Version May 2024
INTRODUCTION — Aromatase inhibitors (AIs) are an important component of adjuvant endocrine therapy in postmenopausal women with estrogen receptor (ER)-positive breast cancer. AIs inhibit aromatase, the product of the CYP-19 gene, a member of the cytochrome P450 superfamily; this enzyme is responsible for the peripheral conversion of androgens to estrogens [1,2]. Treatment with AIs, therefore, results in bone loss due to profound estrogen deficiency [3].
As more women are exposed to AIs, it is important to understand their adverse effects on the skeleton. The evaluation and management of bone loss associated with the use of AIs are reviewed here. The role of AIs as adjuvant therapy for breast cancer is discussed elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)
ESTROGEN DEFICIENCY AND BONE LOSS — The central role of estrogen deficiency in the pathogenesis of osteoporosis in postmenopausal women has been recognized for many years. Estrogen inhibits bone resorption, and after menopause, estrogen deficiency results in increased bone resorption and rapid bone loss [4]. The mechanisms by which estrogen regulates bone remodeling are not fully established. However, estrogen is thought to affect osteoclastogenesis and osteoclast function through its effects on local cytokines and growth factors (eg, produced by either bone cells or adjacent marrow cells). This topic is reviewed separately. (See "Pathogenesis of osteoporosis", section on 'Sex steroid deficiency'.)
AI-induced estrogen deficiency — Although the primary source of estrogen in premenopausal women is the ovaries, the primary source in postmenopausal women is adipose tissue, where aromatase converts adrenal androgens to estrogens. Aromatase inhibitors (AIs) prevent conversion of androgens to estrogens. In postmenopausal women, AIs cause relatively rapid decreases in circulating estrogen [5,6]. AIs are inactive in women with intact ovarian function, including those who experienced therapy-induced amenorrhea, and hence ovarian suppression/ablation must be used in premenopausal women receiving AIs.
The AIs are divided into steroidal inactivators (exemestane) and nonsteroidal inhibitors (letrozole, anastrozole). Exemestane is a steroidal analogue of androstenedione and binds irreversibly to aromatase [7,8]. Nonsteroidal inhibitors, like letrozole or anastrozole, bind reversibly to the heme group of the enzyme by way of a basic nitrogen atom. At clinical doses, these third-generation AIs are successful in inhibiting greater than 97 percent of aromatase activity in vivo [5,9,10]. The half-life of these compounds varies from 27 hours for exemestane to 48 hours for letrozole and anastrozole [8,11,12].
In vivo animal studies suggest that exemestane may be more bone sparing than letrozole, owing to its androgenic structure [13,14]. In healthy postmenopausal women, however, all three AIs increase bone resorption markers to the same extent [15]. The MA-27 trial compared exemestane and anastrozole as adjuvant therapy in postmenopausal women [16]. Clinical fracture data were collected as adverse events. Although self-reported new diagnoses of osteoporosis were significantly less frequent on exemestane than anastrozole, there was no difference in the number of new clinical fragility fractures between the two groups (4 percent in each group).
SKELETAL OUTCOMES — Breast cancer treatments, such as surgical oophorectomy, gonadotropin-releasing hormone (GnRH) agonists, chemotherapy that induces ovarian failure, and aromatase inhibitors (AIs) all decrease endogenous estrogens, cause bone loss, and, in some women, increase the risk of fractures [17-23]. The more sudden and severe the estrogen deprivation occurs, the greater the magnitude of bone loss [18,19,24,25]. The magnitude of the bone loss generally is greater than that observed during natural menopause [24,25]. Bone loss is most rapid in premenopausal women receiving adjuvant or neoadjuvant chemotherapy or both ovarian suppression therapy (GnRH agonist) and an AI [18,19].
Bone mineral density — In several of the AI trials, bone mineral density (BMD) and bone turnover markers (BTMs) were evaluated in a subset of women. BMD of the lumbar spine (LS) and total hip (hip) were significantly reduced in postmenopausal women receiving AIs versus tamoxifen or placebo [14,24,26-28].
As examples:
●In a substudy of the five-year Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (n = 108 evaluable women), postmenopausal women with breast cancer randomly assigned to anastrozole had greater bone loss at the LS and hip (6 and 7.2 percent, respectively) compared with those assigned to tamoxifen (increase of 2.8 and 0.74 percent, respectively) [24].
