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The role of RANK-ligand inhibition in cancer: the story of denosumab.

The diagnosis of bone metastases is an event with certain consequences for the patient. They often mean pain and can also mean pathological fractures, hypercalcemia, and spinal cord compression, all synonymous with a diminished quality of life and often also hospitalization. Since the advent of the intravenous bisphosphonates, things began to look a bit brighter for patients with bone metastases-bone destruction was kept at bay a little longer. The next generation of bone metastasis treatments is well on its way in clinical development, and among them, the most advanced drug is denosumab. Deno

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… When RANK, expressed by both osteoclasts and their precursors, binds to RANK-L, it stimulates osteoclast formation [ 6 ], activation [ 7 ], adherence [ 8 ], and survival [ 9 ], ultimately leading to increased bone resorption. … Osteoclast activity is likely to depend, at least in part, on the relative balance of RANK-L and OPG. …

Hypercalcemia and altered biochemical bone markers in post-bone marrow transplantation osteopetrosis: a case report and literature review.

Autosomal recessive osteopetrosis is a rare disorder of bone resorption defect that results in generalized sclerotic bones and bone marrow failure. Allogeneic BMT is the only treatment for cure. One of the complications following a successful BMT is hypercalcemia that is a unique complication in this group of patients. We report a three-yr-old boy with osteopetrosis who developed hypercalcemia following the successful BMT. His maximal calcium level was 13.3 mg/dL. Markedly increased both bone formation and resorption markers were demonstrated along with hypercalcemia. These findings indicated

[Osteoporosis treatment in patients with hyperthyroidism].

Childhood thyroid hormone (T3) is essential for the normal development of endochondral and intramembranous bone and plays an important role in the linear growth and maintenance of bone mass. In adult, T3 stimulates osteoclastic bone resorption mediated primarily by TR alpha and local conversion by deiodinase D2 may play a role in local activation. TSH seems to be an inhibitor of bone resorption and formation. In thyrotoxicosis patients with Graves' disease, there is increased bone remodelling, characterized by an imbalance between bone resorption and formation, which results in a decrease of b

Inhibin and the regulation of bone mass.

Inhibins A and B are gonadal peptide members of the transforming growth factor-beta superfamily that serve as negative feedback regulators of pituitary follicle-stimulating hormone (FSH). Accumulating evidence suggests that bone turnover and bone loss increase in women before menopause and the decrease in serum estradiol levels. Increased FSH levels have been correlated with some of these perimenopausal changes, whereas decreased inhibins strongly correlate with increases in bone formation and resorption across the menopause transition, and predict lumbar bone mass in perimenopausal women, lik

Vacuolar ATPase as a drug discovery target.

Vacuolar ATPases (V-ATPases) are present not only in the plasma membranes of specialized cells but also in ubiquitous intracellular acidic compartments, which are essential for physiological cellular function. Consequently, although V-ATPases are important etiologically in several diseases, it seems that they might not be good molecular targets. In fact, bafilomycin A1, a potent and specific inhibitor of V-ATPase, exerts severe and acute toxic reaction when administered to animals. On the other hand, disruption of subunit a3 of V-ATPase is not embryonic lethal, but knockout mice merely exhibit

Effects of catecholamines on blood pressure in the long bone marrow cavity in rats with bisphosphonate-induced osteopetrosis.

Osteopetrosis is a congenital metabolic bone disease characterized by skeletal sclerosis resulting from defective osteoclast-mediated bone resorption. The disease may, inter alia, be caused by the administration of bisphosphonates (e.g. pamidronate) particularly in young humans. The issue of the effect of pamindronate-induced osteopetrosis on the function of blood circulation and autonomic nervous system remains open. In order to clarify this problem, the present study concentrated on the effect of catecholamines on blood pressure in the marrow cavity in rats with pamindronate-induced osteopet

Bisphosphonates and atherosclerosis: why?

