Bone Markers as a Predictor of SREs
Osteoclastic activity results in the destruction of mineral matrix, which is composed primarily of type I collagen(Drug information on collagen). Several metabolic products are released as a result, including urinary N-telopeptide (uNTx). Greenspan et al studied the level of one such marker in the setting of men undergoing ADT for prostate cancer and demonstrated that patients with higher levels of these metabolic byproducts were predisposed to greater loss of BMD.[21] Of note, the markers were elevated up to six months in advance of the measured loss in BMD, which suggests that such markers could be used to screen patients at increased risk of experiencing SREs. The possibility of using laboratory tests to determine, in advance, which individuals will most benefit from preventative intervention is tantalizing. Another study showed that patients with high uNTx levels had a greater incidence of SREs compared with patients with low levels of uNTx. Those with low uNTx levels also had better median survival (8.2 months vs 3.2 months).[22] Future prospective studies validating the use of these clinical markers to stratify patients need to be performed.
Burden of SREs
Clinical and Economic Impact of Pathological Fracture
The continued medical care of individuals who experience SREs constitutes a sizable cost that is ripe for targeting with prevention strategies listed herein.[23] A one-year study of the incidence of SREs, including radiation therapy, pathologic fracture, surgery, or spinal cord compression found that half of patients with prostate cancer and bony metastases experienced at least one SRE with a mean cost of
2,469 per patient.[10]
Patients that experienced more than one SRE within the study year (22% of the study population) consumed a mean of $26,384 worth of health care, significantly higher than those who experienced just one event ($8,484). The study also noted that 87% of patients who experienced an SRE did so within one year of their initial diagnosis of bony metastatic disease. These costs are comparable to those of SREs in the setting of advanced lung cancers.[24] Prevention strategies, timely diagnosis, and more cost-effective interventions have the potential to ultimately reduce both the clinical and economic burden of SREs.
Risk Factors, Screening and Diagnosis
A number of different factors increase a patient’s risk for developing skeletal morbidities as a consequence of bony metastasis. Some cancers, regardless of location, auto-secrete PTHrP, which interacts with the PTH receptor in osteoblasts upregulating the synthesis of RANKL. This results in bone resorption, which weakens the bone and increases the likelihood of a SRE.
Patients should be assessed at initial diagnosis of their cancer and worked up for signs and symptoms of bone metastasis. Clinicians should be prepared to note any bone pain, recent fractures, and changes in height or posture. Further testing and imaging will be guided by the type of cancer, stage, and symptomatology.
Secondary Contributors to SREs
Patients with advanced visceral cancers are at high risk for the development of metastatic lesions to the bone that can be devastating for a patient and reduce overall survival. Given the severe consequences, clinicians should be aware of the risk factors for bone loss, osteopenia, osteoporosis, and SREs and diligently screen patients to identify any potential secondary causes of bone loss. This evaluation should include a thorough history and physical to identify any prior SREs such as fracture or vertebral deformity, predisposing medications like glucocorticoids, or the presence of social factors such as alcoholism that would otherwise contribute to the overall picture of skeletal health. A complete list of secondary antecedents to loss of bone mineral density that might potentiate a SRE is shown in Table 2.
The recommendations for screening patients for bony metastasis vary with the type of cancer. Several imaging modalities are available to clinicians to screen patients. Currently, imaging constitutes the mainstay of screening for metastasis to the bone, usually in the form of plain radiographs, magnetic resonance imaging (MRI), CT, PET, or radionuclide bone scan (bone scintigraphy). The sensitivity and specificity of each modality varies with cancer type and burden of disease. Nuclear imaging studies (bone scan and PET) can use a variety of novel radiolabels to detect cancer lesions.[25] Laboratory testing of serum markers of bone turnover (e.g., alkaline phosphatase, osteocalcin) can guide screening but is rarely definitive. Nuclear medicine tests such as PET and bone scan work primarily in the setting of high bone turnover, as their radioactive tracers are most attracted to these areas of metabolic activity.
The radionuclide bone scan is the most sensitive modality for detecting bony metastasis from prostate cancer.[26] In the PSA era, screening for bony metastasis in the absence of symptoms is not seen as necessary given the shift toward earlier diagnosis and more indolent disease; metastasis at initial presentation is rare. However, patients with bone pain or advanced disease (PSA > 20 ng/mL, Gleason > 8, or locally-advanced disease on digital rectal exam) should undergo a radionuclide bone scan. Men on androgen deprivation therapy should also receive attention even in the absence of symptoms, as they are at high risk for osteopenia, osteoporosis, and subsequent SREs.
Current recommendations state that patients with lung cancer should undergo a PET scan during initial staging and workup to evaluate for bony metastases. Alternatively, if this is not available, a bone scan can be performed.
