Paul R. Sieber, MD, FACS
The use of androgen deprivation therapy (ADT) in prostate cancer is now a well-established treatment regimen. Whether in the neoadjuvant setting with high-risk prostate cancer, in biochemical recurrence after definitive therapy, or in the setting of metastatic disease, its use can be described as “routine.” Unfortunately, ADT is associated with an increased risk for bone fracture.
An analysis of SEER-Medicare records of more than 50,000 men with a diagnosis of prostate cancer demonstrated a dose-dependent association between the use of gonadotropin-releasing hormone (GnRH) agonists and the risk of fracture.1
Nineteen percent of men who received ADT for 12 to 60 months experienced a fracture compared with only 12.6% without ADT who had fractures in the same time period (P
<.001). Men treated with 1 to 4 doses of GnRH had a fracture risk similar to those with no ADT, and those treated with 9 or more doses had a fracture risk similar to that of men who underwent orchiectomy, which was associated with the highest rate of fractures.
This study could not rule out pathologic fractures; however, the risk of fracture with ADT was not significantly altered when the analysis was restricted to early-stage disease. Similarly, another large database analysis of men with prostate cancer treated with or without GnRH demonstrated a significantly increased risk for fracture in those treated with GnRH; the relative risk for hip fracture with ADT was 1.76 (95% CI, 1.33-2.33).2
ADT is associated with an accelerated rate of bone resorption. In general, in an older man, the normal rate of loss of bone mineral density (BMD) is approximately 0.5% to 1.0% per year. With bilateral orchiectomy, the rate of loss in BMD is estimated at approximately 8% to 10% over the first 1 to 2 years,3
whereas the subsequent rate of BMD loss with ADT is 3% to 7% per year.
It is important to understand that the rate of BMD loss is greatest when first starting ADT and decreases over time.4
This picture is not dissimilar from patients receiving glucocorticoids, a therapy clearly associated with fracture risk.5
The American Urological Association (AUA) guidelines, however, offer just 2 options for the management of bone health:
- Clinicians should offer preventive treatment (eg supplemental calcium, vitamin D) for fractures and skeletal related events to patients with castration-resistant prostate cancer (CRPC).
- Clinicians may choose either denosumab (Prolia) or zoledronic acid when selecting a preventive treatment for skeletal related events for patients with metastatic CRPC and bony metastases.
With that background, urologists need additional information to better understand risk assessment, monitoring, and appropriate treatments for these patients.
As a clinician assesses whether a patient should initiate ADT, there are appropriate minimal steps to take to address bone health. First, obtain a bone health history, including assessing loss in height as an indicator of prior vertebral compression fractures; a personal and family history of fragility fractures, assessing calcium and vitamin D intake; smoking history; ethanol consumption; history of falls, and review of prior BMD assessments. This may not be in the usual routine of a urologist; for example, a fragility fracture is any fracture from a standing height or an asymptomatic vertebral compression fracture.
Figure 1. FRAX Fracture Risk Assessment Tool6
The free online World Health Organization Fracture Risk Assessment Tool (FRAX), which can be used with or without BMD data (FIGURE 16
) is one suggestion. FRAX estimates the 10-year risk of either a major osteoporotic fracture or a hip fracture. FRAX was developed to calculate the 10-year probability of a hip fracture and the 10-year probability of a major osteoporotic fracture (defined as a clinical vertebral, hip, forearm, or proximal humerus fracture), taking into account femoral neck BMD and clinical risk factors (TABLE).6
Table. Clinical Risk Factors Included in the FRAX Fracture Risk Assessment Tool6
Suggested thresholds for pharmacologic intervention include a 20% or greater risk of major osteoporotic fracture risk in 10 years or a 3% or greater risk of hip fracture in 10 years; however, treatment decisions must be made based on the individual’s situation. FRAX is not reliable once patients are receiving antiresorptive therapy.