Pathogenesis of myeloma bone disease

Multiple myeloma (MM) is the most common cancer to involve bone with up to 90% of patients developing bone lesions. The bone lesions are purely osteolytic in nature and do not heal in the vast majority of patients. Up to 60% of patients develop pathologic fractures over the course of their disease. Bone disease is a hallmark of MM, and myeloma bone disease differs from bone metastasis caused by other tumors. Although myeloma and other osteolytic metastases induce increased osteoclastic bone destruction, in contrast to other tumors, once myeloma tumor burden exceeds 50% in a local area, osteoblast activity is either severely depressed or absent. The basis for this severe imbalance between increased osteoclastic bone resorption and decreased bone formation has been the topic of intensive investigation over the last several years. These studies have helped to identify novel targets for treating myeloma bone disease and will be discussed in this chapter. J. Cell. Biochem. 109: 283–291, 2010. © 2009 Wiley‐Liss, Inc.     

More than metabolic: Considering the broader paleoepidemiological impact of vitamin D deficiency in bioarchaeology

Vitamin D deficiency has traditionally been viewed as a metabolic bone disease by bioarchaeologists and considered primarily in terms of the development of specific musculoskeletal changes used for diagnosis in paleopathological research. These skeletal manifestations are usually interpreted as representing general ill‐health. Clinical research shows that vitamin D is also integral to a number of extra‐skeletal physiological processes including immunoregulation, blood pressure homeostasis, cell division, and programmed cell death. Vitamin D deficiency and sub‐clinical insufficiency are thought to be risk factors for infectious and autoimmune diseases, as well as certain cancers and cardiovascular diseases. Epidemiological work indicates that the skeletal manifestations of vitamin D deficiency represent the extreme end of a spectrum of morbidity associated with negative health outcomes, including increased risk for secondary tuberculosis. This article provides a review of clinical research on the extra‐skeletal roles of vitamin D and the pathological consequences of poor vitamin D status. Additionally, it presents an interpretive model for bioarchaeological analyses of rickets and osteomalacia for consideration of the whole‐body impact of poor vitamin D nutriture and possible comorbidities that may have affected the wider population. Am J Phys Anthropol 160:183–196, 2016. © 2016 Wiley Periodicals, Inc.     

Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications

Focal bone loss around inflamed joints in patients with autoimmune disease, such as rheumatoid arthritis, remains a serious clinical problem. The recent elucidation of the RANK/RANK-ligand/OPG pathway and its role as the final effector of osteoclastogenesis and bone resorption has brought a tremendous understanding of the pathophysiology of inflammatory bone loss, and has heightened expectation of a novel intervention. Here, we review the etiology of inflammatory bone loss, the RANK/RANK-ligand/OPG pathway, and the clinical development of anti-RANK-ligand therapy.     

Low bone mineral density in men with chronic obstructive pulmonary disease

Background

Osteoporosis is common in patients with COPD but the likely multi-factorial causes contributing to this condition (e.g. sex, age, smoking, therapy) mask the potential contribution from elements related to COPD. In order to study osteoporosis and bone mineral density (BMD) related to COPD, we studied a well-defined group of patients and controls.

Methods

BMD, forced expiratory volume in one second (FEV₁), circulating bone biomarkers and biochemistry were determined in 30 clinically stable male ex-smokers with confirmed COPD and 15 age matched "ex-smoker" male controls. None of the patients were on inhaled corticosteroids or received more than one short course of steroids.

Results

Mean (SD) FEV₁% predicted of patients was 64(6)%, the majority having Global Initiative for Chronic Obstructive Lung Disease (GOLD) II airflow obstruction. There were 5/30 patients and 1/15 controls who were osteoporotic, while a further 17 patients and 5 controls were osteopenic. The BMD at the hip was lower in patients than controls, but not at the lumbar spine. Mean values of procollagen type 1 amino-terminal propeptide and osteocalcin, both markers of bone formation, and Type 1 collagen β C-telopeptide, a marker of bone resorption, were similar between patients and controls. However, all bone biomarkers were inversely related to hip BMD in patients (r = -0.51, r = -0.67, r = -0.57, p < 0.05) but did not relate to lumbar spine BMD. 25-OH Vitamin D was lower in patients.

