Review Article Health promotion, disease prevention, and lifestyle pISSN: 2287-4208 / eISSN: 2287-4690 World J Mens Health 2022 Jan 40(1): 74-86 https://doi.org/10.5534/wjmh.210061 Multidisciplinary Consensus on the Prevention and Treatment of Osteoporosis and Fragility Fractures in Patients with Prostate Cancer Receiving Androgen-Deprivation Therapy Enrique Casado1 , Angel Borque-Fernando2 , Manuel Caamaño3 , Jenaro Graña4 , Jesús Muñoz-Rodríguez5 , Juan Morote6,7 1 Department of Rheumatology, University Hospital Parc Taulí, I3PT Research Institute (UAB), Sabadell, Barcelona, 2Department of Urology, University Hospital Miguel Servet, Instituto de Investigación Sanitaria-Aragón, Zaragoza, 3Department of Rheumatology, University Clinical Hospital of Santiago de Compostela, A Coruña, 4Department of Rheumatology, A Coruña University Clinical Hospital, A Coruña, 5 Department of Urology, University Hospital Parc Taulí, Sabadell, Barcelona, 6Department of Urology, Vall d´Hebron Hospital, Barcelona, 7 Department of Surgery, Universitat Autònoma de Barcelona, Barcelona, Spain Patients with prostate cancer (PCa) on androgen-deprivation therapy (ADT) are at high risk of osteoporosis and fragility frac- tures. We aimed to provide some practical insights into the delivery of optimal bone health care for PCa patients, particularly those on ADT. An interdisciplinary group of experts, including urologists and rheumatologists developed recommendations based on their expertise, current evidence and guidelines. The multidisciplinary group’s main recommendations are: fragility fracture risk should be assessed in all PCa patient, especially, in those under ADT. FRAX® tool may be incorporated into clini- cal practice to identify patients at high risk of fracture. Bone mineral density (BMD) should be measured routinely by dual energy X-ray absorptiometry in all patients scheduled for or on ADT. Thoracic and lumbar spine X-ray may be performed at the initial evaluation of patients with the diagnosis of osteoporosis and in case of suspected clinical vertebral fracture. Basic laboratory tests are recommended to exclude secondary osteoporosis. Treatment with bisphosphonates or denosumab should be considered in patients on ADT with fragility fracture, osteoporosis (BMD T-score ≤-2.5), or high risk of fracture according to FRAX®. Referral to a bone metabolism specialist should be contemplated in some cases. The recommendations provided in this document, tailored for clinicians treating PCa patients, may be of help to identify and treat patients at high risk of frac- ture. Keywords: Androgen antagonists; Denosumab; Diphosphonates; Osteoporosis; Prostatic neoplasms This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. INTRODUCTION of osteoporosis and fragility fractures [1], as a result long-term preservation of bone health remains a clini- Patients with prostate cancer (PCa) are at high risk cal challenge. Bone health may be jeopardized by dif- Received: May 4, 2021 Revised: Jul 15, 2021 Accepted: Jul 19, 2021 Published online Jan 1, 2022 Correspondence to: Enrique Casado https://orcid.org/0000-0001-8839-6430 Department of Rheumatology, University Hospital Parc Taulí, Parc Taulí 1, Sabadell, 08208, Barcelona, Spain. Tel: +34-937231010, Fax: +34-937231010, E-mail: quique.casado@gmail.com Copyright © 2022 Korean Society for Sexual Medicine and Andrology Enrique Casado, et al: Osteoporosis in Patients under Androgen Deprivation ferent therapies throughout patients’ life, including A fragility fracture normally appears spontaneously radiotherapy, glucocorticoids and the long-term use of or as a consequence of a low energy trauma, which androgen-deprivation therapy (ADT) [1]. ADT, one of normally would not break a healthy bone [5]. Although the cornerstones of the PCa treatment, is strongly asso- osteoporosis is asymptomatic, it may have serious clini- ciated with high bone turnover rate that may result in cal consequences because of possible fragility fractures, reduction of bone mineral density (BMD) and increased which could cause a severe impact on the patient’s life. risk of fracture, leading to higher morbidity and mor- The most frequent fractures are vertebral, hip, forearm tality of the patients, and a high economic burden [2]. and shoulder. Amongst older patients vertebral and hip Although preserving bone health should be a crucial fractures have higher incidence, causing an increase in goal for all physicians involved in the management of morbidity and mortality. Around 20% of patients die in PCa patients, actually this is not a very widespread the first year after a hip fracture [6]. practice, partly explained because osteoporosis is un- Fragility fractures also represent a huge social cost. derdiagnosed in men [3]. In Spain (47 million of people), the estimated cost re- The purpose of this document is to provide some lated to fragility fractures is more than 4 billion Euros practical insights into the delivery of optimal bone per year [7]. health care for PCa patients, particularly those on BMD can be measured by dual energy X-ray absorp- ADT, which are at high risk of osteoporosis and fragil- tiometry (DXA) at lumbar spine, femoral neck and to- ity fractures. An interdisciplinary group of Spanish ex- tal hip. BMD can be categorized according the T-score perts give some recommendations for clinical practice (difference between