ADT and incidence of bone fractures on in the “real world”


Recent data from the Prostate Cancer Outcomes Study, which followed men diagnosed with prostate cancer for a total of 15 years after their diagnosis, have provided us with valuable information about risk for bone fractures in men with progressive disease.

The Prostate Cancer Outcomes Study enrolled and followed a total of 3,533 patients who had been diagnosed with prostate cancer in 1994 and 1995. A paper by Morgans et al. reports on an analysis of data from patients in this study who had non-metastatic prostate cancer when they were first diagnosed and who completed 15-year follow-up surveys to report on the development of fractures, and the use of bone-related medications over time.

Here is what they found:

  • After 15 years of follow-up there were 961 patients (27.2 percent) who were still surviving and had completed the relevant surveys.
  • Of these 961 patients
    • 157 (16.3 percent) had received “prolonged” androgen-deprivation therapy (ADT) for > 1 year.
    • 120 patients (12.5 percent) had received short-term ADT for ≤ 1 year.
    • 684 patients (72.1 percent received no ADT.
  • Half of the men treated with > 1 year of ADT reported bone medication use (i.e., with agents like zoledronate).
  • Compared to the men who received no ADT, the men who received > 1 year of ADT had
    • Significantly high risk for fractures (odds ratio [OR] = 2.5)
    • Significantly higher likelihood of bone mineral density testing (OR = 5.9)
    • Significantly higher likelihood of bone medication use (OR = 4.3 percent)
  • Also compared to the men who received no ADT, the men receiving ADT for ≤ 1 year reported similar rates of fractures.

The authors conclude that, in this study

… prolonged ADT use was associated with substantial risks of fracture, whereas short-term use was not. This information should be considered when weighing the advantages and disadvantages of ADT in men with prostate cancer.

What is interesting to The “New” Prostate Cancer InfoLink (at least based on the data in the abstract of this paper) is that among the men who were exposed to prolonged use of ADT there appears to have been little to no significant impact on risk for actual fractures whether the patients were being treated with bone medications or not. It should be remembered that in the clinical trials of drugs like zoledronate and denosumab to assess their effectiveness in prevention of fractures, the investigators were collecting data on both true fractures and “skeletal related events” (i.e., things like smaller, hairline fractures and other events that evident on certain types of scan and might not be clinically evident at all).

15 Responses

  1. Hi,

    “Compared to the men who received no ADT, the men who received > 1 year of ADT had … Significantly high risk for fractures (odds ratio [OR] = 2.5)” How does that jibe with your statement that “among the men who were exposed to prolonged use of ADT there appears to have been little to no significant impact on risk for actual fractures?”

    Herb

  2. Herb:

    You seem to have ignored a part of my second statement, which said, in full, that “among the men who were exposed to prolonged use of ADT there appears to have been little to no significant impact on risk for actual fractures whether the patients were being treated with bone medications or not.”

    The point is that taking “bone medications” (i.e., drugs like zoledronate and denosumab) is supposed to lower the risk for fractures for men on ADT, and yet there is no mention of this actually occurring at a significant rate in the Prostate Cancer Outcomes Study.

    Mike

  3. I didn’t read your statement to mean, as I now infer, that, although prolonged use of ADT increased the risk of fracture, bone medications did not protect against this. Are you saying that it is true because the odds ratio was higher for bone medication use (4.3) than it was for high risk of fracture (2.5)? If so, I disagree and I think you would have to tabulate who was doing what. 50% were taking bone medication. Maybe they had no fractures and the folks who did have fractures were not taking bone medication. Anyway, in this paper, “The majority of men who reported use of bone medications used either calcium or vitamin D … The use of bisphosphonates … was less common.” I would be concerned less patients on ADT infer that bone medications will not help them. I’m still not sure if I have understood you correctly.

    Herb

  4. Herb:

    All that I was saying was that the abstract gave no indication that taking bone medications reduced risk for fractures. My assumption at the time was that by “bone medications” the authors meant drugs like zoledronate. Now that I have seen the entire paper (thank you), it is clear (as you note) that almost none of the patients were taking any “real” bone medications like zoledronate or denosumab to prevent fractures. At best they were taking calcium and vitamin D supplements — which have never been proven to prevent fractures anyway! Thus it is unsurprising that such unapproved bone medications failed to lower fracture risk.

