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Prostate cancer is a common malignancy reported among elderly men in the United States. An annual report by the National Cancer Institute estimated 174,650 new cases of prostate cancer (9.9% of all cancers) and 31,620 deaths (5.2% of all cancer-related deaths) in the United States in 2019.1 The skeleton is the predominant site of metastases in prostate cancer (with incidence from 65% to 90%).2,3 These metastatic lesions compromise bone integrity and lead to the development of skeletal-related events (SREs), such as spinal compression, pathological fractures, bone pain, and hypercalcemia.4,5 In addition, androgen deprivation therapy (ADT), the mainstay treatment of prostate cancer, profoundly increases the risk of SRE occurrence. The incidence of SREs directly correlates with the duration and use of hormone therapy.2
In specific patients, the continuous rise of serum prostate-specific antigen (PSA) levels is associated with the progression of pre-existing prostate cancer and/or the appearance of new metastasis, irrespective of ADT. This condition is called castration-resistant prostate cancer (CRPC).6 Bone metastasis is evident in 90% of patients of CRPC, and the vast majority of them develop SREs.7 Additionally, the advent of SREs is remarkable in non-responders to curative therapy, such as radical prostatectomy, radiation therapy, and ADT.
Antiresorptive drugs (ARDs) such as bisphosphonates (BPs) and denosumab (Dmab) are indicated as supportive therapy in prostate cancer. These drugs reduce the incidence of SREs, increase bone mineral density, minimize the risk of fractures and osteoporosis, and delay the onset of skeletal metastasis.8,9 Furthermore, few preclinical studies demonstrated the direct anti-tumor activity of ARD apart from osteoclast suppression.10,11 Despite the aforementioned benefits, an increased risk of osteonecrosis of the jaw (ONJ) was noted with ARD use.12 In addition to the use of ARDs, certain intrinsic factors associated with prostate cancer and local factors might predispose jaws to develop osteonecrosis (Table 1). Further investigation is needed to determine the exact role of these factors in the pathogenesis of ONJ .
Osteonecrosis of the jaw is characterized by avascular necrosis of the maxillary or mandibular bone and is associated with localized pain. Other significant signs include swelling, numbness of the jaw, and the presence of purulent discharge. For many years, the presence of necrotic bone exposure was reported as a classic sign of ONJ; however, recently a variant, known as non-exposed ONJ (NE-ONJ), has been reported.13 NE-ONJ poses a diagnostic challenge to oncologists and dentists.
Marx first reported ONJ due to bisphosphonates in 2003.14 When it occurs as a result of intake of antiresorptive and antiangiogenic drugs, this condition is known as medication-related osteonecrosis of the jaw (MRONJ). A position paper by the American Academy of Oral and Maxillofacial Surgeons stated the diagnostic criteria for MRONJ. It should be noted that, to classify a lesion as MRONJ, neither history of radiotherapy nor obvious signs of metastasis to jaws need to be present. The estimated risk of MRONJ in cancer patients is 0.7% to 6.7% for intravenous (IV) ARDs and 0.004% to 0.21% for oral ARDs.15
Despite widely reported cases of ONJ in various solid tumors, the exact pathophysiology and reason for its unique localization remain inconclusive. Some investigators believe unique microbial colonization associated with deficient immune response favors localization of the infection to the jaws. The exact role of bacteria in the initiation or promotion of a lesion has yet to be elucidated.16 This review will focus on ARD-induced ONJ in prostate cancer.
