# Bone Effects of Anti-Cancer Treatments in 2024

Marie Teissonnière, Mathieu Point, Emmanuel Biver, Peyman Hadji, Edith Bonnelye, Peter Ebeling, David Kendler, Tobias de Villiers, Gerold Holzer, Jean-Jacques Body, et al.

► To cite this version:

Marie Teissonnière, Mathieu Point, Emmanuel Biver, Peyman Hadji, Edith Bonnelye, et al. Bone Effects of Anti-Cancer Treatments in 2024. Calcified Tissue International, 2025, 116, pp.54. 10.1007/s00223-025-01362-0. hal-05349850

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# Bone Effects of Anti-Cancer Treatments in 2024

Marie Teissonnière¹, Mathieu Point², Emmanuel Biver³, Peyman Hadji⁴, Edith Bonnelye⁵,
Peter R. Ebeling⁶, David Kendler⁷, Tobias de Villiers⁸, Gerold Holzer⁹, Jean-Jacques Body¹⁰,
Ghada El Hajj Fuleihan¹¹, Maria Luisa Brandi¹², René Rizzoli¹³, Cyrille B. Confavreux²,¹⁴

1) Pharmacie, Groupement Hospitalier Sud, Hospices Civils de Lyon, Pierre-Bénite, France

2) INSERM UMR1033 - LYOS, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France

3) Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

4) Frankfurt Center of Bone Health & Philipps University of Marburg, Frankfurt am Main, Germany

5) Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France

6) Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia

7) Department of Medicine (Endocrinology), University of British Columbia, Vancouver Canada

8) Department Gynaecology, Stellenbosch University, Cape Town, South Africa

9) Medical University of Vienna, Vienna, Austria

10) Department of Medicine, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium

11) Calcium Metabolism and Osteoporosis Program WHO Center for Metabolic Bone Disorders
American University of Beirut, Beirut, Lebanon

12) FIRMO Foundation, Florence and University Vita-Salute San Raffaele, Milan, Italy

13) Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland

14) Bone Metastasis Expert Center (CEMOS), Rheumatology Department, Hospices Civils de Lyon Cancer Institute (ICHCL), Hopital Lyon Sud, Pierre-Bénite, France

**Corresponding author:**

Pr Cyrille CONFAVREUX, MD PhD
Centre Expert des Métastases Osseuses (CEMOS)
Service de Rhumatologie Sud
Hôpital Lyon Sud
165 chemin du Grand Revoyet
F-69310, Pierre Bénite, FRANCE
Phone: +33 478861231
Email: cyrille.confavreux@chu-lyon.fr
ORCID: 0000-0002-9318-6785

Words: 5642 Tables: 3 Figure: 3 References: 120. Abstract: 199 words

**Keywords:** cancer treatment induced bone loss (CTIBL), bone mineral densitometry, side effects, fracture risk, osteoblast, osteoclast
Abstract

Considerable progress has been made in the management of cancer patients in the last decade with the arrival of anti-cancer immunotherapies (immune checkpoint inhibitors) and targeted therapies. As a result, a broad spectrum of cancers, not just hormone-sensitive ones, have seen several patients achieve profound and prolonged remissions, or even cures. The management of medium- and long-term side-effects of treatment and quality of life of patients are essential considerations. This is especially true for bone, as bone fragility can lead to increased fractures and loss of autonomy, ultimately reducing the possibility of resuming physical activity. Physical activity is essential for lasting oncological remission and prevention of fatigue.

While the issue of hormone therapies and their association with breast cancer has been recognized for some time, the situation is relatively new with regards to targeted therapies and immunotherapies. This is particularly challenging given the wide range of available targeted therapies and their application to numerous cancer types.

This article provides a comprehensive review of the bone effects of the main anti-cancer therapies currently in use. The review goes beyond glucocorticoids and hormone therapies and discusses for each drug category what is known regarding cellular effects, BMD effects, and fracture incidence.
# INTRODUCTION

In the last decade, oncology and hematology fields underwent drastic improvements in cancer care with the onset of novel non-chemotherapy drugs. This has contributed to the transformation of cancer into a chronic disease in an increasing number of patients across all tumor types even in metastatic stages. Beyond survival itself, issues of long-term quality of life in cancer patients becomes increasingly important. In particular, the issue of long-term bone health was a quite common parameter in breast and prostate cancers patients on hormonal therapy. Nowadays this question may be expanded to many other cancer types including pediatric cancers (1-3).

Mobility is one of the major items involved in autonomy and quality of life in patients. This mobility relies on bone strength, muscle strength, healthy joints and movement coordination. Bone strength comprises two components, bone mass and bone quality that may be impaired during cancer treatment. The paradigm of cancer treatment-induced bone loss (CTIBL) is the one observed during hormonal deprivation. Most upcoming drugs in oncology and hematology are not chemotherapy drugs but signaling pathway modulators in cancer cells. Most of bone effects of these long-term treatments remain unknown and to our knowledge, there is no recent review dealing with bone effects of these new drugs used in cancer management. Thus, there is a need to review in adults, the beneficial and adverse bone effects of newer drugs used in cancer management. In childhood cancer patients, the drugs used are associated with particular adverse effects due to their effects on growth and bone development of children, with subsequent consequences as they grow into adults (1,2). This manuscript will not consider bone fragility encountered in metastatic bone disease nor associated measures for bone health prevention (3).

# MATERIALS AND METHODS

We performed a systematic literature research. The search criteria were in vitro, in vivo and human studies of the effects of anti-cancer drugs on bone mineral density (BMD), fracture risk and bone cells (osteoblasts and osteoclasts) in adults. Drugs included in the research were corticosteroids, hormone therapy drugs, proteasome inhibitors, tyrosine kinase inhibitors, anti-VEGF antibodies, immune checkpoint inhibitors, mTor inhibitors, anti-angiogenics and cytostatics. The keywords used on Pubmed/Medline were: ("Bone and Bones/drug effects" [Mesh] OR "Bone and Bones/pathology" [Mesh] OR "Bone Remodeling/drug effects" [Mesh] OR "Osteoblasts" [Mesh]) AND ("Antineoplastic Agents/adverse effects" [Mesh] OR "Antineoplastic Agents/drug effects" [Mesh] OR "Antineoplastic Agents/drug therapy" [Mesh] OR "Antineoplastic Agent" [TiAb] OR
"Anticancer Agent" [OR "Chemotherapy Agent" [TiAb] OR "Antitumor Agent" [TiAb] OR "Protein Kinase Inhibitors" [Mesh] OR "Protein Kinase Inhibitors" [TiAb] OR "Proteasome Inhibitors" [Mesh] OR "Proteasome Inhibitor*" [TiAb]) AND ("Humans" [Mesh]). One article, not referenced on Medline, has also been selected. The last literature search has been performed on August 2023. Anti-resorptive agents and odanacatib have been excluded from the search since they have direct bone effects but they are not considered as anti-cancer drugs themselves. The bibliographic search identified studies, reviews and meta-analyses. All non-English references were excluded.

# RESULTS

## Glucocorticoid therapy

In oncology, glucocorticoids (dexamethasone, prednisone, prednisolone) are used in high doses and as background, support or adjuvant treatment to chemotherapy either to potentiate the effects of anticancer drugs or to prevent adverse effects. Glucocorticoids are also known to induce effects on bone cells. Most data have been obtained in non-cancer inflammatory chronic diseases. Bone effects are more severe when glucocorticoid is prolonged and the daily dose is high, leading to a high cumulative dose. Thus, a dose of more than 7.5mg/day – and for some even 5mg/day- of oral prednisone or equivalent daily, exceeding 3 months of treatment is the commonly agreed upon threshold for considering glucocorticoids as risk factor for osteoporosis (4). Nevertheless, it is a continuum and there may be individual variations but there is no trivial glucocorticoid dose for bone. Regular intermittent high dose regimens in oncology have been less studied. Another frequent side-effect is glucocorticoid-induced osteonecrosis (5). Moreover, there is interaction between underlying bone health, co-treatments and the glucocorticoids. Bone toxicity of glucocorticoids has been largely reviewed elsewhere (4,6). Key points are summarized below.

### Risk of fracture

Fracture risk increases early, as soon as 3-6 months after initiation (7). Notably, the vertebral fracture risk is particularly increased (8). Although fracture risk is related to the glucocorticoids dose, lower doses also have an effect (+20% at 5mg/day compared to +60% at 20mg/day) (7,8).
For a similar BMD value, the relative risk of any fracture in patient on glucocorticoids ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years in comparison with untreated patients. For hip fracture, the risk is 4.42 and 2.48 respectively (9).

Fracture risk may be high, even if BMD loss is not severe. Physicians should be aware of this discrepancy and consider the cumulative doses, duration of exposure and the persisting drug exposure (1). Cumulative doses are correlated with an increased risk of vertebral and non-vertebral fractures, particularly at the hip and forearm (7). These effects appear to be reversible within one year of cessation of treatment, regardless of underlying pathology, age, or gender (4).

### Effect on BMD.

In adults, glucocorticoid therapy is associated with increased bone loss from the first few months and in a dose-dependent manner. Return to normal values upon glucocorticoid withdrawal is not universal, and usually, there is only a partial recovery. Nevertheless, with glucocorticoid therapy there is a discrepancy between the magnitude of BMD changes and the severity of bone strength impairment.

