Major clinical modifiers that commonly coexist in older adults, including sex differences, metabolic disorders (particularly diabetes mellitus), smoking status, polypharmacy, and exposure to antiresorptive or anticancer therapies must be considered when interpreting aging-related effects in the following disease contexts. These factors interact with aging-related immune and skeletal changes and substantially influence the magnitude, trajectory, and reversibility of alveolar bone loss.

Periodontitis and alveolar bone loss in the aged

The hallmark of periodontitis is the loss of attachment, including breakdown of the periodontal ligament and resorption of the alveolar bone, ultimately leading to tooth loosening. In older adults, periodontitis tends to present as a “high-inflammation, low-repair” state in the periodontium.

One key aspect is the contribution of the aged immune response to periodontal bone loss. Periodontal lesions are characterized by the infiltration of neutrophils, macrophages, T cells, and B cells that produce an array of cytokines and proteases. In younger individuals, although these mediators cause bone resorption, the capacity for resolution and tissue repair if the infection is controlled exists. However, the resolution may be impaired in older individuals. Studies have shown that immunosenescence skews the response; for example, neutrophils from aged mice have reduced chemotaxis toward bacterial chemoattractants but paradoxically exhibit a hyperactive phenotype in situ, releasing more superoxide radicals and neutrophil extracellular traps that can damage tissue [30]. Magne et al. [30] have reported that in a ligature-induced periodontitis model, aged mice (versus young mice) had greater alveolar bone loss, and their neutrophils displayed excessive reactive oxygen species generation and NETosis despite sluggish migration. These “hyperfunctional” neutrophils likely contribute to collateral tissue damage in periodontal lesions of older hosts.

Macrophages and lymphocytes behave differently in the aging periodontium. Aged macrophages often exhibit an M1 pro-inflammatory bias and decreased clearance of apoptotic cells, thereby prolonging inflammation [7]. Aging adaptive immunity features an expansion of memory T cells and less naive T cell output. Th17 cells, which secrete IL-17A and RANKL, both potent stimulators of osteoclasts, are increased in periodontitis. Studies have shown that reducing Th17 activity can limit alveolar bone resorption [31]. In older individuals, an elevated basal IL-17 environment has been observed in the bone tissue, suggesting that inflammaging may tilt T cell responses toward osteoclast-activating profiles [21]. Moreover, B cells in periodontal lesions can differentiate into plasma cells that produce RANKL. With age, a higher proportion of differentiated B cells may infiltrate the gingiva [7].

The exaggerated production of osteoclastogenic signals is a direct consequence of these immune changes. Gingival fibroblasts and periodontal ligament cells from older patients may produce more pro-inflammatory mediators in response to bacterial lipopolysaccharide than those from younger cells. For instance, aged gingival fibroblasts show a five-fold decrease in collagen synthesis and increased production of inflammatory prostaglandin E2 and IL-1β when challenged with bacterial components [5]. These cytokines (prostaglandin E2, IL-1β) and others, such as IL-6 and TNF-α, amplify RANKL expression on osteoblasts/stromal cells or are released in soluble form by T and B cells, driving local osteoclast differentiation.

Compelling evidence for the intersection between aging and periodontal inflammation comes from molecular analysis of human periodontal tissues stratified by age. A study by Teixeira et al. measuring inflammatory cytokine expression in the gingiva and reported that older patients (> 60 years) with chronic periodontitis had significantly higher levels of IL-1β, IL-6, and TNF-α in their lesions than in middle-aged adults [32]. This aligns with the concept that “inflammaging” upregulates these bone-resorptive cytokines. Another noteworthy finding is the role of senescent cells in periodontal disease progression: alveolar bone osteocytes showing senescence markers were more prevalent in old mice with periodontitis, and their SASP factors (IL-6, IL-17, etc.) likely fueled further bone destruction. Aquino-Martinez et al. have demonstrated that the accumulation of senescent osteocytes in the periodontium of old mice exacerbates chronic inflammation and reduces bone regeneration, thereby accelerating periodontal breakdown [21]. This raises the intriguing possibility that senolytic strategies have been shown to improve bone parameters in aged animal models; whether similar benefits can be achieved in alveolar bone regeneration in humans remains to be established.

