TPTD is a molecule that contains the first 34 amino acids at the N-terminus of the parathyroid hormone (PTH) sequence, also known as PTH (1–34) (57). It was approved by the U. S. Food and Drug Administration (FDA) in 2002 as the first anabolic agent for the treatment of osteoporosis (58). An RCT demonstrated that TPTD can reduce the risk of new vertebral compressions by up to 65% and increase bone mineral density (BMD) by 9% in the lumbar spine (59). Currently, TPTD is administered daily via subcutaneous injection for 18–24 months to lower the risk of vertebral and non-vertebral fractures (60).

However, controversy remains regarding the safety of TPTD, particularly concerning its potential to induce or accelerate cancer. In preclinical studies, TPTD was associated with a dose-dependent increase in the incidence of osteosarcoma in rats (61). However, no cases of osteosarcoma were reported during clinical trials or in a 5-year post-treatment follow-up study, which included seven long-term trials. Only a few spontaneous cases of osteosarcoma have been observed in patients treated with TPTD. Although the osteosarcoma warning was removed from the official drug labelling in 2020, caution is still advised in certain cases. Contraindications for TPTD include a history of radiation therapy, the presence of primary or metastatic bone tumours associated with hypercalcemia, and Paget’s disease (62). Therefore, the use of TPTD is limited in patients with cancer, particularly in those with primary bone tumours, bone metastasis, or a history of radiation therapy.

The first reported use of TPTD for the treatment of MRONJ was documented in 2013 (63). In this case report, two patients experienced recovery and regional osteogenesis after 3 months of TPTD injections (administered daily in one case and monthly in the other). More recently, additional case reports and case series have been published. Sim et al. (14) conducted an RCT in which patients with MRONJ received subcutaneous TPTD injections (20 μg/d) or placebos, along with calcium and vitamin D supplementation and standard clinical care, for 8 weeks. The study found that TPTD was associated with a higher rate of MRONJ lesion resolution than the placebo group. Ohbayashi et al. (72) compared daily versus weekly TPTD administration over a 6-month period in patients with osteoporosis and observed significant improvements in MRONJ staging in both the overall patient cohort and daily administration group (14). However, the small sample sizes in both studies (34 and 13 patients) and the distinct disease backgrounds in Sim’s cohort (85.3% of patients with cancer and 14.7% with osteoporosis) limited the generalisability of these findings.

The mechanism of action of TPTD involves promoting bone remodelling, enhancing osteoblast (OB) activity, and increasing both calcium absorption and reabsorption (64), ultimately leading to increased BMD. However, the precise mechanism by which TPTD restores MRONJ lesion healing remains unclear. Yu et al. (65) hypothesised that activation of the Wnt/β-catenin signalling pathway, promotion of angiogenesis, and downregulation of inflammatory factors play essential roles in the healing of MRONJ. These hypotheses are supported by animal studies (66, 67) on the role of Wnt/β-catenin and by both in-vitro (67) and in-vivo (68) studies on angiogenesis.

Additionally, rodent models have demonstrated that TPTD can repair osteoarthritis lesions by inhibiting tumour necrosis factor alpha (TNF-α)-mediated upregulation of MMP-13, blocking the infiltration of macrophages and lymphocytes (69), and suppressing the expression of pro-apoptotic and inflammatory molecules, such as Bcl-2-associated X protein (BAX), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), interleukin-6 (IL-6), and TNF-α. This suggests a potential role for the regulation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway (70). However, none of these mechanisms have been directly studied in humans.

TPTD and PENTO both offer promising potential in the treatment and prevention of MRONJ. A comparison of their possible targeting pathways, administration routes, dosages, durations, adverse effects and limitations is summarised in Table 1. TPTD, originally repurposed from treating osteoporosis, targets the Wnt/β-catenin and angiogenesis pathways via multiple related factors. It also has anti-inflammatory effects, reducing levels of IL-1β, TNF-α, IL-6, iNOS, and COX-2. TPTD is administered either daily or weekly, via subcutaneous injection. However, owing to its potential carcinogenic risk, TPTD should not be used in patients with cancer. In addition, hypercalcaemia, dizziness and nausea have been reported as adverse effects of TPTD (114).

