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PubMed1999

Recent advances in bone biology provide insight into the pathogenesis of bone diseases.

Bone is modeled during embryonic development by endochondral and membranous ossification and is continuously remodeled thereafter under the influence of local and systemic factors to provide structural support and assist in calcium homeostasis. Recent studies of knockout and transgenic mice have increased understanding of the regulation of bone modeling during development and of remodeling of mature bone and have shed new light on the pathogenesis of a number of bone disorders. For example, fibroblast growth factor receptor-3, parathyroid hormone-related protein, and tartrate-resistant acid phosphatase affect the function of chondrocytes during endochondral ossification (the latter two by regulating their life spans and thus growth plate thickness and bone length). Some ubiquitously expressed genes seem unexpectedly to have unique functions that are largely confined to bone cells: M-CSF, C-Fos, PU.1, and NF-kappaB are required for osteoclast formation, whereas c-Src and Mitf (microphthalmia transcription factor) are required for osteoclast activity after the cells have formed. Knockout of these genes results in osteopetrosis, a disorder characterized by persistence in marrow cavities of unresorbed osteocartilaginous matrix and, as in some affected humans, by increased mortality. Some proteins seem to act as negative regulators of bone cell function, for example osteoprotegerin (a soluble TNF receptor) in osteoclasts; osteocalcin, bone sialoprotein, and 5-lipoxygenase in osteoblasts. Regulation of osteoclast life span may be an important mechanism by which estrogen and bisphosphonates prevent bone loss in conditions characterized by increased bone resorption, such as postmenopausal osteoporosis. The unique requirement of bone cells for certain gene products raises the possibility that these cells may have specific responses to inhibitory or stimulatory agents, and that signaling molecules in these response pathways could be specific targets for novel therapies to treat or prevent common bone diseases.

Animals↗
PubMed1980

A comparison of bone scanning and radiology in the evaluation of patients with metabolic bone disease.

Bone scans and radiographs were evaluated in 80 patients with metabolic bone disease (27 with osteoporosis, 14 with primary hyperparathyroidism, 24 with renal osteodystrophy and 15 with osteomalacia). The bone scan did not suggest a metabolic bone disorder in any of 27 patients with histologically proven osteoporosis. In 22 (81%) patients radiographs were reported as showing osteoporosis. In 10 (70%) vertebral fractures were seen on X-ray while these were noted in 11 (41%) patients on the bone scan. Vertebral fractures were usually visualised on the bone scan when these had occurred less than one year previously. In primary hyperparathyroidism the bone scan was suggestive of a metabolic bone disorder in 7 of 14 (50%) patients, while radiographs were reported as showing evidence of hyperparathyroidism in three (21%) cases. The bone scan suggested the presence of a metabolic bone disorder in all 24 patients with renal osteodystrophy and 15 patients with osteomalacia while the correct diagnosis was obtained in 14 (58%) and nine (60%) of these patients on X-ray. It is concluded that the bone scan is the more sensitive investigation in patients with osteomalacia, primary hyperparathyroidism and renal osteodystrophy. For osteoporosis radiology is the investigation of choice but the bone scan may be of value in assessing the duration of vertebral collapse.

Animals↗
PubMed2004

Overview of samarium sm 153 lexidronam in the treatment of painful metastatic bone disease.

Bone pain associated with advanced prostate and other cancers is a frequent and significant complication, and the effective management of metastatic bone disease and accompanying symptoms continues to be one of the major problems facing patients and their physicians. Treatment is in part dependent on prior treatments; usually a combination of systemic and local modalities is used because no single treatment regimen is effective for an extended period of time. The 3 radionuclides currently approved for treatment of bone pain (phosphorus-32, strontium-89, and samarium-153) are discussed in this review as viable treatment options, with emphasis on the third-generation agent in this category, samarium Sm 153 lexidronam. Clinical trial data are described that support the use of this agent in patients with hormone-refractory prostate cancer with painful metastatic bone disease, and the efficacy of and role for combination therapies are also discussed.

Journal Article↗
PubMedDate not supplied

Vitamin D deficiency: a culprit in metabolic bone disease.

