Bone health in patients with cancer: a SEOM-SEIOMM consensus review of risk factors, assessment strategies, and management approaches

Abstract

Anticancer therapies frequently compromise skeletal health and increase fracture risk. This narrative review synthesizes information and provides guidance on assessment, prevention, and management of therapy-related bone loss in adults with cancer. Major contributors to bone loss in this population include aromatase inhibitors, androgen deprivation therapy, systemic glucocorticoids, chemotherapy, and selected targeted or immune agents. Recommended assessments include clinical evaluation, laboratory tests (calcium, vitamin D, and renal function), and bone mineral density by dual-energy X-ray absorptiometry with vertebral fracture assessment and, when acute vertebral fracture is suspected, magnetic resonance imaging. Prevention measures include exercise, adequate calcium and vitamin D intake, and fall-reduction strategies. Pharmacological treatment options include bisphosphonates and denosumab. Selection of treatment should consider skeletal efficacy and potential oncological benefits, while ongoing care includes repeat bone density testing at 12–24 months and vigilance for osteonecrosis of the jaw and atypical femoral fractures.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12094-026-04256-1.

Introduction

As advances in cancer therapy have extended survival, many malignancies are now managed as chronic diseases, making bone health an essential component of long-term care [1]. Bone health directly impacts quality of life by influencing mobility, independence and pain levels.

Fragility fractures (FFs) are a major complication of cancer-related bone loss, and are associated with high morbidity and mortality. In patients with cancer (PwC), a major osteoporotic fracture increases all-cause mortality 2.5-fold within one year [2]. Fractures also cause chronic pain, functional decline and increased risk of institutionalization [3]. Despite this, their burden is often underestimated [4].

Cancer treatments frequently impair bone metabolism. Chemotherapy may induce hypogonadism or malnutrition, accelerating bone loss [5, 6]. Radiotherapy can cause local bone damage and insufficiency fractures [7]. Endocrine therapies are a major contributor: aromatase inhibitors (AIs) in women and androgen deprivation therapy (ADT) in men lead to rapid declines in bone mineral density (BMD), further amplified by agents such as enzalutamide or abiraterone [3, 8, 9]. Glucocorticoids, even at moderate doses, can cause significant bone loss within months [3].

Patient-related factors and the cancer itself further exacerbate bone fragility. Older age, postmenopausal status, inactivity, malnutrition, smoking and alcohol all contribute [3]. Certain tumors secrete osteolytic cytokines, such as parathyroid hormone-related protein (PTHrP) and bone metastases, disrupt normal remodeling. Consequently, PwC often develop skeletal fragility earlier and more severely than the general population [3]. These risks underscore the need for proactive, multidisciplinary strategies to preserve bone health across the cancer care continuum [10].

The aim of this narrative review is to provide an updated and comprehensive overview of bone health in PwC, with a focus on risk factors, diagnostic strategies, and current approaches to the prevention and management of cancer treatment-induced bone loss and FFs.

Methods

This narrative review was informed by a literature search conducted in PubMed in June 2025. The full search string is provided in the supplemental methods. The reference lists of retrieved articles and relevant review papers were manually examined to identify further publications of interest.

Impact of cancer on bone health

Bone loss in PwC results from a combination of direct tumor effects, systemic disease consequences, and treatment-related toxicity.

Chemotherapy can disrupt hormonal balance, particularly estrogen and testosterone levels, leading to rapid bone loss, especially in premenopausal women with chemotherapy-induced ovarian failure [11]. It also affects bone remodeling directly by altering osteoblast and osteoclast activity and inducing senescence in bone marrow adipocytes, which promotes receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclast activation [12]. Inflammatory responses triggered by treatment further exacerbate bone resorption [11].

Radiotherapy may lead to osteopenia, osteoradionecrosis and fractures through damage to osteoblasts and osteocytes. Senescence and adipogenic trans-differentiation of mesenchymal stem cells contribute to reduced bone formation and increased marrow fat [13, 14].

Hormonal therapies are a major driver of treatment-induced osteoporosis. AIs sharply reduce estrogen, leading to rapid BMD loss and increased fracture risk (FR), particularly in the first 12–24 months of treatment [8, 15]. Similar effects are seen in premenopausal women receiving ovarian suppression. In men, ADT reduces both testosterone and estrogen, with average BMD reductions of 5–8% in the first year and a doubling of FR. Additional use of androgen receptor inhibitors further increases this risk [9].

Long-term corticosteroid use is another potent risk factor for osteoporosis. Even moderate doses (≥5mg/day for ≥3 months) can significantly impair bone formation and increase resorption. In addition, corticosteroids may worsen glycemic control, especially in patients with diabetes, which can further disrupt bone mineral metabolism through insulin- and osteocalcin-mediated pathways linking glucose homeostasis and bone turnover [16, 17].

Non-treatment factors also contribute, as older age, postmenopausal status and reduced physical activity are common in PwC and elevate baseline FR [3]. Nutritional deficiencies, smoking and alcohol further impair bone strength. Sarcopenia from illness or treatment exacerbates skeletal fragility.

Advanced solid tumors of breast, prostate, and lung frequently metastasize to bone [3]. Tumor cells disrupt bone homeostasis: osteolytic metastases secrete osteoclast-activating factors such as PTHrP or interleukin 6, while osteoblastic metastases stimulate disorganized bone formation via endothelin 1. Many bone metastases exhibit mixed features [3]. These lesions lead to skeletal-related events (SREs), including pathologic fractures, spinal cord compression, debilitating pain and hypercalcemia, particularly in the presence of lytic disease or myeloma.