In contrast, the PENTO protocol, repurposed from ORN treatment, is used for both treating and preventing MRONJ. PENTO affects pathways related to microvascular permeability, red blood cells deformability, vasodilation, ATP supply, and antioxidant activity. PENTO is typically administered orally, and the dosage and duration for prevention MRONJ are significantly lower than those for treatment. Unlike TPTD, PENTO has no reported carcinogenic effect and even shows anti-cancer effects on multiple cancer types (115, 116), making it suitable for a broader patient population, including patients with cancer. For PENTO, common adverse effects include gastrointestinal upset, dizziness, and headaches for PTX, while high doses of TOC can cause nausea or diarrhoea. Overall, PENTO has been reported to be safe for patients with ORN and poses no carcinogenic risk.

TPTD exerts anabolic effects through activation of PTH and downstream signalling pathways involved in bone remodelling, angiogenesis, and cellular proliferation (62), which may theoretically influence tumour–bone interactions. However, the initial rat studies utilised doses 3–60 times higher than.

therapeutic levels for near-lifetime exposure—conditions that do not reflect clinical practise (61). In addition, currently no mechanistic studies have successfully replicated osteosarcomagenic effects in human cell lines or more relevant models.

Unlike TPTD, PENTO improves MRONJ lesion through indirect mechanisms without altering bone metabolism or the tumour-bone microenvironment, thus avoiding theoretical risks in oncologic populations. However, it also faces limitations in cancer polypharmacy. The major constraint is bleeding risk in anticoagulated patients—prevalent in oncology due to thromboprophylaxis needs—requiring INR monitoring (117) and may rarely associated with thrombocytopenia (118). PTX’s hepatic metabolism may be impaired in patients with liver metastases, therefore worsen fatty liver in patients with pre-existing hyperglycaemia (61). For TOC, there are also concerns about the attenuated chemotherapy or radiotherapy efficacay raised by antioxidatnt (119, 120), though clinical evidence is lacking. These factors necessitate careful patient selection and enhanced monitoring, potentially limiting PENTO’s applicability in heavily pretreated or medically complex oncologic populations.

High quality clinical trials for MRONJ are limited. A review by Beth-Tasdogan et al. (4) analysed 1,047 studies focused on MRONJ management, including 13 RCTs in the final analysis (other studies were excluded owing to the high risks of bias). Among the completed studies, five investigated preventive strategies and eight focused on treatment.

Among the 13 trials, 4 used products rich in growth factors, including plasma rich in growth factors (PRGF), platelet rich fibrin (PRF), and concentrated growth factor (CGF), to prevent or treat MRONJ. These products are derived from the patient’s own blood through specific centrifugation processes and are endowed with the capacity to enhance tissue regeneration and repair. This approach has applications in fields, such as oral surgery, orthopaedics, and dermatological regenerative therapies (136, 137).

Surgical interventions have been explored in several studies. Two trials used autofluorescence to guide jawbone resection, while another compared different surgical protocols for post-extraction wound closure. These advances in surgical techniques aim to minimise pharmacological risks and trauma, but they have not significantly improved MRONJ outcomes.

Among the 13 trials, 2 investigated TPTD injections for treating MRONJ, yielding promising results. Sim et al. administered subcutaneous TPTD injections (20 mg/d) or placebos, along with calcium and vitamin D supplementation, to patients with MRONJ over 8 weeks. Their findings showed a higher rate of lesion resolution in the TPTD group than that in the placebo group (14). Ohbayashi et al. compared daily and weekly TPTD administration over 6 months in patients with osteoporosis, observing notable improvements in MRONJ staging in both the entire cohort and daily group (72). However, the small sample sizes (34 and 13 patients, respectively) and differences in patient populations (Sim’s cohort included 85.3% patients with cancer and 14.7% patients with osteoporosis) limit the reliability of these findings.

Additionally, as mentioned above, TPTD was associated with an increased risk of osteosarcoma in a phase III study (138), posing significant risks for patients with cancer and contraindicating its use in patients with pre-existing hypercalcemia, severe renal impairment, metabolic bone diseases (e.g., hyperparathyroidism or Paget’s disease), unexplained elevated alkaline phosphatase, and prior radiation therapy to the skeleton (139). As a result, TPTD use in patients with MRONJ has been greatly restricted.

Two ongoing RCTs are currently examining the effects of the PENTO protocol in patients with MRONJ. Recent studies have shown that patients with MRONJ and osteoporosis who received PENTO experienced faster healing after tooth extraction and a lower recurrence rate than controls (112). Unlike TPTD, PENTO does not carry the risk of osteosarcoma or disruption of bone metabolism, making it a viable option for a wider range of patients.