Bone formation and bone remodeling are complicated processes regulated by systemic hormones and paracrine factors which regulate calcium and phosphate fluxes and cellular differentiation. The many actions of vitamin D reinforces its importance in the process of growth, maturation and aging of bone. An understanding of these important regulators of bone metabolism is important to understanding the clinical disorders as they are related to alterations in vitamin D metabolism and metabolic bone disease. Specific disorders of vitamin D metabolism can be related to clinical disease states of aging, altered lifestyles, gastrointestinal, renal and hepatic disease. A classification of altered vitamin D metabolism as related to its clinical states is presented. The scope of vitamin D deficiency from childhood rickets to adult osteomalacia and osteoporosis is presented, Intermediate syndromes of high turnover osteoporosis, subclinical vitamin D-deficiency states, role of vitamin D analogues in treating type I and type II osteoporosis is discussed. Treatment guidelines for managing this scope of clinical vitamin D disorders are provided.

Aging↗
PubMed2001

The clinical impact of metabolic bone disease in coeliac disease.

Bone mineral density was measured by dual energy x ray absorptiometry (DEXA) at the lumbar spine and femoral neck in 15 adults who had metabolic bone disease in association with coeliac disease (mean age at diagnosis 53.5 years, range 37 to 66). Results were expressed as a T score (the number of standard deviations by which patient's bone density differed from the sex matched young adult mean). Three patients had no skeletal symptoms and normal routine calcium biochemistry but severely reduced axial bone mineral density on DEXA. Eleven patients had symptomatic skeletal fractures, including fractures of proximal femur (3), vertebrae (4), and radius (6). Three patients had osteomalacia confirmed on bone biopsy, two of whom had characteristic biochemistry. Secondary and tertiary hyperparathyroidism were seen. Seventy five further patients (60 female) with coeliac disease (mean age 52.0 years, median duration of gluten-free diet 3.4 years) and 75 paired healthy age and sex matched controls were questioned on past fracture history. Patients with coeliac disease underwent detailed studies of calcium biochemistry, dietary intake, and bone mineral density. Sixteen had a past history of fractures (chi(2) = 10.7, p = 0.0004, v controls), which were of typical osteoporotic type. Ten patients had fracture before diagnosis of coeliac disease and six after diagnosis. Patients who had a fracture were older (56.3 v 50.3 years, p < 0.02, Wilcoxon rank sum test) than those with no fracture. There was no significant difference in bone mineral density (z score -0.31 v -0. 77), serum calcium (2.30 v 2.26 mmol/l), 25-hydroxyvitamin D (19.7 v 23.7 nmol/l), parathyroid hormone (2.6 v 3.1 pmol/l), or dietary calcium intake (1021.0 v 1033.0 mg/day) in patients with fracture compared with those without fracture. Metabolic bone disease is common in coeliac disease and is associated with premature osteoporotic fractures.

Absorptiometry, Photon↗
PubMedDate not supplied

Relationship between metabolic bone disease and bone mineral density measured by dual-energy X-ray absorptiometry in the green iguana (Iguana iguana).

The aim of our work was to study the feasibility of using dual-energy X-ray absorptiometry to obtain reference bone density values in relation to body weight, gender, and metabolic bone disease in the green iguana. The study was performed on 28 animals. The weight, age, and gender of each iguana were recorded. Each lizard was carefully examined and radiographed to detect signs of metabolic bone disease. Blood samples were collected from each animal to evaluate Ca/P and total protein. All animals, both affected (group B; n = 11) and unaffected (group A; n = 17) by metabolic bone disease, were individually scanned using an X-ray densitometer. The regions of interest were the head, lumbar spine, right, and left femur. Statistical analysis was performed separately for each region of interest. Body weight had the strongest relationship with bone density (P < 0.01). Within regions of interest, for iguanas of average weight (710 g), statistically significant differences between healthy and sick animals were found: head (0.140 vs. 0.090 g/cm2; P < 0.01); lumbar spine (0.164 vs. 0.107 g/cm2; P < 0.01); right femur (0.103 vs. 0.076 g/cm2; P < 0.01); left femur (0.103 vs. 0.078 g/cm2; P < 0.01). Regression equations to obtain reference values of bone density as a function of body weight for animals affected and not affected by metabolic bone disease are provided. Our data indicate that X-ray bone densitometry is an additional tool for studying bone pathophysiology in reptiles.

