Osteoporosis management program in patients with prostate cancer receiving androgen deprivation therapy
May 13, 2013
Approximately one third of patients with prostate cancer receive androgen deprivation therapy (ADT). This treatment is associated with higher incidence of fractures and increased mortality of fractures. However, only a minority of patients receiving ADT has their bone mineral density (BMD) documented before or after initiation of ADT. Therefore, the aim of this study was to determine whether the implementation of a screening and treatment protocol reduced the rate of osteoporotic fractures in men with prostate cancer receiving ADT.
This study included 1482 patients with prostate cancer receiving leuprolide identified in the electronic medical system of Kaiser Permanente Southern California. Of them, 1071 were included in the Healthy Bone Program (HBP) comprising BMD measurement by dual energy X-ray absorptiometry and treatment. The indications of anti-osteoporotic treatment were established using T-score corresponding to the number of standard deviations below the mean in young healthy adult men. Men with T-score ≥-2.5 were advised on smoking cessation, regular exercise, adequate calcium intake (1200 mg/d) and adequate vitamin D intake (400-800 IU/d). Men with T-score <-2.5 were also treated with pharmacological intervention (mainly bisphosphonates). The remaining 411 men received standard care. Strict exclusion criteria were used to reduce the selection bias.
The men who were included in the HBP had much lower incidence of hip fracture (5 vs 18 fractures per 1000 person-years). After adjustment for confounders, patients who were not enrolled in the HBP had a fourfold higher risk of hip fracture compared with the HBP patients (hazard risk = 4.19, 95% confidence interval 1.92 – 9.13, p<0.001).
In this study men with prostate cancer receiving ADT and enrolled in an active screening and treatment protocol experienced 72% lower rate of hip fracture compared with the nonscreened group. This difference may seem astonishingly high; however, two facts need to be remembered. Some older men have low BMD and high risk of fracture. ADT accelerates bone turnover leading to a rapid bone loss associated with a deterioration of bone microarchitecture and higher bone fragility. This rapid bone loss may be particularly dangerous in men with low BMD at baseline. ADT-induced hypogonadism may also result in rapid loss of muscle mass and strength leading to a higher risk of falling. Thus, the detection and treatment of men with low BMD may decrease markedly the risk of fracture. Moreover, the implementation if lifestyle changes may have a beneficial effect on bone and muscle.
Some limitations of the study have to be recognized: retrospective identification of patients, observational design, potential imbalance in risk factors and medical care between two groups of men. However, despite these limitations, the paper and accompanying comment are important because they raise two major points. Firstly, ADT increases bone fragility. Thus, critical judgment of indications for ADT is necessary before its initiation in order to avoid the severe adverse effects. Secondly, the implementation of an osteoporosis management program in patients with prostate cancer receiving ADT may have a beneficial effect.
Reference: Zhumkhawala AA, Gleason JM, Cheetham TC, Niu F, Loo RK, Dell RM, Jacobsen SJ, Chien GW. Osteoporosis management program decreases incidence of hip fracture in patients with prostate cancer receiving androgen deprivation therapy Urology. 2013 May; 81(5):1010-7.
Zoledronic acid decreases the risk of vertebral fracture in osteoporotic men
December 31, 2012
Osteoporotic fractures in men are a major health issue. However, studies involving men with osteoporosis have focused on the surrogate outcomes such as bone mineral density (BMD) and biochemical bone turnover markers (BTM). By contrast, data from randomized, double-blind, clinical trials assessing anti-fracture efficacy in men are lacking. Therefore, the recent multicenter randomized prospective trial assessing the effect of zoledronic on the risk of vertebral fracture in osteoporotic men as a primary end point is of particular interest. Previously, zoledronic acid reduced highly significantly fracture incidence in postmenopausal women and increased BMD in several studies carried out in men with low BMD.
This study was performed in 1199 men aged 50 to 85. Eligible men without fracture had BMD T-score≤-2.5 at total hip, femoral neck or lumbar spine. Eligible men with fracture had BMD T-score≤-1.5 and one to three vertebral fractures. (T-score was calculated as the number of SDs below or above the mean in young men.) Men were randomly assigned to receive zoledronic acid at a dose of 5 mg or placebo administered as a 15 to 30 minute i.v. infusion at baseline and month 12. All men received daily calcium (1000-1500 mg) and vitamin D (800-1200 IU). Men were followed up for 24 months; almost 90% of men completed the study.