Bone health assessment

Clinical guidelines emphasize comprehensive evaluation of bone health for PwC at risk of osteoporosis [3, 16, 18]. The National Comprehensive Cancer Network (NCCN) recommends that, at minimum, the assessment should include [16]:

• Clinical history—with special attention to prior fractures (particularly FFs) and any risk factors for osteoporosis (e.g., family history, menopause or hypogonadism, smoking, corticosteroid use; Table 1).

• Physical examination and laboratory tests—including evaluation of bone pain, height measurement, calcium/vitamin D levels evaluation, etc.

• Risk factor appraisal—identifying modifiable lifestyle factors (diet, exercise, fall risk, alcohol, tobacco, drugs) and comorbid conditions affecting bone metabolism.

• BMD measurement—by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and hip (femoral neck and/or total hip).

Table 1.

Key risk factors for bone loss and fragility fractures in patients with cancer

Category	Risk factors
General osteoporosis risk factors	Age (especially women ≥65, men ≥70)
	Female sex (post-menopause)
	Family history of osteoporotic fractures
	Low body weight (BMI <20 kg/m2)
	Smoking (active or passive)
	Excessive alcohol consumption
	Calcium and vitamin D deficiencies
	Long-term inactivity/Inadequate weight-bearing exercise
	Previous fragility fractures
	Coexisting diseases: rheumatoid arthritis, diabetes mellitus (types 1 & 2), chronic renal/liver disease
	Systemic glucocorticoid therapy (e.g., prednisone-equivalent ≥5mg/day for ≥3 months)
Cancer-specific risk factors	CIOF
	AI therapy for breast cancer
	ADT for prostate cancer
	Bone metastases
	Specific tumor types: multiple myeloma, lung, kidney, thyroid, melanoma, lymphoma
	Primary bone cancers (e.g., osteosarcoma, chondrosarcoma, Ewing sarcoma)

ADT Androgen deprivation therapy; AI Aromatase inhibitor; BMI Body mass index; CIOF Cancer treatment-induced ovarian failure

In addition, guidelines emphasize that estrogen deficiency in women (due to AIs, ovarian suppression, or chemotherapy-induced ovarian failure) and androgen deficiency in men (due to ADT) are key mechanisms underlying cancer treatment-induced bone loss (Fig. 1) [3, 11, 16]. On this basis, the authors recommend that assessment should include measurement of sex hormones (estrogens in women, androgens in men), thyroid function tests and parathyroid hormone (PTH) levels.

Fig. 1.

Mechanisms of cancer treatment-induced bone loss. ADT androgen deprivation therapy; AI aromatase inhibitor; GnRH gonadotropin-releasing hormone; ICI immune checkpoint inhibitor; RANKL receptor activator of nuclear factor κB ligand; TKI tyrosine kinase inhibitor.

BMD alone has limited predictive power for fractures since the majority of FFs occur in patients who do not have osteoporosis by BMD criteria (i.e., T-score > −2.5). Thus, best practice is to combine BMD results with clinical risk factors to estimate a patient’s FR [19]. The most widely used tool is the FR Assessment Tool (FRAX), which incorporates BMD and risk factors (Table S1) [18]. An online FRAX calculator is available [20]. However, no FR model is tailored specifically to PwC, and using FRAX in this population comes with caveats. A registry study in breast cancer (BC) showed that FRAX (with BMD input) predicted FR equally well in women receiving AIs and those not on AIs [21]. As a result, some authors caution against relying on FRAX for women on adjuvant AI, especially younger, premenopausal women for whom FRAX is not validated, because the tool can misestimate fracture probability [22].

FRAX’s limitations are even more pronounced in men on ADT, in whom FRAX may under‑predict risk of fractures. For example, in one study of men starting long-term ADT, 91% were categorized as low-risk by FRAX, which likely misclassifies many at-risk patients. Notably, that study did not report the long-term fracture outcomes, so the true fracture incidence is uncertain. This underscores that standard FRAX, which is calibrated for the general population, might fail to identify a substantial subset of high-risk PwC [23]. Therefore, improved strategies to implement FR assessment specifically for men on ADT are needed [24]. Overall, clinicians should interpret FRAX results with caution in oncology settings and consider cancer-specific factors that FRAX omits [25]. Ideally, risk assessment should be individualized, integrating clinical judgment with tools such as FRAX, rather than relying on any single metric (Table 2).

Table 2.

Recommendations for bone health assessment and monitoring in patients with cancer

