Long-term dynamics of bone mineral density during intermittent androgen deprivation for men with nonmetastatic, hormone-sensitive prostate cancer

Abstract

Purpose: To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer.

Patients and methods: Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period.

Results: Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was -3.4% (P < .001) for the spine and -1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma.

Conclusion: Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.

Fig 1.

CONSORT diagram shows the rationale for selection of the 56 patients from the clinical trial for the analysis. ADT, androgen-deprivation therapy; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; IAD, intermittent androgen deprivation; PSA, prostate-specific antigen.

Fig 2.

Study schema illustrates one full cycle of intermittent androgen deprivation. Cycles were repeated until the development of castration resistance or death. Dual-energy x-ray absorptiometry (DXA) scan at baseline with at least two consecutive DXA scans were required to be eligible for this analysis. (*) The prostate-specific antigen threshold for radiation therapy or primary androgen-deprivation therapy (ADT) was 4 ng/mL and for radical prostatectomy was 1 ng/mL.

Fig 3.

Average and 95% CIs of (A) absolute and (B) percentage change in standardized average bone mineral density (BMD) relative to baseline at the spine are represented in the line graph over multiple cycles of intermittent androgen deprivation. Displayed below each graph are the number of patients at risk, median years from initiation of androgen deprivation therapy (ADT), mean change in spine BMD relative to last dual-energy x-ray absorptiometry scan, and P values from one-sided t tests.

Fig 4.

Average and 95% CIs of (A) absolute and (B) percentage change in standardized average bone mineral density (BMD) relative to baseline at the left hip are represented in the line graph over multiple cycles of intermittent androgen deprivation. Displayed below each graph are the number of patients at risk, median years from initiation of androgen deprivation therapy (ADT), mean change in left-hip BMD relative to last dual-energy x-ray absorptiometry scan, and P values from one-sided t tests.

Fig 5.

Number of patients with decreasing or nondecreasing (either stable or increasing) bone mineral density (BMD) between consecutive dual-energy x-ray absorptiometry scans at the beginning of on- or off-treatment periods at the (A) spine or (B) left hip demonstrate the heterogeneity of patient BMD response to androgen deprivation therapy (ADT).