Vertebral fracture incidence was 67% lower in the zoledronic acid group compared with the placebo group (RR= 0.33, 95% confidence interval: 0.16-0.70, p=0.002). Loss of height was smaller in the zoledronic acid group vs placebo group (2.2 vs 4.5 mm, p=0.002). Zoledronic acid induced a significant increase in BMD at the lumbar spine, total hip and femoral neck. The difference vs the placebo group was statistically significant for all the skeletal sites. Serum levels of bone formation markers (N-terminal propeptide of type I procollagen [PINP], bone-specific alkaline phosphatase) were significantly lower in men who received zoledronic acid than in men who received placebo. Levels of bone resorption markers (serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen) were also significantly lower in men receiving zoledronic acid. The effect of zoledronic acid on the fracture incidence, BMD and BTM levels (except PINP) was similar in men with testosterone levels of >350 ng/dl and in men with testosterone levels of 350 ng/dl or less.
The most frequent adverse effect of zoledronic acid was the influenza-like syndrome (pyrexia, myalgia, arthralgia, headaches, chills, pain in the extremities). It occurred in 15% of men and subsided spontaneously. No case of osteonecrosis of the jaw and no case of subtrochanteric or atypical fracture were observed. No significant differences were observed between the groups with respect to death, cardiac arrhythmias or renal dysfunction, except for myocardial infarction which was slightly more frequent in the zoledronic acid group. However, the analysis of each case showed that these events were not related to the study drug.
A key strength of this study was a population that was large enough to detect the anti-fracture efficacy of zoledronic acid in the osteoporotic men in the framework of a placebo-controlled, randomized, prospective trial. Zoledronic acid increased BMD and decreased bone turnover rate. The effect of zoledronic acid was independent of total testosterone levels. The reduction of fracture risk, the increase in BMD, the decrease in bone turnover rate and the safety profile were similar to those found in postmenopausal women treated with zoledronic acid. These results provide support for the value of antiresorptive therapy in osteoporotic men. They may also contribute to a better definition of treatment recommendations of osteoporosis in men.
Reference: Boonen S et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 2012, 367:1714-1723.
Denosumab for Men with Low Bone Mineral Density
September 27, 2012
It has been estimated that over 2 million US men have osteoporosis, and another 12 million may be at risk. While morbidity risks from fracture remain significant, and despite updated guidelines from the Endocrine Society, osteoporosis remains an under-treated and under-evaluated in most men. Bisphosphonates remain the predominant therapy for treatment of osteoporosis with the best evidence to minimize fracture risk.
A recent placebo-controlled, phase 3 study sought to investigate the efficacy and safety of denosumab 60mg given every 6 months versus placebo in men with known low bone mineral density (BMD). After 12 months of therapy, 228 men who received denosumab were found to have BMD increases of 5.7% in the lumbar spine and 2.4% in the total hip. Clinical fractures occurred in only 2 (1.7%) and 1 (0.8%) of men in the placebo- and denosumab-treated groups, respectively. There were no reported adverse events of hypocalcemia, and sensitivity reactions occurred in only 3.5% of men.
This study concludes that 60mg of denosumab is similarly effective in men with low BMD, as it has been proven to be efficacious in post-menopausal women as well. The effects of improvement in BMD in this study were independent of gonadal function level, baseline BMD status, age, or estimated fracture risk.
Reference: Orwoli E, Teglbjaerg CS, Langdahl BL, et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab 2012;97:3161-3169.
