STATE OF THE ART ON SYSTEMIC AND ORAL COMPLICATIONS OF BISPHOSPHONATE USE IN CANCER PATIENTS AND/OR PATIENTS WITH OSTEOPOROSIS

C. Genovesi^1* and R. Grilli²

¹ Skin Centres, Private Practice, Avezzano-Pescara, Italy;
² Dentistry, Private Practice, Chieti-Pescara, Italy.

*Correspondence to:
Corinna Genovesi,
Dentistry, Private Practice,
Chieti-Pescara, Italy.
e-mail: corinnagenovesi@gmail.com

Received: 12 February, 2026 Accepted: 19 March, 2026

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2026 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Background: Bisphosphonates (BP) are anti-resorptive agents used for osteoporosis, skeletal metabolic diseases and to reduce skeletal events in cancer patients. Despite their established efficacy, the introduction of more potent analogues and parenteral regimens has increased attention on systemic and oral adverse events, particularly MRONJ. Methods: Narrative review of the literature up to February 2026 on PubMed/MEDLINE, Embase and Cochrane; key terms: bisphosphonates, zoledronic acid, alendronate, ibandronate, pamidronate, denosumab, MRONJ, atypical femoral fracture, renal toxicity, hypocalcaemia. Systematic reviews, RCTs, large cohorts, guidelines and position papers were included. Results: RCT studies (HORIZON and others) confirm the reduction in vertebral and non-vertebral fractures and benefits in oncology with parenteral BPs. Significant adverse events include nephrotoxicity (especially for high-dose IV administration), post-infusion hypocalcaemia, atypical fractures related to prolonged use, and MRONJ, the incidence of which varies widely between oncological and osteoporotic settings. Risk factors for MRONJ include tooth extractions, odontogenic infections, duration of therapy, and concomitant therapies (antiangiogenic agents, steroids). Guidelines recommend pre-therapy dental screening and a multidisciplinary approach; the usefulness of drug holidays remains uncertain. Conclusions: The benefits of BPs require a personalised risk/benefit assessment, with dental prevention protocols and clinical monitoring. Prospective studies are needed to clarify strategies for treatment duration and MRONJ prevention.

KEYWORDS: Bisphosphonate, cancer, osteoporosis, MRONJ, oral pathology

INTRODUCTION

Bisphosphonates (BPs) are the standard therapeutic class for the treatment of osteoporosis, numerous skeletal metabolic diseases and the management of skeletal complications in cancer patients. These drugs are synthetic analogues of inorganic pyrophosphate- s with high affinity for calcium (Ca2⁺)1. The strong affinity of BPs for bone, and not for other tissues, makes them potent inhibitors of bone resorption and bone remodelling activity, with limited potential for side effects in non-skeletal tissues. All BP compounds accumulate for long periods of time in the mineralised bone matrix, thereby modifying bone metabolism (1). The last twenty years have seen significant pharmacological and therapeutic developments; analogues with greater anti-resorptive potency have been developed and high-dose parenteral administration regimens have been introduced (e.g. zoledronate in annual formulations for osteoporosis or in monthly/quarterly administrations in cancer patients), with documented benefits in terms of clinical efficacy and therapeutic adherence (2). These advances have consolidated the widespread use of BPs but have also posed new clinical challenges related to safety, with increasing attention to systemic adverse events such as nephrotoxicity, hypocalcaemia and atypical fractures, as well as oro-maxillofacial complications such as medication-related osteonecrosis of the jaw (MRONJ). Systemic administration of BPs or denosumab is the routine therapy for osteolysis, but it has significant side effects, such as mandibular osteonecrosis and hypocalcaemia (3). It is therefore essential to exploit optimized drug delivery systems, and some new nanotechnologies and nanomaterials have opened up new horizons for scientists. Targeted and local drug delivery systems can optimise biodistribution depending on nanoparticles or microspheres and implantable biomaterials with controllable properties. Drug delivery kinetics can be optimised by smart and prolonged/local delivery systems for reactive and prolonged delivery. These delicately manufactured drug delivery systems with special matrix, structure, morphology and modifications can minimise unexpected toxicity caused by systemic delivery and achieve the desired effects through the integration of multiple drugs or multiple functions (4). Also relevant is the clinical debate on the management of treatment duration (including the hypothesis of the so-called ‘drug holiday’) and the optimal therapeutic sequence, especially in patients at long-term risk of atypical fractures or with renal comorbidities (Table I).

Table I. The main new bisphosphonates and their systemic and oral side effects associated with their use in the treatment of cancer patients.

Furthermore, the emergence of issues such as MRONJ has stimulated the development of multidisciplinary guidelines, involving dentists, maxillofacial surgeons, oncologists, nephrologists and endocrinologists, aimed at the prevention, monitoring and clinical management of complications (5).

Given the complexity of the interactions between the mechanisms of action of BPs, individual risk factors and the heterogeneity of clinical contexts, a personalised approach that integrates clinical and instrumental assessments, correction of metabolic deficits (calcium/vitamin D), preventive dental screening and periodic laboratory monitoring is essential (6).This article summarises the latest evidence on the efficacy and safety of the main BPs, analyses the risk factors for systemic and oral adverse events, and proposes practical recommendations for prevention and clinical management, in light of the most recent international guidelines and position papers and the increasingly evident need for tailor-made medicine (7).

