SEARCH

SEARCH BY CITATION

Keywords:

  • osteoporosis;
  • androgen deprivation therapy;
  • prostate carcinoma;
  • dual-energy X-ray absorptiometry

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Androgen deprivation therapy (ADT) is a strong risk factor for osteoporosis. The current study identified physician practices in preventing or treating osteoporosis during ADT. The practices of interest are the uses of dual-energy X-ray absorptiometry (DXA) scans, bisphosphonates, calcium or vitamin D supplement, calcitonin, or estrogen.

METHODS

A retrospective medical record review was conducted. Patients were included if they had received ADT with goserelin injection for ≥ 1 year. Multivariable logistic regression analysis was performed to identify independent predictors of receiving at least one intervention.

RESULTS

Analyses included 184 patients. Most were the elderly with multiple risk factors for osteoporosis. Only 8.7% (95% confidence interval [CI], 4.6–13.0%) of patients received a DXA scan at least once during the past 3 years. Oral and intravenous bisphosphonates were prescribed in 4.9% (95%CI, 1.8–8.0%) and 0.5% (95%CI, 0–2.0%) of patients, respectively, during the past year. Overall, 14.7% of patients (95%CI, 9.5–20.0%) received at least one intervention. Concurrent risk factors for osteoporosis, including smoking, alcoholism, advanced age, low body mass index, long duration of ADT, multiple comorbidities, history of fractures, and steroid use, were not independent predictors of having received interventions. However, bone metastasis was, with a hazard ratio of 5.6 (95%CI, 1.99–15.6%). Primary care physicians provided the greatest number of interventions and cancer-related specialists provided the fewest.

CONCLUSIONS

The majority of patients with prostate carcinoma undergoing ADT did not receive interventions to prevent or treat osteoporosis. Having other concurrent risk factors for osteoporosis was not predictive of receiving these few interventions. [An erratum to this Article has been published in Cancer 2006;106(11):2530] Cancer 2005. © 2004 American Cancer Society.

Androgen deprivation therapy (ADT), a standard treatment for high-risk patients with prostate carcinoma after prostatectomy and for those with metastatic or recurrent disease, can lead to accelerated osteoporosis and fracture.1, 2 In general, osteoporosis is defined as a bone mineral density (BMD) measurement of ≥ 2.5 standard deviations below the young adult mean.3 Data from retrospective studies suggest that the incidence of osteoporotic fracture, typically hip or spinal fracture, ranges from 5% after 22 months of ADT to 40% after 15 years.4, 5 A longer duration of ADT is associated with a higher incidence of osteoporosis.6 In fact, many of these men already have osteoporosis before initiation of therapy.7 Osteoporosis fracture impairs quality of life, leads to nursing home placement, and increases the cost of care.8, 9 In addition, it is often fatal in older patients with multiple comorbid diseases.10

Several measures may prevent osteoporotic fracture during ADT although no established practice guidelines exist. Detection of osteoporosis is feasible by dual-energy X-ray absorptiometry (DXA) scan. The BMD at the femoral neck is particularly predictive of future hip fracture.11 Prospective studies with a short follow-up also suggest that intravenous bisphosphonates such as pamidronate and zoledronic acid may prevent bone loss associated with ADT.12, 13 In addition, alendronate, an oral bisphosphonate, has shown efficacy in the treatment of primary male osteoporosis.14 Moreover, calcium and vitamin D supplements maybe beneficial, especially for men with inadequate intake.15 Other potential pharmacologic interventions include calcitonin and estrogens. Finally, modification of life-styles that are not conducive to bone health can also be accomplished by behavioral counseling.

Despite the vast array of available interventions, prevention and treatment of osteoporosis are often inadequate. Examples include those among patients entering menopause, developing hip fracture, or undergoing long-term steroid therapy.16–21 In the current report, physician practices of ordering DXA scan and prescribing drugs to prevent or treat osteoporosis for patients undergoing ADT are investigated. Furthermore, other concurrent risk factors for osteoporosis, including age, smoking, alcoholism, medications, comorbid diseases, duration of ADT, body mass index, and history of previous fractures, were also obtained. More interventions may be prescribed in the presence of other concurrent risk factors for osteoporosis. The following analyses identify whether these concurrent risk factors independently predict receipt of at least one type of intervention to prevent or treat osteoporosis.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

After receiving approval from the institutional review board, the pharmacy registry was searched for patients who had received ADT with goserelin for ≥ 12 months before April 1, 2003 at a large, suburban teaching Veteran Administration hospital. Because goserelin injection was scheduled every 3 months, patients receiving < 3 injections were excluded, along with those who had received primary care outside of the hospital, became androgen independent, or received intermittent ADT. To reflect current practice, patients who discontinued ADT or were deceased before January 1, 2002 were also excluded.