New Male Osteoporosis Guidelines
July 18, 2012
The US Endocrine Society's Clinical Guidelines Subcommittee published the first guidelines specific to men and osteoporosis in June 2012. Key recommendations are as follows:
- Screen men at increased risk for osteoporosis by measurement of bone mineral density (BMD) via dual-energy x-ray absorptiometry (DEXA) at age 70; men ages 50-69 should be tested if additional risk factors are present (e.g. low body weight, prior fracture as an adult, smoking)
- Screen men ages 50-69 for osteoporosis if they have delayed puberty, hypogonadism, hyperparathyroidism, hyperthyroidism, chronic obstructive pulmonary disease, use chronic glucocorticoids or GnRH agonists, or have a history of smoking and/or alcohol abuse
- If history and physical examination do not suggest a specific cause of osteoporosis, further testing should include bioavailable testosterone, sex hormone binding globulin, serum and urine protein electrophoresis, tissue transglutaminase antibodies, thyroid function tests, and parathyroid hormone levels
- Men should take 1000-1200mg calcium daily ideally from dietary sources, supplemented if necessary
- Men with vitamin D levels < 30ng/ml should receive supplementation
- Men at risk of fracture who are receiving testosterone supplementation should take agents proven to reduce fracture risk (e.g. bisphosphonate or teriparatide)
- Hypogonadal men with serum testosterone levels < 200ng/dl should receive testosterone replacement therapy unless contraindicated (e.g. prostate cancer)
- Clinicians should monitor (BMD) via DEXA scan at the femoral neck and lumbar spine every 1-2 years to assess response to treatment
- Men with osteoporosis should quit smoking, consume no more than 1 alcoholic beverage daily, and engage in weight-bearing exercise 30-40 minutes per session for 3-4 sessions per week
Reference: Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2012;97:1802-1822.
Fragility fractures in HIV-infected men – what is a myth and what is the reality?
January 25, 2012
Over several recent years, many studies have shown higher risk of osteoporosis and fragility fracture in HIV-infected individuals. HIV-infected population is getting older and its life expectancy increases. Therefore, the population of HIV-infected older men at high risk of fracture will grow during the next years.
Given the discrepancy between the studies, the paper by Womack et al. is very interesting (1). This prospective observational case-control study is a part of the Veterans Aging Cohort Study Virtual Cohort. It includes 40115 HIV-infected men and 79203 uninfected men matched for age, ethnic group and site of recruitment. During the average follow-up of 7 years, 1615 men sustained at least one fragility fracture (hip, vertebra, upper humerus). In the HIV-infected men, the risk of fracture was higher compared with the uninfected men (HR= 1.32, 95%CI: 1.20; 1.47). The risk weakened but remained significantly increased after adjustment for age, ethnic group, smoking, alcohol abuse, liver disease, use of corticosteroid and proton pump inhibitors. It became non-significant after additional adjustment for body mass index (BMI). In the HIV-infected men, fracture risk was significantly higher (40%) in protease inhibitor users and borderline significantly higher (30%) in tenofovir users.
Two messages should be emphasized. Firstly, HIV infection per se does not increase the risk fracture. Secondly, HIV-infected patients have higher risk of fracture due to many factors related to HIV-infection. Smoking, alcohol abuse and low BMI are associated with higher risk of fracture regardless of HIV infection. However, smoking and alcohol abuse are more frequent in HIV-infected individuals compared with the general population. BMI is lower in HIV-infected patients partially due to bad nutritional habits and partially due to sequelae of HIV infection, e.g. lipodystrophy. Liver diseases (mainly hepatitis B and C) are associated with higher bone fragility and are more frequent in HIV-infected patients. Corticosteroid decrease bone mass and strength, and their use is more frequent in HIV-infected patients. Some drugs used in the HIV-infected patients such as tenofovir and protease inhibitors, mainly ritonavir, have a negative impact on bone and may increase the risk of osteoporosis.
The above factors increase bone fragility. Fracture risk also depends on the frequency and severity of traumas. Some factors associated with higher risk of trauma are more frequent in HIV-infected patients, e.g. alcohol and drug abuse. Corticosteroid use, low physical activity and weight loss may be associated with lower muscle mass and higher risk of falling. Low BMI and lipodystrophy are associated with lower soft tissue thickness and higher impact of the energy of a fall on bones.
Thus, the classification of patients as HIV-infected and uninfected may be risky. Every HIV-infected patient should benefit from the specific assessment of his individual fracture risk on the basis of potential risk factors. Clinical examination should include at least interrogatory, bone densitometry and measurement of 25-hydroxyvitamin D (mainly in patients treated with tenofovir). Results of the tests routinely prescribed in HIV-infected patients may be also helpful, e.g. presence of hepatitis B or C. In many patients assessment of body composition may be recommended.
Reference: Womack JA, Goulet JL, Gibert C, Brandt C, Chang CC, Gulanski B, Fraenkel L, Mattocks K, Rimland D, Rodriguez-Barradas MC, Tate J, Yin MT, Justice AC Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One. 2011 Feb 16;6(2):e17217.