MATERIALS AND METHODS

A non-systematic narrative search was conducted in the main biomedical databases (PubMed/MEDLINE, Embase, Cochrane Library) up to February 2026. The keywords used included: ‘bisphosphonates’, ‘zoledronic acid’, ‘alendronate’, ‘ibandronate’, ‘pamidronate’, and, for comparison, ‘denosumab’; terms related to complications such as ‘osteonecrosis of the jaw’, ‘MRONJ’, ‘atypical femoral fracture’, ‘renal toxicity’, ‘hypocalcaemia’; and terms related to dental management: ‘dental management’. Systematic reviews, key randomized clinical trials, large observational cohorts, professional guidelines, and position papers from scientific societies were included in the review. Primary evidence, meta-analyses, and updated guidelines from international scientific societies were prioritized in the selection of sources; the methodological quality of the studies and their clinical relevance to everyday practice were also considered. No strict language or date restrictions were applied, but priority was given to literature published in the last twenty years to reflect current practices. Where appropriate, preclinical studies and reviews of mechanisms to support pathogenetic interpretations were also included. The resulting recommendations were supplemented with practical guidance derived from position papers and multidisciplinary consensus statements.

RESULTS

Efficacy and clinical context

Regarding Zoledronate, numerous randomized controlled trials, including the HORIZON studies (Pivotal Fracture Trial and Recurrent Fracture Trial), have demonstrated a significant reduction in vertebral and non-vertebral fractures and a reduction in mortality in the period following a femoral fracture (8). In oncology, registration studies and phase III trials have shown that high-dose regimens and parenteral administration reduce the frequency of skeletal events related to bone metastases, with a positive impact on symptom management and patient quality of life (9). However, these benefits need to be balanced against the specific safety profiles in the oncology setting, where concomitant anticancer drugs may increase vulnerability to adverse events.

Alendronate, risedronate

Regarding Alendronate and Risedronate, an extensive literature consisting of RCTs (including the Fracture Intervention Trial and other multicenter studies) shows a robust reduction in fracture risk in postmenopausal women with osteoporosis, with a favorable safety profile in standard oral therapy (10). Its efficacy is well documented, especially for the prevention of vertebral fractures and the improvement of bone mineral density, while the individual response may vary depending on adherence, duration of treatment and concomitant risk factors (11).

Ibandronate

Data support the efficacy of ibandronate in reducing the risk of vertebral fractures, while evidence regarding the reduction of non-vertebral fractures is less consistent than for other BPs. The heterogeneity of formulations (monthly oral versus quarterly IV) also influences the tolerability profile and adherence (12).

Systemic adverse events

Renal toxicity has been mainly associated with high-dose IV administration, as observed in case series and pharmacovigilance reports; suggested mechanisms include direct tubulo-interstitial effects and renal haemodynamic alterations. Regulatory recommendations and clinical guidelines emphasize the need to assess renal function prior to infusion, to adjust the dosage in cases of renal impairment, and to avoid rapid administration, which may increase the risk (13).

Episodes of hypocalcaemia have been reported, particularly after potent infusions and in patients with extensive bone metastases, insufficient vitamin D status, or comorbidities that reduce calcium reserves. RCTs and clinical series report clinically significant cases, emphasizing the importance of correcting vitamin D and calcium deficiencies before therapy and monitoring blood levels in the first few weeks after infusion (14).

The association between prolonged use of BPs and atypical femoral diaphyseal fractures has been documented in large cohorts and meta-analyses; the cumulative risk increases with treatment periods longer than 5 years (15). Current recommendations suggest clinical and radiographic surveillance in the presence of prodromal pain in the lower limbs and consideration of discontinuation or therapeutic re-evaluation in at-risk patients (16).

Infusion reactions: fever, asthenia and acute myalgia are common after the first IV dose, as reported in the HORIZON studies and in oncology trials; these symptoms are generally transient but may require symptomatic measures.

Oral complications

Meta-analyses and systematic reviews show significant variability in the incidence of MRONJ. In cancer patients undergoing high-dose IV therapy, estimates in some series reach 1–15%, with a higher risk in the presence of tooth extractions or oral infections; in patients treated for osteoporosis with oral BPs, the incidence is much lower, with estimates commonly reported between 0.01% and 0.1%. This variability depends on population factors, type and duration of therapy, and diagnostic practices (17,18).

Risk factors and cofactors: observational data and case-control studies agree on the importance of recent tooth extractions, odontogenic infections, duration of therapy, concomitant use of antiangiogenic agents or corticosteroids, diabetes mellitus, and poor oral hygiene as factors that increase the risk of MRONJ. Invasive oral surgery and radiotherapy of the oral/facial region are also relevant cofactors (19,20).