Of the 13 RCTs (140, 141), 2 indicated that applying autologous platelet concentration (APC) to the tooth socket led to lower MRONJ occurrence than that under the standard treatment. Additionally, 3 of the 13 RCTs (142–144) combined APC with surgical interventions, resulting in a higher proportion of mucosal coverage than that of surgical intervention alone. However, the small sample sizes may have affected the ability to detect significant effects.

Overall, methodological constraints of the trials were associated with a high risk of bias, contributing to uncertainty about any estimates of effect (4). While various strategies have been proposed to prevent or treat MRONJ, there is insufficient evidence to confidently claim the effectiveness of any tested interventions. Identifying additional drugs for repurposing may offer safer and more effective treatment options in the future.

Table 2 shows the published clinical studies for TPTD (n = 12) and PENTO (n = 9) in MRONJ management. Both TPTD and PENTO showed potential benefits, but the overall level of evidence remains low. Only 6 out 12 TPTD studies compared with control group, while 1 of 9 PENTO studies did the comparison. Most TPTD data derive from small case reports/series and retrospective cohorts, with only one very small RCT (Sim et al., n = 15) (14), while PENTO is supported by a heterogeneous mix of case series, retrospective cohorts and one large RCT (Colapinto et al., n = 202, stage I MRONJ in osteoporotic patients) (112).

In treatment settings, reported complete resolution or stage-improvement rates with TPTD are generally high (145–148) and daily TPTD appears more effective than weekly dosing in limited comparative data (72, 149). PENTO likewise shows favourable outcomes in several non-surgical cohorts and, in Colapinto’s trial, pre-operative PENTO plus standard surgery achieved 100% clinical and radiographic healing and clearly outperformed surgery alone in early-stage osteoporotic MRONJ (112). However, prevention data are extremely limited: in the only PENTO prophylaxis series (74), 17.6% of high-risk cancer patients still developed MRONJ after tooth extraction, and there was no comparison with a control group, indicating that any preventive effect is unproven.

Critically, the evidence base is characterised by marked heterogeneity and substantial risk of bias. Sample sizes are small, most studies are single-arm and non-randomised. Patient populations are mixed (osteoporosis vs. cancer; BP vs. denosumab), BMA exposure (dose, route, duration) is poorly characterised, and BMA management during treatment (continued, altered, or stopped) varies widely. The extent of concomitant surgical intervention also differs substantially between and within studies, making it difficult to disentangle drug effects from surgical effects. Outcomes are often clinician-defined “healing” or stage change, with limited use of standardised radiographic or patient-reported endpoints. Taken together, current clinical data suggest that both TPTD and PENTO may be useful adjuncts, particularly in osteoporotic and early-stage MRONJ, but they are insufficient to define standard indications, optimal regimens, or comparative effectiveness. Larger, well-designed randomised trials with rigorous stratification (cancer vs. osteoporosis, high- vs. low-dose BMA, surgical vs. non-surgical) and standardised outcome measures are urgently needed.

Consistently, across existing guidelines and consensus statements, TPTD and PENTO are generally regarded as potential or experimental options rather than established MRONJ therapies. The current guidelines and consensus are listed in Table 3. Several position papers from North America, Europe (150), Italy and Belgium (151, 152), as well as the 2025 Korean multidisciplinary task force statement (153) and the North American/European endocrine taskforce (2, 154), mention TPTD but uniformly emphasise that current evidence is limited and further studies are required before routine use can be recommended. In contrast, two documents provide more concrete guidance in selected non-cancer populations: the Colombian multidisciplinary consensus (2020) (154) and the Chinese expert consensus (2024) (155) explicitly suggest TPTD for MRONJ in patients without malignancy, recommending 20 μg subcutaneously once daily, for 24 months and at least 8 weeks, respectively. The Chinese consensus is also the only one to specify a PENTO protocol, listing PTX 400 mg twice daily combined with TOC 400–500 IU twice daily. Overall, these recommendations highlight a cautious, case-selected use of TPTD and PENTO, reserved mainly for refractory MRONJ in non-oncologic patients, within a context of still-insufficient high-quality evidence.

