Understanding and Managing Fracture Risk in Patients With Cancer: A Literature Review.

Introduction and background

Cancer is a disease that affects millions of people worldwide, with more than 10 million associated deaths globally [ 1 ]. One of the most important complications of cancer and its treatments is the increased fracture risk [ 1 ]. Fractures can have a significant impact on the patient's quality of life and may be associated with morbidity, mortality, and reduced functional status. Fracture risk is higher in patients with malignancies than in the general population and remains increased for up to 10 years [ 2 ]. Cancer patients have an estimated 6% cumulative incidence of major fracture over a six-year follow-up [ 3 ]. Fracture risk is 9-fold higher in multiple myeloma patients [ 4 ]. This increased risk is thought to be due to a combination of factors, including the direct effects of cancer on bone metabolism, bone loss due to cancer treatments, and a higher incidence of falls in cancer patients [ 5 ].

In the general population, the impact of fractures on morbidity and mortality is multifaceted and depends on various factors, such as age, sex, and site of fracture. Fractures may lead to up to a 4-fold increase in morbidity and mortality depending on the type of fracture, its location, the age and overall health of the individual, and the quality of medical care received [ 6 ]. Similarly, fractures in cancer patients can significantly impact morbidity and mortality, often intertwined with the underlying cancer and its treatment. The risk of mortality increases 2.5-fold after a major fracture and 3.5-fold after a hip fracture within one year in patients with cancer [ 3 ]. Postmenopausal breast cancer patients with a history of fractures, especially of the hip, are more likely to die of any cause [ 7 ]. Men with prostate cancer have a 2.4-fold higher risk of fracture requiring hospitalization in comparison with the general population [ 8 ].

Several types of cancer have a preference for specific bones and types of fractures. Metastatic cancers, such as breast, lung, prostate, and kidney cancers, can spread to the vertebrae, leading to compression or pathological fractures. Breast cancer commonly metastasizes to the long bones of the arms and legs. Pelvic bones can be affected by metastatic cancers originating from various primary sites, leading to fractures. Cancer-related fractures of the ribs can occur due to metastasis from primary cancers such as breast, lung, or prostate cancer [ 9 ]. The present study aims to investigate the mechanisms underlying the increased risk of fractures in cancer patients, the effect of cancer treatments on fracture risk, and strategies to prevent fractures in this population.

Materials and methods

This is a systematic literature review using the PubMed - National Center for Biotechnology Information (NCBI), Web of Science, Cochrane Library, Scopus, and electronic internet database. The search was based on the keywords "fracture risk" AND "cancer" NOT ("osteoporosis" OR "osteoporotic"). Inclusion criteria were clinical studies assessing fracture pathogenesis and prevention, along with fracture risk estimation in cancer patients. Non-human studies, non-English studies, editorials, and study protocols were excluded. Studies involving cancer in pediatric populations were excluded. After careful evaluation a total of 146 studies were included. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and information regarding the selected studies are demonstrated in Table 1 and Figure 1 while a map graphic of our review methodology is demonstrated in Figure 2 .

Review

Pathophysiology

Direct Effects of Cancer on Bone Metabolism

Cancer can directly affect bone metabolism by promoting bone resorption or inhibiting bone formation or both [ 9 ]. Increased bone resorption occurs when cancer cells produce growth factors, such as transforming growth factor-beta (TGF-β), that stimulate osteoclast activity. This process leads to loss of bone mass and weakening of bone microarchitecture, making bones more susceptible to fracture [ 10 ]. On the other hand, certain types of cancer cells can produce factors that inhibit the activity of osteoblasts [ 9 ]. This inhibition can lead to a decrease in bone mineral density (BMD) and an increased risk of fractures. In several types of cancer, such as breast cancer, prostate cancer, lung cancer, thyroid cancer, kidney cancer, and multiple myeloma, the disrupted balance between bone formation and bone resorption may lead to both localized bone loss with osteolytic lesions as well as diffuse osteoporosis [ 11 ]. There is an association between papillary thyroid carcinoma and a risk of vertebral fractures independent of sex, BMI, glucose metabolism, and BMD, suggesting the importance of fracture risk assessment before thyroid-stimulating hormone (TSH) suppression [ 12 ].

Cancer-Related Factors Affecting Fracture Risk

Bone metastases: Bone metastases are a common complication of advanced cancer, particularly breast, prostate, lung, and multiple myeloma. The incidence of bone metastases varies by cancer type, with breast cancer being the most common cause of bone metastases in women and prostate cancer being the most common cause of bone metastases in men. Bone metastases can structurally weaken bones, leading to fractures [ 13 ].

Cancer-induced bone disease (CIBD): CIBD is a term used to describe the effects of cancer on the bones. CIBD can lead to bone loss, bone spurs, and fractures. Mechanisms underlying CIBD include increased osteoclast activity, decreased osteoblast activity, and altered bone extracellular substance composition [ 9 ].

Hypercalcemia: Malignant hypercalcemia is a condition characterized by abnormally high levels of calcium in the blood, resulting from cancer-related bone destruction or cancer-related factors such as parathyroid hormone-related protein (PTHrP) secretion. Hypercalcemia can weaken bones, leading to fractures [ 14 ]. Hypercalcemia is an independent predictor of overall fracture risk in multiple myeloma patients [ 4 ].

Malnutrition: Cancer patients may experience malnutrition due to the cancer itself, cancer treatment, or comorbidities. Malnutrition concerning proteins, calcium, and vitamin D can lead to reduced bone density and increased fracture risk [ 11 , 15 ].

Higher incidence of falls: Cancer patients may be at higher risk of falls, with an estimated prevalence from 30% to 50%, due to various factors, including weakness, sarcopenia, fatigue, visual disturbances, neuropathy, and dizziness caused by cancer treatments [ 16 ]. Monoclonal gammapathy results in an increase in falls due to peripheral neuropathy [ 16 ]. Falls can lead to fractures and death, especially in patients with weakened bones [ 17 - 20 ]. Factors affecting the risk of falls in cancer patients include age, sex, stage, severity, and type of cancer along with physical and cognitive function, balance/gait, body mass index (BMI), nutrition status, muscle strength, and medication use [ 21 ].

Sleep medications: Sleep medication use was common (40%) in breast cancer survivors and was associated with a 33% increased risk of fractures [ 22 ].

Prostate-selective alpha antagonists work by blocking the action of alpha-adrenergic receptors in the prostate, leading to relaxation of the smooth muscle tissue in the prostate and bladder neck. This relaxation helps to relieve symptoms associated with prostate cancer, such as urinary hesitancy, frequent urination, and incomplete emptying of the bladder. Their use is associated with a 20% increase of the risk of femoral and skull fractures [ 23 ].

Patient-Related Factors Affecting Fracture Risk

In males with lung cancer, smoking status and chronic obstructive pulmonary disease were independently associated with BMD, corrected for age and BMI [ 24 ]. Fractures are more common in current smokers, who also have lower bone density [ 24 ]. According to Schmidt et al., current smoking status, BMI, dementia, and prescription of corticosteroids have significant impacts on fracture risk [ 25 ].

Factors Related to the Comorbidities of Cancer Patients

Osteoporosis: Osteoporosis is a common comorbidity in cancer patients, especially in postmenopausal women and men receiving hormone therapy for prostate cancer. Osteoporosis can lead to reduced BMD and increased fracture risk [ 26 ].

Diabetes mellitus: Diabetes mellitus is a common comorbidity in cancer patients. Diabetes mellitus can lead to reduced BMD and increased fracture risk. Mechanisms underlying bone loss associated with diabetes include increased formation of advanced glycation end products (AGEs), decreased insulin-like growth factor-1 (IGF-1) levels, and increased inflammatory status [ 27 - 28 ].

Rheumatoid arthritis: Rheumatoid arthritis is a chronic inflammatory disease that may increase the risk of fracture in cancer patients [ 29 ].

Impact of chemotherapy on fracture risk

Chemotherapy is one of the main treatments used to treat various types of cancer, but it can also have harmful effects on bone health. Chemotherapy is a systemic treatment that targets rapidly dividing cancer cells. However, it can also affect healthy cells, including bone cells [ 30 ]. Chemotherapy-induced bone loss (CIBL) is a common complication of chemotherapy, particularly in postmenopausal women and men receiving hormone therapy for prostate cancer. It refers to the accelerated loss of BMD and increased risk of fractures that can occur as a side effect of certain chemotherapy medications. It is more common in patients receiving aromatase inhibitors (AIs), glucocorticoids, and platinum-based chemotherapy [ 31 ].

Chemotherapy can cause bone loss and increase fracture risk by several mechanisms, such as [ 32 - 33 ]:

Direct Cytotoxicity to Osteoblasts

Chemotherapy can have a detrimental effect on osteoblasts, leading to reduced bone formation. For example, drugs like methotrexate can inhibit folate metabolism, which is essential for osteoblast function and bone formation [ 34 ]. Platinum-based drugs like cisplatin can induce oxidative stress and DNA damage in osteoblasts, leading to cell death and impaired bone formation [ 35 ].