Definition and Data Extraction

The date of the last visit for goserelin injection in each patient was used as the ending date of the observation period for that particular patient. Study variables were the use of the DXA scan during the past 3 years, as well as receipt of bisphosphonates, calcium or vitamin D supplements, calcitonin, or estrogen during the past year. Cancer-related specialists included oncologists, radiation oncologists, and urologists. Primary care physicians also included geriatricians and internists. Bone metastasis was confirmed by radiologic reports. The number of medications received was recorded at the last visit, but excluded topical agents and the medications considered to be study variables. The presence of hip and spinal fractures was confirmed by available radiologic reports involving the hip and spine conducted during the past 3 years. Visits were categorized into visits to nurses, primary care physicians, cancer-related specialists, cancer-unrelated specialists, and hospital admission. As part of institutional preventive programs, assessment of cigarette smoking and alcohol dependency using the CAGE questionnaire [“Have you ever felt you should cut down on your drinking?” “Have people annoyed you by criticizing your drinking?” “Have you ever felt bad or guilty about drinking?” “Have you ever taken a drink first thing in the moring (eye-opener) to steady your nerves or get rid of a hangover?”]22 was required and was documented routinely in the medical records yearly.

Statistical Analyses

The main outcomes were the presence of the interventions of interest. Among patients who received these interventions, BMD results, if applicable, and specialty of the associated prescribing physicians were obtained. The chi-square test was used to detect a significant difference between proportions. The Fisher exact test was performed when necessary. P values < 0.0 were considered statistically significant. Hazard ratios were calculated with a 95% confidence interval (CI). To determine variables associated with the use of interventions, the dependent variables in the regression model were the interventions received. The independent variables were patient characteristics and other risk factors for osteoporosis or fractures. The relationships were examined in unadjusted models first. Variables with P < 0.25 were then examined using multivariable backward stepwise logistic models. Analyses were performed using SPSS, Version 10.1 (Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Analyses included 184 patients (Table 1). Most were elderly Caucasians. The median duration of ADT was 32 months, but many patients had previously received ADT from other facilities. Patients often had multiple comorbid diseases including other cancers, stroke, arrhythmia, hypertension, diabetes mellitus, congestive heart failure, chronic renal insufficiency, ischemic heart disease, and chronic obstructive pulmonary disease. An average patient was taking seven medications at last visit and making nine visits to physicians yearly.

Table 1. Patient Characteristics
CharacteristicsNo. (mean ± SD) (n = 184) (%)
  1. ADT: androgen deprivation therapy; PSA: prostate-specific antigen.

Age (yrs)76.5 ± 7.2
Race 
 Caucasian119 (64)
 African American 42 (23)
 Unspecified 22 (12)
 Asian  1 (1)
Documented median duration of ADT (mos)32.0
Last serum PSA (ng/ml)1.8 ± 7.8
No. of comorbid diseases2.9 ± 1.7
No. of current medications6.7 ± 3.8
No. of hospital visits in the past 6 mos 
 To nurses3.9 ± 2.6
 To primary care physicians1.4 ± 1.4
 To cancer-related specialists1.6 ± 1.6
 To cancer-unrelated specialists1.4 ± 1.9
 Hospital admission0.3 ± 0.7

Interventions

Approximately 15% of patients received ≥ 1 type of interventions (Table 2). The most common interventions were DXA scans and supplementation with calcium and vitamin D. DXA scans were ordered at the same rate as calcium and vitamin D supplementation, although not by the same physicians. Of the 16 patients who received DXA scans, 8 (50.0%) had osteoporosis and 4 (25.0%) had osteopenia (defined as a BMD t score between −1 and −2.5). Four patients who received DXA scans also had bone metastasis. The mean BMD t scores of the femoral neck and lumbar spine of patients who received DXA scans were −1.76 ± 1.52 and −0.12 ± 1.92, respectively.

Table 2. Use of Osteoporosis Prevention or Treatment
InterventionsPercent (95% confidence interval)
  1. DXA: dual-energy X-ray absorptiometry.

Receive DXA scan at least once in the past 3 yrs 8.7 (4.6–13.0)
Receive calcium supplement in the past year 8.7 (4.6–13.0)
Receive vitamin D supplement in the past year 8.7 (4.6–13.0)
Receive oral bisphosphonate in the past year 4.9 (1.8–8.0)
Receive intravenous bisphosphonate in the past year 0.5 (0–2.0)
Receive estrogen or calcitonin in the past year 0
Any of the above14.7 (9.5–20.0)

A few patients received an oral bisphosphonate and one patient received pamidronate. No calcitonin or estrogen was prescribed. The most commonly prescribed drug was the combined calcium carbonate and vitamin D tablet. Of the 10 patients who received bisphosphonates, 6 also received a DXA scan, which showed osteoporosis in 5 patients and osteopenia in 1 patient.

