Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability), which negatively affect the patient's quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process; long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.

OBJECTIVE -The aim of this study was to determine the predictive value of silent myocardial ischemia (SMI) and cardiac autonomic neuropathy (CAN) in asymptomatic diabetic patients.RESEARCH DESIGN AND METHODS -We recruited 120 diabetic patients with no history of myocardial infarction or angina, a normal 12-lead electrocardiogram (ECG), and two or more additional risk factors. SMI assessment was carried out by means of an ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole, and 48-h ECG monitoring. CAN was searched for by standardized tests evaluating heart rate variations. Accurate follow-up information for 3-7 years (mean 4.5) was obtained in 107 patients.RESULTS -There was evidence of SMI in 33 patients (30.7%). CAN was detected in 33 of the 75 patients (38.9%) who were tested, and a major cardiac event occurred in 11 of them. Among these 75 patients, the proportion of major cardiac events in the SMI ϩ patients was not significantly higher than that in the SMI Ϫ patients (6 of 25 vs. 5 of 50 patients), whereas it was significantly higher in the CAN ϩ patients than in the CAN Ϫ patients (8 of 33 vs. 3 of 42 patients; P = 0.04), with a relative risk of 4.16 (95% CI 1.01-17.19) and was the highest in the patients with both SMI and CAN (5 of 10 patients). After adjusting for SMI, there was a significant association between CAN and major cardiac events (P = 0.04).CONCLUSIONS -In asymptomatic diabetic patients, CAN appears to be a better predictor of major cardiac events than SMI. The risk linked to CAN appears to be independent of SMI and is the highest when CAN is associated with SMI.

Sacral insufficiency fractures (SIF) that usually present as nonspecific pelvic or low back pain are often overlooked in the elderly. In a retrospective study conducted in a department of internal medicine, 16 patients with SIF were identified during a 6-year period. All patients were elderly women (mean age of 81 years) who presented with low back or pelvic pain. Radicular pain in the lower limb was common. Ten patients were bedridden. All 16 patients were osteopenic. Plain radiographs of the pelvis were nondiagnostic in 11 patients. Radionuclide bone scan showed a typical H-shaped pattern of increased uptake in 11 patients, and computed tomographic scan confirmed SIF (9/9 patients). With bed rest and analgesics, outcome was favorable in all patients. This study confirms the nonspecific presentation of SIF and the need to maintain a high index of clinical suspicion to make a prompt diagnosis and avoid unnecessary and sometimes invasive procedures.

This study shows that (1) responses of angiographically normal CAs to CPT and to flow increase are impaired in diabetic patients; (2) abnormal responses are not improved by L-arginine, suggesting that a deficit in substrate for nitric oxide synthesis is not involved; and (3) deferoxamine restores a vasodilator response to the two tests, suggesting that inactivation of NO by oxygen species might be partly responsible for the impairment of CA dilation in diabetic patients.