Assessment modality	Specifics	Indications and frequency
Clinical assessment	Medical History: Previous fragility fractures, bone pain, hypercalcemia symptoms, family history of osteoporotic fractures, lifestyle factors (diet, smoking, alcohol, and activity), comorbidities (rheumatoid arthritis, diabetes, renal/liver disease), medication history (corticosteroids, PPIs, anticoagulants, antidepressants).	Baseline for all PwC, ongoing.
	Physical Exam: Annual height measurement (detect >4 cm historical height loss or >2cm prospective loss), evaluation of new/worsening back pain, assessment for kyphosis.	Annually, or with new symptoms.
	FRAX Tool: Estimate 10-year fracture risk, considering cancer therapy (AI, ADT, glucocorticoids) as secondary osteoporosis.	Baseline for high-risk patients (Note: May underestimate risk in cancer/diabetes patients; integrate with clinical judgment).
Laboratory tests	BTMs: P1NP, CTX. Collect fasting morning samples for CTX.	Consider for monitoring treatment response and compliance (every 3–6 months).
	Essential Blood: Serum calcium, PTH, 25OHD, creatinine (for renal function).	Baseline and periodically as clinically indicated (e.g., before each antiresorptive dose for calcium/creatinine).
Imaging techniques	DXA: Measures BMD at lumbar spine (L1–L4), total hip, femoral neck. Forearm (33% radius) if spine/hip measurements are not possible. T-score interpretation: Normal (≥−1.0), osteopenia (−1.0 to −2.5), osteoporosis (≤−2.5).	Baseline for all patients initiating cancer therapy inducing early menopause, reducing sex steroids (AI, ADT), or including glucocorticoids. Also for women ≥65, men ≥70, or younger with clinical risk factors/fragility fractures. Follow-up: Generally not more than once a year; every 24 months for elevated fracture risk; 12 months for significant risk changes/major therapeutic intervention. Consistency in scanning center is crucial.
	TBS: Derived from lumbar spine DXA images, assesses trabecular microarchitecture.	Appropriate for adults ≥40 years. Useful when BMD alone may not fully predict fracture risk (e.g., hormone deprivation therapy).
	VFA: Lateral spine image by DXA to identify vertebral fractures (e.g., Genant Semi-Quantitative Grading).	Indications: Women ≥70, men ≥80, historical height loss >4cm, self-reported undocumented prior vertebral fracture, long-term glucocorticoid therapy. Consider this approach for patients with unexplained back pain.
	MRI: Detects acute vertebral fractures by showing bone marrow edema; useful for differentiating osteoporotic from malignant fractures.	Indications and frequency: New or worsening back pain with suspected recent vertebral fracture; uncertainty about acuity on VFA or radiographs; suspicion of malignancy, infection or neurological compromise.

25OHD 25-hydroxyvitamin D; AI Aromatase inhibitor; ADT Androgen deprivation therapy; BMD Bone mineral density; BTM Bone turnover marker; CTX Carboxy-terminal collagen type I; DXA Dual-energy X-ray absorptiometry; FRAX Fracture risk assessment Tool; MRI Magnetic resonance imaging; P1NP Procollagen type 1 N-propeptide; PPI Proton pump inhibitor; PTH Parathyroid hormone; PwC Patients with cancer; TBS Trabecular Bone Score; VFA Vertebral fracture assessment

Routine monitoring of BMD during cancer therapy is recommended, with the interval guided by the patient’s treatment and use of bone-protective agents. The European Society for Medical Oncology (ESMO) guidelines advise repeating DXA scans 1 year after starting therapy that threatens bone density (such as an AI) if the patient is not yet on any anti-resorptive medication [3]. If the patient has begun treatment with a bisphosphonate or denosumab, a somewhat longer interval (e.g., every 2 years) is acceptable. A BMD decline of >5% from baseline should prompt re-evaluation and possible initiation or intensification of osteoporosis treatment. The American Society of Clinical Oncology (ASCO) survivorship guidelines similarly recommend follow-up BMD testing about every 2 years for those at risk (with more frequent scans if medically indicated) [18]. These strategies ensure that significant bone loss is detected early during the course of cancer treatment, allowing timely intervention.

In practice, however, BMD surveillance in PwC is often underutilized. Surveys indicate that <20% of postmenopausal women with BC receive a DXA scan as part of their cancer care, and the rate is even lower (10–15%) among men initiating ADT. This under-screening leads to many cases of osteoporosis remaining undiagnosed and untreated in the oncology setting. Improving adherence to bone health monitoring guidelines is therefore a key aspect of quality care for these patients.

Beyond BMD measurements, additional imaging assessments can enhance FR evaluation. Notably, occult vertebral compression fractures are common and can be present even in patients with normal BMD. For example, women with early BC have a high prevalence of asymptomatic vertebral fractures at baseline and during AI therapy. Thus, performing a vertebral fracture assessment (VFA) using lateral spine imaging (via DXA or X-ray) is recommended as part of the initial workup in high-risk individuals. Detecting silent vertebral deformities is crucial as they confer a significantly elevated risk for future fractures and may influence the decision to start treatment regardless of BMD T-score. However, VFA is not universally available and has limitations, particularly in its inability to distinguish acute from chronic fractures [26]. In this context, spinal magnetic resonance imaging (MRI) plays a critical role as it can both detect vertebral fractures and characterize their acuity, providing essential information for clinical decision-making [27]. MRI has demonstrated substantially higher sensitivity than plain radiography for detecting occult vertebral fractures [28].

Another advanced tool available with modern DXA scans is the Trabecular Bone Score (TBS), which provides an index of bone microarchitecture quality [29]. TBS has been shown to be an independent predictor of FR, complementary to BMD. In women undergoing cancer treatments that induce ovarian suppression or menopause (e.g., AIs), TBS values tend to be lower, reflecting therapy-induced degradation of trabecular structure. In women with differentiated thyroid cancer receiving long-term TSH-suppressive therapy, significant reductions in TBS have been reported despite stable BMD, suggesting early micro-architectural deterioration associated with prolonged endocrine treatment [30]. Notably, prospective evidence is lacking on how well TBS predicts fractures specifically in cancer populations. TBS can be a useful adjunct measure, but its routine use in oncology is not yet established.