Antiresorptive Drugs (ARDs) for the Treatment of Prostate Cancer
Bisphosphonates
Bisphosphonates are pyrophosphate analogs. They are classified as nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). Both classifications exhibit an inhibitory effect on osteoclast generation resulting in reduced osteoclast-mediated bone resorption. The acidic pH of osteoclasts favors the internalization of bisphosphonates into the cell. BPs disrupt the chemical process associated with bone resorption. N-BPs induce apoptosis by forming a toxic analog of adenosine triphosphate. Non-N-BPs inhibit the enzyme farnesyl diphosphate synthase required for osteoclast function.17 N-BPs such as zoledronic acid (ZA) and pamidronate and non-N-BPs such as clodronate are currently prescribed for prostate cancer (Table 2).9,18-21
Zoledronic Acid
A third-generation bisphosphonate, zoledronic acid is the most potent drug commonly prescribed for CRPC. Results of a placebo-controlled trial demonstrated a 36% reduction in SREs with ZA in CRPC. The recommended dosage to prevent SREs is 4 mg (a 15-minute IV infusion) every 3 to 4 weeks. Regarding the optimal duration of drug therapy, studies have shown efficacy and safety for a period of 24 months.19 ZA is more effective than pamidronate.
ZA has demonstrated antiproliferative, cytostatic, and apoptotic effects on prostate cancer cells in vitro. Also, it decreased levels of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K, leading to a reduction of osteolytic bone metastases in vivo.11
Denosumab
Denosumab (Dmab) is a monoclonal antibody. Denosumab inhibits the receptor activator of nuclear factor kβ ligand (RANKL), thus inhibiting osteoclast function and subsequent bone resorption. Unlike BPs, RANKL inhibitors do not bind to the bone. Their effect on bone remodeling is short term compared to BPs. The adverse effects reverse eventually after cessation of therapy. In a phase III trial, denosumab delayed initiation of bone metastasis compared with placebo in non-metastatic CRPC.9 Denosumab was found to be superior to ZA in treating SREs in CRPC.22,23 It increases bone mineral density. Interestingly, data from a meta-analysis reported the incidence of Dmab-induced ONJ as 2.4% greater in prostate cancer patients compared to other cancer patients.24
Drug Holiday
Aeran et al placed an implant-supported overdenture in a patient with hormone-refractory metastatic prostate cancer. The patient was on oral BPs for 2 years and had discontinued their use 3 months before and after surgery. Follow-up over a 2-year period demonstrated a good prognosis.25 The drug holiday for 3 months pre- and post-surgery was proven beneficial in this case report, but there is insufficient evidence to support that drug holidays would produce similar results in all patient groups. Animal studies reported beneficial effects of drug holidays with denosumab but not with bisphosphonates.16 Also, IV ARDs are used in most cases of prostate cancer. Stopping them might adversely affect disease progression rate.
ONJ Predisposing Factors and Their Association With ARD Therapy
Data from observational studies showed only a subset of the population develops ONJ when treated with antiresorptive drugs in prostate cancer patients with bone metastasis. It should be noted that dental extraction, denture sores, or trauma from prosthesis contributed to the development of ONJ in most patients when treated with ARDs. In addition, patients treated with multiple ARDs are at increased risk of developing ONJ (Table 3).12,26
Animal studies emphasized the role of mechanical injury, such as tooth extraction, in the initiation of ONJ. Bisphosphonates suppressed new bone formation in the extraction socket and inhibited angiogenesis. The reduction in osteoclasts and osteoblasts accounted for the disturbances in bone remodeling.27 However, studies by De Molon et al found MRONJ in rats occurred after treatment with ARDs in the absence of tooth extraction but in the presence of dental disease.28
More importantly, the ARD dose has paramount importance in the pathogenesis of ONJ. Vehmanen et al investigated 254 prostate cancer patients on ARDs in a retrospective study to understand the effects of dose. Twenty-nine out of 254 patients manifested ONJ (two in the BP group, nine in the Dmab group, and 18 in the combined group). The authors reported ONJ developed after eight doses of ZA and 18 doses of Dmab. Patients who received combination therapy of ZA followed by Dmab developed ONJ after 23 weeks. Of the 29 patients, 18 (62%) had a history of tooth extraction. A drug holiday was given for a variable period. The authors concluded that the risk of ONJ increases with higher ARD doses and with long-term therapy, demonstrating both dose and duration of therapy were important factors in ONJ development.29
Moreover, switching BPs during the treatment course is not recommended. Rodrigues et al evaluated the effect of ZA and clodronate in 324 consecutive prostate cancer patients. During the course of treatment, 14 subjects changed from clodronate to ZA, and among them two developed ONJ. The remaining subjects who continued initially infused drugs did not develop ONJ.30
Corticosteroids
Long-term cumulative doses of dexamethasone were considered as a risk factor in developing avascular necrosis of bone.31 Steroid-induced osteonecrosis most commonly manifests at the head of the humerus or femur.32 Nisi et al reported a case of ONJ occurring in a patient on long-term steroid therapy (prednisone 7.5 mg/day for 2 years). ONJ occurred 3 months after dental extraction.33 In a case series of bisphosphonate- and steroid-related ONJ in osteoporosis patients, the authors concluded concurrent use of both drugs predisposed bone to develop necrotic changes sooner. Also, the recovery rate of bone was prolonged after cessation of therapy.34 It is important to note that steroids, along with chemotherapy and ARDs, are a part of the treatment regimen in prostate cancer patients (Table 3) .
