Bone health in men receiving androgen deprivation therapy for prostate cancer
J Urol. 2007 Jan;177(1):17-24. Bone health in men receiving androgen deprivation therapy for prostate cancer, Eastham, JA. PMID: 17161994.
Introduction. For a nice explanation of androgen deprivation therapy (ADT) see this American Cancer Society Website. The Eastham article is a review of this topic and I will try to summarize the important aspects of ADT as it relates to osteoporosis in men in this update. ADT creates hypgonadism as it works to suppress metastatic prostate tumor growth. Unfortunately one of its side effects is to bring on rapid bone loss with the resultant increased risk of fracture. One problem is that in these older men they are often already osteopenic or have frank osteoporosis even before ADT is started. Thus the importance of a good diagnostic workup on all men with prostate cancer, and especially those about to receive ADT.
Pathophysiology of ADT-associated bone loss. ADT disrupts the normal equilibrium between bone synthesis and degradation due to its effect on estrogen and testosterone, both of which help maintain normal bone mineral density (BMD). The normal rate of loss of BMD in middle age males is 0.5-1% per year, however, after ADT this rate increases to about 4% per year.
Assessing risk: measuring loss of BMD. The most commonly used tool for assessing BMD is dual-energy X-ray absorptiometry (DXA). I'm quoting the following paragraph from the article because it is a really nice summary of T-scores and the fracture risk derived from lower T-scores: “Results of BMD measurements are typically standardized and reported as a T-score. The T-score is the number of SDs (standard deviations) by which patient-measured bone mass deviates from the mean of the young normal population of the same sex at a given site. T-scores are used to confirm a diagnosis of osteoporosis and assess disease severity as well as predict the fracture risk. According to WHO criteria patients with scores of -1 or greater are considered to be within the normal range. T-scores of -1 to -2.5 indicate osteopenia, -2.5 or less defines osteoporosis and -2.5 or less with at least 1 fracture indicates severe osteoporosis. A T-score of -1 represents a 10% to 12% loss of bone mass compared with the mean in normal young adults, which increases the relative risk of fracture 1.5 to 2-fold.” BMD changes can also be inferred from measuring bone metabolism biomarkers: markers of bone formation and bone resorption. Early risk assessment can identify patients on ADT, or about to start ADT, at risk of fracture and in need of preventive or treatment therapy to prevent fractures.
Impact of ADT on bone health. ADT brings about substantial bone loss at multiple sites which results in increased fracture risk for these men. One retrospective study of 288 men found a 4-fold higher incidence of peripheral and vertebral fractures in the men on ADT. This also impacts long-term survival since men on ADT without fractures survived for 160 months compared to 121 months for those with fractures, a 7-fold increase in the relative risk of death.
Bisphosphonates for treatment: Mechanism of action. Bisphosphonates prevent bone resorption by binding to active remodeling sites. There are two main classes: the more potent ones contain a nitrogen atom on a side chain, such as ibandronate, alendronate, risedronate, and the less potent ones without a nitrogen atom, such as etidronate. Additionally the side chain can be modified with a heterocyclic ring to provide extreme potency, such as in zoledronic acid.
Bisphosphonates for ADT bone loss. Both oral and intravenous bisphosphonates have been shown in clinical trials to prevent bone loss, decrease fracture risk, decrease or prevent skeletal-related events (SREs) and limit bone pain related to metastases. The IV form, especially zoledronic acid, has been shown more potent than the oral form. It not only prevented BMD loss, but also increased BMD over baseline. In one study men received 4 mg zoledronic acid every 3 months for 1 year and had significant increases in BMD in the lumbar spine, femoral neck, trochanter and hip when compared to placebo. Additionally there was a significant improvement in SREs in the zoledronic acid group compared to placebo.
