Research ArticleClinical Studies

Bone Health Care Pathway for Non-metastatic Prostate Cancer Patients on Radiation and Androgen Deprivation Therapy

ISABELLA PALUMBO, CARMELINDA RUGGIERO, ELEONORA FESTA, MICHELANTONIO DE FANO, MARTA BARONI, RITA BELLAVITA, GIANLUCA INGROSSO, SIMONETTA SALDI, MICHELE DURANTI, PATRIZIA MECOCCI, ALBERTO FALORNI and CYNTHIA ARISTEI
Anticancer Research January 2023, 43 (1) 493-499; DOI: https://doi.org/10.21873/anticanres.16186

Abstract

Background/Aim: Survival rates of prostate cancer (PCa) patients have improved considerably as a result of earlier diagnosis and therapies, including radiotherapy (RT) and androgen deprivation therapy (ADT). Patients on ADT develop cancer treatment-induced bone loss (CTIBL) and a high risk of fragility fractures. Bone health (BH) assessment is strongly recommended, together with timely initiation of treatments, to counteract CTIBL and preserve bone strength. Therefore, we decided to develop an interdisciplinary pathway of care (IPC) dedicated to non-metastatic PCa patients on long-term ADT and RT. Patients and Methods: An interdisciplinary team allocated resources to support an IPC to manage patients’ CTIBL and prevent fragility fractures. The team provided a diagnostic and therapeutic workflow according to patients’ and professional perspectives, consistent with recommendations and healthcare policies. The hospital’s quality department certified the IPC, the Ethical Committee approved procedures over the workflow. The Fracture Liaison Service (FLS) standards inspired services and professionals’ activities and interactions. Results: Preliminary data support the feasibility of the IPC from professionals’ and patients’ perspectives. Median age of the enrolled patients was 75 years, more than a half (58.9%) had low grade osteopenia or normal BMD (T-score ≥−1.5 standard deviation, SD), while 23.5% and 17.6% had osteoporosis and osteopenia, respectively. The IPC meets the requirements of a FLS concerning crucial indicators. Conclusion: Our IPC was a suitable approach to assure timely identification, assessment, initiation, and monitoring of adherence to anti-fracture treatments among non-metastatic PCa patients on long-term ADT and RT. Further data are required to show its effectiveness on fragility fracture prevention.

Key Words:

In 2020, prostate cancer (PCa) was the most common cancer in Europe and the second cause of cancer-related mortality among older men (1). Survival rates of prostate cancer (PCa) patients have improved considerably as a result of earlier diagnosis and newer therapies, including radiotherapy (RT) and androgen deprivation therapy (ADT). However, ADT may affect patients’ bone quality and mineral density (BMD), increasing bone turnover and accelerating bone loss, leading to osteoporosis and fragility fractures (2). The BMD impairment occurs as early as 6 months after initiating ADT, with the more significant effect during the first year, but continuing throughout the treatment duration (3, 4). The term cancer treatment-induced bone loss (CTIBL) identifies bone loss, osteoporosis, and fragility fractures associated with ADT, and negatively impacts patients’ quality of life (QoL) and overall survival (OS) (5). Indeed, CITBL rates range between 9-53% depending on ADT duration, stage of PCa disease, ethnicity, and BMD site testing (4). Fragility fractures risk in PCa patients on ADT is equal to or greater than that in patients with severe osteoporosis and previous fragility fractures, with a risk of hospitalization 2.8-fold higher than that in the general male population (6). Scientific guidelines recommend that PCa patients receive fracture risk assessment before starting ADT and timely initiate pharmacological and non-pharmacological treatments for prevention of bone long-term adverse events (7-10). However, most non-metastatic PCa patients are not evaluated for bone health (BH) either by urologists and radiation oncologists (ROs) or medical oncologists, nor referred to bone specialists (BSs) (11). The Fracture Liaison Service (FLS) is an interdisciplinary model of care for fracture prevention, with evidence of efficacy and cost-saving (12). Patients with major fractures are a priority due to the risk of re-fracture (13). A FLS for these patients has already been established in our hospital and accredited by International Osteoporosis Foundation (IOF) (14). Our manuscript reports on the methodological aspects related to the implementation of an interdisciplinary pathway of care (IPC) dedicated to the assessment and management of fracture risk among non-metastatic PCa patients on RT and long–term ADT.

