Assessment of zoledronic acid treatment patterns and clinical outcomes in patients with bone metastases from genitourinary cancers

Abstract

Background:

Patients with bone metastases secondary to genitourinary (GU) cancer are at risk for skeletal-related events (SREs), including bone pain requiring palliative radiotherapy, fractures or surgery to bone, spinal cord compression, and hypercalcemia of malignancy. These SREs can be debilitating and potentially life-limiting. This study examined treatment practices and the association of treatment patterns with Zometa (zoledronic acid, ZOL), an intravenous bisphosphonate (IV-BP), with SREs and fractures. (Zometa is a registered trademark of Novartis Pharmaceuticals Corporation, USA.)

Methods:

Retrospective analysis of commercial and Medicare Advantage enrollment and medical claims data was performed to evaluate IV-BP use and SRE patterns in adult patients with GU cancers. Criteria included diagnosis of ≥1 bone metastasis and prostate cancer (PC), renal cell carcinoma (RCC), or bladder cancer (BlC) between January 2001 and December 2006; continuous healthcare plan enrollment for ≥6 months before the index date; and no evidence of prior IV-BP use. Patients were followed until disenrollment from the healthcare plan or December 2007.

Results:

Of 6347 patients (PC, n = 4976; RCC, n = 941; BlC, n = 430; mean [standard deviation] age: 68.9 [11.1] years), only ∼23% received ZOL. The mean time between diagnosis of bone metastasis and ZOL initiation was ∼108 days. Among patients with PC, fracture risk was significantly smaller for ZOL vs no IV-BP (incidence rate ratio = 0.70; p < 0.001), and 2-year survival was significantly longer for ZOL-treated vs no IV-BP patients (p = 0.007). Patients with longer persistency on ZOL had a smaller fracture risk than patients with shorter persistency. Sub-set analyses were not performed for RCC and BIC because the proportion of patients treated was too low.

Limitations:

Interpretation of this claims-based analysis must be tempered by the inherent limitations of observational data, such as limited and accurate available information, and unavailable information including clinical or disease-specific parameters.

Conclusions:

Intravenous BP therapy is not always received in patients with bone metastases secondary to GU cancers, and, when used, there are typically long time periods before treatment initiation. Without IV-BPs, PC patients have significantly larger risks of fracture and death compared with ZOL-treated patients, and benefits appear to be larger with increasing persistency on ZOL.

Keywords::

• Bisphosphonate
• Bone metastasis
• Genitourinary cancer
• Skeletal-related event
• Zoledronic acid

Introduction

Genitourinary (GU) tumors represent a large proportion of the >1.5 million new cancer diagnoses each year in the US; ∼217,000 men are diagnosed with prostate cancer (PC), 70,500 people are diagnosed with bladder cancer (BlC), and 58,000 people are diagnosed with renal cell carcinoma (RCC)1. Bone is the most common site for distant metastases from solid tumors, with an estimated 60–75% of men with PC, 40% of patients with BlC, and 30% of patients with RCC developing bone metastases2–5. Bone metastases can weaken the skeleton2,3. Decreased bone integrity may lead to the development of skeletal-related events (SREs), including pathologic fracture, spinal cord compression, the need for palliative radiotherapy or surgery to bone, and hypercalcemia of malignancy6–8.

Skeletal-related events are relatively common in the setting of advanced GU malignancies. In the absence of bisphosphonate (BP) therapy, men with bone metastases from PC experience an average of one or two SREs per year9. In a retrospective claims analysis of men with metastatic PC (n = 342), 78% experienced ≥1 SRE, and 22% of men experienced several different types of SRE during ≤5-years of follow-up10. Data from a clinical database study in patients with bone metastases from RCC (n = 103) reported an average of three or four SREs per year11. In patients with bone metastases from BlC (n = 40) who were enrolled in a prospective placebo-controlled trial, 18 of 20 patients (90%) who received placebo developed an SRE during a median 12 months of follow-up12.