Absorptiometry, Photon↗
PubMed2005

Clinical use of markers of bone turnover in metastatic bone disease.

Bone metastases profoundly perturb normal bone remodeling. Biochemical markers of bone turnover have been shown to reflect these tumor-induced changes in bone remodeling and might therefore be useful in the diagnosis and follow-up of patients with malignant bone disease. Most markers of bone turnover, particularly those of bone resorption, are elevated in patients with established bone metastases. While this might indicate a role for bone markers as diagnostic tools in cancer patients, the available evidence does not provide any final conclusions as to the accuracy and validity of the markers presently used in the early diagnosis of bone metastases. Markers of bone resorption respond promptly and profoundly to bisphosphonate and antineoplastic therapy, and this response is associated with a favorable clinical outcome. Most markers, however, have been more useful in groups of patients monitored in clinical studies than in studies of individuals. While this makes them a good tool for drug development, it remains unknown whether the use of bone markers in a routine clinical setting has any defined beneficial effects on overall outcome in cancer patients. In particular, no study has addressed the question of whether patients with bone metastases should be treated according to their rate of bone turnover and what the treatment goals are in this respect. While it is unlikely that bone-turnover markers have sufficient diagnostic or prognostic value when used in isolation, the combination of these markers with other diagnostic techniques might be the way forward to improve the clinical assessment of patients with cancers of the bone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Bone sialoprotein in serum of patients with malignant bone diseases.

Bone sialoprotein (BS), a protein synthesized by osteoblasts and osteoclasts and highly modified posttranslationally, constitutes a predominant fraction of the noncollagenous organic matrix in human bone. We report an assessment of serum concentrations of BS in patients with malignant bone diseases. In patients with bone metastases (according to scintigraphic criteria), serum BS concentrations were greater than in patients without bone metastases (P <0.05). However, ROC curve analysis revealed that serum BS was inferior to serum bone alkaline phosphatase in discriminating between patients with and without bone metastases. Patients with bone metastases showed a weak correlation between serum BS concentrations and bone formation markers. Only "traditional" markers of bone formation-but not BS-were correlated with urinary deoxypyridinoline (P <0.01). Liver and kidney dysfunction had no significant influence on BS values in these patients (as assessed by analysis of variance; P >0.05). In multiple myeloma patients treated with corticosteroids and bisphosphonates, BS concentrations were lower than in tumor patients without bone metastases (P <0.001), and the correlation between BS concentrations and the number of bisphosphonate courses applied was significant (r = -0.578; P <0.05). In postmenopausal women, serum BS concentrations averaged 142% greater than in premenopausal women. Further studies should be done, therefore, to elucidate whether serum BS is able to predict high bone turnover after menopause.

Adult↗
PubMed2004

Efficacy and safety of ibandronate in the treatment of neoplastic bone disease.

Bone is an organ commonly involved in spreading neoplastic disease, especially in multiple myeloma and carcinoma of the breast, prostate and lung. Skeletal stabilisation and pain relief are the main treatment goals in metastatic bone disease. Bisphosphonate treatment inhibits osseous breakdown and is well-established as the current standard therapy for reducing complications of neoplastic bone disease (e.g., pain, fractures and hypercalcaemia). Ibandronate is a third-generation bisphosphonate that has recently been approved for the treatment of bone metastases caused by breast cancer. The oral and intravenous formulations of ibandronate appear to have comparable efficacy. Ibandronate has also been shown to provide significant and sustained relief from metastatic bone pain over 2 years of treatment, improving patient functioning and quality of life. With a favourable long-term safety profile and the added convenience and flexibility offered by its efficacious oral formulation, ibandronate represents a new therapeutic option for metastatic bone disease management.

Bone Diseases↗
PubMed2006

Conclusion: Bone markers in metastatic bone disease.

