Advances in
Bone Cancer Treatment:
Preventing Metastasis and Bone Loss
New Data on Preventing Cancer Therapy-Induced Bone Loss
In healthy adults, bone mass declines with age in both men and women because of decreasing estrogen levels.53 The decline in circulating estrogen levels leads to an imbalance favoring bone resorption over new bone formation. The net effect is osteoporosis, a systemic disease characterized by low bone mass and microarchitectural disorganization that increases bone fragility and susceptibility to fracture.
Patients with early-stage breast cancer or high-risk prostate cancer are often treated with hormonal blockade therapy to inhibit disease progression. The hypogonadal state induced by several hormonal and nonhormonal treatments, including corticosteroids, chemotherapy, and bone marrow transplantation, increases bone resorption and bone turnover causing a net bone loss called cancer therapy-induced bone loss (CTIBL). Since these treatments are being introduced earlier in the disease course, many men and women are experiencing longer periods of gonadal suppression, with associated increases in bone loss, fractures, and associated negative effects on quality of life and overall health (Table 2).
Breast Cancer
Bone loss that occurs in association with cancer is generally more rapid and severe than that related to postmenopausal bone loss in women or age-related bone loss in men.59 In premenopausal women, chemotherapy or gonadotropin-releasing hormone (GnRH) agonist therapy heightens the risk for premature menopause. This can lead to rapid bone loss, with BMD loss averaging 4% after the first 6 months of therapy and an additional 3.7% over the next 6 months. Following ovarian ablation, up to 13% of bone mass may be lost within 1 year of treatment.60 In postmenopausal women, endocrine therapy can deplete the already lower levels of residual estrogen that are important for maintaining BMD. Aromatase inhibitor therapy, which is increasingly the preferred adjuvant treatment in postmenopausal women with breast cancer, further increases the fracture risk. Increased fracture risk is seen with both steroidal and nonsteroidal aromatase inhibitors.56,57,61
Prostate Cancer
Increasing numbers of men with prostate cancer are receiving androgen deprivation therapy (ADT) as early detection and aggressive management become the norm. A recent population-based study determined that use of ADT in the United States rose steadily from 1.8% in 1993 to 2.9% in 2000.62 Men with prostate cancer who are receiving ADT experience accelerated bone loss and increased rates of fracture. A rapid loss of BMD occurs within the first 6 to 12 months of therapy. In one prospective study, hip and distal radius BMD decreased by 3.3% and 5.3%, respectively, after 1 year of GnRH agonist therapy compared with control treatment.63 A large database study of more than 50,000 men with prostate cancer who had survived at least 5 years reported a fracture incidence of 19.4% in those who received ADT compared with 12.6% in those who did not receive such therapy. The risk of fracture correlated with the number of doses of ADT received during the first 12 months after diagnosis.54
Assessment of Fracture Risk
Early detection and prevention of bone loss are important goals of therapy. ASCO guidelines, recognizing that many women with newly diagnosed breast cancer are at increased risk of osteoporosis because of their age and treatment, recommend routine assessment of bone health as part of the overall management of women with breast cancer.34 The guidelines provide an algorithm for the management of bone loss in breast cancer patients. Specifically, all women with nonmetastatic breast cancer should be screened for osteoporosis risk, and those at high risk should have BMD evaluated. Factors placing women at high risk include age greater than 65 years, age 60-64 years and a family history of fractures, body weight less than 70 kg, and prior nontraumatic fracture or other risk factors such as smoking and corticosteroids. Postmenopausal women receiving aromatase inhibitor therapy and premenopausal women who have experienced treatment-associated premature menopause are also considered at high risk.
Similarly, for men with prostate cancer, the most recent National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend BMD testing for men who undergo surgical or chemical castration, particularly if long-term ADT is planned.64 Skeletal BMD correlates with bone strength and is predictive of fractures. Men receiving GnRH agonists are a high-risk population and should be screened for fracture risk with BMD testing at baseline and every 1 to 2 years during therapy. Each decrease of 1 standard deviation in BMD doubles the fracture risk.65
Recognizing the limitations of using BMD alone to predict fracture risk, the World Health Organization has developed a fracture risk assessment tool called "FRAX" (available at http:// www.shef.ac.uk/FRAX/index.htm) that uses clinical risk factors to provide estimates of 10-year fracture incidence.66 The FRAX model improves fracture risk assessment by incorporating a group of clinical risk factors in addition to femoral neck BMD. These clinical risk factors are based on large meta-analyses and include prior fragility fracture, family history of hip fracture, current tobacco smoking, chronic use of glucocorticoids, daily consumption of alcohol, rheumatoid arthritis, and other conditions associated with secondary osteoporosis.
