Cancer Treatment–Induced Bone Loss
Other regulators of the bone remodeling process include growth hormone, glucocorticoids, thyroid hormone, and estrogen. Estrogen is critical for bone turnover; it promotes new bone formation and inhibits bone resorption.[11] It inhibits RANK ligand/M-CSF–induced activator protein-1–dependent transcription by regulating c-Jun activity and directly downregulating the RANK ligand and M-CSF–induced differentiation of osteoclasts.[12] Estrogen also upregulates OPG and TGF-ß, which in turn increases expression of OPG by osteoblasts and stromal cells. TGF-ß also inhibits bone resorption by increasing osteoclast apoptosis (Table 1).[13]
Estrogen essentially suppresses expression of osteoclastogenic cytokines, downregulates osteoclast bone resorption, and decreases osteoclast lifespan. Subsequently, with estrogen withdrawal, osteoclast formation increases secondary to overexpression of osteoclastogenic cytokines, increased differentiation of osteoclast precursors, and inhibition of osteoclast apoptosis.[12] In the natural estrogen-deficient state that occurs with menopause, bone resorption occurs at a greater rate than bone formation, thus decreasing bone mass and leading to osteopenia and/or osteoporosis.[14, 15] In patients with breast cancer or prostate cancer who are undergoing endocrine treatment with aromatase inhibitors or androgen deprivation therapy, respectively, the bone resorption to formation ratio is even further imbalanced, leading to greater morbidity and decreased quality of life.
Accordingly, patients with breast or prostate cancer who are receiving treatment with sex hormone ablative therapies have increased osteoclastic activity that results in treatment-induced bone loss. In essence, the estrogen-deficient state that naturally occurs in postmenopausal women is further exacerbated. During normal postmenopausal bone loss, the bone loss initially occurs at a rate of 2% per year and then decreases to 1% per year.[16] In contrast, cancer treatment–associated bone loss (ie, oophorectomy, chemotherapy, and endocrine therapy) occurs at a faster rate and is more abrupt than natural estrogen deprivation.[17] After peak bone mass is achieved at age 25, adults in general start to lose bone mass with further aging; however, women in particular note an enhanced rate of loss during their menopausal years secondary to estrogen deficiency.[16]
A selective estrogen-receptor modulator, is used in early and advanced breast cancer and has tissue-specific estrogen-agonist effects. In premenopausal women, it causes some bone loss; however, during the postmenopausal years, it is actually beneficial to bone health, improving bone density.[17] In contrast, aromatase inhibitors are appropriate only for treatment in the postmenopausal breast cancer population and are associated with increased bone loss and fracture risk. In the postmenopausal state, with the ovaries no longer functioning, estrogen production is limited and occurs only in distant sites—adipose tissue, adrenal glands, smooth muscle, and bone.[18] Aromatase inhibitors target the aromatase enzyme, which converts adrenally derived androgens to estrogens(Drug information on estrogens) in peripheral tissues. The conversion of androgens to estrogens via aromatase is the main source of endogenous estrogens in postmenopausal women. When this pathway is blocked, estrogen production is limited, leading to the known sequelae of the estrogen-deficient state.[17]
The American Society of Clinical Oncology (ASCO) recognizes that postmenopausal breast cancer patients who are treated with aromatase inhibitors are at higher risk for osteoporosis and fracture. Frequent monitoring of bone mineral density in this treatment population is recommended, and baseline dual-energy x-ray absorptiometry (DEXA) scan to evaluate bone health is recommended in all patients receiving aromatase inhibitor therapy. Also, ASCO clinical guidelines recommend that bisphosphonate therapy be initiated in all patients on aromatase inhibitor therapy who have documented osteoporosis (T score less than or equal to -2.5 on DEXA scan).[19]
The guidelines recommend reviewing and limiting other risk factors that may affect bone health, such as prolonged corticosteroid use, smoking, poor calcium intake, excessive alcohol(Drug information on alcohol) intake (more than 2 drinks per day), and limited physical activity. Patients should be counseled to avoid alcohol and tobacco use while on aromatase inhibitor therapy. Current recommendations state that all patients initiating aromatase inhibitor therapy should be on calcium and vitamin D supplementation. Additionally, bisphosphonate therapy is advised for patients initiating or receiving AI therapy who are at high risk. The high risk group is defined as patients with two or more of the following risk factors: T-score < -1.5; age > 65 years; low BMI (< 20 kg/m2); family history of hip fracture; personal history of fragility fracture after age 50; oral corticosteroid use > 6 months; and smoking.[19A]