Laboratory evaluation is an integral part of bone health assessment in PwC [3, 18]. This includes basic tests of calcium and phosphate metabolism, vitamin D status, renal function, and hormone levels, including PTH, since primary hyperparathyroidism is a frequent endocrine disorder that may coexist with malignancy-associated bone loss. There is also interest in bone remodeling markers (bone turnover markers; BTMs), such as serum carboxy-terminal collagen type I (CTX), urine N-terminal collagen type I (NTX), serum procollagen type I N collagen type I (PINP), osteocalcin, and bone-specific alkaline phosphatase, which reflect the rate of bone resorption and formation. These markers provide dynamic information on skeletal turnover and can be useful for monitoring response to osteoporosis therapy as highlighted in reviews and consensus reports [31, 32]. However, their clinical utility remains limited. While BTMs may support treatment decision-making and adherence monitoring and have been associated with FR at the population level, they do not reliably predict individual FR or treatment response in PwC [31, 32]. Both the ESMO and ASCO guidelines note insufficient data to recommend serial monitoring of BTMs for managing cancer treatment-induced bone loss [3, 18]. Therefore, such tests may be considered in research or selected cases, but are not part of standard care for most patients.

Prevention of bone mass loss

Preserving bone health in PwC requires an interdisciplinary approach focused on modifiable risk factors, particularly in those receiving therapies known to accelerate bone loss (Table 3).

Table 3.

General measures for bone health care in patients with cancer

Category	Recommendations
Nutrition	Calcium intake: 1000 mg/day for adults 19–50 years; 1200 mg/day for adults >50 years (from food & supplements combined). Max 2000 mg/day. Food sources: dairy, fortified plant milks, leafy greens, certain fish.
	Vitamin D intake: 400–1000 IU/day for adults 19–50 years; 800–2000 IU/day for adults >50 or with osteoporosis/malabsorption. Optimal 25OHD serum levels >30 ng/mL. Food sources: fatty fish, fortified foods, sun exposure (with caution).
	Protein intake: 1.0–1.25 g/kg body weight/day for older adults. Food sources: meat, fish, poultry, beans, lentils, tofu, nuts, eggs, milk, yogurt, cheese.
	Control harmful factors: Avoid tobacco, limit alcohol (moderate consumption not harmful), limit excessive caffeine and high sodium intake.
Physical exercise	Adapted physical exercise: Regular weight-bearing (e.g., brisk walking, jogging, dancing, stair climbing) and resistance training (weights, bodyweight exercises).
	Sarcopenia prevention: Resistance exercise as first-line treatment for sarcopenia to improve muscle strength, mass and physical performance.
	Exercise adaptation: Consult healthcare provider; avoid exercises that bend or twist the spine with severe osteoporosis.
Fall prevention	Home safety: Remove throw rugs, install grab bars, and ensure adequate lighting.
	Balance and strength exercises: Tai Chi, Pilates, gentle yoga.
	Footwear and vision: Wear sturdy, flat-heeled shoes; optimize vision.
	Medication review: Minimize sedative/psychotropic drugs; monitor medications affecting balance/alertness.
	Assistive devices: Consider canes, walkers, hip protectors.

25OHD 25-hydroxyvitamin D

Nutritional optimization forms the foundation of non-pharmacological management. Adequate calcium, vitamin D, and protein intake is essential, especially for patients undergoing endocrine therapies that disrupt hormonal regulation of bone metabolism. Guidelines recommend a calcium intake of 1000–1200 mg/day and vitamin D supplementation of 800–1000 IU/day for patients at risk of osteoporosis, with higher doses needed if dietary intake is insufficient [18, 33]. In patients with prostate cancer (PC) receiving ADT, calcium intake is frequently below recommended levels, while vitamin D deficiency is common. Similar concerns apply to postmenopausal women on AIs or with ovarian suppression, where both nutrients are vital to mitigate treatment-induced bone loss [18, 34].

Supplementation is mandatory when prescribing bone-modifying agents such as bisphosphonates or denosumab, which can cause hypocalcemia in the absence of adequate calcium and vitamin D [25]. Clinical trials of these agents typically included at least 500 mg calcium and 400 IU vitamin D per day, and product labeling reflects this requirement. Emerging evidence supports the use of high-dose vitamin D in specific populations. For example, weekly cholecalciferol supplementation has been shown to attenuate bone loss in patients with PC on ADT [35]. Although limited, small-scale studies suggest that adjunctive nutraceuticals such as resveratrol may also offer benefit in patients with BC and osteoporosis, though further research is needed [36]. Overall, the importance of calcium and vitamin D intake is consistently emphasized across international oncology and bone health guidelines [3, 18].

Protein intake also plays a key role in skeletal health. Adequate dietary protein supports bone matrix formation and modulates anabolic hormones such as insulin-like growth factor 1. In older adults, higher protein consumption has been associated with greater BMD and reduced FR, provided calcium intake is sufficient [37]. Expert consensus recommends daily protein intake in the range of 1.0–1.2 g/kg for older individuals, with no evidence of harm to the skeleton when calcium and vitamin D requirements are met. Protein supplementation in clinical trials has been shown to reduce bone turnover and maintain BMD, while observational studies link higher protein intake with lower fracture incidence [38]. Very low protein diets, in contrast, may exacerbate both osteoporosis and sarcopenia, particularly in frail or chronically ill patients, where muscle loss further increases FR [39].

