Protecting and improving bone health is critical when managing all stages of prostate cancer. Androgen deprivation therapy (ADT) accelerates bone resorption, which compromises bone mass and integrity starting early in treatment.1 Metastatic prostate cancer is associated with a marked increase in risk of skeletal events (fracture, spinal cord compression, and bone surgery or radiotherapy) associated with both bone metastases and treatment-induced bone loss.
Unfortunately, many patients with prostate cancer do not receive necessary and guideline-recommended interventions to protect bone health, such as calcium and vitamin D supplementation, fracture risk assessments, or antiresorptive therapy with denosumab or bisphosphonates. Consequently, patients who progress to metastatic, castration-resistant prostate cancer face a dramatically increased risk of symptomatic skeletal events secondary to both osteoporosis and bone metastases. In the recent ERA 223 trial, for example, only about 40% of patients had received an antiresorptive agent and the majority of fractures were non-pathologic.2 Such findings highlight the need for physicians who manage patients with prostate cancer to better assess and manage bone health. In this article, I review osteoporosis, treatment-induced bone loss, and pharmacologic strategies
to optimize bone health throughout the prostate cancer disease spectrum.
Osteoporosis
Osteoporosis is a systemic skeletal disease characterized by abnormally low bone mass and micro-deterioration of bone tissue.3 Osteoporosis is strongly associated with aging, affecting at least 10% to 25% of men who are 60 years or older.4 Because osteoporosis is often underdiagnosed in men, this is probably an underestimate. Additional risk factors for osteoporosis include smoking, a substantial loss of height since young adulthood, a recent personal history of fall or fracture, low protein intake, decreased executive function, and a family history of osteoporosis.5
As these data suggest, patients with hormone-naïve non-metastatic prostate cancer often have multiple risk factors for osteopenia and osteoporosis. In one study, 40% of such patients had osteopenia, and 11% had osteoporosis.6 In another recent meta-analysis, osteoporosis was diagnosed in 4% to 38% of patients with hormone-naïve prostate cancer, and prevalence was higher in those with more advanced disease.7
In a large population-based cohort study of men aged 55 years and older, each standard deviation reduction in bone mineral density at the femoral neck was associated with a more than two-fold rise in fracture risk.8 Among older patients, skeletal events such as hip and vertebral fractures not only cause pain but also worsen physical, emotional, and mental functioning and these effects can be difficult to reverse.9,10 Hip fracture is also an independent risk factor for mortality, with adjusted hazard ratios for death ranging from 1.4 to 7.4 in population-based studies of older men.11-14
Osteoporosis is prevalent among men with newly diagnosed hormone-sensitive prostate cancer, including those with non-metastatic disease. A recent meta-analysis of studies reported a 4% to 38% prevalence of osteoporosis in this population.7 These findings reinforce the need for regular bone health assessments for all patients with prostate cancer, regardless of treatment history or current therapeutic regimen.
Treatment-Induced Bone Loss
Androgen Deprivation Therapy
Androgen-deprivation therapy is routinely used in the treatment of hormone-sensitive and castration-resistant metastatic prostate cancer, as well as non-metastatic high-risk or biochemically relapsed disease.15,16 The efficacy of ADT hinges on its reduction of serum testosterone to near-castration levels. Unfortunately, this has significant negative implications for bone health.17,18,19
Dual-energy x-ray absorptiometry (DEXA) studies show that bone mineral density falls by 2% to 6% per year at the lumbar spine and by 2% to 4% at the total hip during the first 1-2 years of ADT, a significantly faster rate of bone loss than in healthy controls or prostate cancer patients who are not receiving ADT.1,20-22 Although bone loss is most pronounced during initial ADT exposure, it persists throughout treatment. In one study of 390 men receiving long-term ADT for prostate cancer, the prevalence of osteoporosis was 35% at baseline, 43% after 2 years, 49% after 4 years, 66% after 8 years, and 81% after 10 or more years of ADT.23
Studies also have estimated the extent to which ADT increases fracture risk. In an analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare linked records from more than 80,000 prostate cancer patients, gonadotropin-releasing hormone (GnRH) agonist therapy was associated with a 34% increase in risk of fracture among men with non-metastatic prostate cancer, and a 51% increase in risk of fracture among men with metastatic prostate cancer.24 Fracture risk increased with greater cumulative ADT exposure, and the mortality rate among patients with post-diagnosis fractures was double that among patients without fractures.24 Androgen deprivation therapy causes sarcopenia, which can exacerbate frailty among older men and may further increase their risk of serious falls, fractures, and subsequent mortality.25
Glucocorticoids
Systemic glucocorticoids are essential to offset the toxicities of certain life-prolonging prostate cancer treatments, such as docetaxel, cabazitaxel, and abiraterone acetate.15 However, these drugs also adversely affect bone health through their effects on cells involved in bone turnover. Glucocorticoids not only suppress the differentiation and proliferation of osteoblasts, induce osteoblast apoptosis, and increase the recruitment, differentiation, and bone-surface binding of osteoclasts, but also suppress osseous growth factor activity and increase renal calcium excretion.26,27 The net result is bone resorption and an increased risk for osteoporosis.