the patient BMD and the young on identifying PCa patients at high risk of fracture male BMD expressed in standard deviation) as [4]: through FRAX®, BMD and spine X-ray; selecting the • T-score ≥-1 standard deviation (SD): normal most suitable laboratory tests; and selecting the best • T-score between -1 and -2.5 SD: osteopenia pharmacological and non-pharmacological treatment. • T-score ≤-2.5 SD: osteoporosis Skeletal-related events associated to metastatic bone In absence of other osteopathy, osteoporosis, in a disease are not considered in this document. clinical setting, can be considered in men older than 50 years according to the following definitions [4]: METHODS • Lumbar  spine, femoral neck or total hip T-score ≤-2.5 SD An interdisciplinary group of experts, including • Fragility hip fracture, regardless of BMD urologists (AB, JMuñoz-Rodríguez, JMorote), and •F ragility vertebral, shoulder or pelvic fracture in rheumatologists (EC, MC, JG), aimed to provide in this patients withlow BMD (T-score <-1.0 SD) publication some practical insights and recommenda- tions on how to deliver optimal bone health care for OSTEOPOROSIS AND FRAGILITY PCa patients, particularly those starting or already on FRACTURES IN PROSTATE CANCER ADT. The recommendations are based on current evi- PATIENTS dence, different national and international guidelines and their own expertise, and are tailored specifically A study performed in 618 men with newly diagnosed for clinicians who treat PCa patients with hormonal PCa (mean age 73 years) showed that 41% had osteo- therapies. porosis, 39% osteopenia and only 20% normal BMD [8]. Many therapies used in PCa patients may lead to an OSTEOPOROSIS AND FRAGILITY even more accelerated bone loss. In a meta-analysis of FRACTURES 14 trials, men who received ADT had a 23% increase of overall fracture risk compared with men with PCa who Osteoporosis is a diffuse skeletal disease character- did not undergo ADT [9]. Bone loss is higher (5%–10%) ized by low bone strength, which leads to a higher risk during the first year of ADT, and continues gradually of fractures, also known as fragility fractures [4]. The throughout the ADT duration [10,11]. One study with concept of “bone strength” comprises elements related 390 men with PCa (mean age 68.9 years) showed that with bone density and bone quality [4]. the prevalence of osteoporosis was 35% in hormone- www.wjmh.org 75 https://doi.org/10.5534/wjmh.210061 naïve patients, 43% after 2 years of ADT, 59.5% after 6 high bone turnover and, eventually, an increased bone years, and 81% after 10 or more years of ADT [12]. loss rate [20]. This increase in bone turnover is often Fragility fractures in PCa patients can occur in associated with an accelerated microarchitectural bone many sites, but are particularly frequent in the tho- damage that is usually not reversible [1]. Both, bone racic and lumbar vertebrae below T4, distal forearm, loss and microarchitectural bone damage explain, in ribs, and hip [13], and they correlate with poor survival part, the high risk of fracture of these patients [1]. outcomes [14]. Although the incidence of hip fractures Although ADT is the mainstay therapy for PCa, af- is lower in men, their mortality rate is higher [15]. Data ter the initial response to this therapy most PCa will from large registries indicate that there is a higher inevitably shift from castration-sensitive PCa to castra- risk of death following a hip fracture for PCa patients tion-resistant PCa (CRPC) [18]. Additional second-line on ADT than for PCa patients not on ADT or PCa-free AR antagonists hormonal treatments (enzalutamide, men, particularly in the first year [16]. PCa patients on apalutamide, or darolutamide), CYP17A inhibition ADT with a hip fracture may be 2.44 times more likely to further decrease androgen biosynthesis with abi- to die compared with the cohort of all PCa patients [16]. raterone acetate and/or chemotherapy are frequently Furthermore, fragility fractures significantly affect the 3 therapeutic mainstays during the CRPC stage [21]. the patients’ quality of life and health status, and have A group of patients with substantial risk of osteoporo- a considerable impact on healthcare resources [1]. As- sis and osteoporotic fractures are those with CRPC in sessing the fracture risk before prescribing long-term the absence of clinically detectable metastatic disease, ADT together with close monitoring of bone health This group is referred to as non-metastatic CRPC [22], during this treatment may reduce the risk of fracture and represents about 2%–8% of the total PCa popula- and improve patients’ quality of life and survival [1]. tion [23]. Prescription of novel and more potent AR inhibitors in this population, in addition to prior long- MECHANISMS OF BONE LOSS IN term use of ADT, results in longer exposure times and PROSTATE CANCER PATIENTS consequently higher risk of osteoporotic fractures [22]. All these novel hormonal treatments such as abi- Skeletal system integrity is maintained by a dynamic raterone/prednisone, enzalutamide or apalutamide, complex process named remodeling or bone turnover, although they are not clearly associated with bone loss, which is regulated by three major types of bone cells: seem to induce a higher risk of falls [24-26]. Enzalu- bone-forming osteoblasts, bone-resorbing osteoclasts, tamide and apalutamide inhibit