited information regarding the clinical manifestations and methods of surgical treatment.The current available literature shows that acrometastases are often encountered in the context of advanced disease and are thus associated with poor patient survival.As metastatic bone disease is generally uncurable,the goal of surgical treatment is to provide the patient with good function with as few complications as possible.In this article,we discuss the clinical manifestation of acrometastases,the methods of surgical intervention,and the expected clinical outcome.Non-surgically managed pathological fractures generally remain ununited;therefore,conservative treatment is reserved for patients with poor general condition or dismal prognosis.The current evidence suggests that in lesions of the lower arm and leg,osteosynthesis(plate and screw fixation or intramedullary nail)is the most common method of reconstruction,whereas local excision or amputation are more commonly used in cases of more distal lesions(such as ankle,foot and hand).Following surgery most patients receive adjuvant radiotherapy,even though its role is poorly documented.Close collaboration between orthopedic surgeons and medical oncologists is necessary to improve patient care and treatment outcome.Further studies are needed in order to provide stronger clinical evidence and improve decision-making,in an effort to optimize the patients’quality of life and avoid the need for revision surgery.

Significance of preoperative peripheral blood neutrophil-lymphocyte ratio in predicting postoperative survival in patients with multiple myeloma bone disease

BACKGROUND The neutrophil-lymphocyte ratio(NLR)is often used to predict a poor prognosis in patients with tumors.This study investigated the preoperative peripheral blood NLR in predicting postoperative survival(POS)in patients with multiple myeloma bone disease(MMBD).AIM To evaluate whether NLR can be used to predict the prognosis of MMBD patients after surgery.METHODS The clinical data of 82 MMBD patients who underwent surgical treatments in Beijing Chao-yang Hospital were collected.The NLR was obtained from the absolute number of neutrophils and lymphocytes,calculated by the number of neutrophils and divided by the number of lymphocytes.The peripheral blood lymphocyte percentage was used as the major marker to analyze the change in characteristics of the immune statuses of multiple myeloma patients.RESULTS The NLR cut-off values of NLR≥3 patients and NLR≥4 patients were significantly correlated with POS.The 3-and 5-year cumulative survival rates of the high NLR group(NLR≥3 patients)were 19.1%and 0.0%,respectively,which were lower than those of the low NLR group(NLR<3 patients)(67.2%and 48.3%)(P=0.000).In the high NLR group,POS(14.86±14.28)was significantly shorter than that in the low NLR group(32.68±21.76).Univariate analysis showed that the lymphocyte percentage 1 wk after the operation(19.33±9.08)was significantly lower than that before the operation(25.72±11.02).Survival analysis showed that postoperative chemotherapy,preoperative performance status and preoperative peripheral blood NLR≥3 were independent risk factors for POS.CONCLUSION The preoperative peripheral blood NLR can predict POS in MMBD patients.MMBD patients with a high preoperative NLR(NLR≥3)showed poor prognosis.

Long-Term Efficacy of Parathyroidectomy onHyperparathyroid Bone Disease

This is a retrospective analysis of long-term efficacy of parathyroidectomy on hyperparathyroid bone disease. The clinical manifestations, bone structure, and bone mineral density in 16 patients averaged 5.1 (1. 0-10. 5) years after parathyroidectomy were assessed. The results showed that although the bone disease could be markedly relieved after surgery, yet at terminal point of follow-up, 10/16 cases (62. 5% ) got incomplete recovery of bone disease, the ratio of incomplete recovery in Y1 group with severe bone disease was higher than that of Y2 group with mild bone disease (P <0. 05). The concentrations of serum BGP and morning void urine pyridinoline were within the refer ence ranges of young and middle aged controls. These imply that the osteoblastic and osteoclastic activities had reached a balancing state. The results suggested that hyperparathyroid patients should be operated on as early as possible, and intensively followed up after operation. subsequent therapy should be given to patients with incomplete recovery of bone disease.