Adolescents may be subject to very high doses, ≥900 mg/m² prednisone equivalent. Compared with adults, adolescents are more likely not to achieve peak bone mass and to develop bone loss due to the effect of glucocorticoids on bone formation and bone growth (10). Nevertheless, some data from nephrology studies with such high doses are reassuring in showing that despite their shorter stature, children have no deficit in bone mineral content of the spine or whole body after adjustment for age, bone size, sex, and degree of maturation (11).

Of note, different types of glucocorticoids differ in potency and side effects. In particular dexamethasone, one of the most powerful glucocorticoid regularly used in multiple myeloma, is associated with a much higher risk of bone loss compared with other glucocorticoids throughout the duration of treatment (10,12).

### Effect on bone cells and metabolism

Glucocorticoid has negative effects on osteoblast physiology. Indeed, on osteoblasts, the bone forming cells, dexamethasone inactivates the transcription factors Osterix and Runx2, involved in osteoblastic differentiation. At high doses, dexamethasone decreases regulatory pathways involved in proliferation and differentiation such as Wnt/β-catenin, BMP and Notch (10). An indirect pathway has also been described through the stimulation of sclerostin that is secreted by osteocytes and which is one of the main physiological inhibitors of Wnt/β-catenin osteoblast anabolic pathway. Indeed, dexamethasone acts on sclerostin promotor that has several glucocorticoid response elements (13). Thus, dexamethasone administration
enhances sclerostin expression that inhibits Wnt pathway and mineralization. Interestingly, *sclerostin* deletion was associated with a marked loss of dexamethasone inhibition effect on bone formation suggesting that sclerostin was a key player in steroid-induced osteoporosis (13). Furthermore, dexamethasone activates the TAK1 signaling pathway, which is involved in apoptotic events in both osteocytes and osteoblastic cells (14).

In addition, high doses of glucocorticoids increase the number and activity of osteoclasts, the bone resorbing cells, by increasing RANKL synthesis and suppressing osteoprotegerin (OPG) levels shifting the ratio in favor of osteoclastogenesis (10).

Glucocorticoid therapy impacts markers of bone turnover by markedly reducing bone formation markers (bone alkaline phosphatase (ALP), osteocalcin, P1NP) and enhancing bone resorption markers such as serum CTX. For example, dexamethasone suppresses ALP during the intensification period of treatment of acute lymphocytic leukemia. Next, ALP partially normalizes after discontinuation. In addition, the use of high-dose glucocorticoids during the induction and intensification phases is associated with an altered longitudinal bone growth. This growth impairment is significantly more severe with dexamethasone (10).

## Hormone therapy

Estradiol and, to a lesser extent, testosterone, are sex steroid hormones essential for bone development, growth and maintenance. These hormones naturally synthesized by the body, have numerous effects on various tissues. Some tumors expressing steroid hormone receptors are called hormone-sensitive since their growth is related to these hormones. In breast cancers, estrogen is a key factor for cancer cells. Estrogen is produced by ovaries but also in adipose tissue by peripheral conversion of androgens into estrogens (aromatization). This peripheral conversion persists after menopause. In addition, breast cancer cells are also able to synthesize estradiol, independent of circulating serum estradiol levels (15).

In men, testosterone and dihydrotestosterone are two major androgens, essential for normal prostate development and maintenance of physiological functions. Testicles, ovaries and adrenal glands are the organs that produce most of these androgens. Just like breast cancer, prostate tumor cells can synthesize the enzymes involved in androgen synthesis, allowing them to survive, grow and resist to hormones deprivation therapies.

Therefore, in hormonal sensitive breast and prostate cancers, the treatment goal is to fully block this synthesis by either surgical means, radiotherapy or pharmacological castration. Pharmacological drugs act either through a central or peripheral blockade. In central blockade, the hypothalamo-hypophyseal GnRH/LH-FSH axis is blocked. This can be achieved by GnRH antagonists or continuous GnRH agonists to induce a decrease in the production of pituitary FSH/LH resulting in a decrease in circulating estradiol/testosterone
concentrations. Onset of action is rapid, within the first week (Table 1). GnRH agonists are used in premenopausal breast cancer and allow ovarian conservation, although the use of GnRH agonists sequentially or concurrently with chemotherapy shows no significant difference in all-cause survival (16,17).

In men with prostate cancer, all-cause survival is improved by GnRH agonist therapy in locally advanced forms of prostate cancer (18). In a meta-analysis, compared with agonists, GnRH antagonists are associated with improved all-cause mortality (RR: 0.48, 95% CI: 0.26-0.90, p = 0.02) but there is no difference on prostate-specific antigen (PSA) progression over a short follow-up period (19). Peripheral blockade may be achieved by antagonising androgen/estrogen receptors; or by blocking peripheral conversion (aromatase inhibitors).

## GnRH analogs

### Risk of fracture

Between 1 and 5 years after cancer diagnosis, the risk of fracture is 19.4% under GnRH agonist treatment and 12.6% without treatment and increases with length of treatment. This excess risk of fracture (RR = 1.21) is associated with increased mortality (20,21). In 218 men on GnRH agonists, the mean age of onset of fractures was 78 years with a mean time to onset of 28 months and consistently associated with a decrease in BMD (22). The rate of musculoskeletal events including fracture risk is significantly higher with GnRH antagonists. One treatment strategy is to offer a GnRH antagonist for a short period of time followed by a GnRH agonist to avoid a large increase in testosterone and the use of anti-androgens (19).

### Effect on BMD

Available data on BMD are more extensive in women with breast cancer than in men with prostate cancer. At low or high doses, GnRH antagonists are associated with a decrease in BMD as early as week 12 of treatment (23).

In premenopausal women on GnRH analogues monotherapy, a decrease in BMD of 8.2%/year of the lumbar spine is observed and 9.3%/year when combined with aromatase inhibitors (AIs) (24). In men, bone loss is significant, especially during the first year of treatment. This trend is observed as long as the subject is on treatment but is even more severe in the first year of treatment when castration is complete and sudden. Upon discontinuation, an improvement in bone loss is observed but this is usually only partial (20,25,26). The therapeutic strategy of intermittent administration reduces the risk of progressive bone loss (27). In children, GnRH agonists induce bone loss in the trabecular and cortical bone as early as 6 months of age. Upon discontinuation, reversibility is only partial (1).
### Effect on bone remodeling

The hormonal deficit caused by GnRH analogues has an impact on bone remodeling (23). This is more pronounced with GnRH agonists than with anti-androgens and involves an acceleration of bone remodeling as shown by urinary NTX or osteocalcin (27,28). With GnRH antagonists, a dose-dependent increase in serum CTX is observed within the first 6 months. GnRH agonists and antagonists also increase bone resorption and accelerate loss of bone strength (23).

### Anti-androgens

Blocking the hypothalamo-hypophyseal axis alone is generally not sufficient to completely block androgen production and induce complete castration in men. This is why a combination of anti-androgens is frequently used. There are steroidal anti-androgens (cyproterone acetate and abiraterone) and non-steroidal anti-androgens (enzalutamide, bicalutamide, apalutamide, flutamide, nilutamide and darolutamide). Abiraterone is a selective inhibitor of P450 C17, a key enzyme in the synthesis of testosterone, allowing the blockage of its production. It is indicated in hormone-sensitive and castration-resistant metastatic forms. Cyproterone is a competitive inhibitor of 5-dihydrotestosterone binding to its receptor. The other non-steroidal anti-androgens are androgen receptor inhibitors. Compared with bicalutamide, the other molecules have a higher affinity for their target without exerting an agonist effect. They are indicated in prostate cancer metastatic or non-metastatic forms, hormone-sensitive or not, depending on the molecule.

### Risk of fracture

Incidence of fractures in patients on anti-androgens is 7.3% at 24 months (vs. 1.1% in control group) corresponding to a 7 fold higher incidence. The difference was already significant after 12 months of follow-up (18). At 5 years, epidemiologic and retrospective studies indicate that approximately 20% of men receiving anti-androgens will have an osteoporotic fracture (29). With new generation (or non-steroidal) anti-androgens, the occurrence of fractures is 6.3% (vs. 4.6% with placebo) with apalutamide (30), 6.5% (vs 4.2% with placebo) with enzalutamide (31) and 4.2% (vs. 3.6% with placebo, ns) with darolutamide (32,33). Fracture risk has been computed in a meta-analysis of 519,168 men (16 studies) by Wu et al. They report that androgen deprivation use is associated with an increased fracture risk of nearly 40% (OR, 1.39; 95% CI, 1.26–1.52). OR for fracture requiring hospitalization is also increased (OR, 1.55; 95% CI, 1.29–1.88) (34).

### Effect on BMD
The extent of bone loss depends on the duration of treatment and whether the anti-androgens are administered continuously or discontinuously. Decrease in BMD is rapid, usually observed as early as 9 to 12 months of treatment (35,36). For example, at 1 year, a decrease in BMD on the spine between 2%-8% and on the femoral neck between 1.8%-6.5% is observed. Beyond 2 years of treatment, BMD continues to decrease under treatment (29). The incidence of osteoporosis (T-score ≤-2.5) is highest in the distal forearm and femoral neck (37). Recovery is dependent on testosterone levels at cessation of treatment. Other studies, on the other hand, have shown the protective role of bicalutamide on BMD (38). Compared with untreated men, postmenopausal women and women treated with aromatase inhibitors, bone loss is greater in men treated with anti-androgens.