the AR, potentially and mechanosensor/mediator osteocytes [17]. Some blocking the bone-protective effects of androgens, of these cells express androgen receptors (ARs) and and are associated with adverse effects related to the estrogen receptors [17]. AR signaling in osteoblasts is central nervous system that may lead to falls and responsible for the protective effects of androgens on subsequent traumatic fractures [24,25]. By contrast, trabecular bone mass. AR activation leads to a decrease darolutamide was not associated with a higher inci- in osteoclasts and bone resorption. Estrogens in men dence of falls in a pivotal trial [27], maybe due to its are produced via aromatization of androgens, and their lower blood–brain barrier penetration and less central activation in mesenchymal cells protects against endo- nervous system-related adverse-events, including falls. cortical resorption [14]. Current evidence suggests that Nevertheless, long-term studies are lacking and fur- estrogens play a much more significant role in regulat- ther analysis would be needed to investigate its impact ing bone metabolism in men than testosterone [14]. on bone health. These new antihormonal therapies The critical driving force for PCa is the AR-regulat- are now being utilized earlier in the treatment of PCa. ed gene expression that is initiated by the binding of Therefore, patients with PCa are receiving more potent androgen to AR [18]. ADT is the backbone of systemic treatments and longer durations of intensified ADT, therapy for men with PCa. Almost one-half of patients which increase further their risk of bone loss and frac- receive ADT treatment during their disease course [19]. tures [22]. ADT in PCa patients lowers serum testosterone to cas- Other PCa treatments including chemotherapy or tration levels (<5% of the normal range) and serum es- glucocorticoids, which are used in addition to back- tradiol levels to <20% of the normal range, inducing a ground ADT for the treatment of advanced PCa, also 76 www.wjmh.org Enrique Casado, et al: Osteoporosis in Patients under Androgen Deprivation have a negative impact on bone health [14]. FRACTURE RISK ASSESSMENT IN Beside treatments, many other factors may be associ- PROSTATE CANCER PATIENTS ated with bone loss in PCa patients, such as age. Most men diagnosed with PCa are over 65 years, and aging The risk of fragility fractures should be assessed is clearly associated with gradual bone loss in men in all PCa patients, in particular, in those starting or [28,29]. With age, there is also a decrease in hormone receiving ADT [20]. Several tools have been developed levels, including testosterone and estrogens. In addi- to estimate fracture risk over time considering clinical tion, levels of sex hormone binding globulin increase risk factors with or without BMD measurements [4]. with age, decreasing free or bioavailable testosterone [29]. Furthermore, males with low body mass index also 1. FRAX® tool have decreased estrogen levels. Apart from sexual hor- The FRAX® (Fracture Risk Assessment) tool (Centre mones, other hormones and proteins are implicated in for Metabolic Bone Diseases, University of Sheffield, bone turnover change with age. An increase in insulin- Shefflied, UK) is the most popular and widely used tool like growth factor-1 levels and a reduction in osteo- to assess fracture risk [31]. Risk factors included in this protegerin levels in serum may be associated to age- tool are shown in Table 1. related osteoporosis [29]. Additionally, many PCa patients may have some Table 1. Risk factors included in FRAX® tool to calculate the absolute modifiable risk factors that can affect BMD, such as 10-year risk of hip fracture and major osteoporotic fractures smoking, alcohol, lower weight or low body mass index, Continuous risk factors Dichotomic risk factors physical/functional limitations, weight loss, prolonged Age Sex corticosteroid use, low dietary calcium intake, or low Body mass index Previous fracture vitamin D levels [29,30]. Femoral neck BMD (optional)a Parent fractured hip Finally, PCa disease itself, mainly mediated by local Current Smoking and systemic inflammation, may promote increased Glucocorticoids use bone loss through altered systemic bone remodeling, in- Rheumatoid arthritis creased bone resorption, and impaired bone formation Secondary osteoporosisb [10]. Alcohol intake (three or more Factors associated with bone loss in PCa patients are drinks per day) summarized in Fig. 1. BMD: bone mineral density. a Although femoral neck BMD is optional, this item increases the ac- curacy of FRAX® in predicting the absolute 10-year fracture risk. b Treatment with androgen-deprivation therapy, as a cause of hypo- gonadism, must be included as a cause of secondary osteoporosis. Androgen deprivation therapy Normal hormonal therapies CYP17 inhibitors (enzalutamide, apalutamide, (abiraterone) LH at pituitary gland darolutamide?) (falls mediated?) Testosterone in the Testosterone in the testis Androgen receptor testis, adrenal glands blockade and intra-tumoral synthesis Age-related factors: Osteoclastogenesis Other factors: Testosterone Chemotherapy Estrogens Radiotherapy IGF-I Glucocorticoids Osteoprotegerin Smoking Alcohol Lack or decline in physical activity Cancer-related inflammation Poor calcium intake Poor sun exposure Fig. 1. Factors associated to bone loss and vitamin D