© Borgis - Postępy Nauk Medycznych 1/2017, s. 16-21
*Agata Bogołowska-Stieblich, Marek Tałałaj
Bone fractures in cancer patients
Złamania kości u pacjentów z chorobą nowotworową
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Associate Professor Marek Tałałaj, MD, PhD
Złamania kości w znaczący sposób zwiększają chorobowość i śmiertelność z powodu choroby podstawowej. U pacjentów z nowotworem istnieje wiele mechanizmów przyczyniających się do utraty masy kostnej. Mechanizmy te mogą być związane z chorobą podstawową oraz być następstwem terapii przeciwnowotworowej. Leczenie hormonalne stosowane u pacjentów z nowotworami hormonozależnymi może powodować hipogonadyzm i postępującą utratę masy kostnej. Chemioterapia stosowana u osób z chorobami nowotworowymi powoduje utratę masy kostnej, która nie ulega odbudowaniu po zakończeniu leczenia. Pacjenci z grupy podwyższonego ryzyka złamań osteoporotycznych powinni otrzymać właściwe leczenie tak szybko, jak to możliwe. Leczenie powinno zapewnić właściwą suplementację wapnia i witaminy D. Bisfosfoniany i denosumab są lekami z wyboru u pacjentów z chorobą nowotworową, gdyż są w stanie hamować utratę masy kostnej, redukować częstość złamań szkieletu i zmniejszać ryzyko wystąpienia hiperkalcemii i/lub hiperkalciurii.
Bone fractures significantly increase both morbidity and mortality of underlying diseases. Many mechanisms are responsible for bone loss among cancer patients, depending on underlying pathophysiological processes. The mechanisms can be related to the disease itself and the therapies used against cancer. Hormonal treatments used in patients with hormonally-responsive neoplasms can result in hypogonadism and progressive loss of bone mass. Chemotherapy employed in cancer patients causes a decrease in bone mass that is not recovered after discontinuation of the treatment. Patients at increased risk of fragility fractures should begin preventive treatment as soon as possible. The treatment need to assure adequate supplementation of calcium and vitamin D. Bisphosphonates and denosumab are the drugs of choice in patients with neoplastic diseases as they are able to inhibit bone mass loss, reduce the incidence of skeletal fractures and decrease the risk of hypercalcemia and/or hypercalciuria of malignancy.
Human skeleton is composed of two structural types of bone tissue: cortical bone, the dense outer layer of the skeleton responsible for supporting the weight of the body, and trabecular bone, the more metabolically active porous matrix located within short bones and ends of long bones. Bone tissue is undergoing continuous dynamic remodeling in a coupled and sequential process of bone resorption and formation, mediated by osteoclasts and osteoblasts respectively.
Many hormones and cytokines are involved in the close cross talk among cells within the bone microenvironment. Osteoclast proliferation and activity are stimulated by interleukin 6 (IL-6), IL-1, prostaglandins, and colony stimulating factors (CSFs) (1, 2). Activated osteoclasts bind to bone matrix via integrin proteins and secrete acid and lysosomal enzymes that degrade bone. Osteoblasts synthesize the collagenous precursors of bone matrix (osteoid) and regulate its mineralization. They are also involved in the control of osteoclast differentiation through expression of receptor activator of nuclear factor κB ligand (RANKL), and osteoprotegerin (OPG), a decoy RANK receptor, which inhibits osteoclast formation.
Cancer, after cardiovascular diseases, is the second leading cause of death (30% of total mortality). Its incidence and prevalence are still rising, partly due to aging of the population (2).
PATHOPHYSIOLOGY OF METASTATIC BONE DISEASE
Multiple steps are involved in the development of metastases from a primary tumor to any distant site. These include angiogenesis, which provides nutritional support for tumor growth, local invasion through the basement membrane, adhesion to vessel endothelium in the target organs, and extravasation into the tissue. These events are supported by secretion of e.g. matrix metalloproteinases and cathepsin K by tumor cells (3, 4).
Bone remodeling units involve an overflow of growth factors, cell adhesion molecules, and cytokines that make them attractive sites for metastatic tumor cells. No definitive studies have linked increased bone resorption to increased tumor cell mass, but limiting of bone resorption was found to reduce tumor expansion in bone (5, 6).
Metastatic bone tumors consist of four types of radiographically defined lesions: osteolytic, osteoblastic, osteoporotic and mixed. Osteolytic lesions are characterized by the destruction of bone, recognized as a hole in the cortex on plain radiographic images. Osteoblastic lesions, often referred to as osteosclerotic, are characterized by excess deposition of new bone and appear on X-ray pictures as more dense bone. Osteoporotic lesions create areas of “faded” bone without cortical destruction and mixed lesions comprise a combination of bone destruction and new bone deposition. Mixed lesions often have a central clear area of cortical lysis surrounded by a zone of increased density (sclerosis). Osteolytic damages are most common in patients with breast cancer and multiple myeloma, while osteoblastic lesions in men with prostate cancer (7).
Bone metastases are usually located in the axial skeleton winded by valveless venous plexuses. The highly vascular metaphyseal tissue, composed predominantly of trabecular bone, appears to be the preferred site for bone metastases. The mechanics of its sluggish sinusoidal vascular supply give the invading tumor cells ample opportunity to move in and out of the marrow. The endothelial cells lining the sinusoids express multiple adhesion molecules, including P-selectin, E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1), that play key roles in extravasation of tumor cells into the marrow. Bone microenvironment contains many bone-stored cytokines and growth factors, such as insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGF-β), that appear to favor the growth of metastases (8).