(click table to view larger version)
The 2008 National Osteoporosis Foundation guidelines recommend calcium (≥1200 mg daily) and Vitamin D (800–1000 IU daily) supplementation for patients age 50 or over. The guidelines also recommend drug therapy for those who have a low T-score (-1.0 to -2.5) at the femoral neck or spine and 10-year risk of at least 3% for hip fracture or at least 20% for any osteoporosis-related fracture according to the US-adapted FRAX model. We believe that existing data support considering aromatase inhibitors and ADT as causes of secondary osteoporosis when using the FRAX tool.
Treatment of Cancer Therapy-Induced Bone Loss (CITBL)
Calcium and vitamin D play critical roles in preserving bone integrity. Vitamin D levels should be in the recommended range of 30–60 ng/mL for cancer patients.67 At the time of writing of this manuscript there are no approved treatments for CTIBL. However, a number of trials have demonstrated that oral bisphosphonates can prevent CTIBL. In randomized, placebo-controlled trials, clodronate, risedronate, and ibandronate have prevented CTIBL,68-70 and a recent phase III study of denosumab in prostate cancer also showed promising results. Basic treatment options for bone loss include supplementation with calcium (at least 1000–1200 mg per day) and vitamin D (800–1000 IU per day), weight-bearing exercise, strategies to prevent falls, and avoidance of tobacco products and excessive alcohol.34,71
Four large studies have demonstrated that IV zoledronic acid can prevent bone loss in patients with early breast cancer who are receiving aromatase inhibitor therapy: ABCSG-12, Z-FAST, ZO-FAST, and E-ZO-FAST.71,72 In many of these trials, bone loss was not only prevented but there was a significant increase in BMD. Whether IV zoledronic acid should be given every 6 months or less frequently remains to be determined. Similar results have been obtained in prostate cancer trials.73-74
The effects of selective estrogen receptor modifiers (SERMs) such as raloxifene and toremifene on bone loss have been evaluated in men with prostate cancer, and appear to mitigate the bone loss accompanying GnRH agonist therapy. A recent international phase III study evaluating the efficacy of toremifene (80 mg daily), a second generation SERM, demonstrated preservation of BMD and for the first time a decrease in vertebral fractures in men with prostate cancer receiving ADT. The trial enrolled 1389 men with low BMD and/or age ≥ 70 and randomized them to receive daily toremifene or placebo for 24 months. In a preliminary report, toremifene significantly decreased new vertebral fractures and increased BMD at all measured skeletal sites. Toremifene was associated with greater risk for venous thromboembolic events.75
RANK, RANKL, and osteoprotegerin regulate the maturation, differentiation, and survival of osteoclasts. Denosumab, an investigational monoclonal antibody that binds and neutralizes RANKL, has been assessed for its ability to mitigate treatment-induced bone loss in women receiving aromatase inhibitors. In breast cancer patients receiving aromatase inhibitor therapy, denosumab (60 mg subcutaneous) or placebo was administered every 6 months for 2 years. At 12 and 24 months, lumbar, vertebral, and distal radius BMD had all increased significantly compared to placebo. Increases in BMD were noted as early as 1 month after therapy began, and the degree of improvement was not influenced by duration of aromatase inhibitor therapy.76 In a randomized, placebo-controlled fracture prevention trial involving 1468 men at high risk for fracture due to ongoing ADT, older age, and/or low BMD, subjects were randomized to 3 years of denosumab (60 mg subcutaneously every 6 months) or placebo.77 Compared to placebo, denosumab significantly increased BMD at the lumbar spine (6.7%; 95% CI 6.2–7.1), total hip (4.8%; 95% CI 4.4–5.1), and distal third of the radius (5.5%; 95% CI 4.5–6.6) at 24 months. Most importantly, denosumab reduced the 3-year incidence of new vertebral fractures by 62% (P=0.006) and fractures at any site by 28% (P = 0.10), and of multiple fractures at any site by 72% (P=0.006). Adverse events were similar in the denosumab and placebo arms.
Conclusion
Since increasing numbers of breast and prostate cancer patients are receiving hormone blockade therapies starting at younger ages and for longer durations, bone loss and associated complications are becoming more prevalent in these patients. It is important that medical professionals are aware of the risks and complications associated with cancer therapy-induced bone loss, that at-risk patients are assessed prior to initiating therapy, and that they are monitored for bone-related complications to facilitate appropriate treatment.