The increasing knowledge on bone calcification processes has revealed some similarities with vascular tissue, where calcifications of arteries and cardiac valves contribute to several cardiovascular problems, such as heart failure, systolic hypertension, and myocardial and peripheral ischemic disease. Bisphosphonates have been used extensively for over two decades for the treatment of diseases associated with excessive bone resorption, i.e., osteoporosis, osteolytic bone metastasis, hypercalcemia and Paget's disease, by blocking osteoclastic function. Etidronate, pamidronate and clodronate has

Possible mechanisms of osteopenia in Rett syndrome: bone histomorphometric studies.

The etiology of frequently occurring osteoporosis in Rett syndrome is unknown. Five girls, ages 9.75, 11, 12, 13.5, and 14 years, with typical Rett syndrome requiring scoliosis surgery presented an opportunity to study bone remodeling by quantitative bone histomorphometry. Anterior iliac crest bone biopsies taken 1 to 2 days after double labeling of the bone surfaces with tetracycline were submitted for histomorphometry. Bone volume was reduced, and the surface parameters of formation (osteoid surface) were normal, whereas the parameters of resorption (osteoclast surface and number) were decre

Increased bone resorption with decreased activity and increased recruitment of osteoblasts in osteogenesis imperfecta type I.

An iliac bone biopsy from an adult male, 58 years of age, with osteogenesis imperfecta type I was studied by bone histomorphometry after double-fluorescence labeling with tetracycline. Low bone mineral density (BMD) of the radius, measured by dual-energy X-ray absorptiometry (DXA) was associated with high levels of urinary deoxypyridinoline and serum bone-specific alkaline phosphatase and osteocalcin. At the tissue level, low cancellous bone volume (BV/TV) was associated with increased eroded surface (ES/BS) and a relatively increased osteoclast number (N.Oc/BS). Osteoid thickness (O.Th) was a

Malignant reversion of a human osteosarcoma cell line, Saos-2, by inhibition of NFkappaB.

Beyond a pivotal role in neoplastic transformation and malignant progression, NFkappaB is intricately involved in bone biology, pointed up by the osteopetrotic phenotype of NFkappaB (p50-p52) double knock-out mice. Osteopetrosis results from intrinsic defects in osteoclastogenesis, loss of osteoclast bone resorptive activity and, questionably, increased osteoblast activity (bone matrix apposition and mineralization). We here report that inhibition of NFkappaB signaling activity in Saos-2 cells results in a marked decrease in cellular proliferation, assessed by the incorporation of radioactive

Modulation of the effects of osteoprotegerin (OPG) ligand in a human leukemic cell line by OPG and calcitonin.

The discovery of osteoprotegerin (OPG), osteoprotegerin ligand (OPGL), and RANK has elucidated the mechanism by which osteoblasts and stromal cells regulate osteoclastic differentiation and function and mediate the effects exerted by other hormones and cytokines. We have investigated the effects of these novel cytokines on the preosteoclastic cell line FLG 29.1. We show that OPGL alone and in combination with macrophage colony-stimulating factor (CSF-1) dramatically reduced replication and increased tartrate-resistant acid phosphatase activity. However, although FLG29.1 cells appear to adhere

Cytodiagnostic patterns of metaplastic breast carcinoma in aspiration samples: a study of 14 cases.

Metaplastic breast carcinomas (MBCs) are not only uncommon neoplasms but also show a myriad of cytomorphologic patterns in aspiration samples. These tumors comprise less than 5% of breast malignancies and have an uncertain prognosis. In this study, the fine-needle aspiration cytologic features of 14 MBCs with the identification of two distinct malignant cell populations are presented, based on which a definitive diagnosis was possible in 12 of the 14 cases. In the remaining 2 cases the diagnosis of MBC was substantiated after study of cell blocks from the aspirate, which were made in all the c

Physiological and pathological roles of parathyroid hormone-related peptide.

Parathyroid hormone-related peptide was originally identified as a tumor-produced factor that mediated malignancy-associated hypercalcemia by binding to the common parathyroid hormone/parathyroid hormone-related peptide receptor to stimulate osteoclastic bone resorption and renal tubular resorption of calcium. Its role as a humoral factor in hypercalcemia of malignancy is well established, and recent work has demonstrated its importance as a tumor-produced factor in the pathogenesis of bone metastasis. Besides these cancer-related functions, work in the past decade has clearly established that

The effect of ovariectomy on periosteal bone formation and bone resorption in adult rats.

