Risk of fracture in men with prostate cancer on androgen deprivation therapy: a population-based cohort study in New Zealand

Abstract

BackgroundAndrogen deprivation therapy (ADT) administered as a prostate cancer treatment is known to exert multiple side effects including bone deterioration leading to bone fracture. The current analysis is to evaluate the burden of fracture risk in the New Zealand prostate cancer (PCa) population treated with ADT, and to understand the subsequent risk of mortality after a fracture.MethodsUsing datasets created through linking records from the New Zealand Cancer Registry, National Minimal Dataset, Pharmaceutical Collection and Mortality Collection, we studied 25,544 men (aged ≥40 years) diagnosed with PCa between 2004 and 2012. ADT was categorised into the following groups: gonadotropin-releasing hormone (GnRH) agonists, anti-androgens, combined androgen blockade (GnRH agonists plus anti-androgens), bilateral orchiectomy, and bilateral orchiectomy plus pharmacologic ADT (anti-androgens and/or GnRH agonists).ResultsAmong patients receiving ADT, 10.8 % had a fracture compared to 3.2 % of those not receiving ADT (p < 0.0001). After controlling for age and ethnicity, the use of ADT was associated with a significantly increased risk of any fracture (OR = 2.83; 95 % CI 2.52–3.17) and of hip fracture requiring hospitalisation (OR = 1.82; 95 % CI 1.44–2.30). Those who received combined androgen blockade (OR = 3.48; 95 % CI 3.07–3.96) and bilateral orchiectomy with pharmacologic ADT (OR = 4.32; 95 % CI 3.34–5.58) had the greatest risk of fracture. The fracture risk following different types of ADT was confounded by pathologic fractures and spinal cord compression (SCC). ADT recipients with fractures had a 1.83-fold (95 % CI 1.68–1.99) higher mortality risk than those without a fracture. However, after the exclusion of pathologic fractures and SCC, there was no increased risk of mortality.ConclusionsADT was significantly associated with an increased risk of any fracture and hip fracture requiring hospitalisation. The excess risk was partly driven by pathologic fractures and SCC which are associated with decreased survival in ADT users. Identification of those at higher risk of fracture and close monitoring of bone health while on ADT is an important factor to consider. This may require monitoring of bone density and bone marker profiles.

Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health

“…One study with over 50,000 participants found that androgen deprivation therapy either through gonadotropin-releasing hormone agonist or orchiectomy increased the relative risk of fracture by 1.54 and 1.45, respectively, and when metastatic disease was excluded, the relative risk of fracture in men on a gonadotropin-releasing hormone agonist was still RR 1.37 [82]. A number of other studies have found similar results in men undergoing androgen deprivation therapy for prostate cancer [85–87]. Overall, with the data from observational studies suggesting a role of testosterone in osteoporotic fractures in men combined with proven increased fracture risk in men undergoing androgen deprivation, it seems likely that low testosterone is indeed associated with fracture risk in older men.…”

The skeletal impact of cancer therapies

“…Consequently, levels of oestradiol (produced via testosterone aromatization to oestradiol) are also severely reduced. Although testosterone is the dominant male sex steroid, there is good epidemiologic evidence that (as in women) bioavailable oestradiol levels more closely correlate with BMD in men, with abrupt lowering of oestradiol levels as occurs with ADT leading to bone loss, bone microarchitectural deterioration and increased fracture risk . More recently, both abiraterone acetate (which inhibits the key enzyme that catalyses androgen biosynthesis [CYP17]) and enzalutamide (an androgen receptor antagonist) have been developed and approved for the treatment of men with castration‐resistant prostate cancer.…”

Measuring testosterone and testosterone replacement therapy in men receiving androgen deprivation therapy for prostate cancer: A survey of UK uro‐oncologists' opinions and practice

“…Numerous systematic reviews and meta‐analyses of observational studies have therefore suggested that men who have received this treatment are at risk of the complications of testosterone deficiency. These are comparable to men with hypogonadism due to other causes and include ED, depression, type 2 diabetes, adverse changes in body composition, increased risk of fractures and decreased bone mineral density, and cardiovascular disease . There are numerous interventions available to manage these adverse effects of ADT.…”