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Bone Health in Patients With Prostate Cancer: Monitoring and Diagnosis
european urology supplements 5 (2006) 873–876
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Bone Health in Patients With Prostate Cancer: Monitoring and Diagnosis§ Noel W. Clarke * Christie Hospital, Department of Surgery, Wilmslow Road, Manchester, M20 4BX, United Kingdom
Article info
Abstract
Keywords: Androgen-deprivation therapy Bisphosphonates Bone Bone loss Bone metastases Bone mineral density DEXA Fracture Prostate cancer Zoledronic acid
Objectives: Androgen-deprivation therapy (ADT) in men with prostate cancer affects bone metabolism and is associated with a decrease in bone mineral density (BMD). The clinical implications of this bone loss have only recently become apparent, and managing skeletal health is an emerging challenge. Methods: Existing and novel methodologies for monitoring and maintaining bone health during ADT were identified and researched through PubMed and published guidelines. Results: Bone loss has been documented in clinical trials of ADT. Recent large-scale analyses have revealed that ADT results in cumulative increases in the risk of fractures and fractures some of which result in hospitalisation. Further studies have shown that bone fractures correlate with reduced survival in men with prostate cancer. These results illustrate that bone loss during ADT is clinically meaningful. Consensus guidelines support measuring BMD before initiation of and regularly during ADT. Dual-energy x-ray absorptiometry is the most common method for monitoring BMD in this setting, although there are several investigational methodologies. Patients with low BMD should receive treatment for bone loss to reduce the risk of fractures. Conclusions: Losses in BMD during ADT may be substantial and can result in increased fracture risk in some men. Such fractures can impede the patient’s mobility and may reduce survival. The goals of BMD testing are to track bone health during ADT and to identify patients who require treatment before BMD loss results in fractures. Maintaining bone health during ADT can provide important benefits to patients and may help to preserve their functional independence.
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. §
Presented by Marc Colombel, MD. * ChM, FRCS (Urol.). Tel. +44 161 446 3364; Fax: +44 161 446 3365. E-mail address: [email protected].
1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2006.07.019
874
1.
european urology supplements 5 (2006) 873–876
Introduction
Androgen deprivation therapy (ADT) is routinely administered to patients with prostate cancer with high-risk disease or with rising prostate-specific antigen (PSA) levels after initial therapy. However, ADT affects bone metabolism and is associated with increased osteoclast-mediated bone resorption, loss of bone volume, and decreases in bone mineral density (BMD) [1–3]. Bone loss is a normal part of the aging process, and many men with prostate cancer have low BMD at diagnosis either due to age and inactivity, the effects of cancer on bone metabolism, or calcium and vitamin D deficiency. Nonetheless, the bone loss associated with ADT is typically more severe than age-related bone loss and can result in a significantly increased risk of fracture, especially during prolonged treatment [1,2]. Indeed, yearly bone loss during ADT is approximately nine times more rapid than that observed during the normal aging process in men and almost five times as rapid as that seen in postmenopausal women (Fig. 1) [1,4].
2.
Results of clinical trials
Clinical trials of different ADT regimens have consistently reported cumulative decreases in BMD [1,4– 7]. Moreover, recent large-scale retrospective analyses of treatment databases have shown that ADT is associated with significant increases in fracture risk. Shahinian et al. [8] reported in a large-scale retrospective study (n = 50,613) that duration of ADT significantly correlated with the risk of fracture and that fractures, when they occurred, resulted in hospitalisation. Smith et al. [9], in a separate
Fig. 1 – Bone loss is accelerated with androgen-deprivation therapy (ADT). Data from Kanis et al. [4] and Maillefert et al. [1].