### Effect on bone cells and remodeling

Urinary markers of bone turnover are significantly increased by anti-androgens (37). *In vitro*, inhibition of osteoclastogenesis with down-regulation of osteoclastic markers (TRAP, κ-cathepsin, metalloproteinase-9) and up-regulation of osteoblastic markers (ALP, osteocalcin) are observed. *In vitro* and *in vivo*, enzalutamide decreases the expression of TGFBR2 on the osteoblast, which is responsible for the development of bone lesions (39). The effects on bone of apalutamide, darolutamide, flutamide and nilutamide have not yet been studied.

### Anti-estrogens

Anti-estrogens bind to estrogen receptors, blocking the binding of natural estrogen to its receptor. There are 2 types of anti-estrogens: "Selective Estrogen Receptor Modulators" (SERM) that are competitive inhibitors of estradiol binding to the receptor (tamoxifen, toremifene and raloxifene) and "Selective Estrogen Receptor Degraders" (SERD) that bind to the ER and cause the ER to be degraded and thus downregulated (fulvestrant).

**Risk of fracture.** Over a long-term period, a 32% reduction in the risk of fracture over 7 years was observed with tamoxifen (RR = 0.68; 95%CI 0.51-0.92) and 50% over 2 years with toremifene. This effect is observed at low doses at 20 mg/day (40-42). Interestingly, a differential effect seems to exist between premenopausal and postmenopausal breast cancer women. In a case control study (n=5520 per group), there is an increased fracture risk in tamoxifen treated premenopausal women vs. untreated women (6.3% vs 3.6%; p<0.001). This is not observed in the postmenopausal women (10.1% vs 9.3%; ns) (43).
Fracture risk on fulvestrant has not been studied.

### Effect on BMD.
Tamoxifen and toremifene preserve or even increase BMD of the lumbar spine, hip, and femoral neck at 2 years in postmenopausal women with breast cancer (42). In
140 postmenopausal women, tamoxifen increased BMD by 0.6% vs. placebo group (1% loss) (44). In premenopausal women, a decrease in BMD of 1.4% was observed at 3 years vs. a gain of 0.2% in the placebo group. This was also reported by Powles *et al.* with a mean annual loss over 3 years of 1.4%/year at lumbar spine vs. a gain of 0.3%/year in placebo in premenopausal women whereas a significant gain was observed in postmenopausal women (1.2%/year) on tamoxifen (45). As for fracture risk, the discrepancy between pre- and post-menopausal women is explained by the SERM mechanism of action in presence (premenopausal) or in absence (postmenopausal) of estradiol. In absence of estradiol, SERM acts as an agonist on bone and thus prevents bone loss. By contrast in premenopausal situation, since SERM is less potent than estradiol, it acts as a partial antagonist competitor of estradiol leading to bone loss (24,46). In combination with gosereline, the decrease at 2 years in total BMD is lower compared with goseroline alone (-5% goseroline alone vs. -1.4% goseroline + tamoxifen) (47). The effect of BMD on fulvestrant has not been studied.

*Effect on bone remodeling.* Alone or in combination with AIs, tamoxifen decreases bone turnover (42,48). Urinary NTX decreases rapidly in the first few months and then gradually over the course of treatment. Bone turnover markers are significantly lower at 1 and 2 years of treatment compared to AIs. Bone ALPs are significantly lower at 2 years of treatment vs. on AI (49).

## Aromatase inhibitors

Aromatase is an enzyme involved in the conversion of androgens to estrogens in postmenopausal women. Aromatase inhibitors block the activity of this enzyme, preventing the binding of estrogens to the receptors of tumor cells and consequently their growth. The most commonly used are exemestane (steroidal), anastrozole and letrozole (non-steroidal).

*Risk of fracture.* Third generation AIs are associated with an increased risk of osteoporosis and fractures in breast cancer studies in comparison with SERMs or placebo (50–55). For example, in the BIG 1-98, fracture incidence on letrozole was significantly higher on AI than tamoxifen (8.6% vs 5.8% respectively; p=<0.001) (56). This was the same with the ABCSG study (54,57). The difference is significant even if the protocol starts with tamoxifene for 2 or 3 years before introducing the exemestane (58). In RCT, the gap with AI seems to be higher with tamoxifen, that has a small protective bone effect, than with placebo (59). In real life, based on Swedish National registers, Colzani *et al.* also highlighted the excess risk of fractures under AI in comparison with tamoxifen (HR = 1.48; 95%CI 0.98-2.22) (60).
Interestingly, long term follow-up at 100 months of the ATAC study confirms this higher fracture rate with anastrozole compared with tamoxifen (2.93% vs. 1.9%; p < 0.0001) during the time on therapy (61). Nevertheless, upon treatment discontinuation, the increased fracture risk is not persistent over the long term suggesting bone loss remains partially reversible (61–63).

A meta-analysis has been performed by Goldvaser et al. including 16,349 postmenopausal women from 7 trials (64). The odds ratio for bone fractures is OR=1.34; 95%CI 1.16-1.55. There is no association between relative OR and median age at random assignment, median duration of follow-up, or the proportion of women previously treated with tamoxifen or chemotherapy. Absolute fracture risk is increased on AI (6.3%) with an absolute difference of +1.39%.

*Effect on BMD.* Bone loss is evidenced in the spine and hip higher on AI compared with SERMs (42,52,65,66). AI bone loss is related to the collapsed residual estradiol levels (67). Therefore, these effects are also most pronounced in the 10 years after the onset of menopause (26,42,63,67,68). All AIs cause a comparable, rather constant decrease of BMD at all sites; likewise, fracture risk is equivalently increased as shown in MA 27 study (69). Direct comparisons of BMD loss between AIs are scarce but there is no significant difference between anastrozole and exemestane on BMD at 2 years (49,63). Nevertheless, in animals, some studies report a difference between AI class with non-steroidal AIs inducing less bone loss in comparison with steroidal AIs due to the mechanism of action (70). Interestingly, in the long-term bone loss analysis of anastrozole vs. tamoxifen, a partial regression was observed upon treatment discontinuation (26).

In addition to aBMD, the MAP.3 study has performed high-resolution peripheral quantitative CT at the distal radius and tibia in non osteoporotic post-menopausal women receiving exemestane vs. placebo. After 2 years on exemestane, total volumetric BMD declines (-6.1% vs. -1.8% and -5.0% vs. -1.3% at the radius and the tibia, respectively). Cortical thickness is also altered (-7.9% vs -1.1% and -7.6% vs -0.7% at the radius and the tibia respectively) (71).

*Effects on bone remodeling.* AIs are associated with elevated markers of bone resorption and increased bone turnover (42,49). These markers (urinary NTX, bone ALP) increase early in treatment and then levels stabilize (49). Upon discontinuation and concomitant with improved BMD, bone remodeling decreases, mineralization and matrix volume increase (26).

## Proteasome inhibitors (PIs)
Ubiquitin-proteasome system has an essential role in controlling cell division, signal transduction, apoptosis and protein quality enhancement. The targets of proteasome-dependent proteolysis may be various oncogenes/antioncogenes such as p21 and p27 proteins, tumor suppressor proteins p53, RB (retinoblastoma protein), BCL-2, MYC, FOS and JUN family of oncogenes, E2A, E2F, STAT transcription factors and NF-κB transcription factor inhibitors. The ultimate goal of PIs (carfilzomib, bortezomib and ixazomib) is to induce tumor cell death and improve survival in myeloma (72), mantle cell lymphoma (73). In terms of efficacy, PIs are comparable (74).

***Risk of fracture.*** Fracture risk of PIs has not been studied in humans. In mice, bortezomib promotes fracture healing in young mice and the combination with bisphosphonates promotes fracture healing in old mice (75).

***Effect on BMD.*** A significant increase in BMD is detected at axial sites under bortezomib and with an increase in trabecular bone volume under ixazomib (76,77).

***Effect on bone cells.*** On the osteoblast, PIs stimulate osteoblastic differentiation without impacting the number of osteoblastic progenitors and the viability of mature osteoblasts (76–78). This activation is enabled by positive modulation of proteolytic degradation of Runx2/Cbfa1 transcription factors, through inhibition of *Dkk-1* gene expression but without impacting the canonical signaling pathway. Bortezomib also significantly increases the expression of *DLX-5*, a transcription factor involved in osteoblast development (76). Finally, ixazomib stimulates osteoblastogenesis from mesenchymal stem cells as it increases the expression level of BMP-2 mRNA (78).

PIs promote bone formation through activation of β-catenin signaling pathways and induction of TCF transcriptional activity on osteoblastic and stromal cells (76). The level of bone formation markers correlates with treatment response (77). *In vitro*, bortezomib induces a moderate though not significant increase in ALP after 4, 7 and 14 days (76).

On osteoclasts, PIs are potent osteoclastogenesis inhibitors by intervening at the early and late stages of osteoclast differentiation without affecting precursor viability. This inhibition is dose-dependent and enabled by modulation of the signaling pathway involving p38, RANK-induced NF-κB signaling pathways, and transcriptional factor AP-1 (76–78). MIP-1α is a key component of osteoclastogenesis, expressed by osteoclasts and myeloma cells. Their concentration correlates with the presence of osteolytic lesions. Bortezomib also inhibits MIP-1α, a key component of osteoclastogenesis (76).