●In a substudy (206 evaluable patients) of the Intergroup Exemestane Study (IES), in which postmenopausal women who had taken tamoxifen for two to three years were randomly assigned to switch to exemestane or continue tamoxifen, women who switched to exemestane experienced a greater decline in BMD at the LS (2.7 percent) and hip (1.4 percent) after six months compared with those who remained on tamoxifen (no change at either site) [26]. Bone loss slowed in the remaining 18 months of the study, declining an additional 1 and 0.8 percent at the LS and hip, respectively, in women assigned to exemestane.
In premenopausal women, in whom the primary source of estrogen is the ovaries, AIs are not effective. However, in combination with the GnRH agonist goserelin, AIs cause more bone loss than tamoxifen. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial, premenopausal women were randomly assigned to tamoxifen plus goserelin versus anastrozole plus goserelin [17]. Half of each group received zoledronic acid (ZA). After three years, overall bone loss in the group that did not receive ZA was more severe in patients receiving anastrozole (17.3 and 11.6 percent reductions in patients receiving anastrozole/goserelin and tamoxifen/goserelin, respectively).
Bone turnover markers — In several of the trials described above, markers of bone resorption (urine N-telopeptide [NTX] and serum C-telopeptide [CTX]) and formation (serum bone-specific alkaline phosphatase [BSAP], N-terminal propeptide of type 1 procollagen [PINP]) were significantly increased with AI treatment [26,27,29]. In contrast, BTMs remained constant [26] or decreased [29] with tamoxifen therapy. The use of BTMs is not routinely recommended for use in monitoring patients receiving AIs. (See "Bone physiology and biochemical markers of bone turnover" and "Use of biochemical markers of bone turnover in osteoporosis".)
Fracture — With the exception of the MA-17 trial, all adjuvant AI trials demonstrated a significant increase in the rate of overall fractures compared with tamoxifen (table 1) [26,30-36].
●In a meta-analysis of seven trials comparing AIs versus tamoxifen in postmenopausal women with early-stage breast cancer, use of AIs significantly increased the risk of bone fractures (7.5 versus 5.2 percent with tamoxifen, odds ratio [OR] 1.47, 95% CI 1.34-1.61) [37].
●In a meta-analysis of seven trials comparing extended (>5 years) adjuvant therapy with AIs versus placebo or no treatment in postmenopausal women with early breast cancer, the risk of fracture (a secondary outcome of the trials) was greater in patients taking extended courses of aromatase inhibitors (6.3 versus 4.8 percent, OR 1.34 [95% CI 1.16-1.55]) [38].
The MA-17 trial examined the efficacy of letrozole versus placebo in postmenopausal women who had completed five years of tamoxifen therapy. Of 5149 women, 256 had a clinical fracture (5.3 percent of patients assigned to letrozole compared with 4.6 percent assigned to placebo) [34]. The MA-17 trial is a "switch" trial, in which trial participants previously received five years of tamoxifen therapy. As tamoxifen mitigates bone loss in postmenopausal women [39], it may have contributed to decreasing the fracture rates in the AI treatment arm. The IES and combined ABCSG-8/Antithrombotic Regimen and Outcome (ARNO) trials are also "switch" trials, but the duration of tamoxifen treatment (two to three years) was shorter than in the MA-17 trial, which could account for the difference in the findings.
In the ATAC trial comparing anastrozole with tamoxifen, described above, the annual incidence of fractures was higher in women receiving anastrozole (11 versus 7.7 percent) throughout the five years of treatment [40]. However, beginning in the sixth year, the fracture rate decreased in the women previously assigned to anastrozole treatment such that, in years 7 to 9, the fracture rates with both treatments were similar [33]. This suggests that AI-related fracture rates will decrease upon cessation of the drug.
EVALUATION
Assessment of fracture risk — Because aromatase inhibitors (AIs) are associated with bone loss and fracture, women who will be initiating AIs require fracture risk assessment. Fracture risk assessment should include evaluation of the following:
●Clinical risk factors for osteoporosis – We typically perform a history and physical examination to elicit clinical risk factors for fracture (table 2) and lifestyle factors (eg, physical inactivity, poor nutrition) that contribute to bone loss. Clinical risk factors for fracture that are independent of bone mineral density (BMD) include advancing age, prior history of fragility fracture, chronic glucocorticoid use, low body mass index (BMI), parental history of hip fracture, cigarette smoking, and excess alcohol.
●BMD measured by dual-energy x-ray absorptiometry (DXA) – We obtain a BMD study (DXA lumbar spine [LS] and hip) in all women who will be starting AIs. Some studies demonstrate that low BMD is associated with an increased risk of fracture, whereas others demonstrate that a large proportion of individuals who experience nontraumatic fractures actually have T-scores in the nonosteoporotic range [41,42].