Stimulation of Osteoclasts

Chemotherapy affects osteoclast activity, resulting in modified increased bone resorption. Chemotherapy drugs, particularly cytotoxic agents, can suppress bone marrow function, leading to a decrease in the production of blood cells, including osteoclast precursor cells. This suppression can indirectly affect osteoclast activity, leading to reduced bone resorption [ 36 ].

Indirect Effects on Bone Cells

Chemotherapy can affect the production of hormones that regulate bone metabolism, such as estrogen, testosterone, and parathyroid hormone. Chemotherapy can damage or suppress the function of the gonads, leading to gonadal dysfunction and hormonal imbalances. For example, chemotherapy-induced ovarian failure in premenopausal women can result in decreased estrogen production, which is associated with accelerated bone loss and an increased risk of osteoporosis. Similarly, chemotherapy-induced testicular dysfunction in men can lead to decreased testosterone levels, which also contribute to bone loss and osteoporosis [ 37 - 38 ].

Nutritional Deficiencies

Chemotherapy-induced gastrointestinal toxicity may lead to malabsorption of calcium and vitamin D, which are essential for bone health [ 39 ].

Increased Frequency of Falls

Chemotherapy leads to an increased risk of falls, resulting in an increased fracture risk [ 40 - 41 ]. Chemotherapy drugs can cause muscle weakness, fatigue, dizziness, and cognitive impairment as side effects, impairing balance and coordination and increasing the risk of falls. Some chemotherapy drugs can cause peripheral neuropathy, affecting sensation and proprioception, making it more difficult for patients to maintain balance and avoid falls [ 41 ].

In premenopausal women with breast cancer, chemotherapy is associated with increased fracture risk by inducing early menopause. Premenopausal women with breast cancer under chemotherapy had significantly decreased lumbar spine BMD in comparison to age-matched patients not receiving chemotherapy. The difference in BMD was attributed to the high incidence of chemotherapy-induced menopause [ 42 ]. It has been calculated that chemotherapy-induced menopause may hasten fractures by approximately 10 years in premenopausal women with breast cancer [ 42 ]. Indeed, CIBL in patients with chemotherapy-induced premature menopause results in a marked decrease in BMD within a short period of time [ 43 ]. Chemotherapy has been found to increase fracture risk in patients with soft tissue sarcomas of the proximal lower extremity and germ cell tumors [ 44 - 45 ].

Impact of radiotherapy on fracture risk

Radiotherapy uses high-energy beams to kill cancer cells and is commonly used in the treatment of various cancers, including breast, prostate, lung, and bone metastases. Radiation can damage bone cells, weakening bones, leading to decreased bone density and increased fracture risk, especially in the radiation field. The risk of fractures is higher in bones exposed to high doses of radiation, such as the spine and hip [ 46 ]. The mechanism of radiation-induced bone loss includes [ 47 ]:

Direct Damage to Bone Cells

Radiation can damage osteoblasts and osteoclasts, leading to decreased bone formation and increased bone resorption, altering the composition of bone extracellular matrix. Direct exposure to radiation can cause DNA damage, cell death, and disruption of cellular functions in osteoblasts, osteoclasts, and bone marrow stromal cells [ 48 ].

Vascular Damage

Radiation can damage blood vessels in bones, leading to reduced blood supply and oxygenation, which can further weaken bones [ 48 ].

Pelvic radiation has been associated with a 9.4% incidence of pelvic insufficiency fractures, especially in women above 50 years of age with gynecological or anal cancers. Risk factors include osteoporosis, menopause, and diabetes mellitus [ 49 ]. In these patients, the fracture risk is especially increased in women at 2-4 years after pelvic radiotherapy [ 50 ]. Women with pelvic cancer treated with pelvic radiation, in comparison to women with pelvic cancer not treated with pelvic radiation, had a 2-fold higher pelvic fracture risk [ 51 ]. Short-course preoperative radiotherapy increases pelvic fracture risk in rectal cancer [ 52 ].

Stereotactic body radiation therapy of 27 Gy dose is associated with a 6% fracture incidence in non-spine bone metastases, especially in females with lytic lesions [ 53 ]. When 30-35 Gy are used, the fracture incidence reaches 8.5% [ 54 ]. According to a study by Ito et al., stereotactic body radiotherapy at a 30-35 Gy dose, for curative intent, should not be contraindicated in long bone oligometastasis because fractures do not directly contribute to life expectancy [ 55 ]. Vertebral compression fractures are a common complication after stereotactic body radiation therapy, with a crude incidence of 12.1%. It is recommended that the maximum point dose should be <24 Gy [ 56 ]. Multifraction stereotactic body radiation therapy for metastatic spinal disease results in a low vertebral fracture risk in comparison with single-fraction stereotactic body radiation therapy [ 57 ].

External-beam radiation therapy combined with limb-sparing surgery is feasible in elderly patients with primary soft tissue sarcomas of the extremities, with a slight increase in fracture risk [ 58 ]. 50 Gy of radiation therapy has been found to increase fracture risk in patients with soft tissue sarcomas of the proximal lower extremity [ 44 ]. In patients with soft tissue sarcoma, the cumulative risk of femur fracture in patients treated with intensity-modulated radiation therapy was 6.7% [ 59 ].

Radium-223 dichloride is a radiopharmaceutical used in the treatment of metastatic castration-resistant prostate cancer (mCRPC). It mimics calcium and tends to accumulate in areas of increased bone turnover, such as sites of bone metastases. Once administered intravenously, radium-223 is taken up by the bone metastases, where it emits alpha particles, thereby delivering targeted radiation to the cancer cells in the bone. Its use has been associated with an increase in fracture risk [ 60 - 62 ].

In breast cancer patients, radiotherapy has been associated with a 5.5-fold increased fracture risk [ 63 ]. In radiated femoral metastases, fractures have been reported to occur a median of 4.4 months after radiotherapy [ 64 ].

Impact of hormone therapy on fracture risk

Hormone therapy is a treatment that targets the hormones that fuel cancer growth. It is commonly used in breast and prostate cancer. Hormone therapy, particularly in the form of androgen deprivation therapy (ADT) for prostate cancer and AIs for breast cancer, can cause bone loss and increased fracture risk [ 65 - 66 ]. Hormone therapy can cause bone loss and increase the risk of fractures by several mechanisms, including:

Decreased Levels of Estrogen and Testosterone

Estrogen and testosterone are key hormones for bone health. Hormone therapy can reduce these hormones, leading to decreased bone density and increased fracture risk [ 66 - 67 ].

Increased Bone Resorption

Hormone therapy can increase osteoclast activity, leading to bone resorption and decreased bone density.

Tamoxifen, commonly used in the treatment of hormone receptor-positive breast cancer, belongs to a class of drugs known as selective estrogen receptor modulators (SERMs). Tamoxifen works by blocking the effects of estrogen in breast tissue, and it is often prescribed for both the treatment of breast cancer and as a preventive measure in certain high-risk populations. The relationship between tamoxifen and fracture risk is complex, and the available evidence suggests a nuanced picture [ 68 ]. Most studies suggest that tamoxifen may have a positive impact on bone density, particularly in postmenopausal women. Tamoxifen has been associated with a 25-50% reduction in the risk of osteoporosis and osteoporotic fractures [ 69 - 70 ].

AIs, such as anastrozole, exemestane, and letrozole, are a class of medications commonly used in the treatment of hormone receptor-positive breast cancer in postmenopausal women. Unlike tamoxifen, AIs work by blocking the enzyme aromatase, which is responsible for converting androgens into estrogen in postmenopausal women [ 63 ]. By reducing estrogen levels, AIs aim to deprive hormone receptor-positive breast cancer cells of the estrogen they need to grow and divide. AIs are commonly used as adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer to reduce the risk of recurrence. Guidelines recommend considering AI therapy as initial adjuvant treatment or after 2 to 3 years of tamoxifen therapy. Adjuvant AI therapy is typically administered for 5 to 10 years, depending on the specific clinical scenario and patient factors [ 71 ]. In young women with breast cancer, AI administration has been associated with an 8-fold increased fracture risk [ 63 ]. AIs have been associated with a 2-4 times increased rate of reduction in BMD in postmenopausal women. Numerous studies have suggested an increased fracture risk, particularly at sites such as the spine, hip, and wrist, in postmenopausal women taking AIs [ 72 - 78 ]. The use of anastrozole is associated with a higher fracture risk [ 79 ]. A recent meta-analysis estimated a relative risk of 1.35 for all osteoporotic fractures, 1.18 for hip fractures, 1.84 for vertebral fractures, and 1.18 for non-vertebral fractures in patients with breast cancer on AI therapy [ 80 ]. The increased fracture risk may be attributed to the reduction in estrogen levels and subsequent bone loss. Fracture risk may increase with prolonged use of AIs. BMD tends to normalize after cessation of AI therapy [ 81 ]. Total nonvertebral fracture risk is higher for users of AIs compared with tamoxifen [ 82 ]. Fracture rates in the first years after cessation of hormonal therapy for breast cancer were 12% and 15% for pre- and postmenopausal women, respectively. The most common fractures in postmenopausal women were hip and major fractures [ 83 ]. Fat body mass may be associated with fragility-related fractures in patients with breast cancer who undergo AI therapy [ 84 ]. A synergism between lean body mass and high-fat body mass has been observed in predicting the risk of vertebral fractures in women with early breast cancer undergoing AIs [ 85 ]. Compliance with AI treatment in women with breast cancer is associated with a clear increase in fracture risk [ 25 ].