Novel Hormonal Agents
The advent of novel hormonal therapies is revolutionizing the treatment of non-metastatic castration-resistant, hormone-sensitive metastatic, and metastatic castration-resistant prostate cancer.28-34 The benefits of these treatments include improved outcomes related to bone health. By preventing or delaying skeletal events such as pathologic fractures and metastatic spinal cord compression, they may significantly improve quality of life.35
At the same time, novel hormonal agents are associated with small but meaningful increases in risk for non-pathologic fracture. By altering gene expression, abiraterone appears to suppress osteoclast function and promote osteoblast differentiation and bone matrix deposition.36 However, abiraterone is co-administered with the glucocorticoid prednisone and is itself associated with an increased risk for non-pathologic (i.e. osteoporotic) fractures. In the COU-AA-301 trial, rates of non-pathologic fracture were 5.9% with abiraterone-prednisone versus 2.3% with placebo-prednisone.37 Similar findings have been reported for enzalutamide and apalutamide. In a recent meta-analysis of data from four phase III trials, the incidence of non-pathologic fractures was 10.2% with enzalutamide versus 4.4% with placebo.38 Likewise, in the phase III SPARTAN trial, fracture rates were 11.7% with apalutamide and 6.5% with placebo.39
Thus, while novel hormonal agents are associated with lower risk for pathologic fracture than ADT alone, they appear to potentially increase the risk of non-pathologic fracture. Therefore, patients receiving novel hormonal agents should receive regular bone health assessments to guide decisions regarding bone health therapy (discussed further in the next section).
Radium-223
The alpha-particle emitter radium-223 is a calcium mimetic that binds the bone mineral hydroxyapatite at sites of increased bone turnover, such as those surrounding bone tumor lesions.40 Radium-223 been approved in the United States since 2013 for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases.41 This therapy is most often used in late-stage prostate cancer, after patients with metastatic castration-resistant disease develop progressive symptomatic bone metastases. However, radium-223’s considerable efficacy in controlling bone metastases has generated substantial interest its use in earlier-stage asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer.
Unfortunately, after a median follow-up of 21 months in the ERA 223 trial, rates of both all-grade and grade 3-4 fractures were approximately three times higher in the abiraterone plus Ra-223 arm compared with abiraterone plus placebo.42 While the biological mechanism for these findings is not fully understood, it has been conjectured that the effects of abiraterone and prednisone on bone resorption, combined with the antiresorptive/anti-cancer effects of abiraterone, cause Ra-223 to be deposited in healthy bone rather than only, or primarily, at sites of metastasis.43 Because radium-223 inhibits osteoblasts and osteoblastic bone growth, this is an undesirable effect. Antiresorptive therapy for patients receiving Ra-223 is biologically justified and has been shown to reduce fracture risk.44
Protecting Bone Health in Prostate Cancer
The key to protecting and improving bone health in prostate cancer is to start early, assess fracture risk regularly, and use the results to create and revisit a bone health plan. To promote adherence and follow-through, it is vital to educate patients, families and other caregivers, and nurse navigators about the importance and management of bone health in prostate cancer. The investment of time pays off.
Calcium and Vitamin D
All patients with prostate cancer who are starting ADT should simultaneously initiate (or be advised to continue) calcium and vitamin D supplementation. Studies using DEXA scans indicate that supplementation helps attenuate loss of bone density during ADT, particularly during the first year of treatment.20,45 The National Comprehensive Cancer Network (NCCN) recommends a daily target of 1000 to 1200 mg calcium and 400 to 1000 IU vitamin D from food and supplements.15 Diet alone tends not to meet this recommendation. Personally, I prescribe a minimum of 1000 mg/day of calcium plus 800 IU/day or 10,000 IU/week of vitamin D. This may need to be adjusted in some patients based on their measured calcium and vitamin D levels.
Unfortunately, my colleagues and I continue to see many patients with prostate cancer who were not educated about calcium and vitamin D when they started ADT. This early lapse can have long-term consequences for bone health. While supplementation alone will not fully protect against the bone-related effects of ADT, supplementation is an important part of bone health management for patients with prostate cancer and should continue throughout treatment, including when patients layer on additional bone health therapies, such as antiresorptive agents.