In order to quantify the rate of bone metabolism after ovariectomy, tetracycline was injected intraperitoneally into 3-month-old female Wistar rats to label the mineralizing front and ovariectomy was performed. The rats were sacrificed 91 days later, whereupon serum calcium and phosphorus were determined. The femurs were sectioned in the upper part, photographed and the area between the tetracycline line and the outer perimeter of the bone was planimetered at a reference point. The area of periosteal bone formed was noted to be 28.3% greater than in control rats (P = 0.0002) and the area of th

Amylin.

Amylin is a 37 amino-acid peptide which is secreted from the pancreatic islets of Langerhans. It has major sequence homology with calcitonin gene related peptide. Amylin can precipitate out in these cells to form amyloid. Amylin is secreted by similar stimuli to those that secrete insulin. Amylin has a number of effects that may counteract the effect of secreted insulin, i.e., decreased second phase insulin secretion, increased hepatic glucose output, and inhibition of insulin effects on skeletal muscle. It must, however, be recognized that in many cases the doses necessary to produce these ef

Hypocalcemic actions of amylin amide in humans.

Amylin (also known as islet amyloid polypeptide and diabetes-associated peptide) has recently been shown by us to have a potent hypocalcemic effect in rat and rabbit owing to inhibition of osteoclast-mediated bone resorption. The hypocalcemic potency of amylin was found to be second only to that of calcitonin (CT) and is 100-fold more potent than calcitonin gene-related peptide. Here we demonstrate that amylin has a hypocalcemic effect in patients with Paget's disease of bone. Both human CT (hCT) and amylin induced a maximum hypocalcemic effect 2 h following intravenous administration of the p

[Bone demineralization and cytokines].

Cytokines are secreted by several cell types in the bone microenvironment. These peptides act on bone cells by a paracrine or autocrine mechanism and play an important role, although not completely clarified, in the regulation of bone remodeling. Postmenopausal osteoporosis could be due to a local overproduction of some osteoclast-stimulating cytokines in response to estrogen deficiency. During chronic inflammatory joint diseases, such as rheumatoid arthritis, synovial cells produce large amounts of cytokines leading to increased local bone resorption and juxta-articular bone destructions. The

Treatment of cancer-related hypercalcemia.

Hypercalcemia, a complication that develops in 10% to 20% of patients with cancer, results from disruption of the normal physiologic mechanisms that closely regulate calcium homeostasis. Most patients with hypercalcemia are seriously dehydrated, and this volume depletion further compromises the kidney's ability to excrete calcium. Replenishment of extracellular fluid, restoration of intravascular volume, and maintenance of saline diuresis are the cornerstones of initial therapy. In most patients, pharmacologic inhibition of abnormally increased osteoclastic resorption is necessary to normalize

Fracture incidence and bone disease in epileptics receiving long-term anticonvulsant drug treatment.

Of 155 institutionalized epileptics, 16 (10%) were noted to have suffered from different kinds of fractures when observed over a period of 1 year. The patients with fractures were further investigated with respect to blood and urine chemistry and bone morphology. The serum and urinary calcium values were below the average values for the population. Elevated values for serum alkaline phosphatase and for immunoreactive parathyroid hormone were found in most patients. The values of serum phosphate were distributed close to those of the normal population, while the urinary phosphate values were lo

[Different radiological, histomorphometrical and biochemical findings in two cases of adult osteopetrosis (author's transl)].

Morphokinetic measurements after tetracycline labeling were performed on bone specimens of the iliac crest in a 30-year-old man and a 38-year-old women. On radiographs, the osteopetrosis (=marble bone disease Albers-Schönberg) was characterized by an almost homogenous osteosclerosis in the man and by variable zones of high and normal density in the woman. Histologically, the man revealed increased rates of bone formation and mineralisation as signs of hyperactivity of the osteoblasts accompanied, biochemically, by an elevation of serum alkaline phosphatase and a high urinary output of hydroxyp