Bone metastases are the most common cause of severe pain in patients with advanced cancer, and SREs can reduce quality-of-life and decrease functional independence13,14. In men with PC, severe bone pain and fractures have been associated with a 43% and 29% increased risk of death, respectively (p < 0.001 and p = 0.04, respectively)15,16. In an exploratory analysis in the phase 3 trial of Zometa (zoledronic acid, ZOL; n = 640), there was a 29% increased risk of death among the 19% of patients who experienced an on-study fracture compared with the fracture-free cohort (p = 0.04)16. (ZOMETA is a registered trademark of Novartis Pharmaceuticals Corporation, USA.) Similar correlations were found in patients with bone metastases from lung cancer or other solid tumors (including RCC and BlC)17,18.

In addition to their effects on morbidity and mortality, SREs can increase healthcare costs for patients with GU cancers19–22. A retrospective database analysis (years 2000–2005) revealed that the per-patient costs associated with treating SREs in men with PC (n = 342) averaged $12,46910, with an $8484 cost of treating one SRE. The occurrence of ≥2 SREs raised this cost to $26,384 (p < 0.001)10. Because of the disease-related and health-economic costs associated with treating bone metastases in patients with GU cancers, bone-supportive therapy is recommended23. In men with bone metastases from PC, the cost of ZOL treatment for 1 year was estimated at $10,960, with a number needed to treat of 1224,25.

Zoledronic acid is the only BP that has been approved to reduce the risk of SREs in patients with bone metastases from multiple tumor types, including breast cancer, castration-resistant PC, lung cancer, RCC, and BlC. In clinical trials in patients with bone metastases from PC or solid tumors (including RCC and BlC), ZOL significantly reduced the risk of SREs compared with placebo, and benefits were durable with long-term therapy7–9. Continued ZOL treatment was shown to be beneficial even after the onset of SREs26. Similar supportive evidence for the utility of ZOL in patients with RCC or BlC and bone metastases has been demonstrated3,5,8,27. These clinical trials provide valuable evidence supporting use of ZOL in patients with GU cancers. What is absent from the literature, however, is an understanding of the real-world utilization of ZOL and its impact on clinical outcomes. Therefore, this study sought to evaluate treatment practices in the US managed-care setting and evaluate clinical outcomes in patients with bone metastases.

Methods

Data sources

This was a retrospective claims-based analysis using medical, pharmacy, and patient enrollment data collected between July 1, 2000 and December 31, 2007. Data were collected from two large, nationally representative care-plan databases in the US with commercial and Medicare Advantage patient enrollment and claims data: a database affiliated with OptumInsight (formerly Innovus), and the OptumInsight/IHCIS Impact National Managed Care Database (IMPACT). To create the IMPACT database, OptumInsight compiles claims data submitted by healthcare providers and pharmacies to ∼45 health plans for reimbursement. Medical claims include multiple diagnosis codes recorded with the International Classification of Diseases, Ninth Revision (ICD-9-CM) diagnosis codes; procedures recorded with ICD-9-CM procedure codes, Current Procedural Terminology (CPT), or Health Care Financing Agency (HCFA) Common Procedure Coding System (HCPCS) codes; National Drug Code (NDC) codes; site of service codes; provider specialty codes; revenue codes (for facilities); and paid amounts. Claims for ambulatory services submitted by individual providers use the HCFA-1500 format, and claims for facility services submitted by institutions use the UB-82 or UB-92 format. Typically, facility claims do not include drugs administered in hospital. For medical data to be considered complete, an interval of ∼6 months following the delivery of services was required. Claims for pharmacy services, typically submitted electronically by the pharmacy at the time prescriptions are filled, include drug name, dosage form, drug strength, fill date, days of supply, and de-identified patient and prescriber codes. Pharmacy claims are typically added to the research database within 6 weeks of dispensing.

Evaluation of treatment practices

As a part of the full database analysis in all solid tumors (n = 28,145), intravenous BP (IV-BP) treatment rates and time from diagnosis of bone metastases to initiation of IV-BP therapy in patients who had been diagnosed with bone metastases and a solid tumor were analyzed, based on the primary tumor type.