Patients and Methods

Interdisciplinary team. A multidisciplinary team designed the IPC for managing CTIBL and preventing fragility fractures among non-metastatic PCa patients admitted to the Radiation Therapy Unit of our hospital. The leaders Radiation Therapy, Radiology, Endocrinology, and Geriatrics, who lead the accredited FLS (14), were included along with hospital improvement and data managers, dedicated nurses, patients’ and general practitioners’ (GPs’) representatives. The BH care recommendations were based on the professionals’ expertise and current evidence from national and international guidelines and tailored for the patients’ risk profile. The IPC was enriched with specific tools empowering patients’ education regarding lifestyle and fall. The IPC was approved by the hospital quality department and implemented among the hospital services. According to FLS requirements, a dedicated database was developed. According to Ethical requirements, the local Ethics Committee approved the IPC (Prot N. 20666/21/ON; 21 January 2021).

Target population. The target population includes non-metastatic PCa patients aged >50 years on RT and long-term ADT (prescribed for at least 18 months). Enrolling at least 100 patients is expected over three years. Patients’ evaluation and management follow the Helsinki Declaration of 1975, revised in 2000, and written informed consents are obtained from all patients.

Diagnostic and therapeutic workflow at patients’ and professionals’ levels. The BS and team members developed a diagnostic and therapeutic workflow to set up patients’ identification, assessment, initiation, and monitoring, and they implemented specific tools to monitor and capture the IPC’s relevant key performance indicators. Figure 1 presents the patients’ diagnostic and therapeutic workflow.

Figure 1.
Figure 1.

The diagnostic and therapeutic algorithm among services and specialists.

Identification. The radiation oncologist (RO) is in charge of PCa patients’ identification and insertion in the IPC. Health-related aspects and information about previous fragility fractures located at the vertebra, humerus, pelvis, tibia, femur, wrist are collected (Figure 1, panel A). A dedicated nurse of the Radiation Therapy Unit provides patients’ schedules for laboratory and radiology exams and for BS assessment within 1 and 2 months from identification, respectively. Prescribed laboratory tests are reported in Figure 1 (panel B). Dual-energy X-ray absorptiometry (DXA) scan of the lumbar spine and hip is performed, dorsal lumbar spine X-ray if previous specific imaging (i.e., thorax-abdominal computed tomography or magnetic resonance) is not available or if the patient reports spinal pain (Figure 1, panel B) (15). Patients receive notes about vitamin D supplementation, dietary recommendations to assure daily calcium intake (1,200-1,500 mg/day) and lifestyle advice, mainly focused on fall prevention, regular exercise program, and smoking cessation, and moderate alcohol intake as required (Figure 1, panel A). Furthermore, the RO carries out the QoL evaluation by using the Italian version of EuroQoL 5-dimension (EQ-5D) (16).

Assessment. By completing the medical assessment, regarding comorbidity, polypharmacy, previous falls and fractures, and evaluation of available diagnostic records, the BS rules out additional causes of secondary osteoporosis, estimates the fracture risk threshold, and enriches patients’ clinical charts with the data above, which is finally conveyed into the dedicated FLS database. The World Health Organization (WHO) classification criteria define patients as having normal BMD (T-score >−1 standard deviation, SD), osteopenia (−2.5 SD to <−1 SD), or osteoporosis (<−2.5 SD), based on the lowest T-score at the lumbar spine or femoral neck. The Genant criteria are used to classify the severity of vertebral fractures by evaluating the vertebral morphometric X-ray scan. The FRAX fracture risk assessment is the most widely used tool to assess fracture risk and it was adopted to estimate the patients’ risk of fragility fractures (17).