Risk Factors for Osteoporosis and the Receipt of Interventions

Concurrent risk factors for osteoporosis were prevalent, but they were not independent predictors of receiving interventions (Table 3). The only predictor, however, was the presence of bone metastasis. Among 19 patients who had bone metastasis, 8 (42.1%) received ≥ 1 intervention: 5 received a DXA scan, 3 received calcium, 3 received bisphosphonates, and 2 received vitamin D. The most frequent fractures were compression fractures of the spine. Although a few patients currently smoked cigarettes, most were previous smokers.

Table 3. Risk Factors for Osteoporosis or Fractures and Interventions
Patient characteristicsPrevalence (%)Hazard ratio for receiving any intervention95% CI
  • N/A: not available; ADT: androgen deprivation therapy; BMI: body mass index; CI: confidence interval.

  • a

    No patient in the category received an intervention.

  • b

    Statistically significant (P < 0.001).

  • c

    BMI was calculated by weight in kilograms divided by the square of height in meters.

Concurrent medications   
 Thyroid hormone (%)5.40.630.08–5.20
 Steroid (%)7.60.970.20–4.58
 Phenytoin (%)1.6N/AaN/Aa
Presence of spinal or hip fractures10.92.150.71–6.51
Presence of bone metastasis (%)10.35.591.99–15.6b
Having diabetes (%)23.41.470.59–3.63
Cigarette smoking (%)16.30.600.17–2.14
Alcohol dependency (%)2.2N/AaN/Aa
Duration of ADT (mos)   
 12–2433.70.980.41–2.33
 25–3624.50.490.16–1.50
 37–488.72.100.64–7.07
 49–6016.90.830.27–2.61
 > 6015.81.660.61–4.57
Age   
 < 602.21.970.19–19.7
 60–7019.61.550.59–3.99
 71–8044.00.590.25–1.39
 > 8034.21.150.49–2.69
BMIc   
 < 207.20.460.06–3.73
 20–2532.61.290.55–3.04
 > 2560.21.000.44–2.29
No. of comorbid diseases   
 0–119.60.920.32–2.63
 2–463.00.830.36–1.91
 > 417.41.440.53–3.91

Specialties of the Prescribing Physicians

Thirty-three physicians provided 58 interventions to 27 patients (Fig. 1). In the current study, 51.5% of the physicians were primary care physicians (internal medicine, 42.4%; geriatrics, 9.1%), 27.3% of the physicians had cancer-unrelated specialties (endocrinology, 12.1%; nephrology, 6.1%; cardiology, 6.1%; pulmonology, 6.1%), and 21.2% had cancer-related specialties (medical oncology, 18.2%; radiation oncology, 3%). Overall, primary care physicians provided the greatest number of interventions and cancer-related specialists provided the fewest.

thumbnail image

Figure 1. Specialties of physicians and the treatments or preventive measures provided by them.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The majority of patients undergoing ADT did not receive osteoporosis prevention. Many of them had additional risk factors for osteoporosis or fracture, particularly advanced age and multiple comorbid diseases. The presence of these additional risk factors, however, was not predictive of having received osteoporosis prevention. Although cancer-related specialists prescribed ADT, they prescribed the fewest interventions.

What leads to the underuse of osteoporosis prevention? Perhaps, it is due to the lack of established guidelines. Currently, the optimal evaluation methods and appropriate interventions to prevent osteoporosis-associated fractures for men undergoing ADT remain unclear. Although practice guidelines for screening and prevention of osteoporosis associated with postmenopausal women, gastrointestinal disease, and chronic steroid therapy are available,23–25 none have been established for men undergoing ADT.

In addition, because osteoporosis is a multidisciplinary problem, uncertainty regarding who should prescribe interventions may arise among multiple specialists who are involved in patient care. Primary care physicians have been the main providers of osteoporosis prevention and treatment. However, cancer-related specialists should also be responsible for therapy-related complications. In fact, among cancer-related specialists themselves, there may be a confusion regarding who should be responsible for prescribing interventions.