in men with prostate cancer. LH: lutein- Bone resorption deficiency izing hormone, IGF-I: insulin-like growth Frailty and sarcopenia factor-I. www.wjmh.org 77 https://doi.org/10.5534/wjmh.210061 The FRAX® tool provides a 10-year probability of a tefactually increased in individuals with spine degen- major osteoporotic fracture (clinical vertebral, forearm, erative conditions, which often occur in older patients proximal humerus, and hip) or a hip fracture. Femoral [33]. BMD of the distal radiousshould be assessed in neck BMD is an optional item in this tool and provides cases where lumbar spine and/or hip cannot be mea- further accuracy of fracture risk [4,31]. Although the sured (e.g., obese patient who exceeds weight limit of FRAX® tool considers some causes of secondary osteo- table) or is unreliable (e.g., patient with lumbar lami- porosis to calculate fracture risk, it’s important to high- nectomy) [34]. light that previous, current or scheduled use of ADT is Recommendations supporting the need for DXA in not considered [20]. PCa patients differ amongst different scientific societ- Fracture risk has a high variability worldwide, so ies: FRAX® must be used considering the country of the •T  he Spanish Society of Rheumatology 2019 Recom- patient, in order to adjust the risk to the appropri- mendations on Osteoporosis recommend measuring ate fracture epidemiology and mortality [32]. Some BMD in the population with risk factors for fragil- guidelines establish determined FRAX® thresholds to ity fractures such as males treated with ADT for define high risk of fracture and pharmacological treat- PCa [4]. These recommendations are in line with ment recommendation to prevent fractures. Examples the French 2019 recommendations for osteoporosis include a ten-year probability of a major fracture of prevention and treatment in patients with PCa 20% in US or Canada, or 15% in Sweden or Japan [32]. treated by ADT, which recommend routine BMD In Spain, these thresholds are ≥7.5% (with BMD) or measurement in patients scheduled for or receiving ≥10% (without BMD) for major fracture, and ≥3% for ADT [33]. hip fracture [4]. Although the FRAX® tool has not been •T  he European Society for Medical Oncology (ESMO) fully validated in the Spanish population, with the 2020 clinical practice guidelines for diagnosis, treat- currently available evidence, some scientific societies ment and follow-up of PCa also consider that men such as the Spanish Society of Rheumatology recom- starting long-term ADT should be monitored with mend the incorporation of FRAX® into clinical practice DXA [1]. to identify patients at high risk of fragility fracture [4]. •T  he International Osteoporosis Foundation (IOF) To our knowledge there are no specific FRAX ® 2017 guidelines state that osteoporosis and fragility thresholds for PCa patients on ADT. However, FRAX® fracture risk should be evaluated by DXA in every can provide a useful estimation of baseline fracture PCa patient, and especially, in the ones startint or risk of these patients for other causes beyond ADT. receiving ADT [20]. In our opinion, FRAX® tool may be incorporated into •T  he 2020 guidelines for PCa issued by the National clinical practice for PCa patients on ADT to identify Comprehensive Cancer Network (NCCN) recom- patients at highfracture risk. The threshold defining mend obtaining a baseline DXA before starting high fracture risk may be different in each country (i.e., therapy in men at increased risk for fracture based >3% for hip fracture, and >7.5%–10% for major frac- on FRAX® screening [35]. ture in Spain; or >3% for hip fracture, and >20% for •T  he American Society of Clinical Oncology (ASCO) major fracture in USA). 2019 guidelines for management of osteoporosis in survivors of adult cancers with non-metastatic dis- 2. Bone densitometry ease [10] consider that patients with non-metastatic Bone densitometry by DXA is the gold standard cancer with one or more risk factors for osteoporotic method for measuring BMD in clinical practice. It is a fracture should be offered BMD testing with DXA; technique with very low radiation exposure [10]. and in PCa patients ADT induced hypogonadism It is used to diagnose osteoporosis and assess an in- should be considered a risk factor [10]. dividual’s risk of developing fragile fractures [4]. The Similarly, recommendations on how often to monitor International Society for Clinical Densitometry (ISCD) BMD with DXA after initiating ADT are not consis- recommends that BMD should be measured in lumbar tent amongst guidelines [10,20,35]. spine (ideally L1-L4), total hip and femoral neck. It’s As a general rule, BMD must be considered in all important to note that lumbar spine BMD could be ar- PCa patients starting ADT, and should not be repeated 78 www.wjmh.org Enrique Casado, et al: Osteoporosis in Patients under Androgen Deprivation more often than once annually [10]. In high-risk pa- introduction of the TBS in the FRAX® algorithm pro- tients placed on antiresorptives for osteoporosis treat- vides a more accurate absolute fracture risk prediction ment, guidelines consider that BMD should be moni- [4]. Despite all these potential benefits from the assess- tored using DXA in 18 to 24 months intervals [10,20], ment of fracture risk, guidelines suggest that further althoughmonitoring after 1 year [35] or after the first research is still necessary