Initiation and monitoring. The BS initiates anti-fracture treatments according to patient risk profile and tailored approach, taking advantage of medical history, lab and X-ray diagnostic exams, functional status, including physical and cognitive performances, as well as patients’ goals and preferences. After optimization of calcium intake, if needed, and vitamin D supplementation to reach 30-50 ng/ml, the BS guides the therapeutic choices by referring to the algorithm shown in Figure 1 (panel C). Antiresorptive therapy with bisphosphonates or denosumab is considered in PCa patients with a high risk of fractures according to national healthcare guidelines (7). In detail, non-metastatic PCa patients on long-term ADT and RT with previous fragility fractures or osteoporosis and those with osteopenia associated with comorbidities affecting BH, including Acquired Immune Deficiency Syndrome (AIDS), chronic inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), corticosteroid treatment (equivalent to 5 mg prednisone a day, for at least 3 months), diabetes, multiple sclerosis, muscle-skeletal disability, or major risk factors for fragility fractures (e.g. previous non-vertebral or non-hip fractures, parental history of fragility fractures, Parkinson’s disease, rheumatoid arthritis or other collagenopathies), receive denosumab. PCa patients with high grade osteopenia (T-score ranging from −2.4 SD to −1.6 SD) are infused primarily with zoledronate in the absence of comorbidities affecting BH, major risk factors for fragility fractures, and renal failure. Non-metastatic PCa patients on long-term ADT and RT with low grade osteopenia or normal BMD (T-score ≥−1.5 SD) are prescribed with alendronate in the presence of comorbidities affecting BH and risk factors for fragility fractures, while in the absence of above conditions are re-assessed after 6 months according to RO protocol (Figure 1, panel C). The BS writes specific notes to the patients’ GPs together with plans for monitoring and follow-ups. Administrative nurse plans and schedules patients’ follow-up and QoL assessment every 6 months with RO, and every 12 months with the BS, unless a specific complication arises. Laboratory exams are scheduled every 6 months, DXA after 24 and 48 months from baseline, and vertebral morphometric X-ray after 5 years from baseline or at the onset of acute spinal pain not responsive to analgesic.

Outcome measures. The primary end-point is the proportion of patients at high risk of fragility fracture admitted to the IPC and completing the identification, assessment, initiation, and monitoring up to 5 years. The final aim is to show the appropriateness of the intervention and the feasibility of the IPC and management in a high-volume clinical scenario. Secondary outcomes include evaluation of the impact of the developed IPC on clinical end-points (mortality, morbidity), economic end-points (direct costs of hospital admissions and/or admissions for falls and fractures), QoL, and patient satisfaction, stratified by risk category.

Statistics. There are no specific guidelines regarding the sample size estimation for evaluating the feasibility of an IPC. Then, we estimated that the enrolment of 100 patients (25 men in each arm of the treatment algorithm) would be sufficient to demonstrate the primary end-point and to evaluate key performance indicators of the IPC.

Results

To date, the IPC is in its early phase of patient enrolment and management, since only seventeen patients have been enrolled. Patient and treatments characteristic are reported in Table I. More than half of PCa patients had T-score ≥−1.5 SD (58.9%), while 23.5% and 17.6% have osteoporosis and osteopenia, respectively. According to our therapeutic algorithm, alendronate was the most prescribed specific antifracture drug (47%), followed by denosumab (35.3%) and zoledronate (5.9%). In two patients, anti-fracture specific drugs were not prescribed yet. Our preliminary results suggest a high level of patient satisfaction with their CITBL management and a high level of adherence to the CITBL prescribed treatment (data not shown).

View this table:
Table I.

Patients and treatments characteristics.