Bone metastases occur frequently in patients with multiple myeloma and breast, prostate, and lung cancer. Presence of metastatic bone disease (MBD) is correlated with abnormal bone remodelling, as high levels of biochemical markers of bone turnover can be detected in serum or urine from patients with these malignancies. The idea of using bone markers in the diagnosis and follow-up of patients with MBD is undergoing validation and gaining acceptance. In this conclusion, we summarise data from leading studies relating to the search for useful markers of bone resorption and bone formation in MBD.

Biomarkers↗
PubMed1994

Posttranslational heterogeneity of bone alkaline phosphatase in metabolic bone disease.

Bone alkaline phosphatase is a marker of osteoblast activity. In order to study the posttranscriptional modification (glycosylation) of bone alkaline phosphatase in bone disease, we investigated the relationship between mass and catalytic activity of bone alkaline phosphatase in patients with osteoporosis and hyperthyroidism. Serum bone alkaline phosphatase activity was measured after lectin precipitation using the Iso-ALP test kit. Mass concentration of bone alkaline phosphatase was determined with an immunoradiometric assay (Tandem-R Ostase). In general, serum bone alkaline phosphatase mass and activity concentration correlated well. The activity : mass ratio of bone alkaline phosphatase was low in hyperthyroidism. Activation energy of the reaction catalysed by bone alkaline phosphatase was high in osteoporosis and in hyperthyroidism. Experiments with neuraminidase digestion further demonstrated that the thermodynamic heterogeneity of bone alkaline phosphatase can be explained by a different glycosylation of the enzyme.

Adult↗
PubMed1995

The diagnostic value of urinary pyridinium cross-links of collagen, serum total alkaline phosphatase, and urinary calcium excretion in neoplastic bone disease.

Bone metastases strongly affect skeletal metabolism by both their growth and their paracrine activities. However, so far no specific laboratory marker has been found to signal the spread of neoplastic disease to bone. We performed a cross-sectional study of 153 cancer patients and an equal number of healthy controls matched for sex and age, in which we determined serum levels of calcium and total alkaline phosphatase (TAP) as well as the fasting urinary excretion of calcium (uCa) and of the collagen cross-links pyridinoline (uPYD) and deoxypyridinoline (uDPD). The aim of the study was to analyze the diagnostic validity of the biochemical parameters measured with regard to neoplastic bone involvement. In the cancer group, 98 patients had overt bone metastases, as judged from radiographic and radioisotopic bone imaging. The remaining 55 patients were also in an advanced stage of disease, but there was no evidence of malignant bone involvement. In comparison to healthy controls, patients both with and without metastatic bone disease had significantly higher levels of TAP, uPYD, and uDPD (P < 0.0001). Only in cancer patients with bone metastases was the median serum calcium level higher than in the healthy controls (P < 0.02). uCa was the same in cancer patients and the control group. Within the collective of cancer patients, individuals with skeletal metastases had higher levels of serum calcium (P < 0.05), TAP (P < 0.01), and uPYD and uDPD (both P < 0.0001), than patients without evidence of malignant bone disease. uCa did not differ between the 2 groups of cancer patients. The cancer patients were then stratified into 4 subgroups according to the serum calcium level (< or = 2.6 mmol/L >) and the absence or evidence of bone metastases. This stratification revealed that in patients with bone metastases, uPYD and uDPD levels were similar in normocalcemic and hypercalcemic subjects, whereas in hypercalcemic patients, uCa levels significantly exceeded those in normocalcemic patients. When the efficacy of TAP, uCa, uPYD, and uDPD in discriminating between patients with and without bone metastases was evaluated by use of receiver-operating characteristic curves and stepwise multivariate regression analysis, uPYD was found to have the highest diagnostic validity. Using 50 mumol PYD/mol creatinine (i.e. the upper limit of normal range) as the cut-off level, the sensitivity of uPYD was 88.7%, whereas the specificity was only 41.8% (odds ratio, 5.598; 95% confidence interval, 2.547-12.306).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2004

[Metabolic bone disease and bone quality].