Lifestyle risk factors, such as smoking and excessive alcohol intake, further compromise bone health. Smoking is associated with reduced BMD and increased fracture rates, mediated by impaired osteoblast activity, altered estrogen metabolism, and disruption of regulatory pathways including PTH, vitamin D, and RANKL/osteoprotegerin balance [40, 41]. Smoking cessation can reverse some of these effects and is recommended as part of survivorship care [42]. Alcohol’s impact on bone is dose-dependent. While light-to-moderate alcohol intake may have neutral or even modestly positive associations with BMD, heavy/binge drinking increases bone resorption, suppresses osteoblast function, delays fracture healing and heightens FF risk [41, 43]. Daily intake exceeding two standard drinks significantly raises the risk of FFs, and even moderate use can impair balance and increase fall risk, especially in underweight individuals [44–46]. Clinical recommendations advise minimizing alcohol consumption, particularly in high-risk populations [46, 47].

Regular exercise is a central component of osteoporosis prevention in cancer survivors. Resistance training and weight-bearing impact exercise stimulate osteogenesis and improve neuromuscular function, reducing fall risk [48]. Meta-analysis has demonstrated that structured exercise interventions improve BMD at the spine and hip in PwC, with greater benefits observed in women [49]. Effective programs typically combine resistance training with weight-bearing or impact activities, performed 2–3 times weekly [50]. In contrast, low-impact aerobic activities such as walking or cycling are generally insufficient to maintain BMD [50]. Supervised, year-long interventions incorporating progressive resistance and impact loading have demonstrated reductions in BMD loss and improvements in physical function in postmenopausal BC survivors. Current evidence indicates that such programs should ideally be continued for at least 12–24 months with a frequency of ≥2 sessions per week to achieve measurable skeletal benefit. However, high-impact or jumping exercises should be modified or avoided in individuals with previous FFs or markedly low BMD to minimize injury risk [51]. Exercise also supports muscle mass, preventing osteosarcopenia, a condition of concurrent bone and muscle loss that increases FR [48, 52]. Balance and core-strengthening exercises are especially important for preventing falls and should be included in tailored activity plans, ideally developed in consultation with physiotherapists [18]. Patients with osteoporosis or other comorbidities require medical evaluation prior to starting high-intensity or impact exercise, and caution is advised in those with bone metastases [53].

Falls are a major cause of fractures in older PwC and can disrupt cancer treatment. Although the overall fall rate in PwC is similar to that in other older adults, certain therapies such as androgen receptor inhibitors have been associated with increased fall incidence [54]. Approximately 5% of community-dwelling older PwC experienced a fall that interferes with treatment [55]. Peripheral neuropathy, particularly from chemotherapy, is a prominent risk factor for falls, alongside impaired gait, muscle weakness, previous falls and pain [56]. Many of these risk factors co-occur in cancer survivors. The US Preventive Services Task Force recommends exercise as the primary intervention to prevent falls in older adults, citing robust evidence of benefit [57]. While multi-component interventions (including vision correction, medication review and home safety assessments) have a smaller average benefit, they may be useful when targeted to individual risk profiles. Clinicians should assess fall risk routinely and implement appropriate interventions, such as physical therapy, medication adjustment, or assistive devices. Ultimately, strengthening bone through nutrition and exercise complements fall prevention efforts by lowering FR if a fall occurs.

Prevention and treatment of osteoporosis

In BC, bone loss is primarily driven by AIs in postmenopausal women and by ovarian suppression in premenopausal patients. Bisphosphonates and denosumab, commonly used for the management of bone metastases, can also be used for the prevention and treatment of osteoporosis, albeit at different doses and schedules. Among premenopausal women undergoing endocrine therapy, zoledronate, a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, prevents treatment-induced bone loss and maintains/increases BMD [22, 58]. In studies conducted in premenopausal women receiving adjuvant endocrine therapy, zoledronate administered at 4 mg either every 3 or 6 months significantly reduced BMD loss [58, 59]. Guidelines support consideration of bisphosphonates in premenopausal women who experience amenorrhea or are otherwise at high risk for treatment-induced osteoporosis [18, 22].

Postmenopausal women receiving AIs experience accelerated bone turnover and FR. Anti-resorptives, including bisphosphonates and denosumab, have demonstrated efficacy in this setting. Among these, zoledronate (4 mg every 6 months) has shown consistent benefit in preventing AI-associated bone loss. In the Z-FAST study, upfront zoledronate prevented significant reductions in BMD compared with delayed treatment [60]. Denosumab (60 mg every 6 months) has also been shown to increase BMD in patients with non-metastatic BC on AIs [61]. The ABCSG-18 trial found that denosumab reduced clinical FR by approximately 50% over 7 years and significantly improved BMD at the lumbar spine and hip [62]. Similarly, zoledronate has shown fracture prevention benefits in the AZURE trial [63]. Observational data confirm these findings, with bisphosphonate use associated with a 30% reduction in fractures among high-risk patients [64].

Treatment selection should consider skeletal efficacy, potential oncological implications and patient-level factors. Both denosumab and bisphosphonates (including oral options, such as alendronate, risedronate, and ibandronate) are guideline-supported for AI-associated bone loss. The choice of agent should be individualized according to efficacy, tolerability and patient preference [65].