From a clinical perspective, older persons with periodontitis may experience more rapid radiographic bone loss and a blunted healing response to conventional therapy. For example, periodontal regenerative procedures (such as guided tissue regeneration or bone grafts) can be successful in older patients; however, healing may be slower and less predictable. The basic biological reasons include reduced cell turnover in the periodontal ligament, diminished angiogenesis in the bone, and perhaps a dominance of pro-inflammatory immune cells that do not easily switch to a healing phenotype. Additionally, the periodontal ligament in older adults has fewer cells and a more irregular structure. Mechanical loading on the periodontium (e.g., chewing forces) in older individuals might cause micro-damage that is repaired more slowly, thereby compounding disease susceptibility.

Some animal studies have suggested that aged subjects may sometimes exhibit less acute bone resorption than young subjects in certain models of periodontitis because of weaker immune activation. For instance, a mouse study of periodontal pathogen infection reported that young mice showed a strong immune response with significant bone loss, whereas older mice had dampened immune cell infiltration and showed lower peak bone resorption; however, they also failed to clear the infection effectively, leading to a chronic low-grade lesion [33]. This highlights that aging can both attenuate and aggravate aspects of the disease. Initial acute responses may be blunted (reducing early tissue breakdown), yet the inability to resolve inflammation can result in prolonged disease activity and cumulative bone damage over time.

In summary, periodontitis in older individuals is influenced by immunosenescence (reduction in protective immune functions), inflammation (increase in destructive inflammatory signaling), and the presence of senescent cells in periodontal tissues. All these factors converge to shift the balance toward bone resorption and away from regeneration. Effective management of periodontitis in older patients may require mechanical removal of bacterial plaque and adjunctive strategies to modulate the host response, as discussed in later sections on immunomodulatory therapies.

Periapical bone resorption due to pulp infection (endodontic lesions)

In chronic periapical periodontitis, bone metabolism and immune responses are closely intertwined. These lesions result from the host’s immune reaction to a bacterial infection, which spreads from the root canal into the periapical tissues, causing localized bone resorption [34]. The effects of aging on periapical lesion development and healing are highly pertinent to endodontic outcomes in older patients.

In the acute phase of pulp infection, neutrophils and macrophages flood the periapical area, releasing enzymes and reactive oxygen species that begin to erode the bone [35]. Over time, chronic granulomatous tissue forms, containing macrophages, lymphocytes, and often an epithelial component. Bone resorption at the apex is driven by many of the same mediators as in periodontitis, such as IL-1β, TNF-α, IL-6, and prostaglandins, which stimulate osteoclast formation [36]. Aging can influence this process in several ways, including differences in immune cell function, inflammatory milieu, and regenerative capacity of the bone.

Human clinical data suggest that older individuals have a more intense expression of inflammatory mediators in chronic apical lesions. In 2021, Teixeira et al. compared the immunohistochemistry of cytokines in chronic apical periodontitis lesions in older patients (> 60 years) and younger adults [32]. The results showed significantly higher levels of IL-1β, IL-6, and TNF-α in lesions of the older group. These cytokines are central to periapical bone resorption; IL-1β in particular has long been known to directly induce osteoclast activation in apical periodontitis. The heightened presence of these cytokines in the lesions of older patients aligns with the concept of inflammaging: older individuals mount a more pro-inflammatory chronic response, potentially leading to larger or more persistent lesions. This also raises concerns that the same factors that impede periodontal healing may hinder the resolution of apical lesions.

Animal studies have also provided further insights. An intriguing mouse model compared apical periodontitis development in young and older mice (e.g., young adult vs. middle-aged mice) by inducing pulp exposure and infection. Older mice developed smaller periapical lesions than younger mice, accompanied by fewer neutrophils and osteoclasts [33]. Young mice show robust neutrophil infiltration and osteoclastic activity, causing more extensive bone destruction [37]. This suggests that the attenuated immune response in older mice leads to less acute bone resorption. Translating this to humans, older patients might not experience pronounced pain or swelling (signs of acute apical abscess) owing to a blunted response; however, they could develop a chronic apical granuloma that remains unresolved.

The capacity of periapical bone regeneration after treatment is also affected by age. Successful endodontic treatment removes the source of the infection, allowing the inflammatory drive for bone resorption to cease and bone healing to commence. Clinical follow-up studies using radiography or cone beam computed tomography have identified age as a factor that affects healing speed. A recent cone beam computed tomography-based retrospective analysis of large apical lesions (10–15 mm) treated non-surgically revealed that although approximately 76% of the lesions healed completely, the time to radiographic healing was significantly longer in older patients. Specifically, an increase in patient age was associated with a prolonged healing time, with many older patients taking well beyond 18 months to fully ossify, whereas lesions in younger patients often healed between 12 and 18 months [38]. This study reported that “periapical lesions in older patients and larger areas of bone loss take longer to heal.”