Fig. 2 – Relative risk of fracture among men with prostate cancer. ADT = androgen-deprivation therapy; PC = prostate cancer; GnRH = gonadotropin-releasing hormone. Data from Smith et al. [9].
large-scale analysis of health care records, reported that patients who underwent ADT (n = 3779) had a 21% increase in the risk of fractures overall and a 76% increase in the risk of hip fractures compared with patients with prostate cancer who did not undergo ADT (n = 8341; Fig. 2) [9]. Fractures can decrease patients’ quality of life and functional independence significantly, with hip fractures being especially detrimental to men. Retrospective studies have shown that mortality rates after hip fractures are approximately 4-fold higher for elderly men than for elderly women and that most men who survive for >1 mo after a hip fracture have impaired mobility, resulting in gait changes or the need for a cane or walker [10,11]. Therefore, bone loss during ADT can lead to potentially devastating complications [10]. Indeed, all varieties of fractures have been associated with a significant increase in mortality in patients with prostate cancer (Fig. 3) [12]. Although the effects of ADT on the skeleton may not be apparent without appropriate monitoring of skeletal health, it is clear that bone loss can result in significant morbidity for treated patients, and the risk of fractures increases significantly with longer durations of treatment [13]. Because patients are now being treated for longer periods with ADT compared with patients in previous decades, monitoring of bone health during ADT is becoming increasingly important. Early diagnosis of bone loss and treatment to improve bone health are important to protect patients from fractures. Dual-energy x-ray absorptiometry (DEXA) can be used to monitor spine, hip,
european urology supplements 5 (2006) 873–876
Fig. 3 – Fractures negatively correlate with survival in patients with prostate cancer. Adapted with permission from Oefelein et al. [12].
or total body BMD, and peripheral DEXA scans can be used to monitor wrist, heel, or finger BMD [14]. An expert panel from the International Society for Clinical Densitometry has determined that the spine is the preferred site of densitometry for the serial measurement of bone mass to monitor changes in BMD [15]. Total hip is suggested when the spine study is technically invalid [15]. The goals of BMD testing are to identify patients at greatest risk, to monitor the rate of bone loss, and to guide the implementation of treatments to preserve bone health. Bone health recommendations from an interdisciplinary panel support BMD assessment of patients before initiation of ADT and recommend regular follow-up to monitor bone loss during ADT [16]. Bone health monitoring and treatment guidelines are typically based on T-score measurements, as
Fig. 5 – Identifying and treating bone loss in men with prostate cancer. ADT = androgen-deprivation therapy; BMD = bone mineral density; CT = computed tomography; DEXA = dual-energy x-ray absorptiometry. Adapted with permission from Diamond et al. [16].
defined by the World Health Organization. A T-score compares a patient’s BMD to that of a 30-yr-old healthy adult as a baseline. For every standard deviation below this baseline, the relative risk of fracture increases 1.5- to 2.5-fold. The number of standard deviations below the baseline is referred to as the T-score. A T-score above 1 is considered normal, from 1 to 2.5 is osteopenic, 2.5 is osteoporotic, and 2.5 with any associated fracture is considered severely osteoporotic. A patient with a T-score below 2.5 has an approximately 11fold higher risk of developing a fracture than a patient with normal BMD [17]. Therefore, measurement of BMD is important for identifying patients at increased risk of fractures, for determining rates of bone loss, and for monitoring the effects of treatment. T-scores can also be used to educate patients about their fracture risk and to encourage compliance with treatments for bone health (Fig. 4) [17–20]. A clinical algorithm for monitoring and treating bone loss in men who are starting or receiving longterm ADT has been developed by an expert panel of urologists and oncologists (Fig. 5) [16]. This algorithm outlines follow-up BMD assessment schedules and treatment recommendations. Administration of bisphosphonates should be considered in patients with fractures or T-scores below 2.5 [16].
3. Fig. 4 – Communicating the results of the bone mineral density (BMD) test [17–20].
875
Conclusions
In summary, bone loss is a known side-effect of ADT. However, the baseline BMD and the rate of
876
european urology supplements 5 (2006) 873–876
bone loss vary in different men. BMD should therefore be measured before ADT is started and be repeated periodically during treatment, depending on the patient’s T-score. Lower T-scores correspond with increased risk of fractures, which, in turn, correlate with decreased survival. Therefore, BMD monitoring can identify patients in whom treatment intervention to prevent fractures is warranted. Effective treatments for bone loss during ADT are now available, and these may preserve bone health in this setting.
