A Commentary discussing bone health and bone protective therapy may not be as eye-catching as new developments in PSMA and Axumin imaging or radioligand therapy with Lu-177, but as the old spiritual says:

   “dem bones, dem bones gonna walk around …”  and we better take care of them as we age and undergo androgen deprivation therapy.  

Fractures are painful, debilitating, and potentially life shortening. Fractures are of two types: fragility fractures occurring in bones weakened by the loss of bone mass and bone quality, i.e. osteoporosis, as associated with aging and suppressed testosterone. Pathologic fractures are the second type – often occurring in association with osteoporosis, but potentially occurring in healthy bone at the site of metastases.

ADT and Bone Health: 

ADT (androgen deprivation therapy) depletes both serum testosterone and estrogen and promotes the loss of bone mass and bone quality. This adverse effect begins at the start of treatment and is progressive with longer duration. The entire skeleton is affected and the most deterioration occurs during the first year, which is why early evaluation and early intervention with bone protective agents are essential. Figures vary, but during the first year of ADT the range of reduction of bone density in the lumbar spine is 5.7% to 8.5%; in the femoral neck (at the hip) the reduction is \1.8% – 2.3%.

Risk Factors for Osteoporosis:

Risk factors can predict for osteoporosis. Clinical risk factors that predict a higher likelihood for weakened bone structure (osteoporosis) include: older age, poor nutrition, a frail frame, infrequent exercise and immobility, low calcium intake (<1200 mg/day), low intake of vitamin D (<800 units/day), chronic glucocorticoid usage (e.g., prednisone), smoking, high alcohol intake and low serum testosterone (as occurs with aging). Any man exhibiting these characteristics should be evaluated with a DEXA before starting on ADT.  An on-line risk calculator (FRAX.com) combines these risk factors with the results of a DEXA scan and predicts the likelihood of an osteoporotic fracture at 10 years. The FRAX Score doesn’t address non-osteoporotic pathologic fractures occurring at the site of bone metastases. “… 7 to 16% of fractures in men with prostate cancer are secondary to bone metastases.” (Shahiniam, ref. see below)

A DEXA scan (Dual-Energy X-ray Absorptiometry) measures bone mineral density (BMD). It assesses bone density on a scale from -4 to +4. The ’T-score’ compares your bone density to the average 30 year-old male (!). A score between -1 and +1 is considered normal risk; between -1 and -2.5, osteopenia, a somewhat weakened bone structure. A score less than -2.5 represents osteoporosis and confers a significantly heightened risk of fracture.   

Increased Rate of Fractures in Men Undergoing ADT:  A Significant Concern.

The increased fracture risk in men on ADT was documented by Shahiniam et al., NEJM Jan 2005, who studied the records of 50,613 men with prostate cancer on ADT. Their conclusion: “Of men surviving at least 5 years after diagnosis 19.4% of those who received androgen-deprivation therapy had a fracture, as compared with 12.6% of those not receiving androgen-deprivation therapy. Four percent of fracture were at the hip and 3.2% in the spine. Osteoporosis developed in 7% of men during ADT. 

Life-style changes addressing the risk factors already listed can ameliorate developing osteoporosis. Especially important is regular resistance exercise. 

Bone Health and BoneTargeted Therapies: Three Recommendations based on the Cancer Care Ontario Guidelines as Endorsed by ASCO, Saylor et al., J Clin Oncol. 38:2020

  1. Before starting ADT men with non-metastatic prostate cancer at high risk for fracture are encouraged to obtain a baseline DEXA scan to determine their potential benefit from denosumab (Xgeva’ at 60 mg subcutaneously q 6 months). “Xgeva was chosen as first choice since denosumab has been shown to reduce fractures in this population.” Second choice: oral Fosamax 70 mg/orally weekly or Zometa 4 mg IV yearly.
  2. In men with high risk localized prostate cancer not on ADT neither Zometa nor Xgeva are recommended to reduce the risk of first bone metastases. (But both agents may be used as discussed above for osteoporosis prevention in this group.)
  3. For men on ADT with castration-resistant prostate cancer metastatic to bone (mCRPC) both Xgeva and Zometa (at their higher metastases-indicated dosages) are recommended to delay additional skeletal metastases. Xofigo (Radium-223) “should be considered for reducing symptomatic skeletal-related events and improving health-related QoL” and to extend overall survival.

 Caution: Denosumab can lower serum calcium, which should be checked periodically. 

Dental evaluation is recommended before starting Zometa or Xgeva, particularly if invasive dental procedure are anticipated. Both agents are associated with a type bone deterioration termed ‘osteonecrosis of the jaw’ (ONJ).  Incidence figures vary.

In one study the 3-yr incidence of ONJ was 2.8 % in recipients of Zometa and increases with longer duration.  A study on the long-term safety reported the incidence of ONJ in men taking one of these agents for >1 year to be 3.4% for Xgeva and 2% for Zometa. (Stopeck et. al., Supportive Care Cancer, 2016)

The Importance of Bone Protective Agents with mCRPC taking ADT Was Validated in Two clinical Trials: 

Abiraterone (AA), enzalutamide (ENZ) and radium-223 are cornerstones in the treatment of mCRPC. Two clinical trials were designed to test if these androgen receptor blocking agents could be safely combined with radium-223.

The ERA223 trial studied AA/prednisone + rad-223 vs AA/prednisone + placebo in 805 men with mCRPC metastatic to bone. This trial was stopped early because a fracture rate of 29% had occurred in the AA/Rad-223 arm vs in 11% for AA/placebo. However, data re-analysis revealed that only 40% of the men in the study had been taking Zometa or Xgeva. 

With that in mind, a reexamination of the data found a marked reduction of the fracture rate in each arm for men taking one of the bone protective agents (BPA.) At his 2019 presentation at ASCO on the PEACE trial Dr. Tombal stated: “The [fracture] risk is almost completely abolished by mandatory continuous administration of bone protective agents starting at least 6 weeks before the first injection of radium-223 …” 

Data from the PEACE trial (similar in schema to the ERA trial) illustrated the benefit of adding BPA to enzalutamide/Lupron in men with mCRPC. The use of BPA reduced fracture rate in the first 12 months to 0% for ENZ/Lupron compared to 13% in men not taking BPA. An inference based on similar data in PEACE trail suggests the same trend of reduced fracture rate would be seen by combining BPA with abiraterone/pred/Lupron.

BOTTOM LINE:  This Commentary presents a straightforward message: treatment with Xgeva or Zometa substantially reduces fracture risk in men with mCRPC undergoing androgen deprivation.

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