Changes in bone health and skeletal-related events following implementation of a multidisciplinary consensus statement guiding surveillance and treatment of men undergoing androgen deprivation therapy for prostate cancer

Abstract

Purpose. Androgen deprivation therapy (ADT) is a cornerstone for inhibiting progression of prostate cancer (CAP) and improving survival. After previously establishing that men with CAP treated with ADT at our institution had significant skeletal morbidity, we evaluate the effectiveness of a multidisciplinary consensus statement (MCS) to improve outcomes.

Materials and methods. We reviewed the records of men treated with ADT in our clinic. Only 38% of men had BMD studies, and 81% of those men had bone loss. Twenty-four percent of men had skeletal-related events (SREs). A minority of men were being treated for bone loss. We decided not to initiate therapy soon enough, and implemented an MCS to guide surveillance and treatment.

Results. Four years after implementing the MCS, half of the men were still being treated with ADT and the average treatment length doubled. Significantly more men were being screened, bone loss remained stable, and there was a trend towards decreased SREs. Significantly more men were being treated for bone loss.

Conclusions. After implementing an MCS we show stable bone mineral density and a trend towards decreased SREs despite doubling of the treatment length. We document significant improvement in our practice pattern.

Keywords:

• Bone loss
• androgen deprivation therapy
• bone mineral density
• prostate cancer

Abbreviations
ADT	=	Androgen Deprivation Therapy
BMD	=	Bone Mineral Density
DEXA	=	Duel Energy X-ray Absorptiometry
CAP	=	Prostate Cancer
SREs	=	Skeletal-Related Events
LHRH	=	Lutenizing Hormone-Releasing Hormone
WHO	=	World Health Organization

Introduction

Androgen deprivation therapy (ADT) is standard treatment for prostate cancer since Huggins and Hodges Nobel prize winning discovery of its androgen dependent nature [1]. The methods to induce hypogonadism include surgical castration and medical castration with lutenizing hormone-releasing hormone (LHRH) agonists, anti-androgen drugs, and combined androgen blockade. Despite the method of ADT, this therapy has been proven to decrease adverse outcomes from prostate cancer, decrease the PSA values, and slow down the growth of metastatic prostate cancer [2,3]. Despite its advantages and widespread use, ADT has been found to have several side effects including significant negative affects on bone.

Androgens stimulate mineralization in human osteoblast-like cells, and ADT disrupts this normal hormonal balance. Hypogonadal men undergo severe bone architecture deterioration and have decreased bone mineral density (BMD) [4]. Bone health is particularly important in men with prostate cancer because they may experience significant bone loss even before the initiation of ADT [5], a finding confirmed in a study reporting that 42% of hormone naïve men diagnosed with prostate cancer have osteoporosis prior to induction of ADT compared to 27% in age-matched controls [6]. The World Health Organization (WHO) osteoporosis criteria defines bone loss as any BMD T-score standard deviation below −1.0 compared to the BMD of a typical healthy, young female. More specifically, osteopenia is defined as a T-score between −1.0 and 2.5, osteoporosis as −2.5 or less, and severe osteoporosis as −2.5 or less with fractures.

Multiple studies have confirmed the impact of ADT on bone health (Table I) and there is a well-established correlation between the duration of ADT and the degree of bone loss [16]. Overall, clinicians can expect BMD reduction of 3–7% per year, with a 20% 10-year risk of ADT-associated fracture [17]. This is important because skeletal fractures negatively correlate with overall survival in men with prostate cancer [18]. The mortality of hip fractures in men is estimated at 30%, which is four times that in women [19]. In addition, skeletal fracture history is one of only three variables independently predictive of survival in patients with CAP treated with ADT for advanced stage or recurrent disease [16].

Table I.  The impact of ADT on bone health.