References [1] Maillefert JF, Sibilia J, Michel F, Saussine C, Javier RM, Tavernier C. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 1999;161:1219–22. [2] Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002;87:3656–61. [3] Clarke NW, McClure J, George NJ. The effects of orchidectomy on skeletal metabolism in metastatic prostate cancer. Scand J Urol Nephrol 1993;27:475–83. [4] Kanis JA. Osteoporosis. Boston: Blackwell Healthcare Communications; 1997. [5] Berruti A, Dogliotti L, Terrone C, et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 2002;167:2361– 7, discussion 2367. [6] Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163: 181–6. [7] Eriksson S, Eriksson A, Stege R, Carlstrom K. Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens. Calcif Tissue Int 1995; 57:97–9.
[8] Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154–64. [9] Smith MR, Boyce SP, Moyneur E, Duh MS, Raut MK, Brandman J. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006;175:136–9, discussion 139. [10] Cree M, Soskolne CL, Belseck E, et al. Mortality and institutionalization following hip fracture. J Am Geriatr Soc 2000;48:283–8. [11] Poor G, Atkinson EJ, O’Fallon WM, Melton LJ III. Determinants of reduced survival following hip fractures in men. Clin Orthop Relat Res 1995, 260–5. [12] Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002;168:1005–7. [13] Morote J, Martinez E, Trilla E, et al. Osteoporosis during continuous androgen deprivation: influence of the modality and length of treatment. Eur Urol 2003;44:661–5. [14] Bae DC, Stein BS. The diagnosis and treatment of osteoporosis in men on androgen deprivation therapy for advanced carcinoma of the prostate. J Urol 2004;172: 2137–44. [15] Lenchik L, Kiebzak GM, Blunt BA. What is the role of serial bone mineral density measurements in patient management? J Clin Densitom 2002;5:S29–38. [16] Diamond TH, Higano CS, Smith MR, Guise TA, Singer FR. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer 2004;100:892–9. [17] 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: 72–5. [18] Melton LJ III, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL. Bone density and fracture risk in men. J Bone Miner Res 1998;13:1915–23. [19] Physician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003. [20] Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254–9.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Bone Health in Patients With Prostate Cancer: Monitoring and Diagnosis§ Noel W. Clarke * Christie Hospital, Department of Surgery, Wilmslow Road, Manchester, M20 4BX, United Kingdom
Article info
Abstract
Keywords: Androgen-deprivation therapy Bisphosphonates Bone Bone loss Bone metastases Bone mineral density DEXA Fracture Prostate cancer Zoledronic acid
Objectives: Androgen-deprivation therapy (ADT) in men with prostate cancer affects bone metabolism and is associated with a decrease in bone mineral density (BMD). The clinical implications of this bone loss have only recently become apparent, and managing skeletal health is an emerging challenge. Methods: Existing and novel methodologies for monitoring and maintaining bone health during ADT were identified and researched through PubMed and published guidelines. Results: Bone loss has been documented in clinical trials of ADT. Recent large-scale analyses have revealed that ADT results in cumulative increases in the risk of fractures and fractures some of which result in hospitalisation. Further studies have shown that bone fractures correlate with reduced survival in men with prostate cancer. These results illustrate that bone loss during ADT is clinically meaningful. Consensus guidelines support measuring BMD before initiation of and regularly during ADT. Dual-energy x-ray absorptiometry is the most common method for monitoring BMD in this setting, although there are several investigational methodologies. Patients with low BMD should receive treatment for bone loss to reduce the risk of fractures. Conclusions: Losses in BMD during ADT may be substantial and can result in increased fracture risk in some men. Such fractures can impede the patient’s mobility and may reduce survival. The goals of BMD testing are to track bone health during ADT and to identify patients who require treatment before BMD loss results in fractures. Maintaining bone health during ADT can provide important benefits to patients and may help to preserve their functional independence.
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. §
Presented by Marc Colombel, MD. * ChM, FRCS (Urol.). Tel. +44 161 446 3364; Fax: +44 161 446 3365. E-mail address: [email protected].
