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.

 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 (

 <.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).

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,

 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.

 This picture is not dissimilar from patients receiving glucocorticoids, a therapy clearly associated with fracture risk.

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 Tool

The free online World Health Organization Fracture Risk Assessment Tool (FRAX), which can be used with or without BMD data (FIGURE 1

) 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).

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.

Second, the National Osteoporosis Foundation (NOF) lists a host of laboratory studies a physician could obtain. At a minimum, the serum chemistry needs to include calcium, renal function, phosphorus, magnesium, vitamin D, and testosterone levels. The last 2 lab values, in particular, if abnormal, indicate that a patient is at risk for osteopenia and/or osteoporosis at baseline.

Third, assess the patient’s BMD. The result may provide the diagnosis of osteoporosis or osteopenia. A low BMD is associated with a high risk of fracture. If low bone mass is identified at baseline during ADT, consideration should be given to secondary causes of osteoporosis, such as primary hyperparathyroidism or vitamin D deficiency. It is estimated that for each standard deviation (SD) drop in BMD, the risk of fracture increases 1.5- to 2.5-fold, thus making the measurement of BMD for fracture risk assessment similar to that of blood pressure for stroke.

BMD is best evaluated with dual energy x-ray absorptiometry (DXA). DXA measurement of the hip and spine is used to establish or confirm a diagnosis of osteoporosis, predict future fracture risk, and monitor patients. Areal BMD is expressed in absolute terms of grams of mineral per square centimeter scanned (g/cm

) and as a relationship to 2 norms: compared with the BMD of an age-, sex-, and ethnicity-matched reference population (Z score) or compared with a young-adult reference population of the same sex (T score). The difference between the patient’s BMD and the mean BMD of the reference population, divided by the SD of the reference population, is used to calculate T scores and Z scores.

Typically, T scores are used to assess risk. However, T scores are less reliable for men with hip replacements and sclerotic changes in the spine resulting from osteoarthritis. Thus, forearm DXA may be required to obtain an accurate risk assessment. In addition, a vertebral fracture is consistent with a diagnosis of osteoporosis, even in the absence of a normal bone density diagnosis, and is an indication for pharmacologic treatment with osteoporosis medication to reduce subsequent fracture risk. Most vertebral fractures are asymptomatic when they first occur and often are undiagnosed for many years. Proactive vertebral imaging is the only way to diagnose these fractures. The finding of a previously unrecognized vertebral fracture would change the diagnostic classification and subsequently alter future fracture risk calculations.

Independent of BMD, age, and other clinical risk factors, the presence of a single vertebral fracture increases the risk of subsequent fractures 5-fold and the risk of hip and other fractures 2- to 3-fold.

 Vertebral imaging can be performed using a lateral thoracic and lumbar spine x-ray or lateral vertebral fracture assessment (VFA), available on most modern DXA machines. VFA thus can be easily performed at the time of DXA assessment. Both DXA and vertebral fracture assessment are recommended by the NOF in these high-risk patients.

Figure 2. BMD Versus Fracture Rate and Incidence

There are other ways to measure bone loss, such as heel ultrasound (QUS), quantitative computed tomography (QCT), and peripheral DXA (pDXA). However, these are not the gold standard. DXA is preferred for several reasons. It provides a lower dose of radiation than QCT, QUS has not been validated over time to monitor for treatment effects, and pDXA has not been validated in men. For all these reasons, DXA is the gold standard for initial evaluation and serial monitoring of both treated and untreated patients. The interval between DXA scans is typically 1 to 2 years,

 although a longer duration may be appropriate, particularly for those on antiresorptive therapy or patients with low risk of fracture. Although BMD is a surrogate marker of bone strength and predictor of fracture, the majority of fractures occur in patients with normal to minimal bone loss (FIGURE 2). Thus, BMD is a component, but not the only element, in understanding and treating bone health.

The treatment of bone health is 3-pronged. The first step is looking at lifestyle modifications. Patients need to be encouraged to reduce alcohol consumption, stop smoking, participate in weight-bearing exercise (in which bones and muscles work against gravity as the feet and legs bear the body’s weight, such as walking, jogging, tai chi, stair climbing, dancing, and tennis), and explore strategies for fall prevention.

The second step is addressing calcium and vitamin D levels and intake. The NOF and the National Academy of Medicine (NAM) recommendations are that men 50 to 70 years consume 1000 mg/day of calcium and men 71 years and older consume 1200 mg/day of calcium. There is no evidence that calcium intake in excess of these amounts confers additional bone strength. On the contrary, intakes above 1200 to 1500 mg/day may increase the risk of developing kidney stones, cardiovascular (CV) disease, and stroke. The scientific literature is highly controversial in this area. There are suggestions that calcium from dietary sources engenders no increase in CV risk. On the other hand, particularly in men, calcium supplements may have a small impact on CV risk.

 Because ADT itself appears to contribute to CV risk, dietary changes may be a better approach than supplement calcium.

This concern is not currently addressed in the AUA guidelines. The average daily dietary calcium intake in adults age 50 and older is 600 to 700 mg/day. Increasing dietary calcium appears to be the first-line approach but clearly requires more education than recommending a simple pill supplement. Vitamin D plays a major role in calcium absorption, bone health, muscle performance, balance, and risk of falling. The NOF recommends an intake of 800 to 1000 international units (IU)/day for adults age 50 and older. The Dietary Reference Intakes recommended by the NAM are slightly more conservative: vitamin D at 600 IU/day until age 70 and 800 IU/day for adults 71 years and older.

The third step comprises pharmacologic treatments. The first step is deciding which patients clearly benefit from therapy. There is uniform acceptance7 that a patient with osteoporosis should receive pharmacologic therapy in addition to steps 1 and 2 above. Patients with a fragility fracture, particularly an asymptomatic vertebral fracture, are also candidates for pharmacologic treatments. The 2 therapies most studied for treatment are denosumab and zoledronic acid. These are the current AUA guideline recommended therapies. The oral bisphosphonate alendronate has seen limited studies in this group of patients. It also has an effect on BMD and bone turnover markers. However, there are no head-to-head studies in regard to equivalence infracture prevention.

The treatment of bone loss associated with ADT is complex. It requires a detailed history and BMD measurement to fully estimate risk of fracture. Treatment with calcium alone is not sufficient, and potential CV risks underscore the need for counseling for calcium intake. High-risk patients require therapy, and the 2 AUA guideline recommended therapies, denosumab and zoledronic acid, are the standard of care.

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Articles

The use of androgen deprivation therapy in prostate cancer is now a well-established treatment regimen but is associated with an increased risk for bone fracture.

Paul R. Sieber, MD, FACS

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