When fracture prevention and convenience predominate, denosumab is often considered. Discontinuation of denosumab is associated with rapid increases in bone turnover, loss of BMD and a risk of multiple vertebral fractures [66]. Guidelines recommend administering intravenous bisphosphonate within months of stopping denosumab to mitigate this rebound phenomenon – typically zoledronate at approximately 6 months – with subsequent dosing informed by BTMs and BMD [67]. Evidence from clinical practice supports this approach. In a retrospective study of 66 patients who discontinued denosumab after a mean of 6.7 years, zoledronate was administered 6 months after the last denosumab injection and at 3, 6, 12 and 24 months after that based on serum CTX or BMD assessments. Mean 12-month changes in BMD were −2.5% at the lumbar spine and −1.9% at the total hip, femoral-neck BMD remained stable and BMD was maintained from 12 to 24 months. No fractures were observed during follow-up. However, acute-phase reactions, most often transient flu-like symptoms occurring within several days of zoledronate infusion, were common [68].

In postmenopausal women at higher recurrence risk, zoledronate may be preferred, as adjuvant bisphosphonates have been associated with reductions in bone cancer recurrence and BC mortality, although a direct anticancer mechanism has not been established [65].

Treatment should be initiated in patients who meet conventional osteoporosis thresholds (T-score ≤ −2.5 or prior FF) and considered in those with osteopenia plus additional risk factors, such as prolonged AI therapy, older age, or corticosteroid use [18]. Some trials have shown benefit even in patients with osteopenia, suggesting a lower intervention threshold may be appropriate in this context. Therapy is typically continued for the duration of endocrine treatment, often 3–5 years, with subsequent reassessment. ‘Bisphosphonate holidays’ may be considered after this period depending on risk, while denosumab requires transition rather than cessation without cover [67].

Monitoring involves periodic DXA scanning every 1–2 years and may include BTMs such as serum CTX to assess response and adherence. In the context of denosumab withdrawal, elevated resorption markers can signal heightened risk and guide timing of sequential therapy [67]. Although not yet standard in all settings, bone markers are increasingly integrated into management decisions.

Adverse effects are uncommon but include acute-phase reactions with bisphosphonates, hypocalcemia (more common with denosumab), especially in patients with renal failure, and rare complications, such as osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF) [69–72]. ONJ risk increases with prolonged therapy but remains <1% with standard adjuvant regimens. Extended follow-up in trials such as ABCSG-18 reported no confirmed cases of ONJ or AFF among postmenopausal women receiving denosumab [62, 73]. AFF are rare stress-type fractures of the sub-trochanteric or diaphyseal femur associated with long-term anti-resorptive therapy, most commonly bisphosphonates, though they have also been described with denosumab [74, 75]. These fractures are characterized by minimal-trauma and predominantly transverse fracture patterns [74, 75]. Although absolute risk is low, several factors appear to increase AFF susceptibility, including longer duration of exposure in some (but not all) studies, femoral geometry (bowing or varus neck–shaft angle), Asian ethnicity, prodromal thigh or groin pain and bilateral involvement [74, 75]. In practice, the benefits of fracture prevention generally outweigh the small risk of AFF in appropriately selected patients. Nonetheless, essential risk mitigation strategies include periodic reassessment of the need for continued anti-resorptive therapy and vigilance for symptoms, alongside standard measures, such as dental evaluation prior to therapy and adequate supplementation [75].

In PC, ADT induces rapid BMD loss and substantially elevates FR. Men on long-term ADT have a 20–30% higher fracture incidence compared with those not receiving hormonal therapy. Both bisphosphonates and denosumab are effective in this population. Zoledronate has demonstrated BMD preservation in trials initiated within the first year of ADT [76], while denosumab has been shown to reduce vertebral fractures by 62% in the HALT trial [77]. Based on this evidence, denosumab is considered a preferred agent for high-risk patients, although bisphosphonates remain a suitable alternative depending on cost, comorbidity or anticipated treatment duration [78, 79].

Guidelines recommend initiating bone-protective therapy soon after ADT begins in men with osteoporosis (T-score ≤ −2.5), prior fractures or osteopenia plus risk factors (e.g., age ≥70). Duration of therapy depends on ADT course: for men on finite ADT (e.g., 1–3 years), anti-resorptive treatment should be concurrent and possibly extended 1–2 years post-ADT. For those on indefinite therapy, longer-term treatment is warranted, with the possibility of a ‘bisphosphonate holiday’ or denosumab transition assessed on an individual basis. Adequate calcium and vitamin D intake must be ensured, particularly to prevent denosumab-induced hypocalcemia.

Safety considerations in men are similar to those in women. ONJ and AFF are rare in this context. Renal function should be assessed prior to each dose of zoledronate. Denosumab may be used in chronic kidney disease (CKD) with caution due to hypocalcemia risk. Periodic BMD monitoring and, when indicated, assessment of BTMs, support long-term management.

Other cancer types, such as gastrointestinal and neuroendocrine tumors, also pose risks for bone loss, often through malabsorption, cachexia, or treatment-related hypogonadism. Gastrectomy, for example, impairs calcium and vitamin D absorption and is associated with accelerated bone loss [80]. Patients with pancreatic cancer or those undergoing pancreaticoduodenectomy frequently experience progressive declines in BMD and elevated fracture rates. In patients with neuroendocrine tumors, studies report concurrent losses in bone and muscle mass, indicating increased frailty [81]. In differentiated thyroid cancer, patients commonly receive long-term levothyroxine therapy to suppress TSH as part of standard postoperative management. Meta-analysis shows that stringent TSH suppression (<0.1 mIU/L) is associated with lower lumbar-spine BMD in postmenopausal women, whereas premenopausal women generally maintain or gain BMD, and men show no clear effect [82, 83]. High levothyroxine doses used to achieve suppression have also been linked to increased fragility-FR in population studies [84].