Bone disease in pediatric idiopathic hypercalciuria

Idiopathic hypercalciuria （IH） is the leading metabolic risk factor for urolithiasis and affects all age groups without gender or race predominance. IH has a high morbidity with or without lithiasis and reduced bone mineral density （BMD）, as described previously in pe-diatric patients as well as in adults. The pathogenesis of IH is complex and not completely understood, given that urinary excretion of calcium is the end result of an interplay between three organs （gut, bone and kidney）, which is further orchestrated by hormones, such as 1,25 dihydroxyvitamin D, parathyroid hormone, calcitonin and fosfatonins （i.e., fbroblast growth-factor-23）. Usu-ally, a primary defect in one organ induces compensa-tory mechanisms in the remaining two organs, such as increased absorption of calcium in the gut secondary toa primary renal loss. Thus, IH is a systemic abnormality of calcium homeostasis with changes in cellular trans-port of this ion in intestines, kidneys and bones. Re-duced BMD has been demonstrated in pediatric patients diagnosed with IH. However, the precise mechanisms of bone loss or failure of adequate bone mass gain are still unknown. The largest accumulation of bone mass occurs during childhood and adolescence, peaking atthe end of the second decade of life. This accumulation should occur without interference to achieve the peak of optimal bone mass. Any interference may be a risk factor for the reduction of bone mass with increased risk of fractures in adulthood. This review will address the pathogenesis of IH and its consequence in bone mass.

The essential roles of m^(6)A modification in osteogenesis and common bone diseases

N6-methyladenosine(m^(6)A)is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs.It affects the fate of the modified RNA,including its stability,splicing,and translation,and plays an important role in post-transcriptional regulation.Bones play a key role in supporting and pro-tecting muscles and other organs,facilitating the movement of the organism,ensuring blood production,etc.Bone diseases such as osteoarthritis,osteoporosis,and bone tumors are serious public health problems.The processes of bone development and osteogenic differen-tiation require the precise regulation of gene expression through epigenetic mechanisms including histone,DNA,and RNA modifications.As a reversible dynamic epigenetic mark,m^(6)A modifications affect nearly every important biological process,cellular component,and molecular function,including skeletal development and homeostasis.In recent years,studies have shown that m^(6)A modification is involved in osteogenesis and bone-related diseases.In this review,we summarized the proteins involved in RNA m^(6)A modification and the latest progress in elucidating the regulatory role of m^(6)A modification in bone formation and stem cell direc-tional differentiation.We also discussed the pathological roles and potential molecular mech-anisms of m^(6)A modification in bone-related diseases like osteoporosis and osteosarcoma and suggested potential areas for new strategies that could be used to prevent or treat bone de-fects and bone diseases.

MOFs and bone: Application of MOFs in bone tissue engineering and bone diseases

Metal-organic frameworks(MOFs), a class of hybrid materials, consist of organic linkers and bridging metal ions or clusters. Their tunable pore sizes, large surface area, good biocompatibility, structural variability in combination with materials and chemicals, and osteogenic effects provide potential approaches for bone tissue engineering and bone diseases. And there are more and more research on MOFs in the field of osteogenesis in recent years. This review presents an overall summary of the application in the bone tissue engineering and bone diseases of MOFs and their composites, starting with the synthesis of MOFs, which discusses the advantages and disadvantages of different syntheses. Then, the biological functions of MOFs are discussed, which are the basics of MOFs applied in the organism. Importantly,mechanisms and abundant applications of MOFs are detailed in the bone tissue engineering and bone diseases. Finally, some prospects of MOFs are discussed, for instance, exploring whether MOFs can be used to treat other bone diseases.