Pathogenesis

BPs have a high bone attraction and interact with hydroxyapatite crystals. As suggested by multiple studies, these drugs function by prohibiting resorptive activity and inducing apoptosis of osteoclasts. Furthermore, they can have secondary effects, such as acting indirectly on osteoblasts by prohibiting differentiation. This effect is seen in the reduction caused by osteoclast cytokines that inhibit the capability of bone healing (Shibahara, 2019). The half-life of BPs can continue for or exceed a decade because of the great connection with bone crystals, although 95% of the drug is excreted within a few hours. The cytokine receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL), which are released by osteoblasts, are also used to control bone remodeling activity. This approach will increase resorption of bone or osteoprotegerin (OPG), enabling the prevention of resorptive bone action through inhibiting RANK/RANKL binding (21).

Management

updated guidelines (AAOMS, EANM/ESMO, MASCC/ISOO/ASCO) and consensus documents recommend pre-treatment dental screening, preventive dental interventions when indicated, and a conservative approach as first line for early-stage MRONJ, reserving surgery for advanced or non-responsive cases. The efficacy of a ‘drug holiday’ (temporary interruption of BP) has not been definitively proven for the prevention or treatment of MRONJ; recommendations emphasize the need to evaluate each case individually, considering oncological factors, the risk of skeletal events and the half-life of skeletal drugs (22,23).

DISCUSSION

The interpretation of individual risk must take into account numerous clinical and contextual factors that clearly differentiate cancer patients from those with osteoporosis. In cancer patients, the primary goal is often to reduce skeletal events related to metastasis and control skeletal pain; this justifies the use of high-potency, high-frequency parenteral regimens, but also increases the risk profile for systemic adverse events (e.g., nephrotoxicity, hypocalcaemia) and MRONJ. Conversely, in patients with osteoporosis, the therapeutic approach favors a balance between long-term efficacy and safety, evaluating the possibility of sequential therapeutic strategies and planned breaks (drug holidays) to reduce the cumulative risk of complications such as atypical fractures. This differentiation requires protocols adapted to the clinical context, with different levels of surveillance and intervention (24).

It is essential to integrate clinical and instrumental assessments (bone densitometry, targeted radiographic examinations in the presence of prodromal symptoms), bone turnover biomarkers and laboratory monitoring (creatinine, calcium, vitamin D) to establish the individual risk profile and guide therapeutic decisions. The use of bone remodeling indicators (e.g. CTX, P1NP) can be helpful in monitoring, although the clinical thresholds for therapeutic decisions are not universally agreed and further prospective studies are needed to define reliable predictive cut-offs (25).

Prevention of MRONJ requires multidisciplinary protocols that include pre-treatment dental screening, treatment of active dental disease before starting therapy, and planning of invasive procedures only after careful risk/benefit assessment. Patient education on self-monitoring and rigorous oral hygiene practices is crucial for risk reduction. In the case of invasive dental procedures during therapy, close collaboration between the dentist and prescribing physician is recommended to evaluate possible risk mitigation strategies, while recognizing that the effectiveness of temporary drug suspension for preventive purposes remains uncertain (26,27).

Although current guidelines provide practical recommendations, areas of uncertainty remain that limit the standardization of clinical choices. There is a lack of randomized trials that definitively evaluate the effectiveness of drug holidays for the prevention of MRONJ or for reducing the risk of atypical fractures; similarly, there is a lack of comparative studies comparing conservative vs surgical strategies for different stages of MRONJ in homogeneous populations. These gaps necessitate the conduct of prospective, preferably multicenter, studies that integrate clinical outcomes, standardized radiological examinations, and biomarkers to validate diagnostic and therapeutic algorithms.

The management of concomitant therapies is another critical issue. The combination with antiangiogenic agents, corticosteroids or cytotoxic agents increases susceptibility to complications and requires coordinated treatment plans. In patients with renal failure or other significant comorbidities, the choice of drug, dosage and frequency of administration must be carefully adapted, including nephrological assessments and possible therapeutic alternatives (e.g. denosumab, with specific considerations regarding hypocalcaemia and rebound) (28).

Finally, advances in knowledge of pathogenesis (including the role of the bone microenvironment, angiogenesis and immune response) open up prospects for targeted preventive and therapeutic strategies (29,30). Preclinical studies suggest potential adjuvant approaches aimed at improving bone regeneration and local immune response; however, the clinical translation of such strategies requires validation with well-designed clinical trials. In conclusion, optimal clinical practice requires a personalized and multidisciplinary model of care, supported by clinical research aimed at addressing current uncertainties and defining protocols based on robust evidence.

CONCLUSIONS

The clinical benefits of new-generation BPs are well established in both osteoporosis and oncology; however, the use of these drugs requires a personalized approach aimed at minimizing systemic and oral risks. Multidisciplinary collaboration between oncologists, endocrinologists, nephrologists and dental professionals, combined with preventive dental assessment and clinical and laboratory monitoring protocols, remains essential to optimize outcomes. Future research should focus on prospective studies evaluating therapeutic duration strategies, therapeutic alternatives, and preventive approaches for MRONJ in order to provide more robust evidence for shared clinical decisions.

Conflict of interest

The authors declare that they have no conflict of interest.

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