## Tyrosine kinase inhibitors (TKIs)
Membrane receptors with tyrosine kinase activity and cytoplasmic tyrosine kinases are important therapeutic targets in cancer treatment, due to their involvement in cell proliferation and survival (79–81). TKI can inhibit one or several tyrosine kinases leading to different inhibition profiles and have become essential tools for eligible tumors and allow to introduce personalize medicine for patients (Table 2).

*Effect on BMD and fracture.* Available data on the bone effect of TKIs on BMD and bone cells are limited and summarized in table 3. There are no data in humans either on BMD or on fragility fracture risk. In mice, data are very scarce. A group of reported TKIs increase BMD: axitinib, cabozantinib, crizotinib, dasatinib, saracatinib, nilotinib. This was not the case for sunitinib, which decreases BMD (82,83).

Globally, TKI treatments are well tolerated. The most frequent adverse events are digestive or hematological. Some bone adverse effects have been also described: periosteal reaction under pazopanib, osteonecrosis under sorafenib and sunitinib, secondary hyperparathyroidism under nilotinib, sunitinib and imatinib (84–90). These adverse effects indicate that TKIs exert an effect on bone metabolism probably depending on their molecular target.

*Effect on bone cells.* Most TKIs inhibit osteoclastogenesis (82,87,91,92). This is not the case for afatinib (93). Bosutinib, as a specific Src kinase inhibitor, has an action on osteoclast and osteoblast function. Interestingly, the c-kit inhibitory effect of bosutinib, is weak, making it a good alternative in children (94). Bone resorption markers are also affected but differently in adults and children (82). A decrease in markers in adults up to more than 50% in men has been noticed. Conversely, an increase in CTX in children on imatinib has been reported (95). This inhibition is reversible or partially reversible upon discontinuation (82).

On the osteoblast, platelet-derived growth factor receptor (PDGFR) inhibition contributes to block osteoblast differentiation, proliferation, and mitogenesis *in vitro* (82,83). But *in vivo*, a large variability in results has been observed depending on the TKI. Saracatinib and bosutinib have no effect on bone formation markers (82,94). Even though a transient increase in Runx2 and osteocalcin at 3 months is observed on imatinib followed by a non-significant decrease at 18 months, this is dependent on the stage of osteoblast maturation (82,87). With nilotinib, the effect on osteoblasts may be neutral and accounts for the balance between c-abl and PDGFR activity (83). Lastly, osteocalcin was shown decreased on vandetanib treatment (82). These effects on bone remodeling can cause disproportionate effect or even destruction of cortical bone, bone demineralization, ischemia or increased trabecular volume or even growth retardation in children (82,95–97). The effects of each TKI on osteoclastogenesis and osteoblastogenesis are summarized in table 3 and figure 2 and 3.
Immune checkpoint inhibitors

Immune check point inhibitors aim at blocking the negative signal that prevents immune T-cells to activate and kill tumor cells. The use of this strategy started in the melanoma and lung cancer fields and is now widely proposed in adjuvant or in metastatic setting.

In a recent study, following the report of Moseley (98), Ye *et al*. reported a 20% increase of fracture incidence in patients on immune checkpoint inhibitors (99). A possible explanation may come from the immune activation that would increase osteoclastogenesis and osteoclast activity and thus decrease bone mass.

In mice, the group of Johnson analyzed the bone phenotype of *PD-L1* knock out mice. They observed a decreased bone volume, an impaired bone micro-architecture and a decreased bone strength (100). The same results have been observed during pharmacological blockade of PD1. Preliminary results support the immune hypothesis stating that an increase in T cells number and increased osteoclast activity alter PD1 blockade.

mTor inhibitors

mTor are kinases that regulate cell growth, angiogenesis and survival. Everolimus and temsirolimus are 2 mTor inhibitors. Everolimus is indicated, in combination, for the management of hormone receptor positive advanced breast cancer. Temsirolimus is indicated for the treatment of renal cell carcinoma and mantle cell lymphoma. The addition of everolimus to exemestane doubles the time to progression-free survival compared with exemestane alone in postmenopausal women with HER2+ breast cancer (101).

*Effect on fractures and BMD.* Effects of mTor inhibitors on BMD in humans have not been studied. In mice, after 4 weeks of treatment, BMD improves and the bone volume/total volume ratio is 37% higher than in the control group (102). There are no available fracture data.

*Effect on bone cells.* In vitro and on intervertebral disc cells, mTor inhibitors showed their anti-senescence and anti-apoptotic properties through anti-IL1β activity inhibition. They also exert an anti-catabolic effect (MMP-2,9,13 and TIMP-1, 2) on the bone matrix through the activation of signaling pathways involving the Akt family (103).

Bone marrow edema associated with fracture has been reported 6 months after initiation of everolimus. Resolution of the adverse effect was observed 2 weeks after discontinuation and appears to be correlated with a decrease in intraosseous perfusion. This event seems to be related to its action on bone metabolism since everolimus exerts a potential inhibitory effect on osteoclast formation and activity and on osteoblast differentiation by inhibiting osteoblast
gene expression (104). Browne *et al*. also show *in vitro* and in mice, that osteoclastic precursor viability and osteoclast differentiation markers decreased significantly under everolimus regardless of its concentration. At higher concentrations, markers of osteoblast activity (ALP, OCN, OPG and Runx2) were also decreased, but without affecting the viability of pre-osteoblasts. Interestingly, everolimus prevents the significant increase of bone turnover and bone loss induced by ovariectomy (102).

## Anti-angiogenic drugs

### Anti-VEGF antibodies

Vascular endothelial growth factor (VEGF) plays an essential role in vasculogenesis and angiogenesis. Levels of VEGF are increased in the serum of patients with primary malignant bone tumors (105,106). Bevacizumab binds to VEGF, inhibiting the binding of VEGF to its receptors on the surface of endothelial cells. At the tumor level, bevacizumab inhibits the formation of new tumor vessels and tumor growth.

No data are available on the risk of fracture and BMD with bevacizumab. However, the combination of a VEGF inhibitor and a VEGF receptor inhibitor is superior to VEGF inhibitor therapy alone on the progression of bone metastases in animals (107). Moreover, anti-angiogenic drugs are known to induce osteonecrosis, particularly when combined with bisphosphonates (>10%). However, osteonecrosis of the jaw has been observed without associated risk factors (108,109). These events are dose- and time-dependent and can be explained by their mechanism of action. In rabbits, VEGF regulates osteoclast differentiation and stimulates bone resorption (110).

### Thalidomide and its derivatives

Thalidomide, lenalidomide and pomalidomide are immunomodulators (IMIDs) used in the treatment of myeloma or lymphoma. These drugs inhibit angiogenesis and belong to the class of anti-angiogenics. However, there are no studies describing the effects of anti-angiogenics on BMD and fracture risk.

Thalidomide and lenalidomide have a significant inhibitory effect on osteoblast differentiation, even at the lowest doses (111). This inhibition is observed at the late stages of differentiation, accompanied by a reduction in matrix mineralization and a decrease in ALP. In addition, the expression of the bone-forming transcription factors *Runx2* and *DLX-5* is decreased while the expression of the inhibitory proteins DKK-1 and inhibin βA is increased. In *vitro*, pomalidomide totally inhibits RANKL-induced osteoclast formation over a 21-day test period. This inhibition is observed early in the differentiation stages of hematopoietic progenitor cells, also resulting from a negative regulation of the transcription factor PU.1.
These data are confirmed by a significant decrease in CFU-GM precursors without any toxic effect (112).

These *in vitro* data were confirmed *in vivo* (112). Lenalidomide and pomalidomide directly inhibit osteoclasts through the inhibition of αVβ3-integrin and cathepsin K expression and indirectly by decreasing in myeloma cells, protein expression levels of RANKL (but not OPG) conducting to a decrease in RANKL/OPG ratio and by limiting APRIL, BAFF and MIP-1α (113,114). Immunomodulating drugs thus exert a direct and indirect inhibitory effect on osteoclasts.

## Intravenous chemotherapy

Anti-cancer management also relies on cytostatics, which are not targeted therapies. For some of them, the effects on bone or BMD are described. Most of the anti-cancer drugs listed are used in neoadjuvant chemotherapy of primary malignant bone tumors (methotrexate, cyclophosphamide, doxorubicin, ifosfamide and 5-fluorouracil), such as primary malignant osteosarcoma and Ewing's family of tumours (115,116). These tumors predominantly affect children or adolescents during accrual of peak bone mass which may be disrupted by the treatment. Animal studies show that chemotherapy has a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture (117). While some drugs appear to significantly reduce BMD, it has not yet been conclusively established that this reduced BMD is correlated with an increased fracture risk (118,119).

### 5-fluorouracil (5-FU)

*In vitro*, both aspects of osteoclast physiology decrease under 5-FU: differentiation in a dose-dependent manner, and activation as assessed by MCP-1, IL-1β, and VEGF production. In mice, the expression of genes involved in osteoclastogenesis is inhibited via the NF-κB signaling pathway (120).