Patient selection

This analysis included commercial and Medicare Advantage health plan members with ≥1 medical claim for BlC (ICD-9-CM code 188.x), PC (ICD-9-CM code 185), or RCC (189.0) from January 1, 2001, through December 31, 2006 (only patients with one type of primary cancer were retained). Additionally, to be included in the analysis, patients were required to have evidence of bone metastasis or ZOL use during that period. Bone metastasis was identified based on the presence of ≥1 claim indicating bone metastasis (ICD-9-CM diagnosis code 198.5x) or ≥1 claim for BlC, PC, or RCC in any position and a diagnosis code 170.x (malignant neoplasm of bone and articular cartilage) in a secondary position. The date of the first claim for bone metastasis or ZOL was set as the index date. To be included in the analysis, patients were required to be ≥18 years of age as of the index date and to have continuous health plan enrollment for ≥6 months before the index date.

Patients were excluded from the study if they had evidence of bone metastasis or monthly ZOL use in the 6 months before the index date. Use of ZOL was identified by NDC or HCPCS codes C9115 or J3487. Members with evidence of oral tiludronate, IV ibandronate, oral or IV etidronate, or yearly ZOL, identified by NDC or HCPCS codes (IV ibandronate: HCPCS C9229, J1740; IV etidronate: J1436; yearly ZOL: J3488, Q4095) at any time during the analysis period (July 1, 2000, to December 31, 2007) were also excluded.

Patients were permitted to have variable follow-up periods, with a maximum follow-up period of 7 years. The duration of follow-up was calculated as the number of days from the index date until disenrollment from the health plan (including because of death) or the end of the study period (December 31, 2007). Patients who died during an inpatient admission were identified from facility claims in the database affiliated with OptumInsight to distinguish disenrollment because of death vs disenrollment because of other factors that may not have been represented in the data.

Patient demographics and treatment selection

Age was determined as of the index year; insurance type (commercial or Medicare) and sex were determined from enrollment data. A Charlson-Quan comorbidity score was calculated based on the presence of diagnosis codes on medical claims in the pre-index period28. Use of oral BPs (alendronate, oral ibandronate, and risedronate) during the pre-index period was identified from pharmacy claims. Adjuvant chemotherapy received during the post-index period was identified by HCPCS and procedure codes.

Treatment discontinuation of ZOL was defined as the first appearance of a >45-day gap between ZOL treatments. The discontinuation date was defined as the service date for the last ZOL claim before the gap. Persistence was defined as the number of days from the first date of treatment with ZOL to the earlier of the date of discontinuation, disenrollment, or end of the analysis period (December 31, 2007). Patients were assigned to a persistency category based on length of treatment with ZOL.

Analysis outcomes

Patient mortality was assessed during the post-index period. Fractures were identified from medical claims based on the presence of ICD-9-CM diagnosis codes (Table 1) or CPT procedure codes for surgery to the bone (Table 2). The occurrence of SREs was also determined in the pre-index and post-index periods. Evaluated SREs included fracture and surgery to bone (as described above), as well as spinal cord compression or radiation to bone. Spinal cord compression was identified from medical claims based on ICD-9-CM diagnosis code 336.9, and radiation to bone was identified from medical claims based on CPT procedure codes (77401–77406, 77418, 77422–77423, 77407–77411, 77412–77416, 79101).

Table 1.  ICD-9-CM codes to identify fractures.