Gonadotropin-releasing hormone (GnRH) agonists, such as goserelin, leuprolide, abarelix, and buserelin, are medications that are often used in the treatment of prostate cancer, breast cancer, and certain gynecological disorders [ 86 - 87 ]. They act by initially stimulating the release of gonadotropins, leading to an increase in sex hormone levels. However, with continued use, GnRH agonists ultimately suppress the production of sex hormones, including testosterone in men and estrogen in women [ 88 ]. The impact of GnRH agonists on bone health and fracture risk is primarily related to the reduction of estrogen and/or testosterone levels. GnRH agonists are associated with approximately 10% decline in BMD at the spine after two years, and when used in combination with AIs, 17% decline in BMD at the spine after three years [ 89 - 90 ]. As a result, individuals treated with GnRH agonists may be at an increased risk of fractures.

ADT is commonly used in the treatment of prostate cancer. It aims to reduce levels of testosterone, which can fuel the growth of prostate cancer cells. Testosterone plays a crucial role in maintaining bone density in men. Reduced testosterone levels (up to <5% of normal) due to ADT can lead to accelerated bone turnover and a decline in BMD, increasing fracture risk, particularly in weight-bearing bones such as the hip and spine [ 28 , 91 - 92 ]. ADT results in approximately a 4% decrease in spine BMD within 12 months of treatment [ 93 - 94 ]. ADT has been associated with a 39% increased overall fracture risk and a 55% risk for fracture requiring hospitalization [ 95 ]. The number of new bone fractures occurring on or after ADT-investigational agent treatment has been reported to be 4.6 per 1000 person-years [ 96 ].

Abiraterone acetate is a medication used in the treatment of prostate cancer, specifically mCRPC. It is also sometimes used in combination with prednisone or prednisolone. Abiraterone acetate works by inhibiting the production of androgens within the body. It blocks CYP17A1, an enzyme involved in the production of androgens in the adrenal glands and the tumor itself. By reducing the levels of androgens in the body, abiraterone acetate can slow down the progression of prostate cancer and alleviate symptoms associated with the disease. Its use is generally safe and has been associated with a very low fracture risk [ 60 ].

Impact of immunotherapy on fracture risk

Immune checkpoint inhibitors are a class of medications used in cancer immunotherapy. They act by targeting specific proteins, known as checkpoint molecules, that regulate immune responses. By blocking these checkpoint molecules, immune checkpoint inhibitors can help the immune system recognize and attack cancer cells more effectively. Immune checkpoint inhibitors have been approved for the treatment of various types of cancer, including melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, Hodgkin lymphoma, and others [ 97 ]. According to a study by Pantano et al., a three-month course of immune checkpoint inhibitors led to a significant increase of CTX-I with a concomitant decreasing trend toward the reduction of PINP, suggesting a relationship between immune checkpoint inhibitors and increased osteoclast activity and potential fracture risk [ 97 ].

Impact of surgical treatment on fracture risk

Surgery, especially on the hip and spine, can increase the risk of fracture in cancer patients. Surgery can weaken bones and alter bone biomechanics. Surgical procedures such as gastrectomy for gastric cancer and hysterectomy with bilateral oophorectomy for gynecological cancers can also lead to deleterious effects on bone health [ 98 - 99 ].

Hibler et al. reported 9% BMD loss at the lumbar spine and 6% BMD loss at the hip in premenopausal women with breast cancer undergoing risk-reducing bilateral salpingo-oophorectomy over 18 months [ 100 ]. Women aged 45-55 years with early menopause and early bilateral salpingo-oophorectomy had lower vertebral and femoral BMD in comparison with women who underwent natural menopause [ 101 ]. Effects on fracture risk after premenopausal bilateral salpingo-oophorectomy are inconsistent. One cohort study observed increased fracture risk in the distal wrist and spine but not in the hip, while another study did not detect increased risk for non-vertebral fractures [ 102 - 103 ]. Five years after bilateral salpingo-oophorectomy, bone turnover biomarkers were higher than age-matched reference values, predicting a higher fracture risk [ 104 ].

Diagnosis

Fracture risk assessment is essential in cancer patients to identify patients at high risk of fracture and to implement appropriate preventive measures. Several tools are available to assess fracture risk, including the Fracture Risk Assessment Tool (FRAX) and measurement of BMD.

FRAX Tool

The FRAX is a widely used tool that estimates the 10-year probability of hip fracture and major osteoporotic fractures. It takes into account many factors, including age, sex, weight, height, smoking, alcohol consumption, family history of hip fracture, individual history of fracture, and the presence of comorbidities such as rheumatoid arthritis, secondary osteoporosis, and diabetes [ 105 - 106 ]. Although FRAX does not directly assess falls, it has been observed to predict falls, especially in elderly men, and may capture some of this associated fracture risk [ 107 - 108 ].

BMD measurement

Bone densitometry is a non-invasive test that measures bone density. It is an essential tool for diagnosing osteoporosis and assessing fracture risk in cancer patients. BMD is usually measured using dual-energy X-ray absorptiometry (DXA) [ 109 ]. A BMD test measures the amount of bone mineral in a specific area, usually the hip, spine, or wrist, and is compared to the average BMD of young healthy women to produce T-scores that are used for the diagnosis of osteoporosis. It can diagnose osteoporosis and predict fracture risk. For osteopenia, the T-score typically falls between -1.0 and -2.5 standard deviations (SD) below the average BMD of a young adult reference population. Osteoporosis is defined as when the T-score is < -2.5 SD, indicating a higher risk of fracture [ 26 ]. However, these tools may not be applicable to all cancer patients, especially those with bone metastases. In these patients, bone imaging techniques such as radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI), or bone scintigraphy may be more appropriate to assess the extent of bone involvement and identify any impending fractures [ 110 - 111 ].

Although BMD is a good predictor for bone strength, it does not take into consideration bone size, geometry, and microarchitecture. This is the reason why a lot of women with fragility fractures have no osteoporosis as measured by DXA and may be termed as suffering merely from osteopenia [ 112 - 113 ]. Periodic BMD measurement is recommended for all women with breast cancer under hormone therapy [ 114 ]. Any annual BMD decrease of 10% or more in comparison with pretreatment levels is suggestive of initiation of antiosteoporotic treatment [ 115 ]. In multiple myeloma, BMD has been found to be lower than age- and sex-matched controls [ 116 ]. BMD is lower at the spine and is associated with female sex, duration of disease, and number of IgA strains [ 117 ].

Laboratory tests

Laboratory tests are necessary to assess the patient's bone metabolism and to identify any underlying metabolic disorders that may contribute to bone loss or bone metastases [ 118 ].

Serum Calcium and Phosphorus Levels

Measurement of serum calcium and phosphorus levels is necessary to assess the patient's bone mineral metabolism. Abnormal levels of calcium and phosphorus may indicate bone loss or bone metastases [ 119 ].

Serum Alkaline Phosphatase and Parathyroid Hormone Levels

Alkaline phosphatase is an enzyme produced by osteoblasts. Elevated alkaline phosphatase levels may indicate increased bone metabolism, which may be a finding of bone metastases or osteoporosis. Parathyroid hormone is a hormone produced by the parathyroid glands that regulates calcium and phosphate metabolism. Abnormal levels of parathyroid hormone may indicate an underlying metabolic disorder that may contribute to bone loss or bone metastases [ 120 ].

Serum Vitamin D Levels

Vitamin D is essential for calcium absorption, and its deficiency can contribute to bone loss or bone metastases. Serum vitamin D levels can help identify patients who may need supplementation [ 120 ].

Markers of bone resorption (CTX, TRAPc5b) and bone formation (osteocalcin, bone ALP, PINP) [ 104 ].

Imaging tests

Imaging studies are essential to diagnose bone metastases and to assess the extent of bone destruction and risk of fracture. Imaging studies commonly used to diagnose increased fracture risk in cancer patients include [ 121 ]:

X-ray

An X-ray is a non-invasive test that uses low-dose radiation to produce images of the bones. Radiography is commonly used to diagnose fractures and to assess the extent of bone destruction in patients with bone metastases [ 122 ]. Axial cortical involvement ≥30 mm had a 5.3 times higher fracture risk [ 122 ]. Radiographic screening for atypical femoral fractures could be relevant in patients who have been on long-term oncologic bone-modifying agents [ 123 ]. X-rays provide direct visualization of bone structures, allowing the assessment of the integrity and alignment of the vertebral bodies. Fractures typically appear as disruptions or discontinuities in the normal contour of the vertebral body on X-ray images.