Conclusions

Men with COPD had a greater prevalence of osteoporosis and osteopenia than age matched male controls, with a marked difference in BMD at the hip. Bone biomarkers suggest increased bone turnover.     

Inhibition of receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation and bone resorption by Gryllus bimaculatus extract: An in vitro study

Excessive bone-resorbing osteoclast activity during bone remodeling is a major feature of bone diseases, such as osteoporosis. Therefore, the inhibition of osteoclast formation and bone resorption can be an effective therapeutic target for various bone diseases. Gryllus biomaculatus (GB) has recently been approved as an alternative food source because of its high nutritional value and environmental sustainability. Traditionally, GB has been known to have various pharmacological properties, including antipyretic and blood pressure-lowering activity, and it has recently been reported to have various biological activities, including protective effects against inflammation, oxidative stress, insulin resistance, and alcohol-induced liver injury. However, the effect of GB on osteoclast differentiation and bone metabolism has not yet been demonstrated. In this study, we confirmed the inhibitory effect of GB extract (GBE) on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. To determine the effect of GBE on RANKL-induced osteoclast differentiation and function, we performed TRAP and F-actin staining, as well as a bone-resorbing assay. The intracellular mechanisms of GBE responsible for the regulation of osteoclastogenesis were revealed by Western blot analysis and quantitative real-time polymerase chain reaction. We investigated the relationship between GBE and expression of osteoclast-specific molecules to further elucidate the underlying mechanisms. It was found that GBE significantly suppressed osteoclastogenesis by decreasing the phosphorylation of Akt, p38, JNK, and ERK, as well as Btk-PLCγ2 signaling, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos, NFATc1, and osteoclastogenesis-specific marker genes. Additionally, GBE inhibited the formation of F-actin ring-positive osteoclasts and bone resorption activity of mature osteoclasts. Our findings suggest that GBE is a potential functional food and therapeutic candidate for bone diseases involving osteoclasts.     

人骨形成蛋白1-cDNA基因工程表达产物抗体的制备及鉴定

应用在大肠杆菌中表达的人骨形成蛋白(human bone morphogenetie protein,HBMP-1)的N端片段作为免疫原,免疫新西兰大白兔,成功地制备了抗人骨形成蛋白的抗血清,经免疫转移电泳证实该抗血清有较好的特异性,用ABC免疫组织化学方法在正常和恶性肿瘤骨的石腊切片上检测抗血清效价为1:100～1:1000,免疫组化染色结果表明,HBMP存在于人胎下颌骨新生的骨质和骨细胞中,颌骨骨肉瘤和软骨肉瘤的瘤细胞呈BMP强阳性反应,这一结果表明,骨的生长、形成和骨肿瘤的发生与BMP密切相关。     

Periodontal disease in ancient populations

Recent clinical and anthropological findings indicate that the conventional concept of the pathogenesis of periodontal disease requires review. The periodontal lesion has been defined as a generalised horizontal loss of crestal bone resulting from host immune and inflammatory responses triggered by the action of commensal bacteria, and the extension of gingivitis into the deeper periodontium to become periodontitis has been assumed to occur slowly but steadily over many years. Anthropological and clinical investigations reveal that the widespread loss of crestal tissue is relatively unusual and that lesions of the alveolus are commonly localised and severe. Longitudinal studies have shown that the disease progresses in bursts and is stable in both the gingivitis and periodontal modes in between the burst activity. The findings of the present study demonstrate that generalized horizontal periodontitis has been unusual and has not been responsible for tooth loss. Other factors responsible for deficient alveolar margins in dry bones have been overlooked in most studies, leading to overassessment of the incidence of periodontal disease in postmortem materials; the same assumptions have led to overassessment of periodontal disease in clinical studies and practice.     