Discussion

This manuscript reports on the development and feasibility of an IPC for preventing fragility fractures among non-metastatic PCa patients on long-term ADT and RT. Fragility fractures are a pivotal issue among non-metastatic PCa patients on ADT. The long-term effects of cancer and CITBL cannot be ignored as they impact patients’ QoL and health status and pose an additional burden to the healthcare services (18). National, international societies and healthcare institutions recommend assessing fracture risk before prescribing long-term ADT and monitoring the BMD changes over time (7-10, 18). The cornerstone of the development process of our IPC has been the inter-professional collaboration. The inter-professional approach may strengthen the focus on the management of modifiable risk factors that can affect BMD, such as low dietary calcium intake, low vitamin D levels, smoking, alcohol, lower weight or low body mass index, physical/functional limitations, weight loss, and prolonged corticosteroid use (19), and may improve adherence to treatments. The last, but not least point, is that we implemented the IPC according to the FLS standards, which include the adoption of standardized tools to sustain the appropriate choices and actions, to improve patients’ and GPs’ participation, and the patients’ awareness about his risks, the opportunity of initiation and adherence to treatments. From a public health perspective, the FLS may provide an opportunity to sustain a pathway of care to adequately assess and manage people at high risk of fracture, so that non-metastatic PCa patients on ADT should not be ignored (12, 20). Regarding fracture risk estimation, we acknowledge that there is no specific tool for non-metastatic PCa patients on ADT. However, the FRAX tool can provide a valid estimate of baseline fracture risk for other causes beyond ADT and may be easily incorporated into clinical practice (3, 20). Indeed, low BMD values (i.e., T-score <−2.5 at the total hip, femoral neck, or lumbar spine) indicate the need of starting appropriate antiresorptive therapy but are not exclusive parameters to identify high-risk patients. A more significant proportion of men experience fractures at higher T-score values; thus, it could be misleading to rely only on the T-score to select men who can take advantage of an anti-osteoporotic treatment (3, 20). According to IOF experts, patients with fracture risk assessed by FRAX exceeding 20% for major fractures or 3% for hip fractures and displaying vertebral fractures were considered to be treated (20). Even though the thresholds above have not been validated in PCa patients, we acknowledge that these indications can be helpful to stratify patients according to their risk. However, in our IPC, these thresholds cannot guide the choice of treatments. Indeed, treatment prescription remains consistent with Italian healthcare reimbursement policies (9). Accounting for these aspects is crucial for understanding the different statements about patients’ eligibility to treatments from other scientific societies and healthcare institutions, ultimately raising questions on cost-saving estimations and thresholds of risk for treatment reimbursement. Although the optimal regimen and long-term effects of antiresorptive must be established, treatments are recommended, since they decrease ADT-mediated bone loss in at-risk individuals and prevent fragility fractures. For instance, the Clinical Practice Guidelines of the European Society for Medical Oncology (ESMO) recommend the use of bisphosphonates in patients with BMD T-score <−2.0 or in patients with T-score <−1.5 and 2 risk factors (e.g., age >65 years, current history of smoking, BMI <24, family history of hip fracture, personal history of fragility fracture above age 50, oral glucocorticoid use >6 months) (9). French guidelines for preventing bone loss due to ADT for PCa recommend treatment with bisphosphonates or in patients with previous severe fracture or in patients with T-score <−2.5 or in patients with T-score >−2.5 and <−1.5 in the presence of at least two factors (age >75 years, high risk of falls, history of non-severe low-energy fracture after 50 years of age, BMI<19, at least three comorbidities – e.g., cardiovascular disease, depression, Parkinson’s disease, dementia - and current glucocorticoid therapy) (21). A more conservative expert opinion from Australia recommended treatment only in patients with prior fragility fracture or T-score <−2.5 or 10-years major osteoporotic fracture risk >20% or hip fracture risk >3% (22). A relevant variable in our setting appears to be the cost of the available treatment and reimbursement by the Health National System. It is noteworthy that global costs for fragility fractures are very high in Italy, higher than in other European Countries (23). Since it has been shown that pharmacologic fracture prevention is cost-effective (23), the Italian Health System enables reimbursement of any osteoporosis treatment for patients in ADT, irrespective of BMD data or history of previous disease or comorbidity (7). In our IPC, BMD, and pre-existing fractures (proximal femur and vertebral fractures) were considered to estimate the individual risk since both are important factors for tailored CTIBL treatment and fracture prevention. Accordingly, based on the Italian data on the cost-effectiveness of prevention of fractures in CITBL, the lines of evidence that denosumab significantly reduces bone fractures risk in patients with PCa and the Italian regulations on the first-line choice of anti-fracture drugs (7), we propose denosumab as a first-line treatment in the more severe cases and aminobisphosphonates (zoledronate or alendronate) in the less severe ones. Amino-bisphosphonate, and denosumab are the best available antiresorptive treatments for the management of CITBL, and the prevention of fragility fractures among non-metastatic PCa patients (3, 8-10, 19, 20). Both zoledronic acid and denosumab have been shown to increase BMD in non-metastatic PCa patients on ADT, while denosumab but not with zoledronic acid have been associated with fracture risk reduction. Zoledronic acid prevented the BMD losses caused by 18 months of leuprorelin treatment at 2 and 4 years from baseline in 1,071 subjects with locally advanced PCa but did not significantly reduce fractures in subjects receiving 6 or 18 months of ADT (24). Denosumab increased BMD a 24 and 36 months at all sites (lumbar spine, total hip, femoral neck, distal third of radius), in 1,648 men undergoing ADT for non-metastatic PCa, including older men, those with lower baseline BMD, higher levels of bone resorption markers and a history of vertebral fracture (25). Denosumab decreased the incidence of new vertebral fractures at 12, 24, and 36 months, and all fractures as compared to the placebo group (5.2% vs. 7.2%) (25). It is noteworthy that patients included in this study had a high-risk profile, due to previous severe fragility fracture or T-score <−2.5 or T-score >−2.5 and <−1.5 in the presence of at least two risk factors and received denosumab only if bisphosphonates failed or were poorly tolerated. In a multicenter, randomized, double-blind prospective study (26), denosumab and alendronate improved lumbar spine BMD, but denosumab showed significantly better results (5.6 % vs. 1.1%, after 24 months). A metanalysis of three (RCTs) controlled trials showed that denosumab reduced the risk of osteoporosis during ADT at 24 and 36 months (27). Furthermore, denosumab counteracted BMD loss up to 36 months at the lumbar and femoral level and increased the BMD both at 24 and at 36 months, maintaining the same amount over time (27). Alendronate 70 mg once weekly increased spine BMD by 3.7% and femoral neck BMD by 1.6%, over one year in 112 men with non-metastatic PCa receiving ADT whereas, men in the placebo group had losses of 1.4% at the spine and 0.7% at the femoral neck (28). Risedronate maintained stable BMD as compared to placebo that had decreased lumbar spine BMD among 100 patients with non-metastatic PCa receiving RT and 2-3 years of ADT (29). In our therapeutic workflow, we considered additional issues, such as kidney function (specifically for the use of bisphosphonates), length of ADT (for the need to offer a short-period treatment with bisphosphonates after denosumab), and safety profile of treatments. The long-term use of bisphosphonates may increase the risk of rare adverse events, i.e., atypical femur fractures and osteonecrosis of the jaw (ONJ). The relative risk of ONJ is 0-90/100,000 patients/year for zoledronic acid, 1.04-69 for oral bisphosphonates, and 0.30-2 for denosumab. Zoledronic acid may also cause musculoskeletal pain renal toxicity after infusion and requires regular monitoring of renal functions. This issue is even more important as PCa patients treated with RT are mostly elderly (30) and may already have renal impairment either due to obstruction or other comorbidities. An eGFR lower than 35-40 ml/min excludes the possibility of treating patients with bisphosphonates. In addition, oral bisphosphonates may be associated with gastric pain and other gastrointestinal disturbances. Denosumab seems an appropriate option in patients with renal impairment and can also be a preferable option in those unable to tolerate oral bisphosphonates and unable to sit or stand, thus improving patients’ adherence to treatments (31).