to recommend TBS in clini- 3 to 5 years [33] has also been suggested. Patients on cal practice [4,37]. ADT at low risk for fracture (T-score >-1, and therefore not receiving antiresorptives) may be monitored by 5. Laboratory DXA every 18 to 24 months [20]. Osteopenic patients Other secondary causes of osteoporosis and other (T-score between -1 and -2.5) taking ADT without anti- bone diseases differential diagnosis should be assessed resorptives, BMD may be assessed every year to detect through basic laboratory tests in all patients with PCa significant changes that could change of fracture risk receiving ADT with osteoporosis or fragility fractures. classification [20]. Several scientific societies recommend the following blood and urine tests to rule out secondary causes of 3. Vertebral fracture assessment osteoporosis: complete hemogram, erythrocyte sedi- Clinical guidelines recommend assessing prevalent mentation rate, transaminases, creatinine, albumin, vertebral fractures in patients on ADT [20]. Although calcium, phosphate, total alkaline phosphatase, 25-hy- thoracic and lumbar spine X-ray is the most frequently droxyvitamin D, serum protein electrophoresis and used tool [4], some DXA equipment incorporates the 24-urine calcium [4,33]. Additional tests may be neces- Vertebral Fracture Assessment (VFA) technology, sary in some cases to rule out specific conditions associ- which is also useful to identify vertebral fractures, ated with osteoporosis such as hyperthyroidism, hyper- with a lower radiation [20]. parathyroidism, mastocytosis, celiac disease, or Cushing A diagnosis of vertebral fracture is made when there syndrome [4]. is loss of height in the anterior, middle, or posterior portion of the vertebral body >20%. When in doubt, ad- 6. Bone turnover markers ditional views or studies are recommended for confir- Although bone turnover markers (BTMs) can offer mation. prognostic information on fracture risk and provide Osteoporotic vertebral fractures can be graded ac- information about osteoporosis treatment efficacy [4,38], cording to height loss as mild (up to 20%–25%), mod- no data are available on the usefulness of BTM in pa- erate (25%–40%) or severe (>40%) [36]. X-ray or VFA tients with osteoporosis induced by ADT. Consequently, interpretation requires some experience to avoid diag- BMT testing is not generally recommended in this nostic errors, like diagnosing other vertebral deformi- population [33]. ties as vertebral fractures. The 2019 Spanish Society of Rheumatology Osteo- PREVENTION AND TREATMENT porosis Recommendations considers that thoracic and OF OSTEOPOROSIS IN PROSTATE lumbar spine X-rays are helpful during the first assess- CANCER PATIENTS ment of every individual with the diagnosis of osteo- porosis, or in those cases where there is an important Patients with PCa, particularly those starting or reduction of height or kyphosis, or clinical features of receiving ADT, should follow some general steps for vertebral fracture, such as newly emerging back pain primary prevention of osteoporosis and fractures. The of traumatic or non-traumatic origin [4]. first step would be to keep a healthy lifestyle, in accor- dance to the following recommendations [4,10]: 4. Trabecular bone score • A healthy diet with sufficient amount of proteins Using data from the DXA, the Trabecular Bone (0.8 gr/kg of body weight), calcium, vegetables, Score (TBS) can be calculated to analyze the bone and fruits should be adopted to cover nutritional texture and obtain bone microarchitecture related pa- demands. An adequate intake of calcium may be rameters [4]. Low TBS values are associated with an around 1,000 to 1,200 mg/day. increased risk of fracture, regardless of BMD, and the •S top smoking and limit alcohol consumption to www.wjmh.org 79 https://doi.org/10.5534/wjmh.210061 fewer than 3 units/day. least above 30 ng/mL [20,33]. It is advisable to monitor •H  ave a regular and prudent exposure to sunlight. 25-hydroxyvitamin D levels in all patients with PCa •E  ngage into physical activity combining different on ADT and treat all patients with vitamin D insuf- exercises, such as balance training, stretching, en- ficiency or deficiency. SEIOMM also provide an online durance and resistance and/or progressive strength- tool to assess the risk of vitamin D deficiency [42]. ening exercises [39]. Notably, there are two exogenous vitamin D supple- mentation options most used in a clinical setting: cho- 1. Calcium and vitamin D lecalciferol (vitamin D3) and calcifediol (25-hydroxyvi- A daily intake of 1,000 to 1,200 mg of calcium, mainly tamin D), which are available only in some countries, from diet, is recommended in all patients for osteoporo- like Spain [44]. sis prevention [4]. Aliments that are particularly high Vitamin D supplementation regimen will depend on in calcium include dairy products, such as milk, yogurt 25-hydroxyvitamin D serum levels and the vitamin D and cheese. Milk and yogurt can provide between 100 metabolite used for treatment. A regimen approach is and 180 mg per 100 g. Nuts and seeds are also rich in detailed on Table 2. calcium, especially almonds, sesame and chia that can provide between 250 to 600 mg of calcium per 100 g. 2. Antiresorptive therapy Some green vegetables such as broccoli or watercress Antiresorptive therapy with bisphosphonates or de- provide between 100 and 150 mg of