Endocrine parameters of cystic fibrosis: Back to basics

Dramatic changes in the life expectancy of cystic fibrosis (CF) patients are occurring, creating a cohort of aging individuals experiencing long‐term complications of this chronic disease. The two most common of these complications include CF‐related diabetes and CF bone disease. The clinical implications of each have become better understood, as have potential therapies. However, data obtained from the basic science studies of both diseases have not been widely recognized. In this review, we focus on the known and hypothesized pathogenesis of these two disorders. Additionally, the molecular underpinnings of CF will be explained along with the potential interactions with endocrine disease phenotypes. J. Cell. Biochem. 108: 353–361, 2009. © 2009 Wiley‐Liss, Inc.     

Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease

Increased bone resorption is a major characteristic of multiple myeloma and is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta, and SDF-1alpha, which also increase osteoclast activity. On the other hand, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g., the Wnt inhibitors DKK-1 and sFRP-2. Moreover, they inhibit differentiation of osteoblast precursors and induce apoptosis in osteoblasts. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression.     

Chemical Conversion of Ribonucleoside 5′-S-Methyl Phosphorothiolates into Ribonucleotide Anhydrides Including Adenosine 5′-Triphosphate and Uridine Diphosphate Glucose

Ribonucleotide anhydrides have been prepared from corresponding ribonucleoside 5′-S-methyl phosphorothiolates by demethylthiolation with iodine in dry pyridine at room temperature in the presence of appropriate phosphates such as inorganic orthophosphate, inorganic pyrophosphate or glucose 1-phosphate. Thus synthesis of ribonucleotide anhydrides have been achieved and three ribonucleoside 5′-triphosphates (ATP, CTP and UTP), three ribonucleoside 5′-diphosphates (ADP, CDP and UDP) and a pyrophosphate coenzyme (UDPG) have been synthesized and isolated as lithium salts by charcoal treatment followed by ion exchange chromatography.     

Effect of parity on bone mineral density in female rhesus macaques from Cayo Santiago

This cross-sectional study investigates the relationship between parity, bone mineral density, and spontaneous osteopenia/osteoporosis in a large skeletal population of female rhesus macaques (Macaca mulatta) from the free-ranging colony of Cayo Santiago, Puerto Rico. The sample consists of 119 mature female monkeys aged 4.0-22.2 years at time of death. The data consist of measurements of bone mineral content (BMC) and bone mineral density (BMD), obtained from dual-energy X-ray absorptiometry (DEXA) of the last lumbar vertebra. After controlling for age, there is a significant increase in BMD of the spine with increasing parity (P = 0.0006), up to a parity of 7 offspring. Thus, high parity initially has a positive effect on BMD in female rhesus monkeys, but this positive effect disappears with parities that are greater than 7 offspring. After controlling for parity, however, age has a negative (P = 0.015) effect on BMD, beginning several years after the attainment of peak BMD (age 9.5 years). Thus, it appears that parity initially mitigates the effects of aging, but the positive effect of parity on BMD is eventually overwhelmed by the aging process. Mean BMC and BMD values are higher in parous females compared to nulliparous females in the same age range. Similarly, females with low parity have significantly lower mean BMD values than do age-matched high-parity controls, and the frequency of osteopenia and osteoporosis is greater in low-parity females. Forty-three percent (43%) of the osteopenic/osteoporotic females in the sample are members of the low-parity group, even though it composes only 13% (16/119) of the entire sample. This study demonstrates that the free-ranging female rhesus monkeys from Cayo Santiago are a good nonhuman primate model for the study of bone mineral density, parity, osteopenia, and osteoporosis.     

Standardization of the immunocytochemical detection of neuroblastoma cells in bone marrow.

