**4. Clinical presentation**

Bone metastases may cause few or no symptoms, being diagnosed incidentally during the initial staging of the primary cancer. However, they can represent a prominent source of morbidity because of skeletal-related events (SREs), which include pain, pathologic fracture, spinal cord compression, and hypercalcemia [3, 5].

**Pain** is the most common symptom of bone metastases and can have a significant impact on the quality of life [3, 9]. It could be of either biologic or mechanical origin. Biologic pain is related to the local release of cytokines and chemical mediators by the tumor cells, periosteal irritation, and stimulation of intraosseous nerves. Mechanical pain is related to the pressure or mass effect of the tumor tissue within the bone, with loss of bone strength, thus turning into activity-related pain. It's usually localized, but not rarely patients can complaint of pain in more than one site, and it might become severe and refractory to analgesia [7]. Sudden severe pain may be caused by a pathologic fracture, and prompt evaluation is necessary.

**Pathologic fractures** occur in 10–30% of all cancer patients, with proximal parts of the long bones being the most frequent fracture site and the femur accounting for over half of all cases [10]. Pain at the fracture site is the most common symptom, but other clinical features may be present depending on the fracture location, such as the inability to bear weight, point tenderness, pain that radiates, ecchymosis or skin discoloration, soft tissue mass or swelling at the site of pain, edema or joint effusion, loss of bony or limb contour, extremity shortening, open wound and bone exposure, decreased range of motion, significantly diminished mobility, and/or sensory disturbance of the distal extremity. The presence of neurologic symptoms should be a red flag for spinal cord compression.

**Spinal cord compression** can be caused by pathologic spine fracture, with the bone compressing the spinal cord or by tumor extension into the epidural space. Symptoms range from pain, which is usually the first symptom, to neurologic deficits, including motor weakness and paralysis, sensory deficits, bowel and bladder dysfunction, and ataxia [3, 11]. In terms of motor symptoms, these will depend on the site of compression – if it's at or above the conus medullaris, it generally produces fairly symmetric lower extremity weakness (if compression is above the thoracic spine, upper

extremities may be affected too); if it's below the level of the conus medullaris, it may present with signs and symptoms of cauda equina syndrome, with asymmetrical and less severe weakness. Sensory findings are common and are usually present prior to the onset of weakness, with patients describing ascending numbness and paresthesia in a radicular distribution [11]. If the site of compression is above the conus medullaris, sacral dermatomes are usually spared, while in the cauda equina syndrome, a saddle sensory loss is common. Proprioceptive loss can also occur, although this is less common and usually occurs later.

**Hypercalcemia** is the most common metabolic complication of malignant disease, and it's usually caused by direct induction of local osteolysis by the tumor cells and generalized osteolysis by humoral factors secreted by the tumor [3, 7, 12]. Patients with mild hypercalcemia may be asymptomatic or have nonspecific symptoms, such as constipation, fatigue, and depression, while patients with higher serum calcium elevations may present polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness, and neuropsychiatric disturbances and may even lead to cardiac arrhythmias and acute renal failure [2, 7].