Fracture type	Fracture site	ICD-9-CM code
Vertebral fracture	Spine, without spinal cord injury	Pathologic 733.13
		Cervical, closed 805.0x
		Dorsal, closed 805.2x
		Lumbar, closed 805.4x
		Sacral/coccygeal, closed 805.6x
		Unspecified, closed 805.8x
		Closed/open not indicated 805
	Spine, with spinal cord injury	Pathologic 733.13
		Cervical, closed 806.0x
		Dorsal, closed 806.2x
		Lumbar, closed 806.4x
		Sacral/coccygeal, closed 806.6x
		Unspecified, closed 806.8x
		Closed/open not indicated 806
Non-vertebral hip fracture	Hip (closed)	Pathologic 733.14
		Transcervical 820.0x
		Pertrochanteric 820.2x
		Unspecified 820.8x
		Closed/open not indicated 820
Non-vertebral, non-hip fracture	Rib(s)	Closed 807.0x
	Ankle (closed)	Medial malleolus 824.0x
		Lateral malleolus 824.2x
		Bimalleolar 824.4x
		Trimalleolar 824.6x
		Unspecified 824.8x
		Closed/open not indicated 824
	Clavicle (closed)	Closed 810.0x
		Closed/open not indicated 810
	Femur (closed)	Pathologic 733.15
		Shaft/unspecified 821.0x
		Lower end 821.2x
		Closed/open not indicated 821
	Humerus (closed)	Pathologic 733.11
		Upper end 812.0x
		Shaft/unspecified 812.2x
		Lower end 812.4x
		Closed/open not indicated 812
	Patella (closed)	Patella (closed) 822.0x
		Closed/open not indicated 822
	Tibia/fibula (closed)	Pathologic 733.16
		Upper end 823.0x
		Shaft 823.2x
		Unspecified 823.8x
		Closed/open not indicated 823
	Wrist/forearm (closed)	Pathologic 733.12
		Upper end 813.0x
		Shaft 813.2x
		Lower end 813.4x
		Unspecified 813.8x
		Closed/open not indicated 813
	Pelvis (closed)	Acetabulum 808.0x
		Pubis 808.2x
		Other specified 808.4x
		Unspecified 808.8x
		Closed/open not indicated 808
	Other pathologic fracture	733.10; 733.19
Other skeletal complications	Fracture with malunion/nonunion	Malunion 733.81
		Nonunion of fracture 733.82

ICD-9-CM, International Classification of Diseases, Ninth Revision.

Table 2.  CPT procedure codes to identify fractures.

CPT procedure code	Procedure code description
Surgery to bone
27230–27248, 27254	Treatment of hip fracture
22305–22328, 22520–22522	Treatment of vertebral fracture
23500–23515	Treatment of clavicular fracture
23665–23680, 23600–23630, 24500–24587	Treatment of humeral fracture
24620–24635, 24650–24685, 25500–25575	Treatment of radius-ulna fracture
25600–25652, 25680–25685	Treatment of wrist fracture
27193–27194, 27217, 27220–27228	Treatment of pelvic fracture
27500–27514	Treatment of femur fracture
27520–27524	Treatment of patella fracture
27530–27540, 27750–27792	Treatment of tibia-fibula fracture
27808–27828	Treatment of ankle fracture
20690, 20692	External fixation of bone
29240–29779	Miscellaneous, unlisted procedure, casting, or strapping

CPT, current procedural terminology.

Statistical analysis

Unadjusted bivariate comparisons of baseline characteristics and outcome measures were performed using appropriate tests (e.g., t-test, Mann Whitney-U test, chi-square test) based on the distribution of the measure. Because the length of follow-up time will vary, person-time was used because it estimates the actual time at risk (in years) that all persons contributed to the study. Incidence rates, allowing for variable follow-up time, were calculated using Stata® stptime version 10.0 (StataCorp, College Station, TX). Because of variability in the length of follow-up periods, analysis outcomes were measured as risk per 100 person-years. To test for trend across persistency categories, we examined whether there were significant differences in the survivor functions across persistency categories (e.g., 91–180 days, 181–365 days, etc.). This test is similar to the log-rank test except that the ordinal ranking across persistency categories was considered. Multivariate analysis adjusting for covariates was conducted using the Cox proportional hazards model. Confounding factors for which adjustments were made include sex, age, pre-index Charlson-Quan comorbidity score, pre-index evidence of oral BP use, and pre-index skeletal events. Analyses were conducted using Stata statistical software version 10.0 (StataCorp).

Results

Patients overall and IV-BP treatment rates

Overall, fewer than one-half of the 28,145 patients diagnosed with bone metastases had any evidence of receiving IV-BP therapy. Treatment rates were markedly lower for patients with GU cancers (26% in PC, 14% in RCC, and 11% in BlC), compared with breast cancer or multiple myeloma, in which rates were 45% (30% ZOL and 15% pamidronate) and 78% (43% ZOL), respectively (Figure 1)29.