Reference	No. of patients	Type of castration	BMD site (% decrease)
			Hip	Radius	Spine
Erikson et al. [7]	11	Surgical	−9.6	−4.5
Maillefert et al. [8]	12	Medical	−3.9		−4.6
Daniell et al. [9]	26	Surgical or medical ± antiandrogen	−2.4		−2.3
Berruti et al. [10]	35	Medical × 6 weeks	−0.6		−2.3
Higano et al. [11]	36	CAB	−2.7		−4.7
Higano et al. [12]	17	Intermittent CAB	−2.5		−4.5
Smith et al. [13]	22	CAB × 4 weeks	−1.8		−3.3
Smith et al. [14]	37	Medical ± antiandrogen	−2.8		−2.2
Mittan et al. [15]	28	Medical	−3.3	−5.3

The negative effect of ADT on bone mineral density has been well documented. Regardless of the type of castration, bone health is shown to decrease. Several methods of prevention have been studied to halt this bone loss.

Herein, we describe our experience with bone loss, skeletal-related events (SREs) and their treatment and prevention at our facility, an equal access federal medical system. We also evaluate the effectiveness of the institution of a multidisciplinary consensus statement (MCS) to improve outcomes.

Materials and methods

We conducted an institutional review board approved prospective observational study at Madigan Army Medical Center. Patients being treated with ADT in our clinic were identified and their charts were reviewed. We collected patient demographics, number of months of ADT, incidence and types of fractures occurring before and after initiation of ADT, results of BMD studies, and types and frequency of treatment prescribed within our facility. We excluded pathologic fractures.

We implemented an MCS to guide the treatment and surveillance of men treated with ADT (Table II) and continued to follow the original men identified in the database to evaluate the effectiveness of implementation of a clear institutional guideline to stabilize or decrease bone loss, limit SREs, and improve practice patterns.

Table II.  Baseline and periodic BMD study.

T-score <1SD below mean	T-score 1–3SD below mean	T-score > 3SD below mean
↓	↓	↓
• Lifestyle modifications*	• Lifestyle modifications*	• Lifestyle modifications*
• Vitamin D, Ca^2 supplementation^†	• Vitamin D, Ca^2 supplementation^†	• Vitamin D, Ca^2 supplementation^†
	• Oral Fosamax^‡	• IV Bisphosphonate^§

Statistical analysis was carried out using SPSS software (SPSS, Chicago, IL). Differences between demographics, T-scores, and Z-scores were analyzed between the pre-and post-consensus statement using t test for equality of means with equal variances assumed, after performing Levene's test for equality of variances. Differences between types of treatment and amount of bone loss were analyzed between the pre-and post-consensus statement using chi-squared statistical analysis.

Results

In 2004, our review showed that 96 men (average age 78 years) were receiving ADT in our clinic with an average treatment length of 43 months. Only 38% of these men had documented BMD studies, and of those, 81% had documented bone loss with an average T-score standard deviation of −1.507, indicating a 4 × increased risk of fracture. The average Z-score was −0.359, suggesting secondary osteoporosis, or bone loss in this population that is not attributable to age alone. Twenty-four percent of all men had at least one non-pathologic SRE. Only 58% of men were being treated with calcium and vitamin D, and only 24% were being treated with bisphosphonates.

Based on this concerning data, we implemented the MCS in early 2004. Four years later, 45 of the original men were still receiving ADT. Within this time period the average age increased from 78 to 80 years, and the average treatment length nearly doubled from 43 to 80 months. Table III lists the patient characteristics before and after initiation of the consensus statement, the BMD scores and the characterization of bone loss, and the number of patients who had at least one non-pathologic SRE.

Table III.  Demographics and results of screening and treatment before and after implementation of the MCS.