Bone diseases in rabbits with hyperparathyroidism: computed tomography, magnetic resonance imaging and histopathology

Background Hyperparathyroidism （HPT） occurs at an early age and has a high disability rate. Unfortunately, confirmed diagnosis in most patients is done at a very late stage, when the patients have shown typical symptoms and signs, and when treatment does not produce any desirable effect. It has become urgent to find a method that would detect early bone diseases in HPT to obtain time for the ideal treatment. This study evaluated the accuracy of high field magnetic resonance imaging （MRI） combined with spiral computed tomography （SCT） scan in detecting early bone diseases in HPT, through imaging techniques and histopathological examinations on an animal model of HPT. Methods Eighty adult rabbits were randomly divided into two groups with forty in each. The control group was fed normal diet （Ca：P = 1：0.7）; the experimental group was fed high phosphate diet （Ca：P = 1：7） for 3, 4, 5, or 6-month intervals to establish the animal model of HPT. The staging and imaging findings of the early bone diseases in HPT were determined by high field MRI and SCT scan at the 3rd, 4th, 5th and 6th month. Each rabbit was sacrificed after high field MRI and SCT scan, and the parathyroid and bones were removed for pathological examination to evaluate the accuracy of imaging diagnosis. Results Parathyroid histopathological studies revealed hyperplasia, osteoporosis and early cortical bone resorption. The bone diseases in HPT displayed different levels of low signal intensity on T1WI and low to intermediate signal intensity on T2WI in bone of stage 0, Ⅰ, Ⅱ or Ⅲ, but showed correspondingly absent, probable, osteoporotic and subperiosteal cortical resorption on SCT scan. Conclusion High field MRI combined with SCT scan not only detects early bone diseases in HPT, but also indicates staging, and might be a reliable method of studying early bone diseases in HPT.

Paget’s disease of bone: Report of 11 cases

BACKGROUND Paget’s disease of bone(PDB)is a rare metabolic bone disease in China and is characterized by increased bone resorption and disorganized bone formation.The main clinical symptoms of PDB are focal or multiple bone pain and deformity with high disability.The disease has high missed diagnosis and misdiagnosis rates.This report summarizes the clinical manifestations,imaging and pathological features,and treatments of 11 patients with PDB at our hospital from 1993 to 2020 in order to improve the recognition and prognosis of PDB.CASE SUMMARY There were eight male and three female patients whose average age was 48.7±11.0 years with a PDB course of 1-16 years.Nine patients had bone pain and bone deformities in different parts of the body,the majority of which involved the long bones.Laboratory examinations revealed elevated serum alkaline phosphatase(ALP)in all patients with an average of 618±460 IU/L(normal range 0-130 IU/L),and serum calcium and phosphorus levels were in the normal range.Imageology showed that osteolysis was usually combined with osteosclerosis and/or bone deformities in single or multiple bones.^(99m)Tc-methylene diphosphonate bone scintigraphy revealed increased radionuclide uptake in the bone lesions.Six patients underwent bone tissue biopsy,and the typical pathological changes were a mosaic structure of the bone trabeculae with irregularly arranged cement lines and multinuclear osteoclasts.Ten of the 11 patients were effectively treated with bisphosphonates.CONCLUSION Early diagnosis of the rare disease PDB can be made through elevated ALP levels and typical presentations on bone X-ray and from bone tissue biopsy.

Pathophysiology and therapeutic advances in myeloma bone disease

Bone disease is the most common complication in patients with multiple myeloma (MM), and it may lead to skeletal-related events (SREs) such as bone pain, pathological fractures, and spinal cord compression, which impair a patients’’ quality of life and survival. The pathogenesis of myeloma bone disease (MBD) involves disruption of bone reconstitution balance including excessive activation of osteoclasts, inhibition of osteoblasts, and participation of osteocytes and bone marrow stromal cells. Various factors, such as the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG), dickkopf-1 (DKK-1), sclerostin, and activin-A, are involved in the development of MBD. Bisphosphonates and the anti-RANKL antibody denosumab are currently the main treatment options for MBD, delaying the onset of SREs. Denosumab is preferred in patients with MM and renal dysfunction. Although effective drugs have been approved, antimyeloma therapy is the most important method for controlling bone disease.