Figure 1.  Bisphosphonate use in patients with bone metastasis from genitourinary cancers and breast cancer. RCC, renal cell carcinoma; ZOL, zoledronic acid.

Compared with other cancer cohorts, there was also a longer time period between bone metastasis diagnosis and the initiation of ZOL in patients with GU cancers. In patients with PC, this interval averaged 108 days. For patients with RCC or BlC, ZOL was not initiated until an average of 106 days after diagnosis of bone metastasis. In contrast, IV-BP therapy was initiated, on average, only 67 or 20 days after the diagnosis of bone lesions in patients with breast cancer or multiple myeloma, respectively (Figure 2).

Figure 2.  Mean time to intravenous bisphosphonate treatment initiation after diagnosis of bone metastasis. MM, multiple myeloma; RCC, renal cell carcinoma.

Patients

In all, 6347 patients with GU cancer (PC, RCC, or BlC) were identified for inclusion in this analysis. Of these, 1484 patients initiated ZOL on or following the index date and were assigned to the ZOL cohort; 4863 did not initiate ZOL on or following the index date and were assigned to the cohort that did not receive IV-BP (no IV-BP; Table 3). Patients in the ZOL cohort tended to be slightly younger (p = 0.009) and have a lower Charlson comorbidity score (p < 0.001); they were more likely to be male (p < 0.001, because of inclusion of men with PC diagnosis) compared with the no IV-BP cohort (Table 3). Also, patients in the ZOL cohort were more likely than patients in the no IV-BP cohort to have used oral BPs during the pre-index period (p < 0.001), although the incidence of SREs during the pre-index period was similar between cohorts (p = 0.174). Patients receiving ZOL were more likely to have commercial insurance (p < 0.001) and had a longer length of follow-up (p < 0.001) than patients in the no IV-BP cohort (Table 3).

Table 3.  Demographic and clinical characteristics.

	ZOL	No IV-BP	p-value
All genitourinary cancers	n = 1484	n = 4863
Mean age, years (SD)	68.2 (10.5)	69.1 (11.3)	0.009
Charlson score (Quan), pre-index, mean (SD)	2.9 (2.1)	3.4 (2.5)	<0.001
Mean length of follow-up, days (SD)	568.2 (427.1)	428.6 (470.9)	<0.001
Male, n (%)	1421 (95.8)	4431 (91.1)	<0.001
Insurance type, n (%)
Commercial	1126 (75.9)	3183 (65.5)	<0.001
Medicaid Advantage	358 (24.1)	1680 (34.6)	<0.001
Skeletal complications, pre-index, n (%)	103 (6.9)	390 (8.0)	0.174
Oral bisphosphonates, pre-index, n (%)	60 (4.0)	109 (2.2)	<0.001
Renal cell carcinoma	n = 128	n = 813
Mean age, years (SD)	57.7 (11.7)	60.3 (12.9)	0.032
Charlson score (Quan), pre-index, mean (SD)	3.6 (2.8)	4.0 (2.9)	0.123
Mean length of follow-up, days (SD)	415.7 (371.1)	344.8 (403.8)	0.062
Male, n (%)	81 (63.3)	527 (64.8)	0.735
Insurance type, n (%)
Commercial	117 (91.4)	686 (84.4)	0.037
Medicare Advantage	11 (8.6)	127 (15.6)	0.037
Skeletal complications, pre-index, n (%)	14 (10.9)	83 (10.2)	0.801
Oral bisphosphonates, pre-index, n (%)	4 (3.1)	19 (2.3)	0.540
Adjuvant chemotherapy, n (%)	95 (74.2)	296 (36.4)	<0.001
Prostate cancer	n = 1309	n = 3667
Mean age, years (SD)	69.4 (9.8)	71.4 (9.7)	<0.001
Charlson score (Quan), pre-index, mean (SD)	2.8 (1.9)	3.1 (2.3)	<0.001
Mean length of follow-up, days (SD)	591.4 (432.3)	461.7 (485.8)	<0.001
Insurance type, n (%)
Commercial	974 (74.4)	2227 (60.7)	<0.001
Medicare Advantage	335 (25.6)	1440 (39.3)	<0.001
Skeletal complications, pre-index, n (%)	86 (3.6)	259 (7.1)	0.547
Oral bisphosphonates, pre-index, n (%)	54 (4.1)	79 (2.2)	<0.001
Adjuvant chemotherapy, n (%)	1194 (91.2)	2022 (55.1)	<0.001
Bladder cancer	n = 47	n = 383
Mean age, years (SD)	64.1 (10.0)	65.2 (12.1)	0.539
Charlson score (Quan), pre-index, mean (SD)	4.7 (2.3)	4.6 (2.9)	0.851
Length of follow-up, days (SD)	329.7 (234.9)	280.9 (409.7)	0.228
Male, n (%)	31 (66.0)	237 (61.9)	0.586
Insurance type, n (%)			0.571
Commercial	35 (74.5)	270 (70.5)
Medicare Advantage	12 (25.5)	113 (29.5)
Skeletal complications, pre-index, n (%)	3 (6.4)	48 (12.5)	0.219
Oral bisphosphonates, pre-index, n (%)	2 (4.3)	11 (2.9)	0.643
Adjuvant chemotherapy, n (%)	41 (87.2)	119 (31.1)	<0.001