### Cyclophosphamide, methotrexate, doxorubicin, ifosfamide

**Effect on BMD.** In the treatment of breast cancer in premenopausal women, after 1 year of amenorrhea, the decrease in BMD is about 6% in the spine and 5% in the femur under cyclophosphamide and methotrexate (25). In children, the cumulative dose of methotrexate > 40,000 mg/m² is associated with a reduction in BMD with a decrease in bone volume and an increased risk of osteopenia (1,118,119). In the long term, ifosfamide causes a decrease in BMD in children (1,118,119).
*Effect on bone.* Methotrexate exerts a cytotoxic effect on the proliferation of pre-osteoblasts and on the osteoblasts with an alteration of bone formation and in parallel to a stimulation of osteoclast activity (1). These same effects are found *in vitro* under doxorubicin (1,12).

## CONCLUSION

Beyond glucocorticoid and hormone therapies, the bone effects of anticancer drugs are only partially evaluated. Since overall survival and recurrence-free survival have been drastically improved in many cancers, the impact of these drugs on bone cells, bone density and fracture risk is a major issue to investigate in order to improve patients’ long-term quality of life during the “post-cancer time”. Therefore altogether the oncologist, the bone metabolism specialist, and the general practitioners need to be aware of the effects of oncology treatments on the skeleton. In the future, clinical trials documenting efficacy of osteoporosis therapies in protecting from adverse skeletal outcomes need to be performed. This is one of the numerous upcoming challenges for cancer and bone physicians alike.

## Declaration of competing interest

The following authors MT, MP, EB, EB, TV, GH, GEHF, MLB and RR declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare the following conflicts of interests: Research grants: PH (Stada), PE (Amgen, Alexion, Sanofi) and CC (Amgen, MSD avenir). Conferences: PH (UCB), PE (Amgen, Kyowa-Kirin, Alexion), DK (Amgen, Radius Pharma), JJB (Amgen), CC (Amgen, BMS, Lilly, MSD, Theramex).

## Acknowledgments

We thank Dr Dominique Pierroz for editorial assistance in finalising the manuscript. The IOF CSA Bone and Cancer Working Group comprises: Emmanuel Biver, Jean-Jacques Body, Maria Luisa Brandi, Claudia Campusano, Jorge Cannata-Andia, Marlene Chakhtoura, Cyrille Confavreux, Peter Ebeling, Ghada El-Hajj Fuleihan, Abdellah El Maghraoui, Joseph Foldes, Claus Glüer, Guiseppe Guglielmi, Peyman Hadji, Gerold Holzer, David Kendler, Nicola Napoli, Tobias de Villiers.
**Table 1:** Treatments used as hormone therapy in cancer.

**Table 2:** Molecular targets of tyrosine kinase inhibitors.

**Table 3:** Bone tyrosine kinase inhibitory effects on bone mineral density and bone cells.

**Figure 1:** Schematic representation of bone effects of anti-cancer drugs according to three levels of evidence: osteoblast and osteoclast, bone mineral density and fracture. BMD: Bone Mineral Density, SERM: Selective Estrogen Receptor Modulator, TKI: Tyrosine Kinase Inhibitor 5-FU: 5-fluorouracil and AI: aromatase inhibitor. In red: increase, in green: decrease and in blue: neutral.

**Figure 2:** Integration of tyrosine kinase inhibitor (TKI) pathways in osteoblast and osteoclast signaling.

**Figure 3:** Integration of tyrosine kinase inhibitor (TKI) pathways in osteoclast signaling.
Bibliography

1. Marcucci G, Beltrami G, Tamburini A, Body JJ, Confavreux CB, Hadji P, et al. Bone health in childhood cancer: review of the literature and recommendations for the management of bone health in childhood cancer survivors. Ann Oncol. 1 juin 2019;30(6):908-20.

2. Wilson CL, Ness KK. Bone mineral density deficits and fractures in survivors of childhood cancer. Curr Osteoporos Rep. déc 2013;11(4):329-37.

3. Confavreux CB, Follet H, Mitton D, Pialat JB, Clézardin P. Fracture Risk Evaluation of Bone Metastases: A Burning Issue. Cancers (Basel). 15 nov 2021;13(22):5711.

4. Rizzoli R, Biver E. Glucocorticoid-induced osteoporosis: who to treat with what agent? Nat Rev Rheumatol. févr 2015;11(2):98-109.

5. Subbu K, Renner JB, Rubin JE. Extensive Osteonecrosis After Glucocorticoids: Clinical Response to Bisphosphonate. JCEM Case Rep. janv 2023;1(1):luac006.

6. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 1 oct 2007;18(10):1319-28.

7. Van Staa T, Leukfens H, Cooper C. The Epidemiology of Corticosteroid-Induced Osteoporosis: a Meta-analysis. Osteoporos Int. 2002;13(7):777-87.

8. Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C. Use of Oral Corticosteroids and Risk of Fractures. Journal of Bone and Mineral Research. 2000;15(6):993-1000.

9. Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton III LJ, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res. juin 2004;19(6):893-9.

10. Velentza L, Zaman F, Sävendahl L. Bone health in glucocorticoid-treated childhood acute lymphoblastic leukemia. Critical Reviews in Oncology/Hematology. 1 déc 2021;168:103492.

11. Leonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA. Long-Term, High-Dose Glucocorticoids and Bone Mineral Content in Childhood Glucocorticoid-Sensitive Nephrotic Syndrome. New England Journal of Medicine. 26 août 2004;351(9):868-75.

12. Wasilewski-Masker K, Kaste SC, Hudson MM, Esiashvili N, Mattano LA, Meacham LR. Bone Mineral Density Deficits in Survivors of Childhood Cancer: Long-term Follow-up Guidelines and Review of the Literature. Pediatrics. 1 mars 2008;121(3):e705-13.

13. Beier EE, Sheu TJ, Resseguie EA, Takahata M, Awad HA, Cory-Slechta DA, et al. Sclerostin activity plays a key role in the negative effect of glucocorticoid signaling on osteoblast function in mice. Bone Res. 9 mai 2017;5:17013.

14. Ding H, Wang T, Xu D, Cha B, Liu J, Li Y. Dexamethasone-induced apoptosis of osteocytic and osteoblastic cells is mediated by TAK1 activation. Biochemical and Biophysical Research Communications. 1 mai 2015;460(2):157-63.

15. Yager JD, Davidson NE. Estrogen Carcinogenesis in Breast Cancer. N Engl J Med. 19 janv 2006;354(3):270-82.
16. Kurebayashi J, Shiba E, Toyama T, Matsumoto H, Okazaki M, Nomizu T. A follow-up study of a randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-month depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer. Breast cancer. 28(3):684-97.

17. Lambertini M, Boni L, Michelotti A, Magnolfi E, Cogoni AA, Mosconi AM, et al. Long-Term Outcomes With Pharmacological Ovarian Suppression During Chemotherapy in Premenopausal Early Breast Cancer Patients. J Natl Cancer Inst. 25 nov 2021;114(3):400-8.

18. Ziaran S, Goncalves FM, Sn JB. Complex Metabolic and Skeletal Changes in Men Taking Long-Term Androgen Deprivation Therapy. Clinical Genitourinary Cancer. 1 mars 2013;11(1):33-8.

19. Abufaraj M, Iwata T, Kimura S, Haddad A, Al-Ani H, Abusubaih L, et al. Differential Impact of Gonadotropin-releasing Hormone Antagonist Versus Agonist on Clinical Safety and Oncologic Outcomes on Patients with Metastatic Prostate Cancer: A Meta-analysis of Randomized Controlled Trials. European Urology. 1 janv 2021;79(1):44-53.

20. Briot K, Paccou J, Beuzeboc P, Bonneterre J, Bouvard B, Confavreux CB, et al. French recommendations for osteoporosis prevention and treatment in patients with prostate cancer treated by androgen deprivation. Joint Bone Spine. janv 2019;86(1):21-8.

21. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 13 janv 2005;352(2):154-64.

22. Hatano T, Oishi Y, Furuta A, Iwamuro S, Tashiro K. Incidence of bone fracture in patients receiving luteinizing hormone-releasing hormone agonists for prostate cancer. BJU Int. sept 2000;86(4):449-52.

23. Mohamad NV, Ima-Nirwana S, Chin KY. The Skeletal Effects of Gonadotropin-Releasing Hormone Antagonists: A Concise Review. Endocrine, Metabolic & Immune Disorders - Drug Targets. 19 juin 2023;21(10):1713-20.

24. Ramchand SK, Cheung YM, Yeo B, Grossmann M. The effects of adjuvant endocrine therapy on bone health in women with breast cancer. Journal of Endocrinology. 1 juin 2019;241(3):R111-24.

25. Bouvard B, Confavreux CB, Briot K, Bonneterre J, Cormier C, Cortet B, et al. French recommendations on strategies for preventing and treating osteoporosis induced by adjuvant breast cancer therapies. Joint Bone Spine. oct 2019;86(5):542-53.

26. Eastell R, Adams J, Clack G, Howell A, Cuzick J, Mackey J, et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol. avr 2011;22:857-62.