    The question thus becomes a different one, which is why so few patients in this study (followed until something like 2008-2010) were ever placed on a drug like zoledronate if they had metastatic disease and were on long-term ADT. After all, this is recommended by almost all guidelines.

  5. VIEWPOINT OF LONG-TERM IADT PROSTATE CANCER PATIENT WHO USED BONE DENSITY DRUGS

    Thanks again Sitemaster for selecting this paper that helps us understand the current professional discourse on this topic.

    Here are some comments based on my own experience. I was diagnosed with a life-threatening case in December 1999 (PSA 113.6, Gleason 4 + 3 = 7 (J. Epstein), all biopsy cores positive, most 100% cancer, a “rock hard” Stage III prostate, perineural invasion, but CT and bone scan negative, and ProstaScint encouraging but one suspicious area). I am now hopefully cured after 13.5 years of ADT, the fourth round ending this April in support of 39 sessions of TomoTherapy IMRT, last year; my PSA last week was 0.02 with testosterone recovering gradually and now at 81. (Big smile here!) I started ADT with Lupron alone within weeks of being diagnosed in 1999, and by the next September I was on Fosamax, a bone density medication, prescribed immediately (even before getting the DEXA results) when I first consulted my medical oncologist. I later switched to Boniva, and to estradiol skin patches for my fourth round of ADT. Here are some thoughts.

    1. RECOGNITION OF THE BONE DENSITY ISSUE FOR MEN ON ADT: Back in 1999 when I was diagnosed there was a huge gap in expertise among doctors prescribing ADT regarding the risk of decreasing bone density for men on long-term ADT. At the expert end, including some practices dedicated to prostate cancer, the risk was fully appreciated, and there was a sound grasp of appropriate, effective countermeasures. The newsletter of the Prostate Cancer Research institute, PCRI Insights, the January 1999, vol. 2, no. 1 issue, still available online today, featured a highly informative article “Bone integrity: in-depth review.” This was before Zometa (zolendronate) had been approved (2001), but Fosamax (alendronate) had won FDA approval in 1995 and was popular, following the first drug, Aredia (pamidronate) approved in 1991, and Actone (risedronate) approved in 1998. Recommended countermeasures included bone density scanning with a DEXA scan or qCT scan, a bisphosphonate drug, coupled with an effective brand of vitamin D3 supplement plus a calcium supplement, and weight-bearing exercise. I became aware of the density risk in early 2000 and for months tried to get my otherwise capable urologist team to help me counter it. They basically gave me the slow roll, finally agreeing with me that they were not comfortable dealing with this unfamiliar risk, nor with the tactic of adding a third drug (a 5-alpha reductase inhibitor, Proscar) to my then two drug ADT (Lupron plus 50 mg Casodex). I am grateful for their referral of my case to the medical oncologist who has guided my care since the late summer of 2000 (with consultant guidance from Dr. Charles Myers).

    My urologist team unfortunately represented what I found to be the standard of care. That began to change as the decade matured, first with the medical oncologic community featuring the bone density risk in their annual conference “education book”, followed by the urologic community doing the same a couple or few years later. However, based on my contacts and reading, many doctors prescribing ADT still are not well versed in either the risk or effective countermeasures. Frankly, bluntly, I believe patients can use a doctor’s handling of their questions about bone density risk as one good indicator of the doctor’s expertise in managing ADT for them. (Patients should know the key answers when they ask the questions; if the doctor is ignorant or unsure, that’s a tell-tale sign.)

    2. NEED FOR BONE DENSITY COUNTERMEASURES: As the research indicates, my impression has been that bone density drugs are not essential for short-term ADT use, such as to support radiation for intermediate-risk cases. While bone density will decrease somewhat shortly after commencing ADT drugs that sharply curtail testosterone and hence estrogen, the loss seems to be not that great for a short term of several months, and bone density should recover as testosterone (and estrogen) recover after ADT is stopped. I am also convinced that the more conventional ADT drugs work fine for at least most of us guys without detectable metastatic disease, but I’ll note here that I’m a savvy patient with no enrolled medical education. For those with metastatic disease, Zometa and denosumab appear to be the drugs of choice today, based on comments by the experts.