Fracture Risk Assessment
Patients with newly diagnosed prostate cancer should receive some form of baseline fracture risk assessment using tools such as the FRAX® algorithm.46 A DEXA scan alone may not be sufficient to assess fracture risk. In a recent study, 47% to 62% of individuals met the threshold for bone-protective therapy based on the FRAX® algorithm (depending on whether or not bone mineral density was included), while only 19% of individuals required treatment based on T-score alone.47 In another large population-based study, only 20% of older men with non-vertebral fractures had T-scores below -2.5.8
The FRAX® algorithm estimates the 10-year probability of major osteoporotic fracture (clinical spine, forearm, hip, or shoulder) and of hip fracture alone based on independent risk factors such as age, body weight, smoking history, glucocorticoid exposure, and family history of hip fracture.46,48 Risk can be assessed with or without accounting for bone mineral density measurement at the femoral neck. Androgen deprivation therapy is classified as secondary osteoporosis when using this algorithm.15 For patients receiving or initiating ADT, clinicians should consider bone-protective (antiresorptive) therapy if the femoral neck, total hip, or lumbar spine T-score is between -1.0 and -2.5 (indicating osteopenia) and the FRAX® assessment indicates a 3% or greater 10-year probability of hip fracture or a 20% or greater 10-year probability of major osteoporotic fracture.15 I agree, and this is based on expert consensus.
Options for Bone-Protective Therapy
Denosumab is a fully human monoclonal antibody targeting receptor activator of nuclear factor-kappaB ligand (RANKL), which is a key mediator of osteoclast differentiation, proliferation, and survival.49 Bisphosphonates (e.g. zoledronic acid, alendronate, and risedronate) are stable analogs of inorganic pyrophosphate that inhibit osteoclast activity and increase osteoclast apoptosis, thereby reducing bone resorption.50 For patients with advanced prostate cancer and other solid tumors, denosumab and bisphosphonates can reduce rates of skeletal-related events associated with bone metastases.51,52 Although zoledronic acid is the most potent bisphosphonate with regard to its antiresorptive effects, head-to-head trials and post-hoc analyses have found that denosumab is superior to zoledronic acid for the prevention of skeletal-related events in bone-metastatic disease.47,51-54
Of note, the high rate of fractures in the ERA 223 prompted investigators to begin mandating bone-protective therapy in an ongoing trial comparing enzalutamide plus radium-223 with enzalutamide alone in patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer. Interim results from the EORTC 1333/PEACE trial have confirmed the value of bone-protective therapy in this patient population.55 Similar to prior studies, enzalutamide was associated with a 13% risk of fracture when administered without bone-protective therapy. Fracture incidence was more than twice as high (33%) when radium-223 was added to enzalutamide. However, continuous bone-protective therapy starting at least 6 weeks prior to treatment initiation nearly eliminated the risk of fracture in both arms of the trial. Fracture rates were 0% with enzalutamide and 3% with enzalutamide plus radium-223. These findings underscore the value need for bone-protective therapy for patients with metastatic castration-resistant prostate cancer.
Bone-protective agents also improve bone health in patients with non-metastatic prostate cancer. As I have discussed, they should be considered in patients who are receiving ADT and are at increased risk for fractures.15 Placebo-controlled trials in this setting have demonstrated significant improvements in bone mineral density after (typically) one year of treatment.56-58 Benefits persist over time: In a 3-year, randomized, double-blind study of more than 1,400 men receiving ADT for non-metastatic prostate cancer, 24 months of subcutaneous denosumab (60 mg every 6 months) improved lumbar spine bone mineral density by 5.6%, compared with a 1% decrease in the placebo arm.57 Denosumab also significantly increased bone density of the total hip, femoral neck, and distal third of the radius, and reduced the risk of new vertebral fractures by approximately 62% compared with placebo (P<.0001).57 These effects did not vary according to patients’ age, fracture history, or baseline bone mineral density.59 Similarly, in a double-blind, randomized trial, one year of intravenous zoledronic acid (4 mg every 3 months) increased bone mineral density of the lumbar spine by 5.6% compared with a 2.2% reduction in the placebo control arm.60 Zoledronic acid also improved bone density at the total hip, trochanter, and femoral neck.
Risk Management in Bone-Protective Therapy
Unfortunately, antiresorptive therapies have been widely underutilized in the management of both non-metastatic and metastatic prostate cancer. Their low prevalence of use and the high proportion of non-pathologic fractures in the ERA 223 trial2 are prompting discussions about how we can better educate the prostate cancer community about these agents, improve treatment adherence, and balance therapeutic benefits and risks.