Computed Tomography

A CT scan is a non-invasive test that uses X-rays and computer analysis to produce detailed images of the bones. CT is useful for the diagnosis of bone metastases and for estimating the extent of bone destruction [ 124 - 127 ]. Biomechanical CT (BCT) is a radiomic technique that measures BMD and bone strength from CT scans. Among men diagnosed with metastatic hormone-sensitive prostate cancer, BCT assessments were strongly correlated with DXA and predicted subsequent pathologic fracture [ 128 ]. CT-based rigidity analysis has a small influence on perceived fracture risk [ 129 - 130 ].

Magnetic Resonance Imaging

MRI is a non-invasive test that uses magnetic fields and radio waves to produce detailed images of bones and soft tissue. MRI is useful for diagnosing bone metastases, spinal cord compression, and other complications of bone loss [ 131 ].

Fluorodeoxyglucose positron emission tomography/CT (FDG PET/CT) is a combined imaging technique that merges the functional information obtained from PET with the anatomical details provided by CT scans. FDG PET/CT may help for the assessment of fracture risk in cancer patients [ 132 ].

Radiomic variables are quantitative features extracted from medical images using advanced image processing techniques. These variables capture information about the shape, texture, intensity, and spatial relationships of structures within the images. Radiomic features, including a bone density score and radiomic signatures from the ribs, can be used to stratify risk of rib fracture after stereotactic body radiation therapy for early-stage non-small cell lung cancer [ 133 - 135 ].

Scores

The Mirel's Score is a scoring system used to assess the risk of pathological fractures in patients with metastatic bone disease. It takes into account several factors related to the tumor and its effect on bone integrity, such as the location of the lesion, the size of the lesion, the type of lesion, and the presence of pain. Based on these factors, each parameter is scored, and the scores are then summed to give an overall Mirel's Score [ 136 - 137 ]. The total score ranges from 0 to 12, with higher scores indicating a greater risk of fracture. A Mirels score of ≥ 8 points had the best predictive profile for fractures at humeral metastases [ 137 ].

The Spinal Instability Neoplastic Score (SINS) is a scoring system used to assess the stability of the spine in patients with metastatic spinal tumors. It takes into account the location of the tumor, the type of spinal involvement, the degree of vertebral body collapse, the presence of posterolateral involvement, pain severity, and neurological deficit. SINS is demonstrated to be a useful tool to assess fracture risk in patients with bone metastases after radiation therapy [ 136 ].

The bone strength score is based on a CT-based patient-specific finite element computer model that objectively calculates bone strength. It may be a useful tool for the assessment of fracture risk in femoral bone metastases [ 134 ]. A prognostic score assessing eight variables (age, race, hormone treatment, Elixhauser score, anxiety, Parkinson's, fall-inducing medications, and disability status) may predict fracture risk in prostate cancer patients [ 135 ].

Prevention

There are several strategies that can be used to prevent fractures in cancer patients, including lifestyle modifications, pharmacological interventions, and monitoring of bone health.

Lifestyle modifications

Lifestyle modifications can improve bone health and reduce fracture risk in cancer patients. These modifications include [ 138 ]:

Adequate Intake of Calcium and Vitamin D

Adequate intake of calcium and vitamin D can improve bone density and reduce the risk of fracture. For cancer patients, the recommended daily intake of calcium is 1200 mg for adults over 50 and 800-1000 IU of vitamin D per day.

Regular Exercise

Weight and resistance exercises can improve bone health and reduce the risk of fracture. Exercise may also alleviate cancer-related fatigue and improve overall quality of life [ 139 - 140 ]. Combined impact loading and resistance exercise attenuates bone loss at the spine and reduces fracture risk in prostate cancer patients undergoing ADT [ 141 ].

Smoking Cessation

Smoking is a risk factor for osteoporosis and fractures. Quitting smoking can improve bone health and reduce fracture risk [ 139 ].

Pharmacological interventions

Pharmacological interventions are an essential component of fracture prevention in cancer patients. The following are some of the pharmacological interventions that can help prevent bone loss and reduce fracture risk:

Bisphosphonates

Bisphosphonates are a class of drugs that can help prevent bone loss and fractures by inhibiting osteoclast activity. Bisphosphonates are commonly used to treat osteoporosis and bone metastases in cancer patients [ 114 , 142 - 143 ]. Risedronate preserves BMD and may attenuate loss of bone microarchitecture over two years in breast cancer survivors on AIs [ 144 ]. However, according to Drieling et al., long-term (> 8 years) use of bisphosphonates is an independent risk factor for fractures in postmenopausal women [ 145 ]. Prolonged use of zoledronate in cancer patients could predispose them to atypical femoral fractures [ 123 ]. Zoledronic acid (Zometa) is the bisphosphonate of choice for the management of malignancy-associated bone disease. Its efficacy in reducing skeletal-related events and preventing bone resorption makes it a cornerstone of supportive care in oncology. The standard dosage regimen is 4 mg, which can be administered multiple times per year in patients with multiple secondary metastases. In the absence of metastatic disease and the absence of specific guidelines for a given neoplastic condition, a yearly administration of 5 mg may be considered to maintain bone health and reduce the risk of skeletal complications. However, in malignancies with established protocols, such as breast cancer, zoledronic acid is typically administered every six months. Treatment schedules should be individualized based on disease status, patient risk factors, and emerging clinical guidelines.

Denosumab

Denosumab is a monoclonal antibody that can help prevent bone loss and fractures. It works by inhibiting the activity of RANKL, which is a protein that stimulates osteoclasts. Denosumab is commonly used to treat osteoporosis and bone metastases in cancer patients [ 143 ]. Prolonged use of denosumab in cancer patients could predispose them to atypical femoral fractures [ 123 ].

Hormone Therapy

Estrogen or testosterone replacement therapy can help prevent bone loss and fractures in cancer patients. Hormone therapy is usually reserved for patients who have low hormone levels and are at increased risk of bone loss [ 10 , 142 , 146 ].

Calcitonin

Calcitonin is a hormone that can help prevent bone loss and fractures. It works by inhibiting the activity of osteoclasts. Calcitonin is commonly used for bone pain management in cancer patients who are unable to tolerate other drugs such as bisphosphonates or denosumab [ 138 ].

Conclusions

Fracture risk in cancer patients is influenced by various factors, including the type of cancer, stage of disease, cancer treatments, bone health status, and presence of bone metastases. Fracture risk is particularly increased in patients with malignancies. This is due to the direct effect of cancer cells on bone metabolism, the existence of cancer-related factors (bone metastases, hypercalcemia, malnutrition, increased risk of falls), coexisting diseases, and side effects of anticancer treatments. Fracture risk assessment is based on the measurement of bone density, the use of the FRAX tool, laboratory tests, and imaging methods. To reduce fracture risk in cancer patients, lifestyle modification and anti-osteoclastic drugs such as bisphosphonates and denosumab are needed. Overall, fracture risk in cancer patients is multifactorial and requires comprehensive evaluation and management to optimize bone health and quality of life.

Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Author Contributions

Acquisition, analysis, or interpretation of data: Konstantinos Zygogiannis, Efstathios Kourtis, Ilias Fanourgiakis, Konstantinos D. Stathopoulos

Drafting of the manuscript: Konstantinos Zygogiannis, Efstathios Kourtis, Ilias Fanourgiakis, Konstantinos D. Stathopoulos

Critical review of the manuscript for important intellectual content: Konstantinos Zygogiannis, Efstathios Kourtis, Ilias Fanourgiakis, Konstantinos D. Stathopoulos, Dimitrios Koulalis

Concept and design: Efstathios Kourtis, Konstantinos D. Stathopoulos, Dimitrios Koulalis

Supervision: Konstantinos D. Stathopoulos

References

1 Prevalence of osteoporosis among cancer patients in Germany: prospective data from an oncological rehabilitation clinic Osteoporos Int Reuss-Borst M Hartmann U Scheede C Weiß J 1437 1444 23 2012 21755400 10.1007/s00198-011-1724-9

2 Fracture risk among patients with cancer compared to individuals without cancer: a population-based study Br J Cancer Gong IY Chan KK Lipscombe LL Cheung MC Mozessohn L 665 671 129 2023 https://pmc.ncbi.nlm.nih.gov/articles/PMC10421906/ 37422530 10.1038/s41416-023-02353-4 PMC10421906

3 Fractures and long-term mortality in cancer patients: a population-based cohort study Osteoporos Int Ye C Leslie WD Al-Azazi S Yan L Lix LM Czaykowski P Singh H 2629 2635 33 2022 36036268 10.1007/s00198-022-06542-4