Standard cytomorphological examination of bone marrow (BM) aspirates does not appear to be sensitive enough to detect single neuroblastoma cells. The SIOPEN Neuroblastoma Bone Marrow Committee developed a sensitive and reproducible anti-GD2 immunocytochemical assay and introduced morphological and immunocytological criteria for the interpretation of results. Fixed cytospins were incubated with a commercially available anti-GD2 monoclonal antibody and an APAAP kit. Cells fulfilling all morphological and immunocytological criteria were called criteria-positive cells (CPCs). Not convincingly interpretable cells fulfilled some, but not all, criteria, and negative cells displayed only exclusion criteria. The genetic profile of doubtful cells was checked by fluorescence in situ hybridization. Ideally, 3 x 10(6) cells were analyzed to reach a 95% probability of detecting one tumor cell in 1 x 10(6) mononuclear cells. Four quality control rounds were organized to validate the method. A total of 111 quality control samples were analyzed. Two main improvements were achieved: in discordant cases, the range between the lowest and highest reported result was reduced by half, and discordant results were only found in samples with less than 10 CPCs per 1 x 10(6). This article describes the first internationally standardized protocol to detect and quantify rare neuroblastoma cells by immunocytochemistry. This method is an indispensable tool for multicenter studies evaluating the clinical significance of minimal residual disease in neuroblastoma.     

Long bone growth variation among Arikara skeletal populations

Long bone growth variation among skeletal samples has had limited application to ecological studies of archaeological groups, in spite of its well-known sensitivity to health and nutritional status. In this study we examine long bone growth variation among ten samples of Arikara skeletal groups, all located in the Middle Missouri subarea of South Dakota and ranging in time from A.D. 1600 to 1832. The samples are analyzed by variant, an archaeological taxonomic unit below Tradition. Children's long bones between about 0.5 and 11.9 years of age were analyzed by means of regression using the model, bone length =b₀ + b₁ (age) + b₂ (log₁₀ age). The three variants, Extended Coalescent, Postcontact Coalescent, and Disorganized Coalescent, differ from one another with regard to health and nutritional status. Extended Coalescent groups probably experienced periods of undernutrition due to unfavorable climatic conditions prevailing at the time. Postcontact Coalescent groups experienced more favorable health and nutrition due to improved climatic conditions and introduction of the horse. Disorganized Coalescent groups were exposed to undernutrition and high levels of morbidity, due to introduction of epidemic diseases, depopulation, and intertribal conflict. Analysis of slopes shows significant heterogeneity among variants for humerus, radius, and tibia, but not femur. In general, the Postcontact Coalescent is characterized by slighter greater rates of increase with age and longer bone lengths for each age than is Extended Coalescent. Disorganized Coalescent exhibits lower rates of increase, particularly in later childhood, with shorter bone lengths in late childhood. Disorganized Coalescent also presents longer radius and humerus lengths than the other two variants in early childhood, an unexpected finding. This may be partly, but not entirely, explained by differential bone response to stress along the lines of maturity gradients.     

Dental implications of bisphophonate-related osteonecrosis

doi: 10.1111/j.1741‐2358.2012.00622.x
Dental implications of bisphophonate‐related osteonecrosis Objectives: The aim is to explore the current theories about clinical , pathological and dental management of bisphosphonate related osteonecrosis of the jaws. Also discussed are the actions of bisphosphonates, pathogenesis related to the susceptibility of jaws, the predisposing risk factors for the development of bisphosphonate‐related osteonecrosis of the jaws (BRONJ) and diagnostic criteria based on the literature review. Discussion: Osteoporosis is a disease that generally affects the mineral status of both cortical and trabecular bone in post menopausal women. Bisphosphonates are a group of drugs that preserve and increase bone mass. Bisphosphonate drugs are classified according to use and method of delivery. The bisphosphonates used for the treatment of osteoporosis are taken orally. Little is known about the side effects and dangers of the long‐term use of therapeutic doses of Bisphosphonates. A recent complication reported is osteonecrosis of jaws. The use of IV bisphosphonates for multiple myeloma and metastatic bone diseases suggests that dosage, length of treatment, and route of administration, as well as cofactors such as use of glucocorticoids and immunosuppressive agents, and dental surgery, could all be related to the incidence of BRONJ. This review provides an update on current knowledge about clinical, pathological and management aspects of BRONJ. Conclusions: Little evidence exists to direct the prosthodontic management of patients with a history of bisphosphonate use. Patients with active osteonecrosis related to bisphosphonate use have reduced tissue tolerance to function with removable prostheses and decreased potential for osseointegration of dental implants. Decisions should be based on clinical judgment tempered by the presenting conditions, medical profile, and patient needs. A better understanding would help in a dental setting to prevent any complication and help to improve the prognosis for those being treated for osteoradionecrosis.Until further evidence emerges regarding management of patients with active bisphosphonate‐ related osteonecrosis, conservative prosthodontic treatment is reasonable and prudent.     