Osteoporosis of the jaw is an uncommon but potentially serious side effect of antiresorptive therapy. Patients should understand that the risk of this adverse event is low even with ongoing treatment. In a large prospective study, the incidence of jaw osteonecrosis was 0.7% per 100 initial patient-years of exposure to denosumab or zoledronic acid, and risk did not significantly differ based on treatment type.61 During prolonged open-label follow-up of denosumab recipients, the incidence of jaw osteonecrosis rose to 4.1% per 100 person-years of exposure, which generally aligns with data from other studies.
Although the pathogenesis of jaw osteonecrosis is not fully understood, reduced bone turnover appears to exacerbate the effects of oral infections resulting from trauma, oral surgery, or poor dental care.62,63 In a study of more than 5,700 patients with bone metastases related to solid tumors or myeloma, 62% of cases were associated with tooth extractions.63 Prior to starting antiresorptive therapy, patients should therefore receive a comprehensive oral examination and resolve any health concerns that are identified. Patients also should be educated to stop antiresorptive treatment and notify their clinician if they experience oral pain, tooth mobility, mucosal swelling or redness, exposed bone or drainage, numbness or heaviness in the chin or jaw (numb chin syndrome), or new or worsening sinusitis, a potential sign of maxillary involvement.64
For patients whose bone-metastatic prostate cancer is fully remitted, with no biochemical, radiographic, or symptomatic evidence of progression, I will discuss taking a break from denosumab or bisphosphonate therapy or spacing treatment out to reduce the risk of jaw osteonecrosis. However, clinicians and patients should keep in mind that the probability of this adverse event is low in appropriately managed patients, and many cases can be managed conservatively.63 In contrast, the risks of skeletal-related complications are substantial in the absence of bone health therapy.
Palliative Radiation
Novel anti-androgen receptor therapies and chemotherapy significantly prolong survival in metastatic castration-resistant prostate cancer, but they are not curative. Symptomatic skeletal events, such as pathologic fractures and spinal cord compression, remain common during the final one to two years of life. They are not eliminated, merely pushed down the road.
Consequently, palliative radiation remains necessary to control bone pain associated with progressive metastatic castration-resistant prostate cancer. In a recent meta-analysis of data from 20 randomized controlled trials, 32 prospective nonrandomized studies, and four pooled analyses, initial and repeat radiotherapy was safe and highly effective for the palliation of bone pain associated with metastases.65
Summary
Osteoporosis is both prevalent and widely underdiagnosed in older men, including those with prostate cancer. Systemic treatments for prostate cancer, such as ADT, glucocorticoids, and novel hormonal agents, can significantly postpone or prevent bone metastases but also are associated with bone loss. This is particularly true for ADT, which is an independent risk factor for osteoporotic fractures.
Given the routine use of these life-prolonging therapies, it is essential to assess and protect bone health during all stages of prostate cancer. Clinical experience shows that early preventive interventions are more effective than waiting until patients have both osteoporosis and bone-metastatic disease. All patients initiating ADT should receive calcium and vitamin D supplementation, a baseline DEXA scan, and a fracture risk assessment. For patients with both metastatic and non-metastatic prostate cancer, increased fracture risk merits strong consideration of antiresorptive therapy. Adherence to injectable antiresorptives has been found to be better than to oral agents. Osteonecrosis of the jaw is a low but important risk of antiresorptive treatments, so dental concerns should be addressed prior to treatment initiation. Oral numbness is an early warning sign of jaw osteoporosis, and patients who develop this symptom should promptly stop the bone-protective agent and contact their treating clinician.
Progression to bone-metastatic castration-resistant prostate cancer marks a striking increase in risk of both osteoporotic and pathologic skeletal events. Because current therapies for metastatic castration-resistant prostate cancer are not curative, they at best postpone these complications. Bone-protective therapy should be considered mandatory in patients receiving radium-223, while palliative radiation remains vital for controlling pain in late-stage disease.
Written by: Fred Saad, MD, FRCS, is Professor and Chairman of Urology and Director of G-U Oncology at the University of Montreal Hospital Centers (CHUM). He holds the U of M Endowed Chair in Prostate Cancer Research and is Director of the molecular oncology research lab in Prostate Cancer. He is also Director of clinical cancer research at the CHUM. Between 2007-2013 he served as Chair of the National Cancer Institute of Canada G-U Group and the Canadian Urologic Oncology Group. Dr Saad has been intimately involved in almost every important clinical trial in castration resistant prostate cancer over the last 20 years and presently sits on 6 steering committees of international clinical trials. He leads the Canadian Prostate Cancer Biomarker Network and is a principal investigator with the Movember bio-marker initiatives in prostate cancer.
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