Treatment Trends
Hormone Therapies Androgen deprivation therapy (ADT), often consisting of luteinizing hormone– releasing hormone (LHRH) agonists, is the preferred first-line therapy for metastatic prostate cancer to the bone. Unfortunately, as alluded to earlier, ADT can also impact skeletal health and often precipitates osteopenia or even osteoporosis, increasing the likelihood of a pathologic fracture.[27] Prostate cancer eventually overcomes androgen blockade and becomes refractory to such therapies, often requiring other interventions.
With breast cancer, there are a number of hormonal therapy options that are often tailored to the expression of estrogen and progesterone(Drug information on progesterone) receptors as detected by histological staining. If large numbers of these receptors are present, pre-menopausal women may benefit from selective estrogen receptor modulators (SERMs), which can selectively downregulate receptors in specific tissues with estrogen receptors, namely metastatic tumors, while sparing other tissues (like bone).[28] For postmenopausal women with advanced breast cancer, selective aromatase inhibitors (SAIs) can reduce estrogen levels by blocking the action of aromatase, the enzyme that converts peripheral circulating androgens to estrogens(Drug information on estrogens).[29] These have been shown to be superior to SERMs in preventing disease progression and increasing survival, but unfortunately also result in greater resorption of bone and increase fracture risk as compared to SERMs.[30,31]
A 2-year, placebo-controlled, multicenter trial in United States and Mexico investigated the clinical significance of a SERM with respect to prostate cancer patients on androgen-deprivation therapy, with a primary endpoint of incident monomorphic vertebral fractures.[32] Secondary endpoints include bone mineral density (BMD), lipid levels, breast pain, and hot flashes. Initial results demonstrate clinically significant decreases in the incidence of vertebral fracture and increases in BMD. While this group of patients does not necessarily have bony metastasis, the results may herald a future for this drug class in the setting of osteolytic/osteoblastic metastases to prevent SREs.
Bisphosphonates This class of drug is unique in that it targets the feedback loop created between the metastatic lesion and bone, thus preventing or delaying onset of SREs.[33,34] Bisphosphonates bind to the active site of resorption of bone, entering osteoclasts and inducing apoptosis, thus preventing further resorption.[35] The goals of bisphosphonate therapy include preventing new and recurrent SREs, palliating bone pain, reducing the need for other therapies, and mitigating further morbidity. The efficacy of this drug class in attaining these clinical goals has been investigated in multiple placebo-controlled, randomized control trials showing significant improvements in clinical outcomes.[8,36,37] The use of bisphosphonates in the treatment of debilitating bone pain reduces the need for NSAIDs and opioid analgesics, which can have unintended consequences for patients with advanced cancer.
Because this type of therapy is systemic and lacks the myelosuppressive side effects of chemotherapy and radiation, it can be used as an adjunct to such therapies, broadening its use. Some studies have even demonstrated synergistic effects between bisphosphonates and chemotherapies.[38,39] Despite being systemic, these drugs localize to bone surfaces with active resorption, potentiating its activity and therapeutic efficacy.[40]
External Beam Radiation and Radiopharmaceuticals The use of external beam radiation prophylactically has been shown to limit clinical consequences for individuals suffering from new bony metastases to weight-bearing bones. Additionally, radiation to affected bone has been shown to palliate intractable bone pain that often results from these metastases but is often underutilized by clinicians.[41] The optimum dose of radiation and timing of delivery has been a hotly contested area of research, but a meta-analysis showed no significant difference between the different schedules.[42] In the United States, a survey of radiation oncologists showed that most employ 30 Gy in ten fractions.[43]
Similar to the nuclear radiolabels used in bone scans and PET scans, there are bone-seeking radiopharmaceuticals that concentrate in areas of high bone turnover and can be used for therapeutic intervention in patients with metastatic disease. These drugs target Src family kinases.[44,45]
Surgery If a bone metastasis threatens a weight-bearing bone (eg, femur), surgical intervention should be considered to prevent fracture. Surgical therapy is often followed by external beam radiation, which is then followed by systemic therapy, such as appropriate chemotherapy or use of bisphosphonates to treat bone pain and prevent future SREs.
Conclusions
Skeletal-related events remain a large source of morbidity and shorter life expectancies, and cost the health care system countless dollars in lengths of stay and outpatient care. Identifying and mitigating risk factors, timely diagnoses, and appropriate interventions can reduce the untoward effects of SREs. Research continues to elaborate mechanisms of osteolytic and osteoblastic lesions that are amenable to pharmacologic targeting to halt the cycle of bone destruction and weakening. With studies showing correlation between increased levels of biochemical markers of bone turnover and increased likelihood of SREs, disease progression and death, it may be possible to select for patients that are at greatest risk of SREs and implement prevention strategies using the medical therapies discussed, leading to more cost-effective and safer care for patients with metastatic bone disease.
Financial Disclosure: Dr. Crawford serves on speakers bureaus for Ferring, Watson, AstraZeneca, GlaxoSmithKline, and Indevus, and advisory boards for Ferring and Indevus. Dr. Rove has no other significant financial interest or 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.