calcium per 100 g nosumab should be considered in patients with higher [40]. risk of fractures. It is advisable to check daily calcium intake using Denosumab (60 mg s.c. every 6 months) is a human self-reported questionnaires in order to provide proper monoclonal antibody that specifically inhibits RANKL supplements if needed or receive suitable nutritional with a potent bone turnover inhibition. It is licensed advice [20]. The IOF and the SEIOMM (Sociedad Espa- by the U.S. Food and Drug Administration (FDA) and ñola de Investigación Ósea y del Metabolismo Mineral) European Medicines Agency (EMA) to treat bone loss provide online tools to estimate daily calcium intake related to hormone ablation in males with PCa and from diet [41,42]. high fracture risk [45,46]. Regarding vitamin D, guidelines suggest an intake Zoledronic acid (5 mg i.v. annually) is an intravenous of at least 800 to 1,000 IU/day [10,20]. The main natural bisphosphonate with a potent resorptive inhibition. source of vitamin D is its synthesis by the skin after It is licensed by FDA and EMA for the treatment of sunlight exposure. Very few aliments contain vitamin osteoporosis in adult men at increased risk of fracture, D, and most of them contain oily fish such as sardines, including those with a recent low energy hip fracture salmon, and mackerel [43]. [47,48], so it could be used in PCa patients at high risk 25-hydroxyvitamin D serum levels, an appropriate of fracture (Table 3). marker of vitamin D status [43], and should be kept at The results from randomized clinical trials in pa- tients with non-metastatic PCa on ADT have shown that treatment with both zoledronic acid and denosum- Table 2. Suggested regimen approach for vitamin D supplementation ab are associated with an increase in BMD. No data on in patients with prostate cancer under androgen deprivation therapy fracture risk reduction are available with zoledronic Vitamin D deficiency (25-hydroxyvitamin D <20 ng/mL) acid, but denosumab 60 mg every 6 months has been • Cholecalciferol 50,000 IU weekly for 8 weeks • Calcifediol 16,000 IU (0.266 mg) weekly for 4 weeks demonstrated to reduce the risk of fracture in PCa pa- • This regimen should be followed by the maintenance dose. tients on ADT [33]. Vitamin D insufficiency (25-hydroxyvitamin D=20–30 ng/mL) Oral bisphosphonates have proven to be also effec- • Cholecalciferol 25,000–50,000 IU weekly for 6 weeks tive in increasing BMD and reducing the risk of frac- • Calcifediol 16,000 IU (0.266 mg) weekly for 3 weeks ture in men, with a good safety profile. According to • This regimen should be followed by the maintenance dose. Maintenance dose of vitamin D supplementation in patients with some guidelines both alendronate and risedronate are optimal 25-hydroxyvitamin D levels (30–50 ng/mL) recommended for PCa patients [4,35], although only • Cholecalciferol 25,000–50,000 IU monthly (800–1,666 IU per day) risedronate (35 mg orally once a week) is licensed by • Calcifediol 16,000 IU (0.266 mg) every 3–4 weeks the EMA for osteoporosis in men (Table 3) [49]. 80 www.wjmh.org Table 3. Antiresorptive agents for the treatment of osteoporosis in men with prostate cancer Indication approved for male osteoporosis Drug U.S. Food and Drug European Medicines Dosage Recommendations for administration Contraindications Administration Agency Alendronate Yes No 70 mg orally once a week Gastroesophageal reflux At least 30 minutes before the first food, [4,35] Inability to stand/sit upright for at least 30 minutes or drink of the day with a glass of plain Hypocalcemia water; do not lie down for at least 30 minutes after taken Renal impairment (CrCl <35 mL/min) Scheduled dental procedures Risedronate Yes Yes 35 mg orally once a week At least 30 minutes before the first food, Gastroesophageal reflux [4,35,49] (only 35 mg weekly 75 mg orally on two consecutive or drink of the day with a glass of plain Inability to stand/sit upright for at least 30 minutes formulation) days each month water; do not lie down for at least 30 Hypocalcemia 150 mg orally once a month minutes after taken Renal impairment (CrCl <35 mL/min) Scheduled dental procedures Risedronate No No 35 mg orally once a week Immediately following breakfast Hypocalcemia delayed-release Renal impairment (CrCl <35 mL/min) tablets [4,35] Scheduled dental procedures Zoledronic acid Yes Yes 5 mg intravenous once a year Infusion given intravenously over no less Hypocalcemia [47,48] than 15 minutes Renal impairment (CrCl <35 mL/min) Scheduled dental procedures Denosumab Yesa Yesa 60 mg subcutaneous every Subcutaneous injection in the upper arm, Hypocalcemia [45,46] 6 month upper thigh, or abdomen Scheduled dental procedures CrCl: creatinine clearance. a Denosumab is the only antiresorptive agent with specific indication for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. www.wjmh.org Enrique Casado, et al: Osteoporosis in Patients under Androgen Deprivation 81 https://doi.org/10.5534/wjmh.210061 In a recent systematic review and network meta- its discontinuation, since a rebound bone turnover ef- analysis in men with PCa receiving ADT for more fect, with a rapid decrease of BMD and an increased than 6 months, oral or intravenous bisphosphonates risk of vertebral fractures has been reported [10]. To and denosumab appeared to be effective in reducing minimize this rebound effect, experts recommend the the rate