IV-BP, intravenous bisphosphonate; SD, standard deviation; ZOL, zoledronic acid.

A sub-set analysis was performed for patients with PC (n = 4976). Patients were divided into two cohorts: the PC-ZOL cohort, patients who had evidence of ZOL use on or following the index date (n = 1309 [26.3%]), and the no IV-BP cohort (n = 3667 [73.7%]). Compared with patients in the no IV-BP cohort, patients in the PC-ZOL cohort tended to be younger (p < 0.001) and to have a lower Charlson comorbidity score (p < 0.001). Occurrence of pre-index SREs was similar between cohorts (p = 0.547). However, patients in the PC-ZOL cohort were more likely to have commercial insurance (p < 0.001) and to have received oral BPs (p < 0.001) and adjuvant chemotherapy (p < 0.001) compared with patients in the no IV-BP cohort (Table 3).

Patients with RCC were divided into two cohorts: the RCC-ZOL cohort, patients who had evidence of ZOL use on or following the index date (n = 128 [13.6%]), and the no IV-BP cohort (n = 813 [86.4%]). No statistically significant differences were observed between these cohorts with regard to age, sex, pre-index comorbidity burden, pre-index SREs, pre-index oral BP use, or length of follow-up. However, a sub-set analysis was not performed because the treatment rate was too low to detect differences (Table 3). For similar reasons, a sub-set analysis was not performed for patients with bladder cancer (Table 3).

Outcomes

Fractures

Patients with bone metastases from PC (n = 4976) were assessed for fracture risk by IV-BP treatment status. In the unadjusted analyses, without adjusting for other factors, patients in the ZOL cohort had a 31% lower risk of fracture at any site compared with the no IV-BP cohort (incidence response rate = 0.69; p < 0.001) (Table 4). Moreover, the ZOL-treated patients had 35% lower risk of vertebral fracture (p = 0.025), 45% lower risk of non-vertebral hip fracture (p = 0.014), and 40% lower risk of non-vertebral non-hip fracture (p = 0.005) compared with patients in the no IV-BP cohort.

Table 4.  Fractures in ZOL-treatment cohort vs no-treatment cohort (prostate cancer).

Fracture site	Incidence rates (rate per 100 person-years)		Incidence rate ratio ZOL vs no IV-BP
	ZOL (n = 1309)	No IV-BP (n = 3667)	Ratio	p-value
Fracture, any site	5.9	8.5	0.691	<0.001
Vertebral fracture	1.6	2.4	0.650	0.025
Non-vertebral hip fracture	0.9	1.7	0.546	0.014
Non-vertebral, non-hip fracture	1.7	2.8	0.599	0.005

IV-BP, intravenous bisphosphonate; ZOL, zoledronic acid.