In clinical practice, delayed periapical healing in older patients is further influenced by systemic metabolic conditions (such as diabetes mellitus), smoking status, and medication exposure, which independently affect angiogenesis, immune resolution, and osteogenic capacity beyond the effects of chronological aging alone.

Immunologically, older age may alter the profile of the cells that orchestrate periapical healing. Younger patients tend to mount a strong initial inflammatory response that transitions into a healing phase dominated by macrophages that shift to the M2 phenotype and recruit osteoblast precursors to lay down new bone. In older patients, there may be an imbalance in the presence of pro-inflammatory M1 macrophages or senescent immune cells. A recent concept in endodontic research is that inflammasome activity in periapical lesions contributes to bone destruction, and aging may upregulate inflammasome components, similar to periodontitis. For example, NLRP3 and caspase-1 have been shown to be active in human periapical tissues, and their blockade could reduce IL-1β levels and lesion size [39]. If older patients have a higher baseline inflammasome activation, they might experience more IL-1β-driven tissue breakdown in the chronic phase of apical periodontitis.

Another factor is the regenerative properties of the periapical periosteum and endosteum. These tissues contain stem cells that form the bone. Available studies report that periapical healing relies on mesenchymal stem cell recruitment from the bone marrow and perhaps the periodontal ligament [40]. Aging can reduce the number or osteogenicity of recruited cells. Additionally, repeated episodes of periapical inflammation can induce scarring or irreversible changes in the local microenvironment, making it less conducive to bone regeneration. Notably, clinical progression of periodontitis in older adults is strongly modified by sex-related hormonal status, smoking, glycemic control, and medication use, which can amplify or mask aging-associated immune and bone remodeling changes.

In summary, although the initial acute response to pulpal infection may be less intense in older individuals, the chronic phase of periapical lesions in older individuals tends to show higher pro-inflammatory cytokine levels and slower or incomplete bone repair. Clinically, endodontists should be aware that teeth in older patients may show persistent apical radiolucencies for longer post-treatment periods, necessitating extended observation periods. Strategies to improve healing include systemic or local adjuvants that enhance bone formation or modulate inflammation in older individuals. The interplay between aging and apical periodontitis underscores the importance of considering host factors in the prognosis and treatment planning for endodontic diseases.

Tumor- or malignancy-associated bone resorption in the oral cavity

Malignant tumors involving the oral and maxillofacial regions frequently lead to destruction of the adjacent bone. Bone loss can be rapid and aggressive and is commonly associated with tumor-induced osteoclast activation and/or direct invasive growth. Although tumor-related bone resorption is principally dictated by the biology of the cancer, the context of aging is relevant because most patients with oral cancer or bone metastases are older adults. Age-related bone conditions (such as osteopenia or Paget’s disease) and immune changes may influence the interaction between the tumor and the bone microenvironment. Additionally, bone regeneration after tumor resection must contend with reduced healing capacity in older patients.

Local invasion by oral cancers

Because direct mechanistic studies of jaw-specific tumor invasion and metastasis are limited, the following discussion integrates available jaw-specific observations with hypotheses derived from systemic and long-bone metastasis models, which are presented as mechanistic frameworks rather than established jaw-specific pathways.

Oral squamous cell carcinoma (OSCC) is a common oral malignancy that often presents in the 6th to 8th decades of life. When OSCC is located in the gingiva or retromolar area, it can invade the underlying mandible or maxilla. Tumor invasion into bone has been described as occurring through a “vicious cycle” similar to mechanisms established in skeletal metastasis models; cancer cells stimulate osteoclasts to resorb bone, and the released growth factors from bone matrix in turn promote tumor growth. A recent clinical study analyzing OSCC with mandibular invasion reported that areas of bone invasion had significantly higher numbers of osteoclasts than non-invaded areas, and that OSCC cells at the bone front showed increased expression of RANKL and RANK. These findings suggest that OSCC cells may upregulate components of the RANK–RANKL pathway at the bone invasion front, which is consistent with the enhanced osteoclast activity observed in invaded regions [41].

