Bone Up on Prostate Cancer Treated With ADT

Nick Mulcahy

August 08, 2017

Bone health drugs are effective in improving bone mineral density (BMD) in patients with nonmetastatic prostate cancer who receive androgen deprivation therapy (ADT), but there is little or no evidence that they prevent fractures, according to a new systematic review and meta-analysis.

Nevertheless, clinicians should prescribe these drugs to patients who have high levels of risk for fracture, say the study authors and other experts. 

"Men with osteoporosis are at the highest risk, followed by men with low bone mass. However, other risk factors beyond bone mineral density increase the risk of fracture, including age, smoking, prior fracture history, and family history of osteoporosis, among others," lead author, Shabbir Alibhai, MD, from the University of Toronto, Ontario, Canada, told Medscape Medical News.

Paying attention to the bones of men treated with ADT is essential because the therapy can induce "significant" bone loss and increased risk for fragility fractures akin to that of people with osteoporosis, say the authors.

Over time, bones are weakened as a result of depletion of testosterone and estradiol from ADT, which has been a mainstay of treatment for 70 years.

"Up to one in five men will have a fracture within 5 to 6 years of starting ADT, so it is not uncommon," said Dr Alibhai.

Unfortunately, other research indicates that related bone healthcare in these men is less than optimal and use of drug therapies is "modest," say the authors.

Consequently, the highly respected Cancer Care Ontario in Canada assembled a working group, including Dr Alibhai, to summarize "recent changes in bone health and bone-targeted therapy" to help clinicians bone up on bone care.

In a new report from that effort, the team focused on interventions to reduce osteoporosis-related outcomes in nonmetastatic disease.

Looking at 27 clinical trials, they found that bisphosphonates were effective in increasing BMD, but no trial was sufficiently powered to detect reduction in fractures.

However, in one "high-quality" trial, the RANKL inhibitor denosumab improved BMD and reduced the incidence of new radiographic vertebral fractures.

Other interventions, such as calcium and vitamin D supplements, lacked trials with placebo controls; lifestyle interventions were found to be ineffective compared with usual care.

"More trials studying fracture outcomes are needed in this population," conclude the authors in their report, published online August 7 in Annals of Internal Medicine.

In the meantime, how should clinicians proceed?

They can start by assessing BMD of their patients with nonmetastatic prostate cancer, say Azeez Farooki, MD, and Howard Scher, MD, from Memorial Sloan Kettering Cancer Center in New York City, in an accompanying editorial.

They cite International Osteoporosis Foundation guidelines and recommend pharmacologic intervention for men with functioning gonads who have osteopenic BMD and a 10-year absolute risk threshold (based on the Fracture Risk Assessment Tool [FRAX] score) of 3% for hip fracture and 20% for any fracture.

BMD is a surrogate for fracture risk, observe the editorialists.

Dr Alibhai also recommends and uses the FRAX and another scale, the Canadian Association of Radiologists and Osteoporosis Canada (CAROC), to stratify risk. Men who are at "high risk" on these scales are the ones for whom "I would most strongly recommend a drug" to prevent fracture, he said.

"For men at moderate risk of fracture, I review the risks and benefits of treatment and let them decide," he continued.

For men at low risk, Dr Alibhai recommends ensuring adequate calcium and vitamin D and rechecking BMD in 1 to 2 years to ensure their risk has not increased.

Notably, any men with radiographic vertebral fractures should receive bone health therapy, independent of their FRAX score and BMD, the study authors also say.

In choosing a bone health agent, clinicians should keep in mind several fine points, the editorialists suggest.

One of these is the issue of choosing between intravenous and oral bisphosphonates.

In the meta-analysis, 14 studies evaluated intravenous bisphosphonates and 6 evaluated oral bisphosphonates.

The meta-analysis showed that bisphosphonates protected BMD at all bone sites, but subgroup analysis suggested more benefit at the total hip for intravenous than for oral administration.

Most studies of intravenous treatment evaluated a 4-mg dose of zoledronic acid given at 3-month intervals. But a once-yearly 5-mg dose has also proven effective in the context of ADT. The second option may be preferable, suggest the editorialists, because more frequent dosing has been associated with higher risk for osteonecrosis of the jaw and other adverse events.

With regard to denosumab, the editorialists point out that it has a unique liability.

The drug (60 mg every 6 months) is approved to increase bone mass in patients at high risk for fracture, including those receiving ADT for nonmetastatic prostate cancer. However, discontinuation of denosumab, say the pair, "can lead to rapid reversal of BMD gains and a rebound increase in bone turnover, possibly resulting in a period of skeletal fragility, an effect not seen with zoledronic acid."

The new study, say the editorialists, was well done, because it followed "rigorous standards."

Nevertheless, given the commonplace nature of both prostate cancer and ADT use, data to guide practice are "surprisingly limited," they add.

For relevant clinical trials, systematic reviews, and earlier meta-analyses, the study authors reviewed Ovid MEDLINE (1946 to 2017), EMBASE (1980 to 2017), and the Cochrane Database of Systematic Reviews (2017).

Among their findings was one trial that evaluated the selective estrogen receptor modulator toremifene (Fareston, Kyowa Kirin), which is not approved in this setting and therefore was not emphasized by the meta-analysis authors. However, that one trial was powered to detect a difference in fracture rate.

Importantly, toremifene was associated with significantly fewer overall fractures (relative risk reduction, 38% [95% confidence interval, 2.2% to 60.2%]; P = .036). This is an improvement upon the efficacy of denosumab, which was significantly effective only in reducing vertebral fractures. Data for overall fractures in the denosumab study did not reach significance (5.2% vs. 7.2%; P = .10).

In recent decades, prostate cancer specialists have improved the amount of attention that they give bone health, said Dr Alibhai.

But lack of training and lack of access to resources are still barriers to care here, he said.

Nevertheless, Dr Alibhai hopes that prostate cancer specialists take the time to address bone health at the start of any cancer treatment. "Low bone mass and osteoporosis are often silent until the first fracture occurs.  Ideally we want to identify these men before the first fracture and institute measures to prevent that fracture," he said.

The study was supported by the Program in Evidence-Based Care of Cancer Care Ontario. Multiple study authors and both editorialists disclosed financial ties to industry.

Ann Intern Med. Published online August 7, 2017. Abstract, Editorial

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