Intellectual property (IP) rights present challenges for drug repurposing. Securing IP protection for a newly repurposed medical use of an existing drug is possible if the new use is novel and inventive (158, 159). However, many repurposing opportunities are already documented in scientific literature, limiting patent protection options. Even when a drug shows promise, market entry can be delayed or blocked by IP conflicts (160). For off-patent drugs, limited return on investment makes industries reluctant to fund trials. Beyond patent issues, regional legal and regulatory obstacles hinder progress (161, 162). Regulatory incentives or formal guidance to encourage repurposing research are often lacking.

Pharmacological challenges arise when estimated effective drug concentrations cannot be clinically achieved through repurposing. Drugs designed for specific receptors or tissues may not have the same efficacy when used for other therapeutic purposes. Higher doses or drug interactions may be necessary to reach therapeutic levels, which could introduce off-target effects and unforeseen side effects. In patients with cancer, polypharmacy can further complicate treatment, leading to unexpected interactions. For instance, TPTD’s potential carcinogenic effects limit its use in patients with cancer, while PENTO may enhance blood flow, potentially increasing the risk of metastasis. The feasibility of repurposed treatments depends on the tolerability of side effects during administration.

None of the trials on TPTD or PENTO have determined whether drug suspension for established MRONJ is necessary during the interventions. In fact, there is a lack of consensus in the guidelines regarding the suspension of antiresorptive therapy for treating MRONJ (163). There is insufficient evidence to suggest that the benefits outweigh the risks to the primary disease; thus, recommendations should be interpreted cautiously (164). Drug suspension should be considered on a case-by-case basis in consultation with the prescribing clinician.

Additionally, dosage adjustments can escalate the risk of adverse events. Repurposing TPTD for MRONJ requires doses of 20 μg/d or 56.5 μg/week, the latter of which is not commonly used for osteoporosis treatment. Although trials have compared these dosing protocols (149), more evidence is needed to determine the safety and effectiveness. In addition, the staging of MRONJ varies among each patient, and there are significant differences in the extent and size of involvement. However, in the published results, the exploration of the optimal dosage is still ongoing, and there are no specific recommendations for patients with MRONJ at different stages yet.

With the ageing population, the demand for anti-resorptive and anti-angiogenic drugs is growing, along with the complexity of patient situations. The use of multiple medications and presence of accompanying diseases in vulnerable populations significantly challenge the management of MRONJ. Studies have shown that in the 3 d before chemotherapy, patients took an average of 9.6 concomitant medications, many of which affect drug metabolism and clearance (165). The interactions among different drugs make selecting appropriate medications even more difficult. Adding medications to prevent MRONJ may increase the risk of overuse, necessitating a more comprehensive and personalised treatment plan for this group of patients.

For patients unable to tolerate oral or injectable drugs, regional drug delivery may be a better option. Compared with systemic administration, applying drugs directly to the jawbone or at-risk areas could improve efficacy and reduce side effects. Further research into regional drug delivery methods should be prioritised.

Despite the severe clinical impact of MRONJ, effective prevention and treatment strategies remain limited. MRONJ poses significant challenges for patients undergoing anti-resorptive or anti-angiogenic therapies, particularly those with cancer. Current interventions, supported by low-level evidence, are not universally applicable and yield inconsistent outcomes across medical centres. With the rise of new cancer therapies and the complex health issues faced by patients with cancer, drug repurposing offers a potential solution for rapid and safe MRONJ management. By adopting drug-, disease-, and target-centric approaches, candidate drugs can be screened for personalised and precise treatment options.

Based on existing evidence, PENTO appears to be the most promising option, particularly for cancer patients, owing to its favourable safety profile and lack of theoretical risk for promoting metastasis. Conversely, TPTD demonstrates significant potential for bone regeneration but is best reserved for non-oncologic osteoporotic patients due to contraindications in active malignancy. Despite these promising findings, a major evidence gap remains: there is a lack of large-scale RCTs directly comparing these protocols against the standard of care. Future research must prioritise establishing standardised dosing regimens and validating these findings in human cohorts to transition these therapies from experimental use to clinical guidelines.

Consequently, this review has several limitations. First, it relies primarily on data from small-sample clinical studies and animal models, as high-quality RCTs remain rare. Second, while the mechanistic hypotheses regarding TPTD and PENTO are theoretically well-detailed, they currently lack robust validation in human subjects. Third, due to inconsistent reporting in the primary sources, the discussion regarding specific adverse events and long-term safety profiles is limited. Finally, cost-effectiveness analyses and patient-reported outcomes were not addressed, as they were beyond the scope of this paper.