4 Fracture risk with multiple myeloma: a population-based study J Bone Miner Res Melton LJ 3rd Kyle RA Achenbach SJ Oberg AL Rajkumar SV 487 493 20 2005 15746994 10.1359/JBMR.041131

5 Fracture risk and assessment in adults with cancer Osteoporos Int Ye C Leslie WD 449 466 34 2023 36512057 10.1007/s00198-022-06631-4

6 Mortality after all major types of osteoporotic fracture in men and women: an observational study Lancet Center JR Nguyen TV Schneider D 878 882 13 1999 10.1016/S0140-6736(98)09075-8 10093980

7 Postmenopausal fracture history and survival after reproductive cancer diagnosis JNCI Cancer Spectr Newcomb PA Adams SV Mayer S 0 2 2018 10.1093/jncics/pky001 PMC6643753 31355356

8 Admissions to hospital due to fracture in England in patients with prostate cancer treated with androgen-deprivation therapy - do we have to worry about the hormones? BJU Int Jefferies ER Bahl A Hounsome L Eylert MF Verne J Persad RA 416 422 118 2016 26857695 10.1111/bju.13441

9 Cancer-induced bone disease Nurs Stand Drudge-Coates L Turner B 48 56 27 2013 10.7748/ns2013.01.27.19.48.c9499 23427627

10 Fracture risk among breast cancer survivors: results from the Women's Health Initiative Observational Study Arch Intern Med Chen Z Maricic M Bassford TL 552 558 165 2005 15767532 10.1001/archinte.165.5.552

11 Fracture risk in patients with different types of cancer Acta Oncol Vestergaard P Rejnmark L Mosekilde L 105 115 48 2009 18607871 10.1080/02841860802167490

12 Association between papillary thyroid carcinoma and vertebral fracture Horm Metab Res Otani H Notsu M Yamauchi M Nawata K Kanasaki K 592 598 55 2023 37068493 10.1055/a-2059-8830

13 Clinical features of metastatic bone disease and risk of skeletal morbidity Clin Cancer Res Coleman RE 6243 6249 12 2006 10.1158/1078-0432.CCR-06-0931 17062708

14 Hypercalcemia of malignancy: An update on pathogenesis and management N Am J Med Sci Mirrakhimov AE 483 493 7 2015 26713296 10.4103/1947-2714.170600 PMC4683803

15 Effect of cachexia on bone turnover in cancer patients: a case-control study BMC Cancer Zwickl H Zwickl-Traxler E Haushofer A 744 21 2021 https://bmccancer.biomedcentral.com/articles/10.1186/s12885-021-08518-9 34182958 10.1186/s12885-021-08518-9 PMC8240310

16 Untangling fracture risk in monoclonal gammopathy of undetermined significance: a population-based cohort study Eur J Haematol Rögnvaldsson S Aspelund T Thorsteinsdóttir S Turesson I Björkholm M Landgren O Kristinsson SY 137 144 107 2021 33840154 10.1111/ejh.13633

17 Falls, injuries due to falls, and the risk of admission to a nursing home N Engl J Med Tinetti ME Williams CS 1279 1284 337 1997 9345078 10.1056/NEJM199710303371806

18 Systematic review of falls in older adults with cancer J Geriatr Oncol Wildes TM Dua P Fowler SA Miller JP Carpenter CR Avidan MS Stark S 70 83 6 2015 25454770 10.1016/j.jgo.2014.10.003 PMC4297689

19 Mortality, disability, and falls in older persons: the role of underlying disease and disability Am J Public Health Dunn JE Rudberg MA Furner SE Cassel CK 395 400 82 1992 1531583 10.2105/ajph.82.3.395 PMC1694374

20 Falls in older adults with cancer: an updated systematic review of prevalence, injurious falls, and impact on cancer treatment Support Care Cancer Sattar S Haase K Kuster S 21 33 29 2021 32671565 10.1007/s00520-020-05619-2

21 Risk factors for falls in adult cancer survivors: an integrative review Rehabil Nurs Campbell G Wolfe RA Klem ML 201 213 43 2018 29957697 10.1097/rnj.0000000000000173 PMC6029723

22 Sleep medication use and risk of fractures in breast cancer survivors Breast Cancer Res Treat Haque R Chlebowski RT Chen L 541 548 190 2021 34586512 10.1007/s10549-021-06392-4 PMC8558269

23 Prostate-selective α antagonists increase fracture risk in prostate cancer patients with and without a history of androgen deprivation therapy: a nationwide population-based study Oncotarget Kao WH Kuo CF Chou IJ 5263 5273 9 2018 29435177 10.18632/oncotarget.23828 PMC5797048

24 Association of chronic obstructive pulmonary disease and smoking status with bone density and vertebral fractures in male lung cancer screening participants J Bone Miner Res de Jong WU de Jong PA Vliegenthart R 2224 2229 29 2014 24715549 10.1002/jbmr.2248

25 The impact of treatment compliance on fracture risk in women with breast cancer treated with aromatase inhibitors in the United Kingdom Breast Cancer Res Treat Schmidt N Jacob L Coleman R Kostev K Hadji P 151 157 155 2016 26687384 10.1007/s10549-015-3661-3

26 Osteoporosis and cancer Curr Osteoporos Rep Drake MT 163 170 11 2013 23877475 10.1007/s11914-013-0154-3 PMC3783531

27 Diabetes mellitus and bone health: epidemiology, etiology and implications for fracture risk stratification Clin Diabetes Endocrinol Valderrábano RJ Linares MI 9 4 2018 29721333 10.1186/s40842-018-0060-9 PMC5918531

28 Androgen deprivation therapy, diabetes and poor physical performance status increase fracture risk in Chinese men treated for prostate cancer Aging Male Teoh JY Chiu PK Chan SY Poon DM Cheung HY Hou SS Ng CF 180 185 18 2015 26004988 10.3109/13685538.2015.1046043

29 Bone fracture risk in patients with rheumatoid arthritis: a meta-analysis Medicine (Baltimore) Xue AL Wu SY Jiang L Feng AM Guo HF Zhao P 0 96 2017 10.1097/MD.0000000000006983 PMC6393106 28885321

30 Influence of chemotherapy and endocrine treatment on fractures in postmenopausal women with breast cancer - a retrospective cohort study J Bone Oncol Stumpf U Kostev K Siebenbürger G Böcker W Hadji P 100292 22 2020 32864322 10.1016/j.jbo.2020.100292 PMC7445435

31 Cancer treatment-related bone disease Crit Rev Eukaryot Gene Expr Brown SA Guise TA 47 60 19 2009 19191756 10.1615/critreveukargeneexpr.v19.i1.20 PMC2762110

32 Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer Br J Cancer Bruning PF Pit MJ de Jong-Bakker M van den Ende A Hart A van Enk A 308 310 61 1990 2310683 10.1038/bjc.1990.58 PMC1971401

33 Cytotoxic chemotherapy is associated with decreased bone mineral density in postmenopausal women with early and locally advanced breast cancer Arch Osteoporos Nisha Y Dubashi B Bobby Z Sahoo JP Kayal S Ananthakrishnan R Ganesan P 41 18 2023 36899284 10.1007/s11657-023-01231-z PMC10004442

34 Effect of methotrexate on bone and wound healing Expert Opin Drug Saf Pountos I Giannoudis PV 535 545 16 2017 28332422 10.1080/14740338.2017.1310839

35 Cisplatin inhibits bone healing during distraction osteogenesis J Orthop Res Stine KC Wahl EC Liu L 464 470 32 2014 https://pubmed.ncbi.nlm.nih.gov/24259375/ 24259375 10.1002/jor.22527 PMC4080883

36 Bone and cancer: pathophysiology and treatment of metastases Bone Kanis JA 101 17 1995 10.1016/8756-3282(95)00194-i 8579890

37 Gonadal dysfunction and fertility problems in cancer survivors Acta Oncol Brydøy M Fosså SD Dahl O Bjøro T 480 489 46 2007 17497315 10.1080/02841860601166958

38 Molecular mechanism and prevention strategy of chemotherapy- and radiotherapy-induced ovarian damage Int J Mol Sci Kim S Kim SW Han SJ Lee S Park HT Song JY Kim T 22 13 2021 10.3390/ijms22147484 PMC8305189 34299104

39 Chemotherapy-induced gastrointestinal toxicity: pathogenesis and current management Biochem Pharmacol He Y Zheng J Ye B Dai Y Nie K 115787 216 2023 37666434 10.1016/j.bcp.2023.115787

40 Fall-related injuries in elderly cancer patients treated with neurotoxic chemotherapy: a retrospective cohort study J Geriatr Oncol Ward PR Wong MD Moore R Naeim A 57 64 5 2014 24484719 10.1016/j.jgo.2013.10.002

41 The association of chemotherapy-induced peripheral neuropathy symptoms and the risk of falling JAMA Neurol Kolb NA Smith AG Singleton JR Beck SL Stoddard GJ Brown S Mooney K 860 866 73 2016 27183099 10.1001/jamaneurol.2016.0383 PMC6715416