of bone loss, without evidence that one drug administration of potent bisphosphonates, such as alen- was superior to another [50]. Hence, there are no uni- dronate or preferably zoledronic acid 6 months after form criteria in guidelines regarding the indications the last dose of denosumab [51,52]. In this case, referral of osteoporosis treatment in PCa patients on ADT to a bone specialist should be considered to assess the [4,10,20,35]. need for additional antiresorptive therapy. However, it seems reasonable to consider antiresorp- Bisphosphonates and denosumab may be associated tive treatment with bisphosphonates (oral or intrave- with a number of adverse events (Table 3). One of the nous) or denosumab in PCa patients on ADT with any most concerning complications is osteonecrosis of the of the following conditions: jaw (ONJ) [53]. Although this event is infrequent, espe- •P revious or current fragility fractures, regardless of cially when these drugs are used at doses for osteopo- BMD. rosis, patients ought to be made aware of this adverse •O steoporosis by DXA (T-score ≤-2.5 SD in the lum- effect. An oral health assessment at baseline and once bar spine, femoral neck or total hip). a year during treatment is recommended in all pa- •H igh fracture risk according to country-specific tients starting antiresorptives [33]. Poor oral hygiene, FRAX® threshold (i.e., >3% for hip fracture, and periodontal disease, poorly fitted dentures, history of >7.5%–10% for major fracture in Spain). dental disease, or invasive dental procedures are risk Selection of oral bisphosphonates, zoledronic acid or factors that should be considered when evaluating a denosumab will depend on patient characteristics and patient’s risk of developing ONJ. All patients should availability of these medications in each clinical set- be encouraged to maintain good oral hygiene, undergo ting. routine dental check-ups, and immediately report any Although oral bisphosphonates can be used as the oral symptoms such as dental mobility, pain or swell- first option for many patients, zoledronic acid or deno- ing, non-healing of sores or discharge during treatment sumab may be a better option for some patients: with bisphosphonates or denosumab. During treatment • Alendronate or risedronate: first option. with denosumab or zoledronic acid, invasive dental pro- •Z oledronic acid: non-adherence or intolerance to oral cedures should be performed with caution and avoided bisphosphonates, in a hospital setting. in close proximity to the treatment administration [45- •D enosumab: non-adherence or intolerance to oral 48]. bisphosphonates, any contraindication to oral or Some scientific societies, as the Spanish Society of intravenous bisphosphonates, as chronic kidney Rheumatology, have developed some recommendations disease with glomerular filtration rate <35 mL/min; for the oral health management of patients receiving and very low BMD (T-score <-3.5). bisphosphonates or denosumab [4]. Although the risk of hypocalcaemia with antire- sorptives is low, it is important to maintain a positive CRITERIA FOR REFERRAL TO A calcium balance and vitamin D intake specially with BONE METABOLISM SPECIALIST zoledronic acid or denosumab [20]. The available therapeutic trials involving PCa pa- The following criteria for referral PCa patients to a tients lasted 6 to 36 months. Therefore, they cannot bone metabolism specialist are suggested: be used to decide the optimal treatment duration [33], •P atients should be referred to another level of however, 3 to 5 years of treatment seems to be effective care if they are going to benefit from the referral and safe with bisphosphonates [33]. A discontinuation or when their treating physician cannot or is not of bisphosphonates is reasonable because they have a used to handle these types of health conditions. The prolonged skeletal retention and a residual therapeutic training of the professional, availability of time, effect after stopping. and organization of the work place may also condi- Regarding denosumab, there is more concern about tion referrals. 82 www.wjmh.org Enrique Casado, et al: Osteoporosis in Patients under Androgen Deprivation Patients with prostate cancer on hormonal treatment Optimal lifestyle: nutrition, physical exercise, stop smoking, etc. Optimal vitamin D status (25-OH vitamin D level>30 ng/mL)+calcium 1,000 1,200 mg/day (supplements or better with calcium-rich foods) Yes Fragility fracture No Yes DXA availability No FRAX (without DXA) Yes T-score<-2.5 SD No -Major Fx>20% (10% in spain) 1. Start treament -Hip Fx>3% 2. Complete evaluation 3. Consider referring to Yes FRAX a bone metabolism No (with DXA) specialist Yes -Major Fx>20% (7.5% in spain) No -Hip Fx>3% 1. Consider DXA 2. Re-evaluate every 12 months Antiresorptive therapy: i.v. zoledronic acid (5 mg once a year) s.c. denosumab (60 mg every 6 months) 1. DXA every 18 24 months p.o. risedronate (35 mg weekly) 2. Re-evaluate treatment need p.o. alendronate (70 mg weekly) every 3 5 years Fig. 2. Osteoporosis management algorithm. DXA: X-ray absorptiometry, FRAX: fracture risk assessment, Fx: Fracture. • In the case of any difficulties related to osteoporosis for ADT and in the case of vertebral fracture sus- assessment or treatment, or in case of inadequate picion (acute back pain, significant height loss, or response to drug treatment. kyphosis) during