Safety of Bisphosphonates. Oral bisphosphonates are poorly absorbed from the gut, so they must be taken in higher doses to overcome this limitation. Patients must not eat for 30 minutes after ingesting these medications and there are some reports of GI problems, mostly overcome by the once-weekly dosing regimen. The IV bisphosphonates are generally well tolerated and not affected by the limitations mentioned for oral medications. Approximately 20% of people treated with IV bisphosphonates suffer flu-like symptoms, generally self-limiting and occurring with the first dose only. And the IV medications should not be given to people with severe renal impairment. Hypocalcemia has been reported, requiring lab tests to evaluate serum calcium, phosphate and magnesium. Osteonecrosis of the jaw is a recently-reported side effect of bisphosphonates, especially those people on high-dose nitrogen-based IV bisphosphonates—but occasionally also reported in people taking oral bisphosphonates. There are several articles on jaw osteonecrosis on this Website, just use the FreeFind search engine to track them down.
Compliance. Long-term compliance is a major issue with oral bisphosphonates. Here is an Update showing just how poor compliance is with the oral medications—often with 50% or more of the people not taking the bisphosphonates properly, or discontinuing therapy. It is hoped that the long interval between IV bisphosphonate dosing—3 months for zoledronic acid—will lead to better compliance.
Treatment options. The authors mention two other options besides oral and IV bisphosphonates for men on ADT: the SERM raloxifene and estrogen-supplemented ADT. In clinical trials both of these options have been shown to be of value as concerns bone density in men on ADT, so discuss these with your care provider if you are starting ADT.
Diagnosing, preventing and treating ADT-associated bone loss. All men receiving ADT or with the history of a fracture, should receive a DXA to evaluate their BMD. Based upon the severity of bone loss on the initial DXA, follow up DXA should be done in 6 to 12 months if the initial T-score indicates osteoporosis or osteopenia. When the initial T-score is -1 or greater, then the repeat DXA should be done in two years. Obviously those patients with a diagnosis of osteoporosis should receive active treatment. In addition lifestyle changes may be indicated, such as an exercise regimen along with avoidance of excessive alcohol, caffeine and smoking cessation. Nutritional intervention may be required to verify that people get adequate calcium, vitamin D and other nutrients. Currently recommendations are for at least 800 IU of vitamin D/daily along with at least 1200 mg calcium via supplements or diet.
Future strategies for prevention and treatment. The RANKL signaling process has been implicated in bone loss in osteoporosis. Current studies are testing therapeutic targeting of RANKL by human monoclonal antibody. Results of current trials should become available soon. Here is one Update on RANKL and here is another. Education of patients and their physicians about the direct correlation between ADT and osteoporosis should be a great preventive and treatment tool for ADT-associated bone loss. The authors note that in one study of 184 patients on ADT, only 15% reported receiving any type of prevention information or therapy to maintain bone health. This puts the burden on urologists and others who treat men with prostate cancer via ADT—they must evaluate men's bone health before initiating ADT—and then treat or observe as indicated by current bone status.
Conclusions. The authors highlight the importance of early screening by health care professionals, followed by proper therapy or further observation, as needed. Patients must then comply with the needed therapy or lifestyle changes. Although many bisphosphonates have been shown to slow or prevent bone loss, zoledronic acid can also increase BMD and decrease SREs and fractures in men with metastatic disease.
Editor's comments. A common theme on this Website is that patients must educate themselves to be sure they are getting proper preventive and treatment tests and therapies. This is especially true for men on ADT, and is true for men with prostate cancer in general. Remember that in one study 34% of people had osteopenia or osteoporosis before starting ADT. So a diagnosis of prostate cancer should tell a man that bone density testing is probably needed at that time, or should at least prompt him to discuss this option with the care provider. My guess is that the suggested therapy when ADT begins will often be just calcium and vitamin D—this is not enough. This review article shows that only zoledronic acid has been shown to increase BMD for men on ADT, with oral bisphosphonates just retarding bone loss or maintaining current levels. So the IV zoledronic acid is the best solution for men with significant bone loss. I also recommend discussing raloxifene and estrogen supplementation with your care provider as methods to deal with ADT-associated bone loss.