Mortality

Analysis of any association between ZOL treatment and mortality was conducted on a sub-set of patients (n = 3216) who had accessible mortality data from the entire GU treatment group. Throughout a 2-year survival analysis, a significantly higher proportion of patients treated with ZOL survived compared with patients in the no IV-BP group (89% vs 85%, respectively; p = 0.007) (Figure 3).

Figure 3.  Kaplan-Meier analysis of survival in patients with prostate cancer. No IV-BP, no intravenous bisphosphonate; ZOL, zoledronic acid.

Treatment duration and clinical outcome

Fractures

Among patients with PC in the ZOL cohort, patients were assigned to a persistency category, as determined by the uninterrupted length of ZOL treatment during the follow-up period. Persistency categories were defined as ZOL-treated for 31–90 days (n = 245), 91–180 days (n = 215), 181–365 days (n = 193), 366–546 days (n = 63), or more than 547 days (n = 49). Fracture incidence was significantly lower with persistency of ZOL treatment (p = 0.003). Incidence rates ranged from approximately nine fractures per 100 person-years in the persistency category of 31–90 days to ∼ 4.7 fractures per 100 person-years for patients treated for 181–365 days. In patients with ZOL persistency for ≥18 months, the fracture rate was ∼2.5 fractures per 100 person-years for patients with PC (Table 5). When longer persistency categories were compared with the persistency category of 31–90 days (used as a reference value for fracture risk), the relative risk of experiencing a fracture had an inverse relationship with persistency throughout the analysis period, although statistical significance was not achieved in the longest persistency categories (Table 5).

Table 5.  Fracture incidence and rate as a function of persistency in patients with prostate cancer receiving zoledronic acid.

ZOL persistency, days	Fracture rate per 100 person-years	Risk ratio	p-value
31–90	9	Reference
91–180	5.5	0.71	<0.175
181–365	4	0.53	0.022
366–546	3	0.44	0.099
547+	2.5	0.38	0.091

Risk ratio adjusted for age, sex, pre-index Quan-Charlson, pre-index evidence of oral bisphosphonate, and pre-index skeletal complications. Significance of overall test, p = 0.0171. ZOL, zoledronic acid.

Discussion

Patients with GU cancer who develop bone metastases are at risk for SREs that can undermine their mobility and quality-of-life and contribute substantially to healthcare costs10,20,30–32. Limited clinical trial data exist on the optimal initiation and duration of bone metastases treatment in clinical practice for patients with GU cancers. The initial findings of our analyses revealed that for the US database studied, IV-BP therapy was never initiated in most patients with bone metastases from GU cancers. Omission of this therapy may leave patients especially vulnerable to SREs. There were significant demographic differences between patients who did and did not receive ZOL, suggesting potential treatment biases, although the underlying risk factors for SREs in this setting remain poorly understood.

Treatment rates were 26% in PC, 14% in RCC, and 11% in BlC, compared with IV-BP treatment rates as high as 45% in breast cancer and 78% in multiple myeloma. The availability of generic pamidronate for breast cancer and multiple myeloma could contribute to the high IV-BP treatment rates for these indications; however, when ZOL-only treatment rates are considered for comparison, usage was also higher for breast cancer and multiple myeloma (30% and 43% treatment rates with ZOL, respectively) compared with patients with GU cancers. Patients with GU cancers also had a longer time period between diagnosis of bone metastases and start of IV-BP treatment (106 days vs 20 days for multiple myeloma).