In conclusion, we report the development process and implementation strategy of an IPC dedicated to non-metastatic PCa patients treated with RT and long-term ADT in a high-volume teaching hospital. By taking into consideration international scientific recommendations and reimbursement rules concerning anti-fracture treatments by the Italian Health System, we implemented a tailored approach according to patients’ risk stratification. Our preliminary data confirm the feasibility of the IPC showing the advantages of embedding the pathway within an accredited FLS. The efficacy of the IPC to prevent fragility fractures and preserve BH and QoL needs to be confirmed.

Footnotes

  • Authors’ Contributions

    IP: Study concept and design, methodology, writing-original draft. CR: Study concept and design, methodology, writing-original draft. EF: Writing-original draft, data curation. MDF: Writing-original draft, data curation. MB: Literature research, data curation. RB: Methodology, data curation. GI: Methodology, data curation. SS: Literature research, data curation. MD: Methodology, data curation. PM: Reviewing, editing. AF: Study concept and design, reviewing. CA: Study concept and design, reviewing, editing.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Received October 19, 2022.
  • Revision received October 24, 2022.
  • Accepted October 25, 2022.

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Bone Health Care Pathway for Non-metastatic Prostate Cancer Patients on Radiation and Androgen Deprivation Therapy
ISABELLA PALUMBO, CARMELINDA RUGGIERO, ELEONORA FESTA, MICHELANTONIO DE FANO, MARTA BARONI, RITA BELLAVITA, GIANLUCA INGROSSO, SIMONETTA SALDI, MICHELE DURANTI, PATRIZIA MECOCCI, ALBERTO FALORNI, CYNTHIA ARISTEI
Anticancer Research Jan 2023, 43 (1) 493-499; DOI: 10.21873/anticanres.16186
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