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At least 145 records · Page 8Linked to original sources

New potential targets for treating myeloma bone disease.

PURPOSE: Myeloma bone disease results in severe pain and pathologic fractures in >80% of patients. Myeloma bone disease is characterized by both increased osteoclast activity and suppressed new bone formation. The basis for both the increased bone destruction and decreased bone formation has been a topic of extensive investigation during the last several years. EXPERIMENTAL DESIGN: Marrow samples from patients with myeloma were screened by both molecular biological and gene expression profiling techniques to identify factors that may be responsible for the enhanced bone destruction and suppressed bone formation in patients with the disease. RESULTS: Several novel factors have been identified that directly stimulate osteoclastic bone destruction in myeloma. These include receptor activator of NF-kappaB ligand, macrophage inflammatory peptide 1alpha, and interleukin (IL)-3. All of these factors are increased in most patients with myeloma. Furthermore, osteoprotegerin levels are markedly suppressed, further driving osteoclast formation. In addition, four novel inhibitors of osteoblast differentiation or activity have been identified. These include two inhibitors of the Wnt signaling pathway, DKK1 and soluble frizzled protein 2. The Wnt signaling pathway is critical for osteoblast differentiation. Two cytokines, IL-3 and IL-7, have also been reported that directly or indirectly inhibit osteoblast differentiation in patients with myeloma. Interestingly, increased macrophage inflammatory peptide 1alpha, IL-3, and IL-7 result from abnormal transcriptional regulation of these genes by increased levels of acute myelogenous leukemia-1 to acute myelogenous leukemia-1B transcription factors. CONCLUSIONS: The recent identification of novel stimulators of osteoclast activity and inhibitors of osteoblast differentiation provide new therapeutic targets for treating this devastating bone disease in patients with myeloma.

Animals↗

Role of the microenvironment in multiple myeloma bone disease.

Multiple myeloma bone disease occurs in over 70-80% of patients with myeloma and represents a significant source of morbidity and mortality. Early in multiple myeloma bone disease there is a balance between osteoclast activation and osteoblast suppression. However, this balance appears to be lost in advanced disease, resulting in the development of lytic lesions and bone destruction. Osteoclast activation occurs through a variety of factors, including receptor activator of nuclear factor-kappaB ligand, macrophage inflammatory protein-1alpha, interleukin-3 and interleukin-6, resulting in osteoclast stimulation and bone resorption. There is also significant osteoblast suppression through the inhibitory actions of interleukin-3, dickkopf 1, secreted frizzled-related protein-2 and interleukin-7. Understanding the mechanisms behind myeloma bone disease will help to identify potential future therapeutic interventions to help ameliorate or prevent osteoblast suppression and decrease osteoclast activation, with the goal of improving the overall quality of life for patients with multiple myeloma.

Bone Diseases↗

Iron overload and bone disease in chronic dialysis patients.

Bone pathology was studied in 27 patients showing either iron or aluminium accumulation in bone. These patients belonged to a group of 120 unselected chronic haemodialysis patients in whom transiliac bone biopsies had been obtained. Group A consisted of 12 patients with bone iron deposits (positive Perls' staining at the calcified bone boundary, CBB) and only minimal aluminium accumulation (bone aluminium below 20 micrograms/g wet weight). Group B included 15 patients with pronounced aluminium accumulation (positive aluminium staining at the CBB and bone aluminium of 20 micrograms/g wet weight or more) and without significant bone iron deposition (negative Perls' staining at the CBB). Bone diseases were classified as early hyperparathyroidism, osteitis fibrosa, mixed disease, osteomalacia, adynamic bone disease or other bone condition using osteoid volume, relative osteoblastic activity (ROBA%), and the presence of fibrosis, as criteria. In group A, 5 of 12 patients showed adynamic bone disease, a fairly uncommon condition in the general population of non-parathyroidectomised dialysis patients. In fact, in a control group of 80 patients without iron and without aluminium overload, only five patients showed adynamic bone disease. In group B, 8 of 15 patients showed osteomalacia, and 2 of 15 presented with mixed disease, which is in agreement with the established relationship between bone aluminium accumulation and the occurrence of defective bone mineralisation. It is concluded that iron overload in dialysis patients is associated with an increased frequency of adynamic bone disease.

Aluminum↗

Bone involvement in Gaucher's disease: 'bone crisis' or disease complication?

Bone involvement can represent the inaugural symptom of Gaucher's disease (GD). Here, we report the case of a 68-year old man diagnosed as having GD since 1963. In June 1994 the patient was referred to our Rheumatology Unit because of a long-lasting coxalgia on the left hip and progressive walking impairment following traumatic fracture of the left femur. Multicystic osseous changes at standard X-ray and hyper-gamma-globulinemia with an elevated ESR (122 mm, 1st hour) suggested the diagnosis of either osteonecrosis of the femoral head or multiple myeloma. On bone marrow biopsy examination, Gaucher's cell infiltrates were detected and an increased uptake in the distal left femur and proximal tibia were demonstrated by lipophilic tracer scan (99mTc-Sestamibi). Subsequently, the patient suffered another femoral fracture at a site of Gaucher's infiltrates previously documented by bone scan. We conclude that in patients with GD, 99mTc-Sestamibi bone scan can selectively evaluate the presence of bone lipid deposits, and could indirectly differentiate this bone condition from other serious skeletal complications of the disease.

Aged↗

Influence of genetic polymorphisms on bone disease of preterm infants.

Bone disease is an important complication among very low birth weight (VLBW, <1500 g) infants. In adults, osteoporosis is associated with polymorphisms of vitamin D receptor (VDR), estrogen receptor (ER), and collagen Ialpha1 (COLIA1) genes. However, limited information is available regarding the role of these polymorphisms in bone disease in premature infants. We have investigated the possible association between bone disease and the allelic polymorphisms of these three genes in 65 VLBW infants. Twenty infants (30.8%) were diagnosed with bone disease based on high activity of bone formation (serum alkaline phosphatase and osteocalcin), bone resorption (urinary excretion of calcium and pyridinium crosslink) markers, and positive radiologic signs. Statistically significant correlation between thymine-adenine repeat [(TA)(n)] allelic variant of ER gene and bone disease was observed. Infants without bone disorder more often carried a high number of repeats [(TA)(n) >18] [odds ratio (OR): 0.17, 95% confidence interval (CI): 0.05-0.55]. A low number of repeats [(TA)(n) <19] was found more frequently in infants suffering from bone disease (OR: 6.00, 95% CI: 1.77-20.31). Significant interaction (p = 0.009) between VDR and COLIA1 genotypes was observed. In a logistic regression model, bone disorder of preterms significantly correlated with male gender (p = 0.002), lower gestational age (p = 0.015), homozygous allelic variants of high number of (TA)(n) repeats (p = 0.006), and interaction between VDR and COLIA1 genotype (p = 0.009).

Adult↗

Invasive versus non-invasive diagnosis of renal bone disease.

At present, bone histomorphometry remains the gold standard for the diagnosis of the various types of renal bone disease. In the search for a non-invasive method of diagnosis, biochemical serum markers of bone remodelling, in addition to serum intact parathyroid hormone and aluminium determinations, have been proposed as the most reliable tools and are at present widely used in clinical practice. Their respective diagnostic values, as separate items and in combined analysis, are thoroughly discussed in the present review.

Aluminum↗