Chemotherapy as a Cofactor for MRONJ
Chemotherapeutic agents commonly used for prostate cancer include docetaxel, cabazitaxel mitoxantrone, and estramustine. Among these, docetaxel has been considered a mainstay drug. Docetaxel along with prednisone prolonged the lifespan of prostate cancer patients.35 Ortega et al found a positive correlation between docetaxel chemotherapy and ZA in inducing ONJ (statistically not significant).12 This might be attributed to the anti-angiogenic properties of both drugs. Further investigations are needed to validate the synergistic association of these two drugs in developing ONJ.
Teriparatide
Teriparatide is a parathormone (PTH) analog. Experimental data demonstrated that the prolonged use of teriparatide may lead to bone loss, but intermittent usage of low-dose PTH promotes osteoblastic activity. Teriparatide (20 mg) was reported to reduce the fracture rate. In addition, many case studies suggest teriparatide as a treatment modality for MRONJ.36 Teriparatide, however, cannot be recommended for prostate cancer patients with osseous metastases.37
Conclusion
The judicious use of antiresorptive drugs reduces complications associated with drug therapy. In patients with non-metastatic disease, lifestyle changes complemented with balanced nutrition and vitamin D supplementation are recommended. ARDs should be prescribed based on T-score (bone density test) or Frax score (osteoporosis-related fracture risk). In metastatic prostate cancer patients, considering the crucial role ARDs play, stopping the drugs before dental treatment is still ambiguous. When prescribing these drugs, the oncologist must analyze risks versus benefits and follow a multidisciplinary approach. The patient's disease status should be taken into consideration before dental treatment planning. The task force on design and analysis in oral health research on MRONJ emphasized the role of prevention prior to ARD therapy.16
Several key considerations must be made before ARD usage in prostate cancer patients. Prior to the prescribing of ARDs, a trained dental professional capable of recognizing clinical and radiographic signs of MRONJ should perform a comprehensive oral health assessment. Also, the risk of MRONJ is higher in patients on IV ARD compared to oral antiresorptive drugs. When treating dental lesions, a conservative approach should be followed, if possible. In cases where extractions are inevitable, alveolectomy and biological membrane placement can significantly lower the risk of MRONJ.38 Regular follow-up visits with a dentist are recommended during and after BP therapy. The patient should be educated regarding the maintenance of good oral hygiene. Lastly, interchanging BPs during treatment ideally should be avoided.
About the Authors
Anusha Vaddi, BDS, MDS
Oral Radiology Resident, Section of Oral and Maxillofacial Radiology, Division of Oral and Maxillofacial Diagnostic Sciences, University of Connecticut School of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut
Sunita Manuballa, DDS
Clinic Chief, Department of Dentistry and Maxillofacial Prosthetics, Program Director, General Practice Residency, Assistant Professor of Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
Sebastiano Andreana, DDS, MS
Professor and Director of Implant Dentistry, Department of Restorative Dentistry, School of Dental Medicine, State University of New York at Buffalo, Buffalo, New York
Queries to the author regarding this course may be submitted to authorqueries@aegiscomm.com.
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