A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation.The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.Certain solid tumors, such as breast and prostate cancer, have a propensity to metastasize to bone and cause osteolysis and abnormal new bone formation (1, 2). The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. In fact, bone metastases are heterogeneous: data gleaned from a rapid autopsy program indicate that the same prostate cancer patient often has evidence of osteolytic and osteoblastic disease as shown by histologic examination (3). The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone, illustrated in Fig. 1. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases. Breast Cancer: The Prototypic OsteolyticTumorBreast cancer commonly metastasizes to and destroys bone, causing pain and fracture. Tumors produce many factors that stimulate osteolysis: parathyroid hormone-related protein (PTHrP), interleukin (IL)-11, IL-8, IL-6, and receptor activator of nuclear factor-nB ligand (RANKL;. Substantial data support a role for bone-derived transforming growth factor-h (TGF-h) and tumor-derived osteolytic factors, such as PTHrP, in a vicious cycle of local bone destruction in osteolytic metastases. Bone matrix stores several immobilized growth factors, particularly TGF-h, which is released in active form during osteoclastic resorption (10) and stimulates PTHrP production by tumor cells. PTHrP in turn mediates bone destruction by stimulating osteoclasts. A dominant-negative mutant of the type II TGF-h receptor inhibited TGF-h-induced PTHrP secretion in vitro and development of bone metastases in an MDA-MB-231 experimental metastasis model (5, 6). In addition, TGF-h regulates several genes that are responsible for enhanced bone metastases in MDA-MB-231: IL-11 and connective tissue growth factor (CTGF; refs. 8, 9). Collectively, these studies provided proof of principle to support a role for TGF-h blockade in the treatment of breast cancer bone metastases.SD-20...

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis, but optimal duration of therapy is unknown. This ASBMR report provides guidance on BP therapy duration with a risk benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score between −2 and −2.5 in FLEX and below −2.5 in HORIZON extension predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, women should be reassessed. Women with previous major osteoporotic fracture, those who fracture on therapy, or others at high risk should generally continue therapy for up to 10 years (oral) or 6 years (intravenous), with periodic risk-benefit evaluation. Older women, those with a low hip T-score or high fracture risk score are considered high risk. The risk of osteonecrosis of the jaw and atypical femoral fracture increases with BP therapy duration, but such rare events are far outweighed by fracture risk reduction with BPs in high risk patients. For women not at high fracture risk after 3–5 years of BP treatment, a drug holiday of 2–3 years can be considered, with periodic reassessment. The algorithm provided for long term BP use is based on limited evidence in mostly Caucasian postmenopausal women and only for vertebral fracture reduction. It is probably applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future osteoporosis trials will provide data for formulating definitive recommendations.

Hereditary multiple exostoses (EXT) is an autosomal dominant condition characterized by short stature and the development of bony protuberances at the ends of all the long bones. Three genetic locl have been identified by genetic linkage analysis at chromosomes 8q24.1, 11p11-13 and 19p. The EXT1 gene on chromosome 8 was recently identified and characterized. Here, we report the isolation and characterization of the EXT2 gene. This gene shows striking sequence similarity to the EXT1 gene, and we have identified a four base deletion segregating with the phenotype. Both EXT1 and EXT2 show significant homology with one additional expressed sequence tag, defining a new multigene family of proteins with potential tumour suppressor activity.

Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the 'seed and soil' hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-b that further stimulates local cancer cells. This 'vicious cycle' of bone metastases represents reciprocal bone/ cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the 'vicious cycle' is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.