Special considerations

Patients with CKD require tailored bone health strategies due to altered mineral metabolism and variable tolerance to osteoporosis treatments [85]. Renal impairment is common among older PwC and may be exacerbated by nephrotoxic therapies, such as platinum-based chemotherapy, ifosfamide, and tyrosine kinase inhibitors [86]. In advanced CKD, distinguishing osteoporosis from renal osteodystrophy becomes essential [87, 88]. Bisphosphonates, which are excreted through the kidneys, are generally contraindicated in patients with creatinine clearance below 30 ml/min [85]. For zoledronate, renal function-based dose adjustment is recommended (4.0mg for creatinine clearance >60 mL/min, 3.5mg for 50–60 mL/min, 3.3mg for 40–49 mL/min and 3.0mg for 30–39 mL/min) [89]. Zoledronate is not advised when creatinine clearance is <30 mL/min [90]. Denosumab, which is not cleared renally, offers a viable alternative in advanced CKD; however, the risk of hypocalcemia is markedly increased in stage 4 or 5 CKD due to impaired calcium mobilization [91]. When used in this population, denosumab requires concurrent calcium and active vitamin D (calcitriol) supplementation, along with close biochemical monitoring [91]. In some patients, particularly those on dialysis, management of bone loss may prioritize correction of renal osteodystrophy using agents such as calcitriol or cinacalcet to manage secondary hyperparathyroidism [92]. Denosumab has shown efficacy in patients on dialysis when used with appropriate safeguards [93]. In cases of light-chain deposition disease or multiple myeloma with renal involvement, bisphosphonates must be used with caution [94]. A multidisciplinary approach involving nephrology is essential to optimize treatment and avoid complications, such as aluminum exposure and poor PTH control [87]. While CKD does not preclude fracture prevention, therapeutic choices and monitoring must be adapted accordingly [85].

Diabetes mellitus is another prevalent comorbidity in adult cancer survivors that increases FR [95]. Type 1 diabetes is associated with low BMD, while type 2 diabetes typically presents with normal or elevated BMD but reduced bone quality [96]. Factors, such as advanced glycation end products, autonomic neuropathy, and visual impairment, increase fall risk in this population [97, 98]. Cancer therapies may induce or exacerbate diabetes, particularly with prolonged corticosteroid use or immune checkpoint inhibitors (ICIs), which can cause type 1 diabetes as an immune-related adverse event [99]. Diabetic PwC should be recognized as high FR regardless of BMD values [95]. FRAX allows for adjustment based on diabetes as a secondary cause of osteoporosis. Optimizing glycemic control may reduce fall risk but does not directly restore bone strength. Ensuring vitamin D sufficiency, encouraging weight-bearing activity and reviewing medications are essential [95]. Thiazolidinediones are known to reduce BMD and increase FR [100]. Earlier concerns that sodium–glucose cotransporter 2 (SGLT2) inhibitors might increase FR have not been supported by more recent meta-analysis, which show no significant effect on fracture incidence or BMD [101–103]. In contrast, metformin appears to have neutral or potentially protective skeletal effects [104]. Clinical judgment should guide management, with heightened vigilance for bone fragility even in patients with T scores above –2.5 [95, 96].

ICIs and targeted therapies have introduced new bone health considerations. ICIs can lead to endocrinopathies such as hypophysitis, resulting in adrenal insufficiency and hypothyroidism and sometimes to hypogonadotropic hypogonadism requiring hormone replacement [105]. These endocrine disruptions can contribute to bone loss [106]. Thyroid dysfunction, whether hyper- or hypothyroid, can affect bone turnover or increase fall risk, respectively [106]. Additionally, emerging data suggest ICIs may directly increase bone resorption through immune-mediated inflammation, with some studies reporting elevated fracture incidence [107]. Monitoring BMD and bone turnover in patients on ICIs may allow early intervention [108]. Targeted therapies such as vascular endothelial growth factor (VEGF) inhibitors can impair fracture healing and bone remodeling, while mammalian target of rapamycin (mTOR) inhibitors may suppress osteoblast function [109]. Surveillance for skeletal effects should be incorporated into survivorship care when these agents are used for a long term [8].

Medication-related ONJ (MRONJ) is a rare but serious complication associated primarily with high-dose bisphosphonates or denosumab in PwC [110, 111]. The cumulative incidence with oncology dosing ranges from 1% to 5%, whereas the risk is much lower with osteoporosis regimens [109]. Preventive strategies include dental assessment before therapy and minimizing invasive dental procedures during treatment [110]. For patients requiring dental surgery, temporary interruption of therapy may be considered [112]. When MRONJ occurs, management typically involves conservative measures, such as antibiotics and antiseptic rinses, with surgical intervention reserved for refractory cases [110]. However, current European Calcified Tissue Society (ECTS) recommendations specify that in patients at low-risk, bisphosphonate or denosumab should not be discontinued. In the case of denosumab, dental procedures should ideally be scheduled 5–6 months after the last injection, when bone turnover begins to recover. In high-risk cases, bisphosphonates may be interrupted until mucosal healing, but denosumab discontinuation is discouraged; instead, procedures should be performed approximately 5–6 weeks after the last injection, with the next dose delayed but administered no later than 4 weeks beyond the planned schedule [113]. Early detection and interdisciplinary collaboration are critical to minimize morbidity. Despite the risk of MRONJ, the benefits of antiresorptive therapy in reducing fractures and SREs generally outweigh the potential harm, particularly when preventive measures are observed [109, 110].