    3. ESTRADIOL ESTROGEN SKIN PATCHES AS A BONE DENSITY CHOICE. Some doctors now favor these skin patches as the preferred bone density countermeasure, especially after many years of being on a bisphosphonate drug, such long-term experience appearing to heighten risk of fractures of the femur. Dr. Myers advised my oncologist and me to switch to the patches for my fourth round of 18 months of ADT, and I did that. The main side effect is enlarged breasts, which can be countered in advance, during the treatment (Cabergoline), or afterward (surgery), but there are also a number of benefits, which I won’t mention now except for elimination of hot flashes and sweats. While my own case is only anecdotal as evidence, I suspect I am fairly typical regarding bone density. In September 2000 my DEXA scan revealed osteopenia in the spine, with two of the vertebrae in the osteoporosis range. My last DEXA about a year ago showed my bones had recovered to the normal range of density.

    4. UNFORTUNATE LIMITATIONS OF THIS STUDY: I’m glad this study was published, as it provides some useful evidence, such as the lack of impact on density for short-term ADT use. However, there is a great reduction in the number of patients available at the end of the 15 years, especially those on so called “long-term” ADT, meaning ADT more than 1 year. Also, as Sitemaster noted and Herb emphasized, only half of the patients on so-called long-term ADT were on any BMD countermeasure drugs/supplements, with Sitemaster’s clarification that calcium and vitamin D supplements seemed to be the countermeasures used in that half. Moreover, as some of the experts in ADT have repeatedly informed us, their clinical experience indicates that some vitamin D brands are of little use, while others are reliable.

    5. NO EVIDENCE OF LACK OF IMPACT OF DRUGS FOR LONG-TERM ADT PATIENTS: Regarding the comment “What is interesting to The “New” Prostate Cancer InfoLink (at least based on the data in the abstract of this paper) is that among the men who were exposed to prolonged use of ADT there appears to have been little to no significant impact on risk for actual fractures whether the patients were being treated with bone medications or not.” I’ll join Herb in being convinced the study just does not provide the data to judge this issue. Sitemaster’s comment of 3:12 PM supports this line of thought as it indicates limited drug use, at best, in the “half” who seemed to be using a density countermeasure. I’m convinced there are many studies that do document the effectiveness of bone density drugs. (They certainly have worked for me!)

    MY SHORT BOTTOM-LINE: As a now savvy patient with no enrolled medical education, I’m convinced prostate cancer patients on long-term ADT are nuts if they do not use bone density countermeasure including a BMD scan, an appropriate drug, calcium, and a good vitamin D3 supplement with periodic 25-hydroxy vitamin D monitoring, and weight-bearing exercise.

  6. I must be really dense! I have never been good at statistics so the phrase “OR = 2.5” means nothing to me. Can someone clarify that for me?

    Beyond that, I question why “non-metastatic” patients would be receiving ADT in the first place.

    Beyond that, I find it really disturbing that only 27.2 percent of “non-metastatic” patients were alive after 15 years. That is a depressing statistic.

    I don’t even want to think about the statistics for metastatic patients like me!

    Jake

  7. I can only comment to my own experience with ADT since 1996. My protocol has been ADT/IAD repeatedly until continuous ADT became a continuing requirement. For me it wasn’t until 2010 that my ADT had to become continuous when moving from Lupron, Casodex, and Avodart to Lupron, Zytiga, and Avodart. Since that time this combination has continued to control and enable management of my continuing prostate cancer. In the meantime, I have never experienced any fractures attributable to this long history of ADT.

  8. OR is odds ratio, pertaining to odds, just like at a horse race. Suppose you had a weird coin that came up heads 8 times out of 10, or with odds of 8:2 or simplifying as 4. Compare it with a normal coin with odds of 1:1 — or 1. The odds ratio is 4. This can be applied to compare a population who have a certain medical situation with those who don’t. I think I’ve got that right. For more detail, this link looks promising.

    Herb

  9. John-Pierre:

    Herb Klein’s explanation is correct. In other words an OR = 2.5 means that the odds are 2.5 times more likely than what would be expected of the “normal” comparator.

    Does that make sense to you?

  10. Chuck,

    Hearty congratulations on doing well with this new regimen!

  11. QUESTION RE ADT FOR NON-METASTATIC PATIENTS

    Hi John-Pierre. I’m responding to your question on September 29, 2014 at 7:45 pm in which you said: “… Beyond that, I question why “non-metastatic” patients would be receiving ADT in the first place. …”

    To me there is unfortunate controversy about the timing of ADT, with too many doctors preferring to defer it until the patient has well-advanced disease that is often metastatic. The experts in ADT that I have followed for years have long been convinced, based in part on results in their large practices that are dedicated to prostate cancer, that ADT works best and highly effectively in patients with earlier stage disease.