1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2006.07.019
874
1.
european urology supplements 5 (2006) 873–876
Introduction
Androgen deprivation therapy (ADT) is routinely administered to patients with prostate cancer with high-risk disease or with rising prostate-specific antigen (PSA) levels after initial therapy. However, ADT affects bone metabolism and is associated with increased osteoclast-mediated bone resorption, loss of bone volume, and decreases in bone mineral density (BMD) [1–3]. Bone loss is a normal part of the aging process, and many men with prostate cancer have low BMD at diagnosis either due to age and inactivity, the effects of cancer on bone metabolism, or calcium and vitamin D deficiency. Nonetheless, the bone loss associated with ADT is typically more severe than age-related bone loss and can result in a significantly increased risk of fracture, especially during prolonged treatment [1,2]. Indeed, yearly bone loss during ADT is approximately nine times more rapid than that observed during the normal aging process in men and almost five times as rapid as that seen in postmenopausal women (Fig. 1) [1,4].
2.
Results of clinical trials
Clinical trials of different ADT regimens have consistently reported cumulative decreases in BMD [1,4– 7]. Moreover, recent large-scale retrospective analyses of treatment databases have shown that ADT is associated with significant increases in fracture risk. Shahinian et al. [8] reported in a large-scale retrospective study (n = 50,613) that duration of ADT significantly correlated with the risk of fracture and that fractures, when they occurred, resulted in hospitalisation. Smith et al. [9], in a separate
Fig. 1 – Bone loss is accelerated with androgen-deprivation therapy (ADT). Data from Kanis et al. [4] and Maillefert et al. [1].
Fig. 2 – Relative risk of fracture among men with prostate cancer. ADT = androgen-deprivation therapy; PC = prostate cancer; GnRH = gonadotropin-releasing hormone. Data from Smith et al. [9].
large-scale analysis of health care records, reported that patients who underwent ADT (n = 3779) had a 21% increase in the risk of fractures overall and a 76% increase in the risk of hip fractures compared with patients with prostate cancer who did not undergo ADT (n = 8341; Fig. 2) [9]. Fractures can decrease patients’ quality of life and functional independence significantly, with hip fractures being especially detrimental to men. Retrospective studies have shown that mortality rates after hip fractures are approximately 4-fold higher for elderly men than for elderly women and that most men who survive for >1 mo after a hip fracture have impaired mobility, resulting in gait changes or the need for a cane or walker [10,11]. Therefore, bone loss during ADT can lead to potentially devastating complications [10]. Indeed, all varieties of fractures have been associated with a significant increase in mortality in patients with prostate cancer (Fig. 3) [12]. Although the effects of ADT on the skeleton may not be apparent without appropriate monitoring of skeletal health, it is clear that bone loss can result in significant morbidity for treated patients, and the risk of fractures increases significantly with longer durations of treatment [13]. Because patients are now being treated for longer periods with ADT compared with patients in previous decades, monitoring of bone health during ADT is becoming increasingly important. Early diagnosis of bone loss and treatment to improve bone health are important to protect patients from fractures. Dual-energy x-ray absorptiometry (DEXA) can be used to monitor spine, hip,
european urology supplements 5 (2006) 873–876
Fig. 3 – Fractures negatively correlate with survival in patients with prostate cancer. Adapted with permission from Oefelein et al. [12].
or total body BMD, and peripheral DEXA scans can be used to monitor wrist, heel, or finger BMD [14]. An expert panel from the International Society for Clinical Densitometry has determined that the spine is the preferred site of densitometry for the serial measurement of bone mass to monitor changes in BMD [15]. Total hip is suggested when the spine study is technically invalid [15]. The goals of BMD testing are to identify patients at greatest risk, to monitor the rate of bone loss, and to guide the implementation of treatments to preserve bone health. Bone health recommendations from an interdisciplinary panel support BMD assessment of patients before initiation of ADT and recommend regular follow-up to monitor bone loss during ADT [16]. Bone health monitoring and treatment guidelines are typically based on T-score measurements, as
Fig. 5 – Identifying and treating bone loss in men with prostate cancer. ADT = androgen-deprivation therapy; BMD = bone mineral density; CT = computed tomography; DEXA = dual-energy x-ray absorptiometry. Adapted with permission from Diamond et al. [16].