FGF23 associated bone diseases

Recently,fibroblast growth factor 23(FGF23)has sparked widespread interest because of its potential role in regulating phosphate and vitamin D metabolism.In this review,we summarized the FGF superfamily,the mechanism of FGF23 on phosphate and vitamin D metabolism,and the FGF23 related bone disease.

Gut microbiota as a target in the bone health of livestock and poultry: roles of short-chain fatty acids

The regulation and maintenance of bone metabolic homeostasis are crucial for animal skeletal health.It has been established that structural alterations in the gut microbiota and ecological dysbiosis are closely associated with bone metabolic homeostasis.The gut microbiota and its metabolites,especially short-chain fatty acids(SCFAs),affect almost all organs,including the bone.n this process,SCFAs positively affect bone healing by acting directly on cells involved in bone repair after or by shaping appropriate anti-inflammatory and immunomodulatory responses:Addi-tionally,SCFAs have the potential to maintain bone health in livestock and poultry because of their various biological functions in regulating bone metabolism,including immune function,calcium absorption,osteogenesis and oste-olysis.This review primarily focuses on the role of sCFAs in the regulation of bone metabolism by gut microbiota and provides insight into studies related to bone health in livestock and poultry.

TGF-β and BMP signaling in osteoblast,skeletal development,and bone formation,homeostasis and disease

INTRODUCTIONThe transforming growth factor-β （TGF-β） superfamily com- prises TGF-βs, Activin, bone morphogenetic proteins （BMPs） and other related proteins. TGF-β superfamily members act through a heteromeric receptor complex,, comprised of type I and type II receptors at the cell surface that transduce intracellular signals via Smad complex or mitogen-activated protein kinase （MAPK） cascade.

Surgical management of metastatic disease of long bone

Objective To improve the life quality of cancer patients with metastasis to long bone and to long bone and to select suitable surgical treatment. Methods Fifty-two patients with metastasis 27 men and 25 women, were June 2003 Vol12 No2 treated from 1990 to 1999. Their average age was 56. 8 years (33 - 74). In 16 patients with multiple lesions, underwent surgery at bone shaft (29 patients) and bone epiphysis (26). Thirty patients were treated for pathologic fracture and the rest for impending fracture. Operations included limb-salvage (51 patients) and amputation (4) Limb salvage consisted of intralesional curettage (3 patients ), intramedullary nailing reconstruction (29 ), endoprosthesis ( 18 ), and temporary spacer ( 1 ). 21 patients accepted postoperative chemotherapy or radiotherapy. Results Follow-up of 52 patients for a mean of 28. 2 months (2 - 122 months) showed pain relief (41 patients), (75%) and full or part weight-bearing stability ( 36 ) 69 % . Local tumor recurrence occurred in 11 patients.

From liver to hormones:The endocrine consequences of cirrhosis

Hepatocrinology explores the intricate relationship between liver function and the endocrine system.Chronic liver diseases such as liver cirrhosis can cause endocrine disorders due to toxin accumulation and protein synthesis disruption.Despite its importance,assessing endocrine issues in cirrhotic patients is frequently neglected.This article provides a comprehensive review of the epidemiology,pathophysiology,diagnosis,and treatment of endocrine disturbances in liver cirrhosis.The review was conducted using the PubMed/Medline,EMBASE,and Scielo databases,encompassing 172 articles.Liver cirrhosis is associated with endocrine disturbances,including diabetes,hypoglycemia,sarcopenia,thyroid dysfunction,hypogonadotropic hypogonadism,bone disease,adrenal insufficiency,growth hormone dysfunction,and secondary hyperaldosteronism.The optimal tools for diagnosing diabetes and detecting hypoglycemia are the oral glucose tolerance test and continuous glucose monitoring system,respectively.Sarcopenia can be assessed through imaging and functional tests,while other endocrine disorders are evaluated using hormonal assays and imaging studies.Treatment options include metformin,glucagon-like peptide-1 analogs,sodium-glucose co-transporter-2 inhibitors,and insulin,which are effective and safe for diabetes control.Established standards are followed for managing hypoglycemia,and hormone replacement therapy is often necessary for other endocrine dysfunctions.Liver transplantation can address some of these problems.