It is worrisome that other concurrent risk factors for osteoporosis did not lead to increased osteoporosis prevention. Theoretically, these patients have higher risks of osteoporotic fracture and should be deemed a priority, although ADT alone already may have markedly elevated the risk. The presence of bone metastasis, although associated with increased preventive measures, was, in fact, addressed inadequately by the current standard of care. During the study period, however, zoledronic acid had not yet been indicated for such patients to prevent skeletal complications.26

The limitations of the current study involve the definition of outcome variables, which represents an intention of the physician, rather than an effective means to prevent osteoporosis. In fact, calcium and vitamin D alone are unlikely to be adequate to prevent osteoporosis during ADT.12, 13 In addition, calcium, vitamin D, or bisphosphonates could have been prescibed for other clinical purposes with no intention to prevent or treat osteoporosis. Moreover, DXA scans may become unreliable among patients with osteoblastic metastasis or degenerative joint disease because osteophytes, especially in the spine, may falsely elevate the BMD if included in the measurement.27 In the current study, however, only 4 of the 16 patients who received DXA scans had bone metastasis.

A great opportunity to improve osteoporosis prevention among men receiving ADT exists. Their frequent visits, especially nursing visits for goserelin injection, though reflect many missed opportunity, can be used for future interventions. Established practice guidelines for BMD measurement and pharmacologic intervention for patients undergoing ADT are necessary. Ideally, interventions should be safe, effective, and convenient for a typical patient population, e.g., the elderly with multiple chronic illnesses who take several medications.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999; 341: 17811788.
  • 2
    Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol. 1997; 79: 235246.
  • 3
    World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a World Health Organization study group. WHO Tech Rep Ser. 1994; 843: 1129.
  • 4
    Townsend MF, Sanders WH, Northway RO, Graham SD Jr. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer. 1997; 79: 545550.
  • 5
    Melton LJ III, Alothman KI, Khosla S, Achenbach SJ, Oberg AL, Zincke H. Fracture risk following bilateral orchiectomy. J Urol. 2003; 169: 17471750.
  • 6
    Morote J, Martinez E, Trilla E, et al. Osteoporosis during continuous androgen deprivation: influence of the modality and length of treatment. Eur Urol. 2003; 44: 661665.
  • 7
    Hussain SA, Weston R, Stephenson RN, George E, Parr NJ. Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation. BJU Int. 2003; 92: 690694.
  • 8
    Bonar SK, Tinetti ME, Speechley M, Cooney LM. Factors associated with short- versus long-term skilled nursing facility placement among community-living hip fracture patients. J Am Geriatr Soc. 1990; 38: 11391144.
  • 9
    Ray NF, Chan JK, Thamer M, Melton LJ III. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997; 12: 2435.
  • 10
    Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999; 353: 878882.
  • 11
    Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet. 1993; 341: 7275.
  • 12
    Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001; 345: 948955.
  • 13
    Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003; 169: 20082012.
  • 14
    Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000; 343: 604610.
  • 15
    Peacock M, Liu G, Carey M, et al. Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60. J Clin Endocrinol Metab. 2000; 85: 30113019.
  • 16
    Solomon DH, Katz JN, Jacobs JP, La Tourette AM, Coblyn J. Management of glucocorticoid-induced osteoporosis in patients with rheumatoid arthritis: rates and predictors of care in an academic rheumatology practice. Arthritis Rheum. 2002; 46: 31363142.
  • 17
    Kiebzak GM, Beinart GA, Perser K, Ambrose CG, Siff SJ, Heggeness MH. Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med. 2002; 162: 22172222.
  • 18
    Gallagher TC, Geling O, Comite F. Missed opportunities for prevention of osteoporotic fracture. Arch Intern Med. 2002; 162: 450456.
  • 19
    Lee E, Zuckerman IH, Weiss SR. Patterns of pharmacotherapy and counseling for osteoporosis management in visits to US ambulatory care physicians by women. Arch Intern Med. 2002; 162: 23622366.
  • 20
    Yood RA, Harrold LR, Fish L, et al. Prevention of glucocorticoid-induced osteoporosis: experience in a managed care setting. Arch Intern Med. 2001; 161: 13221327.
  • 21
    Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for postmenopausal osteoporosis: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002; 137: 529541.
  • 22
    Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry. 1974; 131: 11211123.
  • 23
    American Gastroenterological Association. American Gastroenterological Association medical position statement: guidelines on osteoporosis in gastrointestinal diseases. Gastroenterology. 2003; 124: 791794.
  • 24
    U.S. Preventive Services Task Force. Screening for osteoporosis in postmenopausal women: recommendations and rationale. Ann Intern Med. 2002; 137: 526528.
  • 25
    American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum. 1996; 39: 17911801.
  • 26
    Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002; 94: 14581468.
  • 27
    Liu G, Peacock M, Eilam O, Dorulla G, Braunstein E, Johnston CC. Effect of osteoarthritis in the lumbar spine and hip on bone mineral density and diagnosis of osteoporosis in elderly men and women. Osteoporos Int. 1997; 7: 564569.