In men the most common neoplasm is prostate cancer which develop osseous metastases in 90% of patients with generalized disease (9, 10). Bone metastases typically occur in the axial and/or proximal appendicular skeleton as osteosclerotic lesions, being the result of stimulation of osteoblasts by prostate cancer cells (7, 11).
Multiple myeloma (MM) is a hematological neoplasm characterized by the proliferation of cancerous plasma cells in the bone marrow and the presence of abnormal monoclonal protein in plasma and/or urine (12). Bone lesions are the result of imbalance between osteoclasts and osteoblasts activities. It was found that suppression of osteoblasts is caused mainly by inhibition of the Wingless/integrase-1 pathway, while an increase in the osteoclasts function is the result of amplification of the RANK/RANKL pathway and the activity of macrophage inflammatory protein 1-α (13, 14).
DIAGNOSIS OF METASTATIC BONE DISEASE
Bone scintigraphy is a nuclear scanning test that allows to diagnose a number of conditions relating to bones, including primary or metastatic neoplastic lesions, bone fractures not visible at traditional plain X-ray images, and damages to bones due to certain infections. The technique used for bone imaging utilizes labeling with Tc99mmethylene diphosphonate (Tc99mMDP) that is incorporated into bone tissue during its formation. It means that osteolytic lesions in patients with multiple myeloma are unlikely to be visualized. Metastatic cortical lesions may be best demonstrated on computed tomography, while trabecular lesions with magnetic resonance imaging. The lesions are found mostly at the bones with large quantity of bone marrow, such as cranium, spine, ribs, pelvis and proximal epiphyses of long bones. Increased bone resorption results in accelerated bone mass loss, hypercalcemia, and pathological fractures. Hypercalcemia is found in about 30-40% of patients, and pathological fractures are localized most often at the spine and may cause injury of the medulla (7, 14).
BONE MASS LOSS AND FRACTURE RISK IN CANCER PATIENTS
Various mechanisms responsible for bone loss in patients with neoplasm may exert different impact on the skeleton depending on the characteristics of the disease and therapies used against cancer. Some hormonal treatments employed in patients with breast or prostate cancers cause hypogonadism that accelerates bone mass loss. The chemotherapies, especially those including glucocorticoids, significantly decrease bone mineral density (BMD) and increase the risk of fractures (7, 11).
It has been documented that in women with localized breast cancer the incidence of vertebral fractures was almost five times greater than in healthy patients (odds ratio = 4.7), and in women with soft tissue metastases was over twenty times greater (OR = 22.7). Additional risk factors that increase bone fracture risk include treatment with aromatase inhibitors, low BMD (T-score < -1.5), elderly age > 65 years, low body mass index (< 20 kg/m2), personal history of fragility fracture after the age of 50 years, family history of hip fracture, systemic glucocorticoid use for more than 6 months, and cigarette smoking (15).
In men with advanced prostatic cancer treated with androgen deprivation therapy, who experienced at least one fracture after their diagnosis overall survival was significantly decreased compared with patients without fractures (median 121 vs 160 months) (16).
Treatments used in women with neoplastic diseases, such as surgical castration, hormonal treatment, radiation therapy and chemotherapy can result in hypogonadism and accelerated loss of bone tissue. Radiation therapy employed in advanced cancer of the uterine cervix and endometrium may contribute to the development of pelvic fractures. It was shown that focal, high dose radiation therapy can induce atrophy of the trabecular bone due to injury of blood vessels.
Estrogen deficiency is the major cause of accelerated bone loss leading to an increased incidence of fractures. In premenopausal women suffering from breast cancer ablation of ovarian function was found to decrease BMD by 8% at the spine and by 4% at the femur (17, 18).
Tamoxifen is a selective estrogen receptor modulator (SERM) currently prescribed for estrogen receptor positive (ER+) breast cancer. The mechanisms of action of SERM class compounds depend on their tissue-selective ER agonist or antagonist activities. SERMs affect bone homeostasis by reducing the activity of osteoclasts in a transforming growth factor-β-dependent manner and decreasing bone resorption. Tamoxifen was suggested to be a viable choice for initial hormonal therapy in women with low probability of carcinoma recurrence and at high risk of skeletal fractures. Tamoxifen acts as an estrogen receptor antagonist on breast tissue, but as a ER agonist in bones and uterus, where it may cause endometrial hyperplasia, polyp production, and possibly increased risk of endometrial cancer. It was found, that in postmenopausal women with breast cancer tamoxifen was able to maintain BMD and to reduce the risk of osteoporotic fractures. Given for five years in premenopausal women, however, the drug diminished bone remodeling and increased the risk of osteoporotic fractures by 32% (15, 18, 19).
Aromatase inhibitors (AI) are used for the treatment of ER+ breast cancer in postmenopausal women. The drugs have been shown to have superior efficacy in reducing the risk of cancer recurrence compared with tamoxifen. In postmenopausal women most of the androgens are converted into estrogens by cytochrome P450 aromatase in the adipose tissue. Currently used the 3rd generation AI, such as anastrozole, letrozole and exemestane inhibit 96-99% of activity of the enzyme, decreasing the levels of endogenous estrogens far below the levels found at natural menopause (20-22).
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