Men commonly experience hip or vertebral body () fragility fractures with advancing age.56
The consequences of osteoporosis are not confined to women, as one third of all hip fractures occur in men.57
The 3 most common causes of osteoporosis in men are alcohol abuse, chronic glucocorticoids, and hypogonadism.58
Figure 4 Vertebral compression fracture. Vertebral body compression fracture (arrow) is a potential complication of therapy-related osteoporosis. These fractures can lead to pain, loss of height, and decreased quality of life. Denosumab and toremifene have now (more ...)
Available evidence convincingly shows that ADT is detrimental to bone health. Prospective trials have shown that ADT causes accelerated bone turnover59,60
and decreases BMD.59–64
Retrospective population-based analyses have shown that ADT is associated with elevated fracture risk as a continuous function of treatment duration. Among more than 50,000 men with prostate cancer in a SEER-Medicare database, incidence of fracture 5 years after diagnosis of prostate cancer was higher among those treated with ADT (19.4% vs. 12.6%).19
A separate but similar claims-based analysis also found a significant association between GnRH agonist treatment and clinical fractures (relative risk [RR], 1.21; P
Bisphosphonates, including pamidronate,66,67
have consistently been found to increase BMD and decrease markers of bone turnover among men during ADT. Notably, however, no bisphosphonate study has been large enough to evaluate impact on treatment-related fractures. Two additional classes of drugs, however, were recently found to prevent clinical fractures in randomized phase III studies exclusively involving men treated with ADT.
Receptor activator of nuclear factor κ-B ligand (RANKL) regulates osteoclast differentiation, function, and survival.72–76
Denosumab is a fully human monoclonal antibody against RANKL that was studied for the prevention of osteoporotic fractures in a recently reported, randomized, placebo-controlled phase III trial that enrolled 1468 men receiving ADT and at high risk for fracture because of history of fracture, age of 70 years or older, or low BMD. When given subcutaneously every 6 months, denosumab significantly increased BMD at all measured sites and reduced the incidence of new vertebral fractures by 62% (P
= .006), fractures at any site by 28% (P
= .10), and multiple fractures at any site by 72% (P
Ongoing trials are evaluating denosumab for the prevention and treatment of prostate cancer bone metastases.
SERMs raloxifene and toremifene have both been shown to improve BMD and markers of bone turnover among men on ADT.78,79
Toremifene was studied for its ability to prevent fractures in a randomized, placebo-controlled, phase III trial enrolling 1389 men aged 50 years or older treated with ADT and at elevated facture risk because either their age was 70 years or older or they had low BMD. The primary analysis was positive because the toremifene arm experienced fewer vertebral fractures (2.5% vs. 4.9%; RR, 0.50; P
< .05 by modified intent to treat analysis).80
The toremifene arm also had superior BMD (lumbar spine and hip), lower LDL, lower triglycerides, higher HDL, less breast pain, and less frequent hot flashes among men who had at least 6 hot flashes each day at baseline.
Accurate assessment of fracture risk is essential to guide clinicians to treat only those most likely to benefit from drug therapy to prevent fractures. Historically, risk assessment centered on dual-energy radiograph absorptiometry scan measurement of BMD. Reliance on this measurement alone, however, is inadequate because most fractures occur in men who do not have osteoporotic-range BMD.81
Screening and treatment recommendations can reasonably be drawn from the NOF guidelines for the general population (). Screening with BMD testing should be performed in high-risk populations, such as men receiving ADT. The authors recommend BMD testing at baseline, after 1 year of ADT, then every 2 years or as clinically indicated. Guidelines recommend that all men aged 50 and older take supplemental calcium (≥ 1200 mg/d) and vitamin D (800–1000 IU/d). They also recommend drug therapy for those who have low T-score (−1.0 to −2.5) and a 10-year risk for hip fracture of at least 3%, or at least 20% for any osteoporosis-related fracture, according to the United States–adapted Fracture Risk Assessment Tool (FRAX) model.82
Existing data support ADT as a cause of secondary osteoporosis when using the FRAX tool.
Fracture Risk: Recommendations for Screening and Treatment
FRAX is an online fracture risk-assessment tool (http://www.shef.ac.uk/FRAX/
) that uses age, BMI, and a group of clinical risk factors to estimate 10-year fracture risks in individual patients.83
Meta-analyses have shown that each risk factor independently contributes to risk. These risk factors include family history of hip fracture, personal history of fragility fracture, ongoing tobacco smoking, history of chronic glucocorticoid use, daily alcohol consumption of 3 units or more, rheumatoid arthritis, and other causes of secondary osteoporosis.84–91
The algorithm can be used with or without BMD data.