follow-up. Baseline X-ray could be replaced by DXA for a VFA. CONCLUSIONS •T  he following laboratory tests are recommended to rule out other secondary causes of osteoporosis Summary of recommendations for an appropriate in PCa patients: complete hemogram, erythrocyte management of bone health in PCa patients (Fig. 2): sedimentation rate, transaminases, creatinine, albu- •T he risk of fragility fractures should be assessed in min, calcium, phosphate, total alkaline phosphatase, all PCa patients, and especially, in those starting or 25-hydroxyvitamin D, serum protein electrophore- receiving ADT. sis, and 24h-urine calcium. Only in case of clinical •F RAX ® tool may be incorporated into clinical suspicion additional tests may be necessary to rule practice to identify PCa patients at higher risk of out other conditions associated with osteoporosis (i.e., fragility fracture, according to the country-specific hyperthyroidism, hyperparathyroidism, mastocyto- fracture threshold (i.e., >3% for hip fracture, and sis, celiac disease, or Cushing syndrome). >7.5%–10% for major fracture in Spain). •C linicians should encourage patients to follow a •H ip and spine BMD should be measured by DXA in healthy lifestyle, including adequate nutrition, stop all patients scheduled for or on ADT. BMD monitor- smoking, limit alcohol intake, and engage into regu- ing with DXA should be done every 18–24 months, lar physical activity. although in high-risk patients it could be done ear- • A daily intake of calcium between 1,000 and 1,200 lier (at 12 months) and in lower risk patients later mg, preferably from diet is recommended. If needed, (at 3–5 years). patients should receive calcium supplements. • A thoracic and lumbar spine X-ray is recommended • A daily intake of vitamin D between 800 and 1,600 for the initial evaluation of all patients scheduled IU/day, from diet, sunlight exposure or supplements www.wjmh.org 83 https://doi.org/10.5534/wjmh.210061 is recommended to achieve serum levels of 25-hy- expert panel opinion. ESMO Open 2020;5:e000652. droxyvitamin D over 30 ng/mL. 2. Rachner TD, Coleman R, Hadji P, Hofbauer LC. Bone health •T reatment with bisphosphonates or denosumab during endocrine therapy for cancer. Lancet Diabetes Endo- may be indicated in patients on ADT with any of crinol 2018;6:901-10. the following: 1) fragility fracture; 2) osteoporosis, 3. Todenhöfer T, Stenzl A, Hofbauer LC, Rachner TD. Target- defined as T-score ≤-2.5 SD in lumbar spine, femoral ing bone metabolism in patients with advanced prostate neck, or total hip, and ; 3) high risk of fracture ac- cancer: current options and controversies. Int J Endocrinol cording to the country-specific FRAX® threshold. 2015;2015:838202. • In case of clinical issues or doubts related to osteo- 4. Naranjo Hernández A, Díaz Del Campo Fontecha P, Aguado porosis assessment or treatment, the patient should Acín MP, Arboleya Rodríguez L, Casado Burgos E, Castañeda be referred to a bone specialist. S, et al. Recommendations by the Spanish Society of Rheuma- tology on osteoporosis. Reumatol Clin (Engl Ed) 2019;15:188- ACKNOWLEDGEMENTS 210. 5. Borgström F, Karlsson L, Ortsäter G, Norton N, Halbout P, The authors thank Content ed Net, Madrid, Spain Cooper C, et al.; International Osteoporosis Foundation. Fra- and Dr. Pablo Rivas for writing and editorial assis- gility fractures in Europe: burden, management and opportu- tance. Writing and editorial assistance has been pro- nities. Arch Osteoporos 2020;15:59. vided by Content ed Net with funding by Bayer His- 6. International Osteoporosis Foundation (IOF). Facts & statis- pania SL. tics [Internet]. Nyon: IOF [cited 2020 Sep 18]. Available from: https://www.iofbonehealth.org/facts-statistics. Conflict of Interest 7. International Osteoporosis Foundation (IOF). Huesos rotos, vidas rotas: guía para mejorar la atención a las fracturas por Casado E has received consulting fees or speaker remunera- fragilidad en España [Internet]. Nyon: IOF [cited 2020 Sep tion from Eli Lilly, Amgen, UCB, Rubió, Theramex, Gebro, Ital- 18]. Available from: https://share.osteoporosis.foundation/ fármaco, Gedeon-Richter, STADA, Bayer, and GP-Pharma. EU-6-Material/Reports/IOF%20Report_SPAIN_DIGITAL_ Borque-Fernando A has received consulting fees or speaker SP.pdf. Spanish. remuneration from Janssen, Astellas, Bayer, Sanofi, Astra- 8. Wadhwa VK, Weston R, Mistry R, Parr NJ. Long-term chang- Zeneca, MSD, Ipsen, Rovi, Opko, MDx Health, Ferrer, and Lacer. es in bone mineral density and predicted fracture risk in Caamaño M has received speaker remuneration from Eli patients receiving androgen-deprivation therapy for prostate Lilly, Amgen, MSD, Gedeon-Richter, and Grünenthal Pharma. cancer, with stratification of treatment based on presenting Graña J has received speaker remuneration from Eli Lilly, values. BJU Int 2009;104:800-5. Amgen, UCB, Theramex, Gebro, Italfármaco, Gedeon-Richter, 9. Taylor LG, Canfield SE, Du XL. Review of major adverse ef- and STADA. fects of androgen-deprivation therapy in men with prostate Muñoz-Rodriguez J has received consulting fees or speaker cancer. Cancer 2009;115:2388-99. remuneration from Amgen, Astellas, Bayer, Ipsen, and Janssen. 10. Shapiro CL, Van Poznak C, Lacchetti C, Kirshner J, Eastell Morote J do not declare any conflict of interest related to this R, Gagel R, et al. 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