Candidate salivary biomarkers associated with alveolar bone loss: cross-sectional and in vitro studies

This cross-sectional study evaluated the association between radiographic evidence of alveolar bone loss and the concentration of host-derived bone resorptive factors (interleukin-1 beta, tumor necrosis factor-alpha, interleukin-6, prostaglandin-E2), and markers of bone turnover [pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), osteocalcin, osteonectin] in stimulated human whole saliva collected from 110 untreated dental patients. Alveolar bone loss scores for each patient were derived from radiographic examination. Variables positively associated with increased bone loss score were: age, current smoking, use of bisphosphonate drugs, and salivary interleukin-1beta levels above the median. Salivary osteonectin levels above the median were associated with a decreased bone loss score. Additional in vitro studies were carried out to determine the fate of interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha added to whole and parotid saliva. All cytokines added to saliva were detected in significantly lower concentrations than when added to buffer alone. Protease inhibitors added to saliva did not prevent the reduction in detection of biomarkers. Variation in time of incubation, repeated cycles of freezing and thawing, or exposure to dimethylsulfoxide did not appreciably affect the measurement of cytokines in saliva. These results suggest that detection of biomarkers by conventional immunoassays may underestimate the actual quantity of molecules in saliva.     

Detection of minimal residual disease (MRD) after bone marrow transplantation (BMT) by multi-parameter flow cytometry (MPFC)

Multi-parameter flow cytometry (MPFC) was used to detect minimal residual disease (MRD) following bone marrow transplantation (BMT) in 21 patients. Bone marrow (BM) was analyzed pre-transplant and 3–4 months post-BMT while the patients were in clinical and morphological remission. MRD was detected by identifying cells with aberrant antigen expression and/or leukemia-associated phenotype (LAP) using MPFC. Prior to BMT, 8 out of 21 patients exhibited normal antigen expression based on normal BM samples while 13 BM aspirates had abnormal MPFC. Pre-BMT MPFC was abnormal in all 10 patients who were not in complete remission (CR) (>5% blasts in BM) as well as 3 patients acute lymphoblastic leukemia (ALL) who were in CR. In BM from ALL patients, an abnormal uniform B cell population was observed however antigen expression patterns varied greatly between patients. BM from acute myeloblastic leukemia (AML) patients showed an abnormal distribution of CD34+ cells. In addition, a correlation was observed between pre-BMT cytogenetics and MPFC. Only 2 out of 8 (25%) patients with normal MPFC pre-autologous bone marrow transplantation (ABMT) relapsed (AML), while 6 out of 13 (46%) patients with abnormal pre-BMT MPFC relapsed including 2 out of 3 patients who were transplanted in clinical CR. Pre-BMT MPFC may thus be an effective tool for detection of MRD by detection of a pre-transplant MPFC abnormality.     

Liver and bone

Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in cases with chronic cholestasis, hemochromatosis and alcohol abuse. The problem is more critical in transplant patients when bone loss is accelerated during the period immediately after transplantation, leading to a greater incidence of fractures. Advanced age, low body mass index and severity of the liver disease are the main risk factors for bone disease in patients with cholestasis. Mechanisms underlying osteoporosis in chronic liver disease are complex and poorly understood, but osteoporosis mainly results from low bone formation, related to the effects of retained substances of cholestasis, such as bilirubin and bile acids, or to the effects of alcohol on osteoblastic cells. Increased bone resorption has also been described in cholestatic women with advanced disease. Although there is no specific treatment, bisphosphonates associated with supplements of calcium and vitamin D are effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation. The outcome in reducing the incidence of fractures has not been adequately demonstrated essentially because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future.