42 Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment Eur J Cancer Vehmanen L Saarto T Elomaa I Mäkelä P Välimäki M Blomqvist C 2373 2378 37 2001 11720830 10.1016/s0959-8049(01)00317-3

43 Bone loss and fracture risk associated with cancer therapy Oncologist Guise TA 1121 1131 11 2006 17110632 10.1634/theoncologist.11-10-1121

44 Treatment-related fractures after combined modality therapy for soft tissue sarcomas of the proximal lower extremity: can the risk be mitigated? Pract Radiat Oncol Bishop AJ Zagars GK Allen PK Moon BS Lin PP Lewis VO Guadagnolo BA 194 200 6 2016 27126136 10.1016/j.prro.2015.09.004

45 Changes in bone mineral density in newly diagnosed testicular cancer patients after anticancer treatment J Clin Endocrinol Metab Willemse PM Hamdy NA de Kam ML Burggraaf J Osanto S 4101 4108 99 2014 25119312 10.1210/jc.2014-1722

46 Pelvic insufficiency fracture (PIF) incidence in patients treated with intensity-modulated radiation therapy (IMRT) for gynaecological or anal cancer: single-institution experience and review of the literature Br J Radiol Bazire L Xu H Foy JP 20160885 90 2017 28291401 10.1259/bjr.20160885 PMC5605110

47 Risk of pelvic fracture with radiation therapy in older patients Int J Radiat Oncol Biol Phys Vitzthum LK Park H Zakeri K 485 492 106 2020 31610251 10.1016/j.ijrobp.2019.10.006 PMC8906845

48 The influence of radiation on bone and bone cells-differential effects on osteoclasts and osteoblasts Int J Mol Sci Donaubauer AJ Deloch L Becker I Fietkau R Frey B Gaipl US 21 2020 10.3390/ijms21176377 PMC7504528 32887421

49 Pelvic insufficiency fractures after intensity modulated radiation therapy combined with chemotherapy for cervix carcinoma: incidence and impact of bone mineral density Clin Transl Radiat Oncol Duranson A Thevenet V Guyon F 100650 41 2023 37441540 10.1016/j.ctro.2023.100650 PMC10334122

50 Increased risk of pelvic fracture after radiotherapy in rectal cancer survivors: a propensity matched study Cancer Med Kang YM Chao TF Wang TH Hu YW 3639 3647 8 2019 31104362 10.1002/cam4.2030 PMC6639197

51 Long-term pelvic fracture and overall mortality risk after pelvic cancer and pelvic radiation J Natl Cancer Inst Nelson RA Blakely AM Larson JC 104 111 115 2023 36305666 10.1093/jnci/djac197 PMC9830483

52 Short-course preoperative radiotherapy increases pelvic fracture risk in rectal cancer Clin Transl Radiat Oncol Vesa V Jaana M Ia K 100656 42 2023 37457020 10.1016/j.ctro.2023.100656 PMC10339188

53 Bone density and fracture risk following SBRT for non-spine bone metastases J Radiosurg SBRT Cao Y Stachelek GC Fu W 199 206 7 2021 https://pmc.ncbi.nlm.nih.gov/articles/PMC8055232/ 33898083 PMC8055232

54 Local control and fracture risk following stereotactic body radiation therapy for non-spine bone metastases Radiother Oncol Erler D Brotherston D Sahgal A 304 309 127 2018 29706460 10.1016/j.radonc.2018.03.030

55 Fracture risk following stereotactic body radiotherapy for long bone metastases Jpn J Clin Oncol Ito K Nakajima Y Ogawa H Taguchi K 47 52 52 2022 34648002 10.1093/jjco/hyab164

56 A volumetric dosimetry analysis of vertebral body fracture risk after single fraction spine stereotactic body radiation therapy Pract Radiat Oncol Lee MY Ouyang Z LaHurd D 480 487 11 2021 https://colab.ws/articles/10.1007%2Fs11060-024-04892-z 34303836 10.1016/j.prro.2021.07.004

57 Local failure and vertebral body fracture risk using multifraction stereotactic body radiation therapy for spine metastases Adv Radiat Oncol Mehta N Zavitsanos PJ Moldovan K 245 251 3 2018 https://pmc.ncbi.nlm.nih.gov/articles/PMC6128022/ 30202794 10.1016/j.adro.2018.04.002 PMC6128022

58 External-beam radiation therapy combined with limb-sparing surgery in elderly patients (>70 years) with primary soft tissue sarcomas of the extremities: a retrospective analysis Strahlenther Onkol Andrä C Klein A Dürr HR 604 611 193 2017 28229172 10.1007/s00066-017-1109-x

59 Femoral fracture in primary soft-tissue sarcoma of the thigh and groin treated with intensity-modulated radiation therapy: observed versus expected risk Ann Surg Oncol Folkert MR Casey DL Berry SL Crago A Fabbri N Singer S Alektiar KM 1326 1331 26 2019 30706225 10.1245/s10434-019-07182-5 PMC6458075

60 Fracture risk and survival outcomes in metastatic castration-resistant prostate cancer patients sequentially treated with abiraterone acetate and RADIUM-223 Eur J Nucl Med Mol Imaging Caffo O Frantellizzi V Tucci M 2633 2638 47 2020 32249345 10.1007/s00259-020-04796-w

61 Fracture risk in men with metastatic prostate cancer treated with radium-223 Clin Genitourin Cancer Hijab A Curcean S Tunariu N 0 305 19 2021 10.1016/j.clgc.2021.03.020 PMC8514085 33958296

62 Concurrent or layered treatment with radium-223 and enzalutamide or abiraterone/prednisone: real-world clinical outcomes in patients with metastatic castration-resistant prostate cancer Prostate Cancer Prostatic Dis Shore N Higano CS George DJ 680 688 23 2020 32404868 10.1038/s41391-020-0236-0 PMC7655504

63 Fracture risk and adjuvant therapies in young breast cancer patients: a population-based study PLoS One Chang CH Chen SJ Liu CY 0 10 2015 https://doi.org/10.1371/journal.pone.0130725 10.1371/journal.pone.0130725 PMC4479486 26107848

64 Fracture after radiation therapy for femoral metastasis: incidence, timing and clinical features J Radiat Res Shimoyama T Katagiri H Harada H 661 668 58 2017 28992299 10.1093/jrr/rrx038 PMC5737329

65 Aromatase inhibitor-associated bone loss in breast cancer patients is distinct from postmenopausal osteoporosis Crit Rev Oncol Hematol Hadji P 73 82 69 2009 18757208 10.1016/j.critrevonc.2008.07.013

66 Risk of fracture during androgen deprivation therapy among patients with prostate cancer: a systematic review and meta-analysis of cohort studies Front Pharmacol Wu CC Chen PY Wang SW 652979 12 2021 34421586 10.3389/fphar.2021.652979 PMC8378175

67 Negative impact of aromatase inhibitors on proximal femoral bone mass and geometry in postmenopausal women with breast cancer Calcif Tissue Int Lee SJ Kim KM Brown JK 551 559 97 2015 26232103 10.1007/s00223-015-0046-x

68 Selective estrogen receptor modulators and bone health Climacteric Goldstein SR 56 59 25 2022 34169801 10.1080/13697137.2021.1936485

69 Effect of tamoxifen on the risk of osteoporosis and osteoporotic fracture in younger breast cancer survivors: a nationwide study Front Oncol Lee J Alqudaihi HM Kang MS 366 10 2020 32266146 10.3389/fonc.2020.00366 PMC7098996

70 Tamoxifen use and osteoporotic fracture risk: a population-based analysis J Clin Oncol Cooke AL Metge C Lix L Prior HJ Leslie WD 5227 5232 26 2008 18838712 10.1200/JCO.2007.15.7123

71 Aromatase inhibitors: role in postmenopausal breast cancer Arch Pharm (Weinheim) Kharb R Haider K Neha K Yar MS 0 353 2020 10.1002/ardp.202000081 32449548

72 Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study Lancet Oncol Coleman RE Banks LM Girgis SI 119 127 8 2007 17267326 10.1016/S1470-2045(07)70003-7

73 Aromatase inhibitor-associated bone loss and its management with bisphosphonates in patients with breast cancer Breast Cancer (Dove Med Press) Bauer M Bryce J Hadji P 91 101 4 2012 https://pmc.ncbi.nlm.nih.gov/articles/PMC3846762/ 24367197 10.2147/BCTT.S29432 PMC3846762

74 Adjuvant aromatase inhibitors for breast cancer Lancet Howell A 431 433 6 2005 10.1016/S0140-6736(05)67036-5 16084234

75 Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer J Cancer Res Clin Oncol Kyvernitakis I Rachner TD Urbschat A Hars O Hofbauer LC Hadji P 1671 1680 140 2014 24903965 10.1007/s00432-014-1726-z PMC11823747