Although retrospective analysis of a large claims database allows an unprecedented opportunity to evaluate the outcomes of real-world use of IV-BPs in patients with cancer and bone metastases, there are some inherent limitations to the use of claims data. First, the presence of a claim for a filled prescription does not indicate that the medication was consumed or administered as prescribed. Second, the presence of a diagnosis code on a medical claim may, in some cases, not indicate disease presence, as the diagnosis code could be incorrectly coded or included as rule-out criteria rather than actual disease. Therefore, undetected differences in patient characteristics and prior treatment may have affected outcomes. Moreover, the codes for bone metastases do not include information on the extent of the metastases, and the magnitude of potential benefit from treatment is uncertain. Third, certain information is not readily available in claims data that could have an effect on study outcomes, such as certain clinical and disease-specific parameters (e.g., renal function or prostate-specific antigen levels). For example, there is guidance regarding ZOL dosing adjustments for patients with impaired renal function. However, laboratory values were not available for the full study sample and were not used in the current analysis. Overall, the observed differences are most likely a sub-set of all differences that may have affected treatment decisions as well as outcomes. Lastly, the results are based on analysis of observational data of patients not randomized to treatment and thus should be considered exploratory. Although analytical methods can adjust for some of these limitations and ascertain differences, results from a claims database cannot establish the causality of the associations.

Despite the limitations, these analyses provide important findings about current treatment practices and the potential benefits of IV-BP therapy in the GU setting. Although only ∼25% of patients with PC and bone metastases received ZOL, this could be because of the label limitation that the PC be castration-resistant. Nonetheless, bone metastases are typically refractory to anti-cancer therapies. Moreover, ∼90% of patients with bone metastases from RCC and BlC never received IV-BP therapy, and ZOL treatment was not initiated until an average of >3 months after bone metastases were diagnosed. Indeed, the numbers of patients with RCC or BlC who were treated with ZOL were insufficient for further analyses of outcomes. Among patients with PC, use of ZOL was associated with significant reductions in fracture risk (by 31%) and risk of death (by 34%) compared with no IV-BP treatment. These results are consistent with SRE-preventing efficacy and bone pain reductions with ZOL shown in clinical trials7,9,33,34. Although these were not randomized comparisons, the significantly lower risk of morbidity and mortality in the ZOL-treated vs no IV-BP cohorts suggest important clinical benefits from ZOL in the real-world setting.

The current analysis is consistent with recent publications hypothesizing that early initiation and persistency with ZOL treatment can maintain skeletal health and may provide additional effects beyond the bone35. Indeed, ZOL has been shown to significantly delay overall disease progression in patients with early breast cancer who were receiving adjuvant endocrine therapy36,37, and ZOL significantly delayed disease progression in patients with advanced RCC in an exploratory sub-set analysis of a randomized clinical trial38. In the current analysis, patients with PC treated with monthly infusions of ZOL had a significantly reduced risk of fracture compared with patients who were treated less frequently. Persistent use of monthly ZOL for ≥18 months was associated with a 73% lower fracture risk compared with persistent use for only 3 months. Application of Cox proportional hazards models controlling for sex, age, pre-index Charlson-Quan score, pre-index evidence of oral BPs, and pre-index skeletal complications confirmed that longer persistency with ZOL treatment was associated with a reduction in fracture incidence.

In conclusion, patients with GU cancers and bone metastases may not receive IV-BP therapy in the US managed-care setting. Patients with bone metastases from PC who were treated with ZOL had a lower risk of fractures and death compared with patients who did not receive IV-BP treatment. Longer persistence with ZOL was associated with lower risks of fractures and deaths in this setting. Future studies are warranted to confirm the results presented by this analysis. Furthermore, these data are an important consideration for oncologists in the US, and further studies are needed comparing the relative costs of treating fractures and other SREs vs the costs of IV-BP therapy to lower the risk of these events.

Transparency

Declaration of funding

Novartis Pharmaceuticals Corporation provided funding for this research and financial support for medical editorial assistance.

Declaration of financial/other relationships

HJH is an employee of OptumInsight. OptumInsight received funding from Novartis to conduct the research. SK was employed by Novartis Pharmaceuticals Corporation during the time that this manuscript was developed.

Acknowledgments

The authors would like to thank John O’Flaherty, PhD, ProEd Communications, Inc., for his medical editorial assistance with this manuscript. Results of this study were presented in part at the 25th Anniversary European Association of Urology Congress; April 16–20, 2010; Barcelona, Spain.