Androgen deprivation therapy, in the form of gonadotropin-releasing hormone agonists or bilateral orchiectomy, is standard therapy in metastatic prostate cancer, and also has been used as adjuvant therapy for limited-stage prostate cancer. Although androgen deprivation therapy has been shown to improve disease-free and overall survival,[20] it reduces bone mineral density and increases the risk of fractures. Just as estrogen deficiency shifts the bone remodeling equilibrium towards more resorption, testosterone deficiency results in a similar imbalanced state. When testosterone is deficient, less estrogen is produced because less testosterone is available to be aromatized. Thus, osteoclast apoptosis is inhibited, and osteoblast apoptosis is increased.[20]
Studies have shown that rapid loss of bone mineral density occurs within the first 6 to 12 months of androgen deprivation therapy. Importantly, fracture development is associated with worse survival in prostate cancer.[21] Bisphosphonate therapy has been shown to reduce skeletal-related events and has an important effect on bone health when instituted with androgen deprivation therapy in prostate cancer.[22]
Multiple Myeloma
Finally, multiple myeloma is one of the most common hematological malignancies in the United States, with approximately 16,000 new cases per year and 11,000 deaths per year.[23] It is a B cell malignancy characterized by overgrowth of plasma cells and catastrophic lytic bone disease. All of the following factors have been implicated in the pathogenesis of bone destruction in multiple myeloma: interleukin-1, interleukin-6, macrophage inflammatory protein 1 alpha and, most importantly, RANK ligand.[4] Myeloma cells express RANK ligand, upregulate RANK ligand expression by bone marrow cells, and downregulate expression of OPG.[24] When plasma cells invade the bone marrow, they induce secretion of osteoclast-activating factors such as interleukin-6, interleukin-1, and TNF-B, which in turn signal stromal cells and osteoblasts to secrete RANK ligand. Myeloma cells secrete a molecule called syndecan-1, which inactivates OPG, the decoy receptor that normally restrains osteoclastic activity.[25] Thus, in multiple myeloma, the RANK ligand to OPG ratio is imbalanced, resulting in uncontrolled osteoclastic activity that leads to characteristic bone destruction.
Although osteoclastic bone destruction is increased in both multiple myeloma and lytic metastatic disease from other tumors, the lytic bone disease of multiple myeloma differs in a significant way, leading to even greater morbidity and poorer quality of life. Specifically, in multiple myeloma, when the tumor burden exceeds 50% in a particular area, osteoblast activity becomes suppressed or absent. Myeloma cells can produce TNF-alpha, which interrupts osteoblastic growth and differentiation; however, this is not the proven mechanism of osteoblast suppression in multiple myeloma.[26] The actual mechanism of osteoblast suppression is still unclear. Because of this lack of osteoblast activity, bone lesions in multiple myeloma are purely lytic. Secondly, in multiple myeloma, plasma cells downregulate OPG.[24] Without this regulation, tumor burden increases, and greater bone destruction ensues, exacerbating the vicious cycle of metastatic disease described above.
In summary, in multiple myeloma, increased osteoclastic activity, suppression of osteoblastic activity, and uncoupled bone remodeling lead to significant disease morbidity. Patients suffer from pathologic fractures, hypercalcemia, and significant bone pain. The lytic lesions usually affect the vertebrae, skull, sternum, ribs, pelvis, and proximal long bones.[25] Within the first year of diagnosis, 45% of patients with multiple myeloma suffer from a fracture, and 65% of patients will have a fracture sometime during their disease course. [23] As in breast cancer or prostate cancer patients with cancer treatment--induced bone loss, the use of intravenous bisphosphonates has a palliative role in the multiple myeloma population as well. Antiresorptive therapy has been shown to significantly reduce the number of skeletal-related events (fractures, hypercalcemia, bone surgery, and bone radiation) by inhibiting the formation of osteoclasts and by inducing their apoptosis.[25]. This palliative treatment has been shown to reduce significantly the number of skeletal-related events (fractures, hypercalcemia, surgery to bone, and radiation to bone) by inhibiting formation of osteoclasts and by inducing apoptosis of osteoclasts.[23]
Conclusion
Skeletal remodeling is key to bone health and normally occurs in a balanced manner. Key players include osteoclasts, osteoblasts, the bone matrix, hormones, systemic factors, local factors and, most importantly, members of the TNF superfamily of proteins—RANK receptor, RANK ligand, and OPG. When imbalanced bone remodeling occurs in the setting of metastasis, cancer treatment–induced bone loss, and/or multiple myeloma, the RANK ligand pathway has been implicated, and understanding its key role will help to reduce morbidity and improve quality of life in patients who suffer from the resulting illnesses.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
This article was conceived of and fully funded by Amgen, and Amgen provided background direction for the article.
