Understanding cancer-associated bone loss in adults
Nearly all cancers can have clinically significant negative effects on the skeleton. Cancer is a major risk factor for both generalized and local bone loss, with bone loss in cancer patients substantially greater than in the general population.
Cancer-associated bone loss is due to the direct effects of cancer cells and the effects of therapies used in cancer treatment, including chemotherapeutics, corticosteroids, aromatase inhibitors and androgen deprivation therapy (ADT). The skeleton is also the most common site of metastatic disease, because cancer cells growing within bone induce osteoblasts and osteoclasts to produce factors that stimulate further cancer growth. Accordingly, skeletal effects have become increasingly important because of improved oncologic treatments that have enhanced both patient survival and longevity.
Morbidity due to bone disease in patients with breast cancer can have a major impact on patient quality of life because of the often long clinical course. Bone-related complications in women with breast cancer include hypercalcemia, fractures, need for irradiation or surgery, and spinal cord compression. Placebo-controlled trials have shown that in the absence of bone-protective therapies, patients have roughly 2.2 to 4.0 skeleton-related events annually.
Although estrogen plays a central role in bone homeostasis, hormonal therapy-based treatment regimens to affect estrogen action at the estrogen receptor (ER) are frequently used. Tamoxifen is an ER antagonist in breast tissue that is often used for patients whose breast cancer is ER positive and as prophylaxis in patients at high risk of breast cancer. Tamoxifen may lead to bone loss in premenopausal women. By comparison, in postmenopausal women, tamoxifen can act as an ER agonist in bone and increase bone mass. However, neither tamoxifen nor raloxifene appear to reduce fracture incidence in postmenopausal women with breast cancer.
Aromatase inhibitors decrease cancer recurrence and improve disease-free survival. Multiple studies have demonstrated that these inhibitors also result in significant bone loss and increased fracture incidence. Additional research has shown that upfront, vs. delayed, zoledronate therapy improves bone mineral density (BMD) in postmenopausal women receiving adjuvant aromatase inhibitor therapy and that denosumab was shown to increase the time to first skeleton-related event in breast cancer patients.
ADT is often used for palliation in prostate cancer patients. It induces clinically significant bone loss and increases fracture risk. Yet, despite these profound skeletal effects, the majority of prostate cancer patients continue to be inadequately treated for their bone loss.
Zoledronate is the best-studied bisphosphonate and has been shown to decrease bone loss and fracture risk and reduce bone loss induced by gonadotropin-releasing hormone agonist in prostate cancer patients. More recently, denosumab was shown to increase BMD in prostate cancer patients receiving ADT and to prolong the time to first skeleton-related event relative to zoledronate.
Myeloma is the second most common hematologic cancer, accounting for 10 percent of all hematologic cancers. Patients have both generalized bone loss and focal osteolytic lesions. Nearly two-thirds of patients with myeloma have bone pain at presentation, and fracture rates are increased 16-fold relative to the general population in the year preceding diagnosis. Even with disease remission, skeletal lesions rarely heal.
Both pamidronate and zoledronate are approved by the Food and Drug Administration for the treatment of myeloma-related bone disease and have been shown in placebo-controlled trials to reduce hypercalcemia, bone pain and fracture incidence. Importantly, patients with monoclonal gammopathy of undetermined significance (MGUS), a common premalignant condition with an approximately 1 percent annual risk of progression to myeloma, have substantially increased fracture rates. Patients with MGUS have decreases in both cortical and trabecular thickness, as well as increases in circulating cytokines known to increase osteoclast activity and suppress osteoblast activity. Together, these findings may provide insight into the increased fracture incidence seen in MGUS.
Potential complications of pharmacologic therapies
Osteonecrosis of the jaw (ONJ) is now a well-recognized potential complication of anti-resorptive therapy. Risk factors for ONJ include:
- Invasive dental procedures
- Poor oral hygiene
- Prolonged anti-resorptive therapy
Initial results suggest that rates of ONJ are comparable between zoledronate and denosumab in cancer patients. Preventive dental measures in high-risk patients can substantially reduce risks; conservative management with oral rinses, pain control, antibiotics and limited surgical intervention will lead to healing in most cases.
Although now recognized as very uncommon events in osteoporosis patients, atypical femoral fractures are currently limited to rare case reports in the oncologic literature. Hypocalcemia is most common in patients receiving intravenous bisphosphonate therapy; rates appear similar between zoledronate and denosumab. Risk can be limited by optimizing the intake and levels of calcium, vitamin D and magnesium.
Other factors for optimizing skeletal health
In addition to pharmacologic interventions, conservative measures are extremely important for cancer patients in limiting fracture risk. Conservative measures include:
- Counseling about high-risk activities (falls and heavy lifting)
- The introduction of appropriately supervised physical therapy for muscle strengthening to limit fall risks
- Ensuring adequate calcium and vitamin D intake after resolution of any existing hypercalcemia
Finally, it is important to recognize that cancer patients are often at increased fall risk due to the use of analgesics and sedatives.
In conclusion, careful monitoring of bone health must be an essential component of any cancer treatment plan. Specialists in bone disease at Mayo Clinic often collaborate with other caregivers to provide valuable consultations to help manage skeletal health in adult cancer patients.