From a molecular standpoint, OSCC and other cancers have been reported to express various osteolytic mediators, including parathyroid hormone-related peptide, IL-6, IL-8, vascular endothelial growth factor, and proteases, all of which have been implicated in promoting bone degradation in experimental and clinical studies. In skeletal metastases, the RANKL:OPG ratio in the bone often shifts drastically in favor of RANKL [42]. Although data specific to jaw metastases are limited, findings from long-bone metastasis models suggest that similar osteoclast-activating signaling pathways may be engaged following tumor colonization of jawbone. For example, breast cancer cells frequently secrete parathyroid hormone-related peptide in the bone environment, which binds to osteoblasts and stromal cells and triggers the upregulation of RANKL while downregulating OPG [43]. This mechanism has been well-documented as a driver of osteolytic metastases in long bones [44], and analogous processes may occur in the jaw, although direct experimental validation remains limited.

Distinguishing local OSCC-driven bone invasion from metastatic osteolysis in the jaw is crucial. Local invasion reflects direct tumor–bone interactions at the primary tumor margin and is influenced by local inflammatory, mechanical, and stromal factors specific to the oral microenvironment. In contrast, metastatic osteolysis involves hematogenous tumor dissemination, bone marrow colonization, and systemic tumor–bone signaling mechanisms, which are biologically distinct processes and far less common in the jaw.

Impact of aging on tumor–bone interactions

Older patients may experience more severe consequences of tumor-related bone loss for a few reasons. First, they may have a pre-existing low bone density or osteoporosis, which means that less reserve is available before a pathological fracture or tooth loss occurs from tumor osteolysis. Second, the ability of the peritumoral bone to mount reactive bone formation can be diminished. In younger patients, the host response to a tumor invading the bone sometimes includes laying down new bone at the margins; in older patients, this osteogenic response might be weaker, allowing more extensive infiltration. Immunosenescence may play a role in this process. Research is emerging on how an aging immune microenvironment facilitates cancer progression. In the bone microenvironment, age-related immune changes may be associated with reduced containment of tumor cells and prolonged osteoclast activity, although direct clinical evidence in the jaw remains limited, unchecked by immune regulation.

Many therapies for cancers that cause bone loss involve antiresorptive agents, which have implications for the aging population. These drugs are often administered to prevent skeletal events in metastatic cancer or multiple myeloma (median age ~ 70 years), curb osteoclast activity, and protect bone mass. For instance, clinical studies have shown that denosumab (a monoclonal antibody against RANKL) reduces tumor-associated osteolysis by inhibiting RANKL-mediated osteoclast activation though blocking the RANKL–osteoclast pathway [45]. Although beneficial for controlling bone destruction, their use in the jaw is tempered by the risk of medication-related osteonecrosis of the jaw, especially in older patients with comorbidities. Medication-related osteonecrosis of the jaw is a failure of bone healing that can occur spontaneously or after dental extraction when potent antiresorptives are used. This underscores that manipulating bone remodeling in the context of malignancy and aging is a double-edged sword: halting osteoclasts protects bone from cancerous destruction but may also impair normal regenerative turnover, particularly in alveolar bone regularly subjected to micro-injury and dental interventions.

Bone regeneration after tumor resection

In oral cancer therapy, a common scenario is surgical resection of a part of the jaw to remove the tumor, followed by efforts to restore the form and function of the jaw. Older patients also have disadvantages regarding regeneration. They often have slower wound healing, and autogenous bone graft quality may be compromised by age-related factors [46]. Additionally, radiation therapy, which is frequently used as an adjunct treatment in head and neck cancers, causes further damage to bone vascularity and cells, compounding the challenge of regeneration. The intersection of aging and radiation leads to a highly compromised healing environment, which can result in osteoradionecrosis if not carefully managed.

From a pathophysiological perspective, after tumor removal, the healing of bone defects depends on periosteal and marrow cells to produce new bone, as well as on angiogenesis to vascularize the regenerating tissue. In older patients, periosteal ossification tends to be less robust, and the periosteum itself may be less cellular. The growth factor levels that drive repair may be lower or less responsive in aged tissues.

In conclusion, malignancy-associated alveolar bone resorption is largely governed by tumor biology; however, the extent of damage and success of subsequent regeneration can be influenced by the age of the host. Older patients may experience greater net bone loss and reduced regenerative capacity, consistent with age-related changes in bone and immune function. Therapeutically, this necessitates a combination of oncological control and regenerative strategies tailored to the aged bone environment.