Chronic liver inflammation:Clinical implications beyond alcoholic liver disease

Chronic alcohol exposure can lead to alcoholic liver disease, including hepatitis, cirrhosis and hepatocellular carcinoma, and chronic inflammation can simultaneously cause systemic medical illness. Recent evidence suggests that alcoholic liver disease is a predictor for liver-related diseases, cardiovascular disease, immunologic disease, and bone disease. Chronic inflammation in alcoholic liver disease is mediated by a direct inflammatory cascade from the alcohol detoxification process and an indirect inflammatory cascade in response to gut microflora-derived lipopolysaccharides (LPS). The pathophysiology of alcoholic liver disease and its related systemic illness is characterized by oxidative stress, activation of the immune cascade, and gut-liver interactions. Integrative therapeutic strategies for alcoholic liver disease include abstaining from alcohol consumption; general anti-inflammatories such as glucocorticoid, pentoxifylline, and tumour necrosis factor-&#x003b1; antagonist; antioxidants such as N- acetylcysteine; gut microflora and LPS modulators such as rifaximin and/or probiotics. This review focuses on the impact of chronic liver inflammation on systemic health problems and several potential therapeutic targets.

Doxycycline induces bone repair and changes in Wnt signalling

Doxycycline （DOX） exhibits anti-inflammatory and MMP inhibitory properties. The objectives of this study were to evaluate the effects of DOX on alveolar bone repair. Controls （CTL） and DOX-treated （10 and 25 mg. kg- 1） molars were extracted, and rats were killed 7 or 14 days later. The maxillae were processed and subjected to histological and immunohistochemical assays. Hematoxylin-eosin staining （7th day） revealed inflammation in the CTL group that was partly reversed after DOX treatment. On the 14th day, the CTL group exhibited bone neoformation, conjunctive tissue, re-epithelization and the absence of inflammatory infiltrate. DOX-treated groups exhibited complete re-epithelization, tissue remodelling and almost no inflammation. Picrosirius red staining in the DOXlO group （7th and 14th days） revealed an increased percentage of type I and III collagen fibres compared with the CTL and DOX25 groups. The DOXlO and DOX25 groups exhibited increases in osteoblasts on the 7th and 14th days. However, there were fewer osteoclasts in the DOXlO and DOX25 groups on the 7th and 14th days. Wnt-lOb- immunopositive cells increased by 130% and 150% on the 7th and 14th days, respectively, in DOX-treated groups compared with the CTL group. On the 7th day, Dickkopf （Dkk）-I immunostaining was decreased by 63% and 46% in the DOXlO and DOX25 groups, respectively. On the 14th day, 69% and 42% decreases in immunopositive cells were observed in the DOXlO and DOX25 groups, respectively, compared with the CTL group. By increasing osteoblasts, decreasing osteoclasts, activating Wnt lOb and neutralising Dkk, DOX is a potential candidate for bone repair in periodontal diseases.

Effects of Cadmium on BMP Induced Bone Formation

To demonstrate the direct effects of cadmium on activities of bone morphogenetic protein (BMP), a complex containing BMP and cadmium chloride (CdCl 2) was implanted beneath the abdominal skin of young male Wistar rats. The activity of BMP was studied by observing the histological changes, and measuring the activity of alkaline phosphatase (ALP) and acid phosphatase (ACP) and calcium content of the implants at different time points. Our results showed that during bone formation induced by BMP, cadmium inhibited the activities of osteoblasts and osteoclasts, and slowed the deposition of calcium. It is concluded that cadmium can directly affect biological activities of BMP directly.