76 Long-term effect of aromatase inhibitors on bone microarchitecture and macroarchitecture in non-osteoporotic postmenopausal women with breast cancer Osteoporos Int Hong AR Kim JH Lee KH 1413 1422 28 2017 28083668 10.1007/s00198-016-3899-6

77 Adjuvant aromatase inhibitors in early breast cancer may not increase the risk of falls J Bone Rep Recomm Choksi P Williams ME Kidwel KM Stella J Soyster M Hanauer D Van Poznak C 2 2016 10.4172/2469-6684.100023 PMC5036389 27689141

78 The effects of adjuvant endocrine therapy on bone health in women with breast cancer J Endocrinol Ramchand SK Cheung YM Yeo B Grossmann M 0 24 241 2019 10.1530/JOE-19-0077 30991355

79 Fractures due to aromatase inhibitor therapy for breast cancer: a real-world analysis of FAERS data in the past 15 years Oncol Res Treat Song Y Xu YL Lin Y Zhao B Sun Q 96 102 43 2020 31945768 10.1159/000505376

80 Osteoporotic fractures of the spine, hip, and other locations after adjuvant endocrine therapy with aromatase inhibitors in breast cancer patients: a meta-analysis J Korean Med Sci Lee YK Lee EG Kim HY 0 35 2020 https://pmc.ncbi.nlm.nih.gov/articles/PMC7707928/ 10.3346/jkms.2020.35.e403 PMC7707928 33258332

81 Bone health evaluation one year after aromatase inhibitors completion Bone Pineda-Moncusí M Servitja S Casamayor G 54 59 117 2018 30223134 10.1016/j.bone.2018.09.010

82 Effectiveness of organized mammography screening for different breast cancer molecular subtypes Cancers (Basel) Ding L Greuter MJ Truyen I 268 275 14 2022 36230754 10.3390/cancers14194831 PMC9562677

83 Fracture incidence in pre- and postmenopausal women after completion of adjuvant hormonal therapy for breast cancer Breast Koopal C Janssen-Heijnen ML van de Wouw AJ van den Bergh JP 153 158 24 2015 25618224 10.1016/j.breast.2014.12.008

84 Association of fat body mass with vertebral fractures in postmenopausal women with early breast cancer undergoing adjuvant aromatase inhibitor therapy JAMA Netw Open Pedersini R Amoroso V Maffezzoni F 0 2 2019 10.1001/jamanetworkopen.2019.11080 PMC6777242 31560383

85 The interaction of lean body mass with fat body mass is associated with vertebral fracture prevalence in women with early breast cancer undergoing aromatase inhibitor therapy JBMR Plus Monteverdi S Pedersini R Gallo F 0 5 2021 https://pubmed.ncbi.nlm.nih.gov/33615109/ 10.1002/jbm4.10440 PMC7872339 33615109

86 GnRH and GnRH receptors in the pathophysiology of the human female reproductive system Hum Reprod Update Maggi R Cariboni AM Marelli MM Moretti RM Andrè V Marzagalli M Limonta P 358 381 22 2016 26715597 10.1093/humupd/dmv059

87 Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action Reprod Biomed Online Ortmann O Weiss JM Diedrich K 1 7 5 2002 12537774 10.1016/s1472-6483(11)60210-1

88 Bone health during endocrine therapy for cancer Lancet Diabetes Endocrinol Rachner TD Coleman R Hadji P 901 910 6 2018 29572126 10.1016/S2213-8587(18)30047-0

89 Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group J Clin Oncol Gnant MF Mlineritsch B Luschin-Ebengreuth G 820 828 25 2007 17159195 10.1200/JCO.2005.02.7102

90 Bone mineral density in premenopausal women treated for node-positive early breast cancer with 2 years of goserelin or 6 months of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) Osteoporos Int Fogelman I Blake GM Blamey R 1001 1006 14 2003 14530912 10.1007/s00198-003-1508-y

91 Bone mineral density, structure, distribution and strength in men with prostate cancer treated with androgen deprivation therapy Bone Dalla Via J Daly RM Owen PJ Mundell NL Rantalainen T Fraser SF 367 375 127 2019 31189088 10.1016/j.bone.2019.06.005

92 Effect of androgen-deprivation therapy on bone mineral density in Japanese patients with prostate cancer In Vivo Miyazawa Y Sekine Y Syuto T 409 412 32 2018 29475929 10.21873/invivo.11254 PMC5905214

93 Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer J Clin Endocrinol Metab Greenspan SL Coates P Sereika SM Nelson JB Trump DL Resnick NM 6410 6417 90 2005 16189261 10.1210/jc.2005-0183

94 The effect of androgen deprivation therapy on body composition in men with prostate cancer: systematic review and meta-analysis J Cancer Surviv Haseen F Murray LJ Cardwell CR O'Sullivan JM Cantwell MM 128 139 4 2010 20091248 10.1007/s11764-009-0114-1

95 The risk of fragility fractures in men with prostate cancer treated with androgen deprivation therapy Osteoporos Van Oostwaard MM Wyers CE Driessen JHM 2037 2045 35 2024 10.1007/s00198-024-07180-8 PMC11499317 39289210

96 Bone fracture incidence after androgen deprivation therapy-investigational agents: results from Cancer Therapy Evaluation Program-sponsored early phase clinical trials 2006-2013 Front Oncol Myint ZW Kunos CA 1125 10 2020 32760670 10.3389/fonc.2020.01125 PMC7372304

97 Changes in bone turnover markers in patients without bone metastases receiving immune checkpoint inhibitors: an exploratory analysis J Bone Oncol Pantano F Tramontana F Iuliani M 100459 37 2022 36338920 10.1016/j.jbo.2022.100459 PMC9633734

98 Osteoporosis and fracture after gastrectomy for stomach cancer: a nationwide claims study Medicine (Baltimore) Seo GH Kang HY Choe EK 0 97 2018 10.1097/MD.0000000000010532 PMC5944502 29703028

99 Increased risk of osteoporotic fracture in postgastrectomy gastric cancer survivors compared with matched controls: a nationwide cohort study in Korea Am J Gastroenterol Shin DW Suh B Lim H 1735 1743 114 2019 31658122 10.14309/ajg.0000000000000436

100 Bone loss after oophorectomy among high-risk women: an NRG oncology/gynecologic oncology group study Menopause Hibler EA Kauderer J Greene MH Rodriguez GC Alberts DS 1228 1232 23 2016 27433858 10.1097/GME.0000000000000692 PMC5079806

101 Bone density patterns after normal and premature menopause Maturitas Hadjidakis DJ Kokkinakis EP Sfakianakis ME 279 286 25 2003 10.1016/s0378-5122(03)00040-9 12697368

102 Surgical menopause and nonvertebral fracture risk among older US women Menopause Vesco KK Marshall LM Nelson HD 510 516 19 2012 22547252 10.1097/gme.0b013e318239caeb PMC3342015

103 Fracture risk following bilateral oophorectomy J Clin Epidemiol Melton LJ Crowson CS Malkasian GD 1111 1115 49 1996 8826990 10.1016/0895-4356(96)00211-9

104 Elevated bone turnover markers after risk-reducing salpingo-oophorectomy in women at increased risk for breast and ovarian cancer PLoS One Fakkert IE van der Veer E Abma EM 0 12 2017 10.1371/journal.pone.0169673 PMC5218401 28060958

105 FRAX predicts incident falls in elderly men: findings from MrOs Sweden Osteoporos Int Harvey NC Johansson H Odén A 267 274 27 2016 26391036 10.1007/s00198-015-3295-7

106 Falls predict fractures independently of FRAX probability: a meta‐analysis of the osteoporotic fractures in men (MrOS) study J Bone Miner Res Harvey NC Odén A Orwoll E 510 516 33 2018 29220072 10.1002/jbmr.3331 PMC5842893

107 High serum adiponectin predicts incident fractures in elderly men: osteoporotic fractures in men (MrOS) Sweden J Bone Miner Res Johansson H Odén A Lerner UH 1390 1396 27 2012 22407876 10.1002/jbmr.1591

108 Measures of physical performance and muscle strength as predictors of fracture risk independent of FRAX, falls, and aBMD: a meta-analysis of the Osteoporotic Fractures in Men (MrOS) study J Bone Miner Res Harvey NC Odén A Orwoll E 2150 2157 33 2018 30011086 10.1002/jbmr.3556 PMC6272117

109 Evaluation of baseline fracture risk in younger postmenopausal women with breast cancer using different risk assessment methods Skeletal Radiol Schaffler-Schaden D Kneidinger C Schweighofer-Zwink G Flamm M Iglseder B Pirich C 1015 1019 49 2020 31980852 10.1007/s00256-020-03378-z PMC7170974

110 Bone health in cancer: ESMO clinical practice guidelines Ann Oncol Coleman R Hadji P Body JJ 1650 1663 31 2020 32801018 10.1016/j.annonc.2020.07.019

111 Assessment of fracture risk in women with breast cancer using current vs emerging guidelines Br J Cancer Hadji P Ziller M Albert US Kalder M 645 650 102 2010 20087347 10.1038/sj.bjc.6605548 PMC2837568