27. Miyaji Y, Saika T, Yamamoto Y, Kusaka N, Arata R, Ebara S, et al. Effects of gonadotropin-releasing hormone agonists on bone metabolism markers and bone mineral density in patients with prostate cancer. Urology. 1 juill 2004;64(1):128-31.

28. Smith MR, Fallon MA, Goode MJ. Cross-sectional study of bone turnover during bicalutamide monotherapy for prostate cancer. Urology. 1 janv 2003;61(1):127-31.

29. Bargiota A, Oeconomou A, Zachos I, Samarinas M, L Pisters L, Tzortzis V. Adverse effects of androgen deprivation therapy in patients with prostate cancer: Focus on muscle and bone health. J BUON. 2020;25(3):1286-94.
30. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 4 juill 2019;381(1):13-24.

31. Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 10 nov 2019;37(32):2974-86.

32. Bouleftour W, Boussoualim K, Sotton S, Vassal C, Thomas T, Magne N, et al. Second-generation hormonotherapy in prostate cancer and bone microenvironment. Endocrine-Related Cancer. 1 août 2021;28(8):T39-49.

33. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 28 mars 2019;380(13):1235-46.

34. Wu CC, Chen PY, Wang SW, Tsai MH, Wang YCL, Tai CL, et al. Risk of Fracture During Androgen Deprivation Therapy Among Patients With Prostate Cancer: A Systematic Review and Meta-Analysis of Cohort Studies. Front Pharmacol. 6 août 2021;12:652979.

35. Spry A, Galvão S, Davies R, La Bianca S, Joseph D, Davison A. Long-term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33-months observation study. BJU Int. 2009;6(104):806_12.

36. Formenti AM, Dalla Volta A, di Filippo L, Berruti A, Giustina A. Effects of Medical Treatment of Prostate Cancer on Bone Health. Trends in Endocrinology & Metabolism. 1 mars 2021;32(3):135-58.

37. Preston DM, Torréns JI, Harding P, Howard RS, Duncan WE, McLeod DG. Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss. Prostate Cancer Prostatic Dis. 2002;5(4):304-10.

38. Wadhwa VK, Weston R, Parr NJ. Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer. BJU International. 2011;107(12):1923-9.

39. Su S, Cao J, Meng X, Liu R, Vander Ark A, Woodford E, et al. Enzalutamide-induced and PTH1R-mediated TGFBR2 degradation in osteoblasts confers resistance in prostate cancer bone metastases. Cancer Lett. 28 janv 2022;525:170-8.

40. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the Prevention of Breast Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. JNCI: Journal of the National Cancer Institute. 16 nov 2005;97(22):1652-62.

41. Vestergaard P, Rejnmark L, Mosekilde L. Effect of Tamoxifen and Aromatase Inhibitors on the Risk of Fractures in Women with Breast Cancer. Calcif Tissue Int. 1 mai 2008;82(5):334-40.

42. Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE, et al. Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res. août 2006;21:1215-23.
43. Kyvernitakis I, Kostev K, Hadji P. The tamoxifen paradox-influence of adjuvant tamoxifen on fracture risk in pre- and postmenopausal women with breast cancer. Osteoporos Int. nov 2018;29(11):2557-64.

44. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 26 mars 1992;326:852-6.

45. Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol. janv 1996;14:78-84.

46. Maximov PY, Lee TM, Jordan VC. The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice. Curr Clin Pharmacol. mai 2013;8(2):135-55.

47. Sverrisdottir A, Fornander T, Jacobsson H, von Schoultz E, Rutqvist LE. Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. J Clin Oncol. 15 sept 2004;22:3694-9.

48. Hadji P, Ziller M, Kieback D, Menschik T, Kalder M, Kuck J. The effect of exemestane or tamoxifen on markers on bone turnover : results of a German sub-study of the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. Breast. 2009;3(18):159-64.

49. Aihara T, Suemasu K, Takei H, Hozumi Y, Takehara M, Saito T, et al. Effects of exemestane, anastrozole and tamoxifen on bone mineral density and bone turnover markers in postmenopausal early breast cancer patients: results of N-SAS BC 04, the TEAM Japan substudy. Oncology. 2010;79:376-81.

50. McCloskey EV, Hannon RA, Lakner G, Fraser WD, Clack G, Miyamoto A, et al. Effects of third generation aromatase inhibitors on bone health and other safety parameters: results of an open, randomised, multi-centre study of letrozole, exemestane and anastrozole in healthy postmenopausal women. Eur J Cancer. nov 2007;43:2523-31.

51. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 1 janv 2005;365:60-2.

52. Coleman RE, Banks LM, Girgis SI, Kilburn LS, Vrdoljak E, Fox J, et al. 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. févr 2007;8(2):119-27.

53. Rabaglio M, Sun Z, Price KN, Castiglione-Gertsch M, Hawle H, Thurlimann B, et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol. sept 2009;20:1489-98.

54. Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 6 août 2005;366:455-62.

55. Arimidex, Tamoxifen, Alone or in Combination Trialists' Group, Buzdar A, Howell A, Cuzick J, Wale C, Distler W, et al. Comprehensive side-effect profile of anastrozole and tamoxifen as
adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial.
Lancet Oncol. août 2006;7(8):633- 43.

56. Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 10 févr 2007;25(5):486-92.

57. Jakesz R, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst. 19 déc 2007;99:1845-53.

58. Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 17 févr 2007;369(9561):559-70.

59. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 7 sept 2005;97:1262-71.

60. Colzani E, Clements M, Johansson ALV, Liljegren A, He W, Brand J, et al. Risk of hospitalisation and death due to bone fractures after breast cancer: a registry-based cohort study. Br J Cancer. 22 nov 2016;115(11):1400-7.

61. Arimidex TA or in CTG, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. janv 2008;9:45-53.

62. Jerzak KJ, Raphael J, Desautels DN, Blanchette PS, Tyono I, Pritchard KI. Bone-Targeted Therapy in Early Breast Cancer. Oncology (Williston Park). 15 nov 2018;32(11):562-9.

63. Goss PE, Hershman DL, Cheung AM, Ingle JN, Khosla S, Stearns V, et al. Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial. Lancet Oncol. avr 2014;15:474-82.

64. Goldvaser H, Barnes TA, Šeruga B, Cescon DW, Ocaña A, Ribnikar D, et al. Toxicity of Extended Adjuvant Therapy With Aromatase Inhibitors in Early Breast Cancer: A Systematic Review and Meta-analysis. J Natl Cancer Inst. 1 janv 2018;110(1).

65. Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol. 1 août 2006;24:3629-35.

66. Decensi A, Sun Z, Guerrieri-Gonzaga A, Thurlimann B, McIntosh C, Tondini C, et al. Bone mineral density and circulating biomarkers in the BIG 1-98 trial comparing adjuvant letrozole, tamoxifen and their sequences. Breast Cancer Res Treat. avr 2014;144:321-9.

67. Confavreux CB, Fontana A, Guastalla JP, Munoz F, Brun J, Delmas PD. Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole. Prevention with bisphosphonates. Bone. sept 2007;41(3):346-52.
68. Eastell R, Adams J, Coleman R, Howell A, Hannon R, Cuzick J. Effect of anastrozole on bone mineral density: 5-years results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol. 2008;26(26):1051-7.

69. Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 10 avr 2013;31:1398-404.

70. Goss PE, Qi S, Josse RG, Pritzker KP, Mendes M, Hu H, et al. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone. mars 2004;34:384-92.

71. Cheung AM, Tile L, Cardew S, Pruthi S, Robbins J, Tomlinson G, et al. Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial. Lancet Oncol. mars 2012;13:275-84.

72. Scott K, Hayden PJ, Will A, Wheatley K, Coyne I. Bortezomib for the treatment of multiple myeloma. Cochrane Database of Systematic Reviews. 2016 Apr 20;4(4):CD010816.

73. Li SJ, Hao J, Mao Y, Si YL. Effects of the Proteasome Inhibitor Bortezomib in Combination with Chemotherapy for the Treatment of Mantle Cell Lymphoma: A Meta-analysis. Turk J Haematol. mars 2020;37(1):13-9.

74. Xu W, Sun X, Wang B, Guo H. Pooled analysis of the reports of carfilzomib/ixazomib combinations for relapsed/refractory multiple myeloma. Ann Hematol. 1 févr 2018;97(2):299-307.

75. Wang H, Zhang H, Srinivasan V, Tao J, Sun W, Lin X, et al. Targeting Bortezomib to Bone Increases Its Bone Anabolic Activity and Reduces Systemic Adverse Effects in Mice. Journal of Bone and Mineral Research. 2020;35(2):343-56.

76. Accardi F, Toscani D, Bolzoni M, Dalla Palma B, Aversa F, Giuliani N. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling. Biomed Res Int. 2015;2015:172458.

77. Zangari M, Suva LJ. The effects of proteasome inhibitors on bone remodeling in multiple myeloma. Bone. 1 mai 2016;86:131-8.

78. Tibullo D, Longo A, Vicario N, Romano A, Barbato A, Di Rosa M, et al. Ixazomib Improves Bone Remodeling and Counteracts Sonic Hedgehog Signaling Inhibition Mediated by Myeloma Cells. Cancers (Basel). 30 janv 2020;12(2):323.