Patient care pathway

Figure 2 summarizes a care pathway for bone health in adults with cancer, including recommendations for follow-up and improved outcomes.

Fig. 2.

Care pathway for bone health in adults with cancer. ADT androgen deprivation therapy; AFF atypical femoral fracture; AI aromatase inhibitor; BMD bone mineral density; BTM bone turnover marker; Ca calcium; CKD chronic kidney disease; DXA dual-energy X-ray absorptiometry; FRAX Fracture Risk Assessment tool; IV intravenous; MRI magnetic resonance imaging; ONJ osteonecrosis of the jaw; PTH parathyroid hormone; TBS trabecular bone score; VFA vertebral fracture assessment.

Conclusions and recommendations

Bone health is a critical, yet often under-recognized component of cancer care. Cancer therapies can significantly compromise bone integrity, increasing FR and associated morbidity. Early identification of at-risk patients and timely implementation of preventive and therapeutic strategies are essential to preserving skeletal health. Integrating bone health management into routine oncology practice can improve quality of life and long-term outcomes.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Carmen Beato-Zambrano: Investigation (bibliographic review); writing, review and editing; approved the final manuscript. Xavier Nogués: Investigation (literature review and evidence appraisal); writing, review and editing; approved the final manuscript. Natalia Ramírez-Merino: Investigation (literature review and evidence appraisal); writing, review and editing; approved the final manuscript. Maria Soledad Librizzi: Investigation (bibliographic review); writing, review and editing; approved the final manuscript. Santos Castañeda: Investigation (bibliographic review); writing, review and editing; approved the final manuscript. Iñigo Etxebarria Foronda: Investigation (bibliographic review); writing, review and editing; approved the final manuscript. Fernando Henao-Carrasco: Investigation (bibliographic review); writing, review and editing; approved the final manuscript. Javier Puente: Investigation (bibliographic review); writing, review and editing; approved the final manuscript. Ibon Gurruchaga Sotés: Investigation (bibliographic review); writing, review and editing; approved the final manuscript. Guillermo Martínez-Díaz-Guerra: Investigation (literature review and evidence appraisal); writing, review and editing; approved the final manuscript.

Funding

The medical writing assistance was funded by the SEOM (Spanish Society of Medical Oncology) and SEIOMM (Spanish Society for Bone and Mineral Metabolism Research).

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

Carmen Beato-Zambrano has received honoraria for lectures and participation on advisory boards from AstraZeneca, Bristol Myers Squibb, Laboratorios Farmacéuticos ROVI and LEO Pharma; and travel support from Amgen. Xavier Nogués has received honoraria for lectures and participation on advisory boards from Amgen, UCB, Geden-Richter and Theramex. Natalia Ramírez-Merino has received travel support from F. Hoffmann-La Roche Ltd and Pfizer Inc. María Soledad Librizzi has received travel support from UCB Pharma and Amgen and has received honoraria for lectures from Theramex, UCB Pharma and Amgen. Santos Castañeda has received travel support from Amgen, Eli Lilly and Company, Pfizer Inc. and UCB Pharma; and fees for participation on advisory boards for Amgen, Gedeon Richter Plc, Sandoz, STADA Arzneimittel AG and UCB Pharma. Iñigo Etxebarria Foronda declares that he has no conflicts of interest associated with this work. Fernando Henao-Carrasco has received fees for participating in advisory boards from AstraZeneca, Daiichi-Sankyo, Novartis, Pfizer, Lilly, and Roche. Javier Puente has received research grants from F. Hoffmann-La Roche Ltd, Astellas Pharma Inc., Pfizer Inc. and Merck KGaA (Darmstadt, Germany); honoraria for lectures and participation on advisory boards from AstraZeneca, Bayer AG, Eisai Co., Ltd., Ipsen, Janssen (Johnson & Johnson), Novartis Pharma AG, MSD (Merck & Co., Inc., Rahway, New Jersey, USA), Pfizer Inc., Gilead Sciences, Inc., Bristol Myers Squibb, Laboratorios Farmacéuticos ROVI and Merck KGaA (Darmstadt, Germany); and travel support from Janssen, Merck KGaA (Darmstadt, Germany), Ipsen and Pfizer Inc. Ibon Gurruchaga Sotés has received honoraria for lectures from GlaxoSmithKline, Bristol Myers Squibb and MSD (Merck & Co., Inc., Rahway, New Jersey, USA); and travel support from Merck KGaA (Darmstadt, Germany), Bristol Myers Squibb, MSD (Merck & Co., Inc., Rahway, New Jersey, USA), Pierre Fabre and Ipsen. Guillermo Martínez-Díaz-Guerra has received travel support from UCB Pharma, Amgen and Theramex; and fees for participation on advisory boards for UCB Pharma, Amgen and Italfarmaco S.p.A.

Ethical approval and consent to participate

This article is a review of previously published studies and does not contain any new studies with human participants or animals performed by any of the authors.