defined by the World Health Organization. A T-score compares a patient’s BMD to that of a 30-yr-old healthy adult as a baseline. For every standard deviation below this baseline, the relative risk of fracture increases 1.5- to 2.5-fold. The number of standard deviations below the baseline is referred to as the T-score. A T-score above 1 is considered normal, from 1 to 2.5 is osteopenic, 2.5 is osteoporotic, and 2.5 with any associated fracture is considered severely osteoporotic. A patient with a T-score below 2.5 has an approximately 11fold higher risk of developing a fracture than a patient with normal BMD [17]. Therefore, measurement of BMD is important for identifying patients at increased risk of fractures, for determining rates of bone loss, and for monitoring the effects of treatment. T-scores can also be used to educate patients about their fracture risk and to encourage compliance with treatments for bone health (Fig. 4) [17–20]. A clinical algorithm for monitoring and treating bone loss in men who are starting or receiving longterm ADT has been developed by an expert panel of urologists and oncologists (Fig. 5) [16]. This algorithm outlines follow-up BMD assessment schedules and treatment recommendations. Administration of bisphosphonates should be considered in patients with fractures or T-scores below 2.5 [16].
3. Fig. 4 – Communicating the results of the bone mineral density (BMD) test [17–20].
875
Conclusions
In summary, bone loss is a known side-effect of ADT. However, the baseline BMD and the rate of
876
european urology supplements 5 (2006) 873–876
bone loss vary in different men. BMD should therefore be measured before ADT is started and be repeated periodically during treatment, depending on the patient’s T-score. Lower T-scores correspond with increased risk of fractures, which, in turn, correlate with decreased survival. Therefore, BMD monitoring can identify patients in whom treatment intervention to prevent fractures is warranted. Effective treatments for bone loss during ADT are now available, and these may preserve bone health in this setting.
References [1] Maillefert JF, Sibilia J, Michel F, Saussine C, Javier RM, Tavernier C. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 1999;161:1219–22. [2] Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM. Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002;87:3656–61. [3] Clarke NW, McClure J, George NJ. The effects of orchidectomy on skeletal metabolism in metastatic prostate cancer. Scand J Urol Nephrol 1993;27:475–83. [4] Kanis JA. Osteoporosis. Boston: Blackwell Healthcare Communications; 1997. [5] Berruti A, Dogliotti L, Terrone C, et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 2002;167:2361– 7, discussion 2367. [6] Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163: 181–6. [7] Eriksson S, Eriksson A, Stege R, Carlstrom K. Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens. Calcif Tissue Int 1995; 57:97–9.
[8] Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154–64. [9] Smith MR, Boyce SP, Moyneur E, Duh MS, Raut MK, Brandman J. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 2006;175:136–9, discussion 139. [10] Cree M, Soskolne CL, Belseck E, et al. Mortality and institutionalization following hip fracture. J Am Geriatr Soc 2000;48:283–8. [11] Poor G, Atkinson EJ, O’Fallon WM, Melton LJ III. Determinants of reduced survival following hip fractures in men. Clin Orthop Relat Res 1995, 260–5. [12] Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002;168:1005–7. [13] Morote J, Martinez E, Trilla E, et al. Osteoporosis during continuous androgen deprivation: influence of the modality and length of treatment. Eur Urol 2003;44:661–5. [14] Bae DC, Stein BS. The diagnosis and treatment of osteoporosis in men on androgen deprivation therapy for advanced carcinoma of the prostate. J Urol 2004;172: 2137–44. [15] Lenchik L, Kiebzak GM, Blunt BA. What is the role of serial bone mineral density measurements in patient management? J Clin Densitom 2002;5:S29–38. [16] Diamond TH, Higano CS, Smith MR, Guise TA, Singer FR. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer 2004;100:892–9. [17] 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: 72–5. [18] Melton LJ III, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL. Bone density and fracture risk in men. J Bone Miner Res 1998;13:1915–23. [19] Physician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003. [20] Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254–9.