112 Bone mineral density thresholds for pharmacological intervention to prevent fractures Arch Intern Med Siris ES Chen YT Abbott TA Barrett-Connor E Miller PD Wehren LE Berger ML 1108 1112 164 2004 15159268 10.1001/archinte.164.10.1108

113 Bone quality - the material and structural basis of bone strength and fragility N Engl J Med Seeman E Delmas PD 2250 2261 354 2006 16723616 10.1056/NEJMra053077

114 Management of cancer treatment-induced bone loss in patients with breast and hormone sensitive prostate cancer: AIOM survey Tumori Valsecchi AA Fusco V Di Maio M 174 185 110 2024 38462772 10.1177/03008916241236279

115 Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment Ann Oncol Hadji P Aapro MS Body JJ 2546 2555 22 2011 21415233 10.1093/annonc/mdr017

116 Biologic and therapeutic determinants of bone mineral density in multiple myeloma Leuk Lymphoma Dhodapkar MV Weinstein R Tricot G Jagannath S Parfitt AM Manolagas SC Barlogie B 121 127 32 1998 10037007 10.3109/10428199809059252

117 Bone mineral density utilization in patients with newly diagnosed multiple myeloma Hematol Oncol Muchtar E Dagan A Robenshtok E 703 710 35 2017 27329574 10.1002/hon.2303

118 The value of laboratory tests in diagnosing secondary osteoporosis at a fracture and osteoporosis outpatient clinic Geriatr Orthop Surg Rehabil de Klerk G Hegeman JH van der Velde D van der Palen J van Bergeijk L Duis HJ 53 57 4 2013 24093077 10.1177/2151458513501176 PMC3789505

119 Impact of serum calcium levels on total body bone mineral density: a mendelian randomization study in five age strata Clin Nutr Sun JY Zhang H Zhang Y Wang L Sun BL Gao F Liu G 2726 2733 40 2021 33933738 10.1016/j.clnu.2021.03.012

120 Preventive effects of low parathyroid hormone levels on hip fracture in patients with vitamin D deficiency J Bone Metab Byun SE Lee S Kim JW 89 95 26 2019 31223605 10.11005/jbm.2019.26.2.89 PMC6561850

121 Advances in imaging approaches to fracture risk evaluation Transl Res Manhard MK Nyman JS Does MD 1 14 181 2017 27816505 10.1016/j.trsl.2016.09.006 PMC5357194

122 Axial cortical involvement of metastatic lesions to identify impending femoral fractures; a clinical validation study Radiother Oncol van der Wal CW Eggermont F Fiocco M 59 64 144 2020 31733489 10.1016/j.radonc.2019.10.007

123 Prevalence of precursory signs of atypical femoral fractures in patients receiving bone-modifying agents for bone metastases: a cross-sectional study JBMR Plus Kaku T Oh Y Sato S 0 7 2023 10.1002/jbm4.10749 PMC10339079 37457876

124 Combining computed tomography-based bone density assessment with FRAX screening in men with prostate cancer J Clin Densitom McDonald AM Jones JA Cardan RA Saag KS Mayhew DL Fiveash JB 430 435 19 2016 27241940 10.1016/j.jocd.2016.04.011

125 Risk assessment of femoral pathological fracture in prostate cancer patients by computed tomography analysis J Bone Miner Metab Rikitake H Horiuchi K Miyai K 704 711 40 2022 35637395 10.1007/s00774-022-01338-2

126 Potential for early fracture risk assessment in patients with metastatic bone disease using parametric response mapping of CT images Tomography Hoff BA Toole M Yablon C Ross BD Luker GD VanPoznak C Galbán CJ 98 104 1 2015 26771006 10.18383/j.tom.2015.00154 PMC4710140

127 Prediction of pathological fracture in patients with lower limb bone metastasis using computed tomography imaging Clin Exp Metastasis Shinoda Y Sawada R Ishibashi Y 607 616 37 2020 32737738 10.1007/s10585-020-10053-z

128 Validation of biomechanical computed tomography for fracture risk classification in metastatic hormone-sensitive prostate cancer Eur Urol Oncol Lin JK Hearn CM Getzen E 794 803 7 2024 37926618 10.1016/j.euo.2023.10.016 PMC11268319

129 Does CT-based rigidity analysis influence clinical decision-making in simulations of metastatic bone disease? Clin Orthop Relat Res Nazarian A Entezari V Villa-Camacho JC 652 659 474 2016 26022114 10.1007/s11999-015-4371-1 PMC4746188

130 Treatment planning and fracture prediction in patients with skeletal metastasis with CT-based rigidity analysis Clin Cancer Res Nazarian A Entezari V Zurakowski D 2514 2519 21 2015 25724521 10.1158/1078-0432.CCR-14-2668 PMC4452435

131 MRI assessment of bone structure and microarchitecture J Magn Reson Imaging Chang G Boone S Martel D 323 337 46 2017 28165650 10.1002/jmri.25647 PMC5690546

132 FDG PET/CT assesses the risk of femoral pathological fractures in patients with metastatic breast cancer Clin Nucl Med Ulaner GA Zindman AM Zheng J Kim TW Healey JH 264 270 42 2017 28166159 10.1097/RLU.0000000000001580 PMC5334437

133 Radiomic modeling of bone density and rib fracture risk after stereotactic body radiation therapy for early-stage non-small cell lung cancer Adv Radiat Oncol Rydzewski NR Yadav P Musunuru HB Condit KM Francis D Zhao SG Baschnagel AM 100884 7 2022 35647405 10.1016/j.adro.2021.100884 PMC9133372

134 A patient-specific fracture risk assessment tool for femoral bone metastases: using the bone strength (BOS) score in clinical practice Cancers (Basel) Eggermont F van der Linden Y Verdonschot N 14 29 2022 https://www.mdpi.com/2072-6694/14/23/5904 10.3390/cancers14235904 PMC9740241 36497388

135 Development and validation of a prognostic index for fracture risk in older men undergoing prostate cancer treatment J Geriatr Oncol Graham-Steed TR Soulos PR Dearing N Concato J Tinetti ME Gross CP 343 351 5 2014 25240918 10.1016/j.jgo.2014.08.004 PMC4252659

136 Assessing the utility of the spinal instability neoplastic score (SINS) to predict fracture after conventional radiation therapy (RT) for spinal metastases Pract Radiat Oncol Shi DD Hertan LM Lam TC 0 94 8 2018 10.1016/j.prro.2018.02.001 29703703

137 Predicting pathological fractures at metastatic humeral lesions JB JS Open Access Tat J Bodansky D Sheth U Ung Y Whyne C Nam D 8 2023 10.2106/JBJS.OA.22.00070 PMC10132712 37123507

138 Cancer treatment-induced bone loss in patients with breast or prostate cancer Oncol Nurs Forum Maxwell C Viale PH 589 603 32 2005 15897934 10.1188/05.onf.589-603

139 A review of lifestyle, smoking and other modifiable risk factors for osteoporotic fractures Bonekey Rep Abrahamsen B Brask-Lindemann D Rubin KH Schwarz P 574 3 2014 https://pmc.ncbi.nlm.nih.gov/articles/PMC4162465/ 25228987 10.1038/bonekey.2014.69 PMC4162465

140 Spinal stabilization exercises for cancer patients with spinal metastases of high fracture risk: feasibility of the DISPO-II training program Cancers (Basel) Rosenberger F Sprave T Clauss D 13 13 2021 10.3390/cancers13020201 PMC7827062 33429892

141 Exercise mode specificity for preserving spine and hip bone mineral density in prostate cancer patients Med Sci Sports Exerc Newton RU Galvão DA Spry N 607 614 51 2019 30395051 10.1249/MSS.0000000000001831

142 Reducing the risk of cancer treatment-associated bone loss in patients with breast cancer Semin Oncol Hadji P Bundred N 0 10 34 2007 10.1053/j.seminoncol.2007.10.005 18068489

143 Management of osteoporosis in survivors of adult cancers with nonmetastatic disease: ASCO clinical practice guideline J Clin Oncol Shapiro CL Van Poznak C Lacchetti C 2916 2946 37 2019 31532726 10.1200/JCO.19.01696

144 Risedronate may preserve bone microarchitecture in breast cancer survivors on aromatase inhibitors: a randomized, controlled clinical trial Bone Prasad C Greenspan SL Vujevich KT 123 126 90 2016 27018037 10.1016/j.bone.2016.03.010

145 Long-term oral bisphosphonate use in relation to fracture risk in postmenopausal women with breast cancer: findings from the Women’s Health Initiative Menopause Drieling RL LaCroix AZ Beresford SA 1168 1175 23 2016 27433859 10.1097/GME.0000000000000696 PMC5079762

146 Selective estrogen receptor modulators in gynecology practice Clin Obstet Gynecol Pinkerton JV 803 812 64 2021 34310353 10.1097/GRF.0000000000000647