    Also, while anecdotal, the examples posted by Chuck Maack and me for this thread are illustrative: both of us have done very well on intermittent sophisticated ADT long-term. Despite a highly adverse initial presentation in 1999, no metastases were found for me by sophisticated bone and node scans in 2011 and 2012. I am convinced that effective ADT played a key role in enabling me to avoid metastasis and to take a shot at a cure with radiation last year that seems to have been effective.

    Those ADT experts believe that conventional ADT (prior to Zytiga and Xtandi) provided men with average cancer control success of about 10 to 11 years for one large proportion of patients on sophisticated ADT or indefinitely for another large proportion. (I seem to have fallen into the “indefinite” group, though there was some evidence the antiandrogen leg of my therapy was failing and required a switch to a different antiandrogen.)

    Some of those same experts have even found success of limited-term sophisticated ADT as primary therapy for a substantial proportion of low- and intermediate-risk patients. However, there have been no large and high-quality studies to back this up.

    The Scholz, Strum, Lam and colleagues group has been the most effective in publishing their encouraging results in major journals.

  12. Yes, thank you Herb and Mike.

  13. SURVIVAL OF NON-METASTATIC PATIENTS AT 15 YEARS: 27.2%

    Hi again Jake. I’m responding to the latter part of your comment in which you were concerned about survival in the study:

    “… Beyond that, I find it really disturbing that only 27.2 percent of “non-metastatic” patients were alive after 15 years. That is a depressing statistic.

    “I don’t even want to think about the statistics for metastatic patients like me!”

    That survival statistic is not anywhere near as bad as it looks at first glance. If you read about this study, you will find that 68% of all patients were 65 years or older at the start of the study, way back in the mid-90s. Therefore, at the 15-year point, 68% would be 80 or older if they were still living. Moreover, within this 68%, 18% of all patients in the study were age 74 or older at the start, meaning that they would be at least 89 years old at the 15-year point if still surviving. When you consider life expectancy statistics and causes of death other than prostate cancer, it is clear that a high proportion of patients no longer alive would have died from other causes. In view of research published on active surveillance, we can be sure that a hefty proportion of patients who were either alive or not at the 15-year point had cases of prostate cancer that would not have bothered them during their lifetimes.

    You can get free and easily accessible information about this study by going to http://www.pubmed.gov and using this search string: “Prostate Cancer Outcomes Study” AND Penson [au]. I just did that and got twelve hits, including several that had links to the complete full papers. I got the statistics in the preceding paragraph from Table 2 of the last hit (the oldest), which is entitled “General quality of life 2 years following treatment for prostate cancer: what influences outcomes? Results from the prostate cancer outcomes study.”

    By the way, there is emerging evidence that men with only a few bone metastases, such as five or fewer, may be curable with radiation, even at that late stage. I also hope you are following the encouraging news here and elsewhere about the effectiveness of newly approved drugs for late-stage disease such as Zytiga, Xtandi, and Xofigo.

    I hope you find this reassuring.

  14. Thank you for the clarifications, Jim. After I posted, I realized that patient ages would have been a factor in life expectancy. Fifteen years is a long time and I’m sure many of these men died from causes other than prostate cancer. I probably would have edited my post if I’d had the capability to do so.

    By the way, I’m happy to hear that you are doing well with your current regimen. I tried IAD but only made it about 7 months before my PSA started climbing and I began having significant pain in my butt. I did continue with monthly Zometa infusions during that time. Because of the increased pain and steadily increasing PSA levels, I had to go back to the continuous Lupron shots. So far, it is working and my PSA remains in the 0.5 to 0.8 range. I also take a calcium/D3 vitamin every day. And, from the limited research I’ve seen, the aspirin and statins I take every day for cholesterol is probably having some beneficial effect on my prostate cancer.

    Yes, I do try to follow the research on Zytiga, Xtandi, and Xofigo and the “pipeline” drugs. It’s reassuring to know that additional treatments are available if and when the Lupron fails.

    Thanks to Mike for his fantastic contributions to this site. It has been an invaluable resource for me. But, as I said in my original post, some of the terms and statistics make it hard for me to follow even with a 4-year degree. I am dense. That part of my post is true!

    Thanks again for your thoughtful responses!

    Jake

  15. Hello,

    It is interesting that there was no mention of the difference between men diagnosed with or without initial bone metastases.

    PaulP

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