79. Rath S, Elamarthi P, Parab P, Gulia S, Nandhana R, Mokal S, et al. Efficacy and safety of palbociclib and ribociclib in patients with estrogen and/or progesterone receptor positive, HER2 receptor negative metastatic breast cancer in routine clinical practice. PLoS One. 22 juill 2021;16(7):e0253722.

80. Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 24 juin 2021;384(25):2394-405.
81. Chan A, Moy B, Mansi J, Ejlertsen B, Holmes FA, Chia S, et al. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clinical Breast Cancer. 1 févr 2021;21(1):80-91.e7.

82. Alemán JO, Farooki A, Girotra M. Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies. Endocrine-Related Cancer. 1 juin 2014;21(3):R247-59.

83. O'Sullivan S, Lin JM, Watson M, Callon K, Tong PC, Naot D, et al. The skeletal effects of the tyrosine kinase inhibitor nilotinib. Bone. 1 août 2011;49(2):281-9.

84. O'Sullivan S, Horne A, Wattie D, Porteous F, Callon K, Gamble G, et al. Decreased bone turnover despite persistent secondary hyperparathyroidism during prolonged treatment with imatinib. J Clin Endocrinol Metab. avr 2009;94(4):1131-6.

85. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosis of jaw: a case report. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 1 mars 2012;113(3):e1-3.

86. Garuti F, Camelli V, Spinardi L, Bucci L, Trevisani F. Osteonecrosis of the Jaw during Sorafenib Therapy for Hepatocellular Carcinoma. Tumori. 1 nov 2016;102(2_suppl):S69-70.

87. Terpos E, Apperley J, Milojkovic D. Imatinib and chronic myeloid leukemia: close to the bone. Leukemia & Lymphoma. 1 août 2013;54(8):1581-2.

88. Canzano F, Di Lella F, Manuguerra R, Vincenti V. Osteonecrosis of the External Auditory Canal Associated With Oral Sorafenib Therapy: Sorafenib and Temporal Bone Osteonecrosis. Otology & Neurotology. sept 2019;40(8):e812.

89. Hosokawa T, Hara T, Arakawa Y, Oguma E, Yamada Y. Periosteal Reaction Possibly Induced by Pazopanib: A Case Report and Literature Review. Journal of Pediatric Hematology/Oncology. nov 2020;42(8):e822.

90. Ramzan M, Verma R, Chopra YR, Yadav SP. Post-fracture excessive callus formation in a child on imatinib therapy. Pediatric Blood & Cancer. 2013;60(12):2087-8.

91. Maita S, Yuasa T, Tsuchiya N, Mitobe Y, Narita S, Horikawa Y, et al. Antitumor effect of sunitinib against skeletal metastatic renal cell carcinoma through inhibition of osteoclast function. International Journal of Cancer. 2012;130(3):677-84.

92. Pokhrel NK, Kim YG, Kim HJ, Kim HJ, Lee JH, Choi SY, et al. A novel Bruton's tyrosine kinase inhibitor, acalabrutinib, suppresses osteoclast differentiation and Porphyromonas gingivalis lipopolysaccharide-induced alveolar bone resorption. Journal of Periodontology. 2019;90(5):546-54.

93. Ihn HJ, Kim JA, Bae YC, Shin HI, Baek MC, Park EK. Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways. BMB Rep. mars 2017;50(3):150-5.

94. Campone M, Bondarenko I, Brincat S, Hotko Y, Munster PN, Chmielowska E, et al. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Annals of Oncology. 1 mars 2012;23(3):610-7.
95. Giona F, Mariani S, Gnessi L, Moleti ML, Rea M, De Vellis A, et al. Bone metabolism, growth rate and pubertal development in children with chronic myeloid leukemia treated with imatinib during puberty. Haematologica. mars 2013;98(3):e25-7.

96. Hoehn D, Cortes JE, Medeiros LJ, Jabbour EJ, Hidalgo JE, Kanagal-Shamanna R, et al. Multiparameter Analysis of the "Off-Target Effects" of Dasatinib on Bone Homeostasis in Patients with Newly Diagnosed Chronic Myelogenous Leukemia. Clin Lymphoma Myeloma Leuk. août 2016;16(Suppl):S86-92.

97. Nguyen HM, Ruppender N, Zhang X, Brown LG, Gross TS, Morrissey C, et al. Cabozantinib Inhibits Growth of Androgen-Sensitive and Castration-Resistant Prostate Cancer and Affects Bone Remodeling. PLoS One. 25 oct 2013;8(10):e78881.

98. Moseley KF, Naidoo J, Bingham CO, Carducci MA, Forde PM, Gibney GT, et al. Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: a seminal case series. J Immunother Cancer. 1 déc 2018;6(1):104.

99. Ye C, Lee K, Leslie WD, Lin M, Walker J, Kolinsky M. Fracture rate increases after immune checkpoint inhibitor treatment: a potential new immune related adverse event. Osteoporos Int. 1 avr 2023;34(4):735-40.

100. Johnson, Rachel. PD-1 blockade disrupts bone microarchitecture and compromises bone strength in breast cancer bone metastasis. Vancouver, ASBMR meeting; 2023.

101. Gnant M, Baselga J, Rugo HS, Noguchi S, Burris HA, Piccart M, et al. Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Inst. 1 mai 2013;105(9):654-63.

102. Browne AJ, Kubasch ML, Göbel A, Hadji P, Chen D, Rauner M, et al. Concurrent antitumor and bone-protective effects of everolimus in osteotropic breast cancer. Breast Cancer Res. 2017;19:92.

103. Kakiuchi Y, Yurube T, Kakutani K, Takada T, Ito M, Takeoka Y, et al. Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction. Osteoarthritis and Cartilage. 1 juin 2019;27(6):965-76.

104. McDevitt RL, Quinlan C, Hersberger K, Sahai V. Bone marrow edema associated with everolimus. American Journal of Health-System Pharmacy. 1 janv 2018;75(1):e23-7.

105. Holzer G, Obermaier A, Koschat M, Preyer O, Kotz R, Trieb K. Concentration of vascular endothelial growth factor (VEGF) in the serum of patients with malignant bone tumors. Med Pediatr Oncol. juin 2001;36(6):601-4.

106. Zhang Q, Dong G, Wang F, Ding W. Correlation between the changes of serum COX 2, APE1, VEGF, TGF-β and TSGF levels and prognosis in patients with osteosarcoma before and after treatment. J Cancer Res Ther. 2020;16(2):335-42.

107. Bachelier R, Confavreux C, Peyruchaud O, Croset M, Goehrig D, Pluijm G. Combination of anti-angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis. Int J Cancer. 2014;6(135):1319-29.
108. Bettini G, Blandamura S, Saia G, Bedogni A. Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process. BMJ Case rep. 2012 Oct 22:2012:bcr2012007284.

109. Pakosch D, Papadimas D, Munding J, Kawa D, Kriwalsky M. Osteonecrosis of the mandible due to anti-angiogenic agent, bevacizumab. Oral Maxillofac Surg. 2013;4(17):303-6.

110. Nakagawa M, Kaneda T, Arakawa T, Morita S, Sato T, Yomada T, et al. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett. 12 mai 2000;473(2):161-4.

111. Bolomsky A, Schreder M, Meißner T, Hose D, Ludwig H, Pfeifer S, et al. Immunomodulatory drugs thalidomide and lenalidomide affect osteoblast differentiation of human bone marrow stromal cells in vitro. Experimental Hematology. 1 juill 2014;42(7):516-25.

112. Anderson G, Gries M, Kurihara N, Honjo T, Anderson J, Donnenberg V, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood. 15 avr 2006;107(8):3098-105.

113. Bolzoni M, Storti P, Bonomini S, Todoerti K, Guasco D, Toscani D, et al. Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules. Experimental Hematology. 1 avr 2013;41(4):387-397.e1.

114. Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia. oct 2008;22(10):1925-32.

115. Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, et al. Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 1 oct 2018;29(Suppl 4):iv79-95.

116. Gaspar N, Hawkins DS, Dirksen U, Lewis IJ, Ferrari S, Le Deley MC, et al. Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. J Clin Oncol. 20 sept 2015;33(27):3036-46.

117. Hayward R, Iwaniec UT, Turner RT, Lien CY, Jensen BT, Hydock DS, et al. Voluntary wheel running in growing rats does not protect against doxorubicin-induced osteopenia. J Pediatr Hematol Oncol. mai 2013;35(4):e144-148.

118. Holzer G, Hobusch G, Hansen S, Fischer L, Patsch JM. Is There an Association Between Bone Microarchitecture and Fracture in Patients who were Treated for High-grade Osteosarcoma? A Controlled Study at Long-term Follow-up Using High-resolution Peripheral Quantitative CT. Clin Orthop Relat Res. 1 nov 2021;479(11):2493-501.

119. Pirker-Frühauf UM, Friesenbichler J, Urban EC, Obermayer-Pietsch B, Leithner A. Osteoporosis in children and young adults: a late effect after chemotherapy for bone sarcoma. Clin Orthop Relat Res. oct 2012;470(10):2874-85.