	Pre	Post	p-value
Patients (no.)	96	45	–
Age (years)	78	80	0.187
Treatment length (months)	43	80	<0.0001
At least one BMD test (%)	38	89	<0.0001
Calcium/Vitamin D (%)	56	97	<0.0001
Bisphosphonates (%)	23	64	<0.0001
T-score (femur)	0.875	0.847	0.528
T-score standard deviation (femur)	−1.507	−1.678	0.609
Z-score	0.359	0.442	0.703
Total bone loss (no.)	29	25	0.742
Osteopenia, no. (%)	15 (52)	16 (63)	0.420
Osteoporosis, no. (%)	8 (28)	7 (29)	0.850
Severe osteoporosis, no. (%)	6 (20)	2 (8)	0.283
Skeletal-related events (no.)	23	13	0.145

There was a significant increase in the number of men screened for bone loss with at least one BMD test, from 36 to 89% (p < 0.0001). In addition, there was a statistically significant increase in the number of men treated with vitamin D and calcium supplements and bisphosphonates before and after the consensus statement was implemented. Lastly, BMD scores were stable in the two groups despite a doubling of treatment length, during which time a 9–21% reduction in BMD would normally be expected.

Discussion

Nationwide, there is an expanding number of men being treated with ADT for prostate cancer. Many of these men have significant bone loss before initiating treatment, and once they are started on ADT are at increased risk for bone loss and related fractures [6]. This is important because fractures lead to decreased quality of life and decreased survival [18]. Bone loss is cumulative, and the most significant loss occurs within 1 year [20]. Regular screening of patients at risk for bone loss is needed for early detection and treatment.

There are multiple treatment options that differ in efficacy and toxicity profiles. Most experts agree that diet and lifestyle modifications, calcium and vitamin D supplementation, and bisphosphonates are the fundamental treatment options. Multiple treatment and prevention strategies have been described, including pharmacological treatment, lifestyle modifications, dietary changes, and intermittent treatment with ADT.

Calcium and vitamin D are necessary to maintain healthy bone mass. 1200–1500 mg Ca and 400 – 600 IU of vitamin D per day are likely to be sufficient. 500 mg Ca per day and 400–500 IU of vitamin D per day alone did not prevent or reverse bone loss [21]. Bisphosphonates bind to bone surfaces at active remodeling sites and are internalized by osteoclasts to inhibit precursor differentiation and decrease survival and attachment to bone. While Alendronate is the only bisphosphonate approved by the FDA for age-related osteoporosis in men, none are approved for men receiving ADT for advanced prostate cancer. Alendronate in combination with calcium and vitamin D has been shown to increase BMD by up to 3.7% over 12 months in men treated for ADT-induced bone loss when given once a week compared to a 1.4% loss in men receiving placebo (p < 0.001) [22]. Zolendronic acid in combination with calcium and vitamin D, has been shown to increase BMD by up to 5.6% over 1 year, compared to a 2.2% loss in men receiving placebo (p < 0.001) and also decreased bone turnover markers [14,23]. Recommended lifestyle and dietary changes include avoidance of excessive alcohol and caffeine, smoking cessation, and a regular exercise program including a combination of weight bearing exercise and strength training performed for 30 min a day two to four times weekly.

We implemented an MCS to help guide the screening and treatment of men with prostate cancer being treated with ADT at our institution to evaluate possible improvement in short-term outcomes. While we found no statistically significant change in T-scores, there was a trend toward decreased SREs. We also showed stabilization of bone loss and a significant improvement in screening, prevention, and treatment of bone loss in these patients treated with ADT for prostate cancer despite a doubling treatment length. Also observed, was a shift towards less severe bone loss with more men classified as having osteopenia, and less men classified as having severe osteoporosis according to the WHO osteoporosis criteria.

Conclusions

An institutional consensus statement can lead to significant improvements in practice patterns. The increase in screening, prevention, and treatment may have resulted in improved outcomes. Specifically stable BMD and a trend toward decreased SREs despite double the treatment length. Further studies are warranted to see whether bone loss can be reversed over longer periods of time.

Declaration of interest: The opinions or assertions herin are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense. The authors report no conflict of interest.