Evaluation for Fracture Risk
Previously, several organizations including the World Health Organization (WHO), the National Osteoporosis Foundation (NOF), and the North American Menopause Society have recommended pharmacologic therapy for those with osteoporosis (T score on BMD of less than -2.5) or those with a prior fragility fractures (hip or vertebral fracture). More recently, as interest in more comprehensive models for fracture has emerged,[21,22] it has become possible to more accurately predict fracture risk. In this regard, the WHO has developed a web-based Fracture Risk Assessment Tool (FRAX) that integrates clinical risk factors as well as BMD information. Model components include age, sex, weight, height, previous fracture, parent with hip fracture, smoking, glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol(Drug information on alcohol) (> 3 units/d), and femoral neck BMD (Figure 2).
Using the web-based FRAX model or simplified paper versions, readily available at the FRAX website (http://www.shef.ac.uk/FRAX/), the 10-year probability of hip fracture and the 10-year probability of a major osteoporosis fracture (clinical spine, forearm, hip, or shoulder fracture) can be calculated. Treatment decisions generally follow country-specific guidelines. The US-based NOF recommends pharmacologic interventions when the BMD T score is between -1.0 and -2.5) and the 10-year probability of hip fracture is ≥ 3% or major osteoporosis-related fracture is > 20%.
At this time, the effect of hormone-ablative therapy is not incorporated in the FRAX model. The rate of bone loss with aromatase inhibitors is greater than that seen with smoking but less than that associated with corticosteroid use. In any event, the clinical fracture risk of about 10% after 5 years of aromatase inhibitor use (Figure 1) places women at substantial fracture risk supporting pharmacologic intervention.
Prevention and Management of Bone Loss
Prevention and management of bone loss involves both lifestyle modification and pharmacologic therapy (Table 1). Lifestyle modifications focus on weight-bearing and muscle-strengthening exercise, smoking cessation, alcohol moderation/avoidance, and fall prevention.
Calcium and Vitamin D
While calcium and vitamin D supplementation represent an integral component of bone health guidelines and vitamin D deficiency is a recognized secondary cause of bone health, there is controversy regarding optimal monitoring and intervention approaches with respect to vitamin D. A full discussion of this issue is beyond the scope of this report.
The current evidence in this area has been summarized in a recent Cochrane database systematic review which concluded that, based on randomized controlled trials, vitamin D (dose 400–800 IU/D) when given with calcium supplementation reduces risk of nonvertebral and hip fractures, perhaps mainly in subgroups. In the Women’s Health Initiative (WHI) randomized clinical trial evaluating supplementation with calcium and vitamin D3 (400 IU/d), an increase in BMD of about 1% was seen. In addition, a meta-analysis of randomized controlled trials evaluating vitamin D (with the WHI trial a major contributor) where the mean daily dose in the trials was 528 IU identified a significant reduction in total mortality with vitamin D use (HR 0.92; 95% confidence interval 0.86–0.99). Thus, routine supplementation in appropriate populations can be recommended. Postmenopausal women and older men need about 1,500 mg of calcium daily. Vitamin D at a dose 800 to 1,000 IU a day is also recommended.
While some recommend monitoring 25-hydroxyvitamin D levels and aggressive vitamin D supplementation with parenterally administered high-dose vitamin D regimens, such an approach can be questioned given the limited clinical trial evidence for such a strategy. A recent systematic review found “inconsistent evidence” of an association between lower 25-hydroxyvitamin D levels and increased fracture risk and went on to state that it is “difficult to define optimal 25-hydroxyvitamin D levels for bone health.” In addition, only a modest component of person-to-person variability in 25-hydroxyvitamin D levels can be explained by differences in dietary and supplement vitamin D intake and/or sunlight exposure.
Health-care providers should follow developments in this area as studies beginning with individuals with low 25-hydroxyvitamin D levels, provision of supplementation sufficient to increase vitamin levels to a prospective target, and subsequent impact on clinical endpoints such as fracture risk are currently lacking and represent a research priority.
Bisphosphonates are clinically utilized to preserve BMD as they inhibit osteoclast-mediated bone resorption through the structural characteristic phosphonate-carbon-phosphonate which promotes binding to bone mineral matrix. Clinical studies have demonstrated that bisphosphonates increase BMD and can largely abrogate the bone loss associated with hormone-ablative therapy in women.[29,30] Multiple prospective studies involving postmenopausal women with osteoporosis treated with bisphosphonates have shown significant reductions in vertebral and nonvertebral fracture risk.[31,32] However, there have been no studies specifically designed to evaluate the reduction in osteoporotic fracture risk among cancer survivors. Therefore, the aforementioned recommendations for bisphosphonate use for bone loss prevention in cancer survivors are based on studies showing prevention of osteoporotic fractures in a healthy population. In terms of side effects, patient adherence to long-term oral bisphosphonate regimens has proven problematic. Osteonecrosis of the jaw can occur but is rarely encountered with bisphosphonates dosed for bone health. Intravenous bisphosphonates can be associated with infusion-related bone pain and myalgias.
Use of menopausal hormone therapy is not recommended to treat bone loss in breast cancer survivors, given the potential influence on recurrence risk. Similarly the use of a bone anabolic agent is generally avoided in cancer survivors given the theoretical risk of bone cancer seen in animal models.[20,36]
The ASCO guidelines for bone health maintenance in women with diagnosed breast cancer recommend treatment based on DEXA score: For T scores of -2.5 or lower (osteoporotic range), increased physical activity, calcium and vitamin D supplementation, and treatment with a bisphosphonate is recommended. For osteopenia (T score is between -1 and -2.5) or normal bone health (T score > -1), lifestyle modification and calcium with vitamin D supplementation are recommended and bisphosphonate therapy can be considered. For those not at high risk for osteoporosis it is also recommended that they adhere to appropriate lifestyle modifications and initiate calcium and vitamin D supplementation but BMD screening is not recommended. In their current practice guidelines, the National Comprehensive Cancer Network recommends BMD monitoring for premenopausal women with ovarian failure secondary to adjuvant chemotherapy and postmenopausal women treated with an aromatase inhibitor.
The management of bone loss in men with prostate cancer is evolving. The recommendations for lifestyle modification and calcium and vitamin D supplementation apply to older men as well as women. The data support assessment of BMD with a DEXA scan in all men with newly diagnosed prostate cancer. Treatment with a bisphosphonate is prudent for those who are osteoporotic. If the BMD is between -1.5 and -2.5, the decision for treatment should be based on the patient’s comorbidities and fall risk.
One of the major factors contributing to bone health compromise in patients with prostate and breast cancer is hormone-ablative therapy resulting in reduction in androgen and estrogen levels. Moreover, the natural course of postmenopausal development of osteoporosis, as well as other secondary causes of osteoporosis, may also contribute to bone loss in the cancer setting. All patients undergoing treatment for breast cancer and prostate cancer need evaluation of their state of bone health and fracture risk. If there is evidence of osteopenia or osteoporosis at baseline, secondary causes of bone loss should be excluded and a discussion of lifestyle modification factors, supplementation with calcium and vitamin D, and if appropriate, pharmacologic treatment needs to be initiated. Ongoing studies are evaluating newer agents for potential use in this setting.
Financial Disclosure: Dr. Chlebowski has received speaker’s fees and honoraria for advisory boards and consulting from AstraZeneca and Novartis; honoraria for advisory boards and consulting for Lilly, Amgen, and Pfizer; and grant support from Amgen, NIH, and the National Cancer Institute of Canada.
This article was conceived of and fully funded by Amgen, and Amgen provided background direction for the article.