120. Song D, Meng T, Xu W, Hou T, Lin Z, Yin H, et al. 5-Fluoruracil blocked giant cell tumor progression by suppressing osteoclastogenesis through NF-kappaB signals and blocking angiogenesis. Bone. 1 sept 2015;78:46-54.
<table><caption>**Table 1:** Treatments used as hormonotherapy in cancer</caption><thead><tr><th>Mechanism of action</th><th>Physiological consequences</th><th>Indication</th><th>Class</th><th>Molecule</th><th>Administration</th><th>Brand name</th><th>Comment</th></tr></thead><tbody><tr><td rowspan="3">GnRH agonist</td><td rowspan="3">Indosable E and T</td><td rowspan="3">Breast and prostate</td><td rowspan="3"></td><td>triptorelin</td><td>injection</td><td>Decapeptyl®Gonapeptyl®</td><td>T flair up effect at initiation</td></tr><tr><td>leuprorelin</td><td>injection</td><td>Enantone®, Eligard®</td><td>T flair up effect at initiation</td></tr><tr><td>goserelin</td><td>injection</td><td>Zoladex®</td><td>T flair up effect at initiation</td></tr><tr><td>GnRH antagonist</td><td>Indosable T</td><td>Prostate</td><td></td><td>degarelix</td><td>injection</td><td>Firmagon®</td><td></td></tr><tr><td rowspan="2">Estrogen inhibitor - Selective Estrogen Receptor Modulator (SERM)</td><td rowspan="2">E favorable actions on bone, cardiovascular system, brain and lipids<br/>Inhibition of action of E on mammary gland, endometer, breast cancer</td><td rowspan="2">Breast</td><td rowspan="2"></td><td>tamoxifen</td><td>oral</td><td>Nolvadex®</td><td></td></tr><tr><td>toremifen</td><td></td><td>Fareston®</td><td></td></tr><tr><td rowspan="2">Estrogen inhibitor - Selective Estrogen Receptor Degrader (SERD)</td><td rowspan="2">Indosable E</td><td rowspan="2">Breast</td><td rowspan="2"></td><td>elacestran</td><td>oral</td><td>Orserdu®</td><td rowspan="2">Indicated in case of ESR1 mutation</td></tr><tr><td>fulvestrant</td><td>oral</td><td>Fazlodex®</td></tr><tr><td rowspan="3">Aromatase inhibitor (AI)</td><td rowspan="3">Indosable E</td><td rowspan="3">Breast</td><td>steroidal</td><td>aromasine</td><td>oral</td><td>Exemestane®</td><td></td></tr><tr><td rowspan="2">non steroidal</td><td>letrozole</td><td>oral</td><td>Femara®</td><td></td></tr><tr><td>anastrozole</td><td>oral</td><td>Arimidex®</td><td></td></tr><tr><td rowspan="7">Anti-androgen receptor</td><td rowspan="7">Indosable T</td><td rowspan="7">Prostate</td><td>steroidal</td><td>cyproteron acetate</td><td>oral</td><td>Androcur®</td><td>in association with GnRH agonist</td></tr><tr><td rowspan="3">1st generation</td><td>bicalutamide</td><td>oral</td><td>Cazodex®</td><td>in association with GnRH agonist</td></tr><tr><td>flutamide</td><td>oral</td><td>Prostadirex®</td><td>in association with GnRH agonist</td></tr><tr><td>nulutamide</td><td>oral</td><td>Anandron®</td><td>in association with GnRH agonist</td></tr><tr><td rowspan="3">2nd generation</td><td>enzalutamide</td><td>oral</td><td>Xtandi®</td><td>in association with GnRH agonist</td></tr><tr><td>apalutamide</td><td>oral</td><td>Erleada®</td><td>in association with GnRH agonist</td></tr><tr><td>darolutamide</td><td>oral</td><td>Nubeqa®</td><td>in association with GnRH agonist</td></tr><tr><td>Androgen synthesis inhibitor (CyP17) in adrenal gland</td><td>Indosable T</td><td>Prostate</td><td></td><td>abiraterone acetate</td><td>oral</td><td>Zytiga®</td><td>in association with prednisone 5mg</td></tr></tbody></table>
<table><caption>**Table 2:** Molecular targets of tyrosine kinase inhibitors in clinical cancer field.</caption><thead><tr><th>TKI inhibitor</th><th>cdk4,6</th><th>btk</th><th>erbb</th><th>alk</th><th>ret</th><th>pik alpha</th><th>vegfr</th><th>egfr</th><th>bcr-abl</th><th>scr</th><th>c-kit</th><th>pdgf</th><th>ros</th><th>igf-1r</th><th>met</th><th>raf</th><th>trk</th><th>vgfr</th><th>flt3</th><th>braf</th></tr></thead><tbody><tr><td>Abemaciclib</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Acalabrutinib</td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Afatinib</td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Alectinib</td><td></td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Alpelisib</td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Axitinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Bosutinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Brigatinib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td></tr><tr><td>Cabozantinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ceritinib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cobimetinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Crizotinib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Dabrafenib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td></tr><tr><td>Dasatinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Entrectinib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td></tr><tr><td>Erdafitinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td></tr><tr><td>Erlotinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Gefitinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ibrutinib</td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Imatinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lapatinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Larotrectinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Lenvatinib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td></tr><tr><td>Lorlatinib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Midostaurine</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td></tr><tr><td>Nilotinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Osimertinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Palbociclib</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Pazopanib</td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ponatinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Pralsetinib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Regorafenib</td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Ribociclib</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ripretinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td></tr><tr><td>Saracatinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Sorafenib</td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Sunitinib</td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Trametinib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td><td></td><td></td></tr><tr><td>Vandetanib</td><td></td><td></td><td></td><td>x</td><td></td><td></td><td>x</td><td>x</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Vemurafenib</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>x</td><td></td></tr></tbody></table>
<table><caption>**Table 3:** Bone tyrosine kinase inhibitory effects on bone mineral density and bone cells</caption><thead><tr><td>Drugs</td><td>BMD</td><td>Bone cells</td></tr></thead><tbody><tr><td>Abemaciclib</td><td>uk</td><td>uk</td></tr><tr><td>Acalabrutinib</td><td>uk</td><td>OC: inh</td></tr><tr><td>Afatinib</td><td>uk</td><td>OC: inh</td></tr><tr><td>Alectinib</td><td>uk</td><td>uk</td></tr><tr><td>Alpelisib</td><td>uk</td><td>uk</td></tr><tr><td>Axitinib</td><td>+ (mice)</td><td>uk</td></tr><tr><td>Bosutinib</td><td>uk</td><td>0</td></tr><tr><td>Brigatinib</td><td>uk</td><td>uk</td></tr><tr><td>Cabozantinib</td><td>+</td><td>OC: inh</td></tr><tr><td>Ceritinib</td><td>uk</td><td>uk</td></tr><tr><td>Cobimetinib</td><td>uk</td><td>uk</td></tr><tr><td>Crizotinib</td><td>+</td><td>uk</td></tr><tr><td>Dabrafenib</td><td>uk</td><td>uk</td></tr><tr><td>Dasatinib</td><td>+ (mice)</td><td>OC: inh</td></tr><tr><td>Entrectinib</td><td>uk</td><td>uk</td></tr><tr><td>Erdafitinib</td><td>uk</td><td>uk</td></tr><tr><td>Erlotinib</td><td>uk</td><td>OC: inh</td></tr><tr><td>Gefitinib</td><td>uk</td><td>OC: inh</td></tr><tr><td>Ibrutinib</td><td>uk</td><td>uk</td></tr><tr><td>Imatinib</td><td>+/-</td><td>OB: 0<br>OC: inh</td></tr><tr><td>Lapatinib</td><td>uk</td><td>OC: inh</td></tr><tr><td>Larotrectinib</td><td>uk</td><td>uk</td></tr><tr><td>Lenvatinib</td><td>uk</td><td>uk</td></tr><tr><td>Lorlatinib</td><td>uk</td><td>uk</td></tr><tr><td>Midostaurine</td><td>uk</td><td>OC: inh (mice)</td></tr><tr><td>Nilotinib</td><td>uk</td><td>OB: inh<br>OC: inh</td></tr><tr><td>Osimertinib</td><td>uk</td><td>uk</td></tr><tr><td>Palbociclib</td><td>uk</td><td>uk</td></tr><tr><td>Pazopanib</td><td>uk</td><td>uk</td></tr><tr><td>Ponatinib</td><td>uk</td><td>uk</td></tr><tr><td>Pralsetinib</td><td>uk</td><td>uk</td></tr><tr><td>Regorafenib</td><td>uk</td><td>uk</td></tr><tr><td>Ribociclib</td><td>uk</td><td>uk</td></tr><tr><td>Ripretinib</td><td>uk</td><td>uk</td></tr><tr><td>Saracatinib</td><td>+</td><td>OB: 0<br>OC: inh</td></tr></tbody></table>
<table><tr><td>Sorafenib</td><td>uk</td><td>OC: inh</td></tr><tr><td>Sunitinib</td><td>- (mice)</td><td>OB: 0<br>OC: inh</td></tr><tr><td>Trametinib</td><td>uk</td><td>uk</td></tr><tr><td>Vandetanib</td><td>uk</td><td>OB: inh</td></tr><tr><td>Vemurafenib</td><td>uk</td><td>uk</td></tr></table>

BMD: Bone mineral density, OC: osteoclastogenesis, OB: osteoblast formation activity, uk: unknown, inh: inhibition, + indicates an increase of BMD, - indicates a decrease of BMD and 0 indicates an absence of effect.