On the progress of study concerned with pathology of metabolic bone disease such as osteoporosis, it has been known that most of bone strength can be explained by bone volume. As bone volume can be determine by bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA), it has been widely used for diagnosis of osteoporosis or efficacy of treatment. However, with the advance of bone morphometry, decrease of bone strength or existence of insufficiency fracture is influenced by not only loss of BMD but also deterioration of bone quality especially bone microstructure. In this chapter, we will give an outline of change of bone quality in metabolic bone disease.

Bone Diseases, Metabolic↗
PubMed2000

[Bone scintigraphy in metastatic bone disease].

Bone scintigraphy has been widely used in the evaluation of metastatic bone disease. It can provide easy performance of whole body evaluation and high sensitivity for the detection of lesions. However, the indication for bone scintigraphy is revised from views of the less specificity and relatively higher cost than newly introduced diagnostic tools such as CT and MRI in Japan. In order to maintain the present state as a screening test for the evaluation of bone metastasis, more appropriate image acquisition and newly developed radiopharmaceuticals which show the specific accumulation to the metastatic bony lesions will be considered in future.

Aged↗
PubMed1988

Bone scanning and photon absorptiometry in metabolic bone disease.

Bone scan imaging with the current bone-seeking radiopharmaceuticals, the technetium-99m labelled diphosphonates, provides a functional display of skeletal metabolism and has dramatically improved our ability to investigate skeletal pathology. While the role of bone scanning in metastatic disease was recognized early, and welcomed by oncologists and other specialists alike, in the field of metabolic bone disease the realization of its potential value has been slower, with perhaps more reluctant acceptance. Nevertheless, the skeleton remains an extremely difficult organ to investigate, and a familiarity with bone scanning should be an essential part of the investigational armamentarium for anyone with an interest in the metabolic bone disorders. The measurement of bone mineral by photon absorptiometry is a relatively new technique, which is rapidly gaining acceptance. The ability to accurately detect and quantify changes in bone mass is potentially of considerable value in the diagnosis and management of osteoporosis. The technique provides us with an extremely important and powerful research tool but, at the present time, its role in clinical practice has yet to be established.

Animals↗
PubMed1996

Relationship between bone metabolism and plasma cytokine levels in patients at risk of post-transplantation bone disease after bone marrow transplantation.

Bone marrow transplant recipients may carry an increased risk of bone diseases, involving numerous factors that affect bone mineral metabolism. Interleukin-6 is a potent stimulator of bone resorption in vivo. The soluble fraction of interleukin-6 receptor is reported to trigger osteoclast formation by interleukin-6 in vitro. In a cross-sectional study we measured serum bone alkaline phosphatase concentrations and the urinary excretion of pyridinium cross-links in 21 patients after bone marrow transplantation, and investigated the relationship between these values and those for the plasma levels of interleukin-6 and soluble interleukin-6 receptor. Following bone marrow transplantation female--but not male--patients showed higher serum bone alkaline phosphatase values than age- and sex-adjusted controls (p < 0.05). Both female and male patients were characterized by increased urinary excretion values of pyridinium cross-links (p < 0.05). In contrast to a marked increase of interleukin-6 plasma levels (p < 0.001) no significant difference in the soluble interleukin-6 receptor levels was found between patients and apparently healthy persons (p = 0.838). Multiple regression analysis (taking into account different variables of the immunosuppressive regimen applied) revealed the plasma concentration of interleukin-6 as an independent predictor of the urinary excretion of pyridinium cross-links (p < 0.05). In conclusion, in patients following bone marrow transplantation, these findings indicate (a) an increase of bone formation in female--but not in male--patients possibly reflecting primary ovarian failure and (b) an enhancement of bone resorption possibly mediated by circulating interleukin-6.

Adult↗
PubMed1999

Measurements of bone mineral density. Mineral density in metabolic bone disease.

Bone metabolism and thus bone remodelling and bone mineral content are profoundly influenced by many hormonal and metabolic factors. This review presents the state of the art procedures for bone mineral absorptiometry and examines the interactions of endocrine and metabolic diseases and bone mineral content. Preventive and therapeutic modalities of osteoporosis are discussed in this context.

Bone Density↗