The clinical risk factors and femoral neck BMD can be used to estimate risk of fracture using the Fracture Risk Assessment Tool (FRAX). FRAX is designed to estimate 10-year risk of hip and major osteoporotic fracture (clinical spine, forearm, hip, or shoulder fracture) in individuals between ages 40 and 90 years, using easily obtainable clinical risk factors and femoral neck BMD (when available). FRAX can be used to select candidates for osteoporosis treatment, particularly when the BMD T-score is between -1.0 and -2.5 and there is no history of a fragility fracture. However, FRAX is not designed to estimate fracture risk in women with breast cancer; it was thought it would underestimate fracture risk in women taking AIs, but not all evidence supports this [43]. (See 'Patient selection' below and "Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk'.)
Several groups have published recommendations for the evaluation of fracture risk in women initiating AIs. These guidelines for evaluating bone density were developed largely from guidelines for screening, monitoring, prevention, and treatment of osteoporosis in postmenopausal women (see "Screening for osteoporosis in postmenopausal women and men"). It is important to remember that none of the guidelines or specific recommendations are prospectively validated using a fracture endpoint in women with breast cancer.
●The American Society of Clinical Oncology (ASCO) recommends BMD testing (DXA) for women taking AIs with at least one risk factor for osteoporosis (table 2) [44].
●The Belgian Bone Club (BBC) recommends measuring BMD (DXA) and assessing risk factors for fracture in all women starting AIs or medical castration therapy [45].
●A consensus statement from a United Kingdom Expert Group recommends measuring BMD (DXA) within three to six months of commencing AIs in all women except for those ≥75 years of age, in whom the decision to treat can be based upon age and clinical risk factor assessment, independent of BMD [46]. (See 'Patient selection' below.)
●Seven international societies recommend fracture risk assessment in all women starting AIs; FRAX can be used, but it does not fully capture AI-induced bone loss [47,48]. They recommend obtaining an image of the spine using DXA (vertebral fracture assessment) as part of the evaluation.
A survey of clinicians in the United Kingdom regarding practice patterns in treatment-induced bone loss in women with breast cancer revealed that a majority of them were not monitoring BMD in women receiving AIs, nor had confidence in their interpretation of DXA scans and knowing when to recommend treatment with bisphosphonates [49]. This survey suggests that more work is needed to educate clinicians about these issues.
Laboratory evaluation — Women initiating or already taking AIs may have risk factors for low bone mass other than estrogen deficiency. In a retrospective study of women (64 with breast cancer) referred to a bone health clinic during a six-year interval, 78 percent of the women with breast cancer had at least one cause of bone loss other than cancer or cancer-related therapies [50]. The most common finding was vitamin D insufficiency (38 percent with vitamin D <30 ng/mL [74.9 nmol/L]). Other causes of bone loss included idiopathic hypercalciuria and normocalcemic hyperparathyroidism.
In women who have low bone mass, laboratory evaluation may help identify other causes of osteoporosis, such as renal or liver disease, hyperthyroidism, and hyperparathyroidism (table 3).
Women with low bone mass (T-score equal to or below -2.5) who are initiating or already taking AIs should have the following basic tests:
●Biochemistry profile (especially calcium, phosphorous, albumin, total protein, creatinine, liver enzymes including alkaline phosphatase, electrolytes)
●25-hydroxyvitamin D (25[OH]D)
●Complete blood count (CBC)
Measuring urinary calcium excretion (24-hour collection) may identify women with idiopathic hypercalciuria.
Women who have abnormalities on the initial laboratory testing or who have suspicious findings on history and physical examination may also require additional laboratory tests (table 4). The evaluation of osteoporosis is reviewed in detail separately. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women", section on 'Evaluation'.)
PREVENTION AND TREATMENT OF AI-INDUCED BONE LOSS
Nonpharmacologic — We encourage all women to adopt lifestyle changes that promote not only bone health, but overall health as well. These include increasing physical activity (including weightbearing exercise), reducing or stopping smoking, reducing alcohol intake, and getting adequate calcium and vitamin D [51-53]. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Lifestyle measures to reduce bone loss'.)
Adequate calcium and vitamin D intake can result in positive calcium balance and a reduction in the rate of loss of bone. However, the effect upon fracture risk is less clear. Despite the uncertainty whether calcium and vitamin D supplementation prevents fractures, guidelines for cancer treatment-induced bone loss include supplementation with calcium and vitamin D [44,54-56]. We suggest 1200 mg of elemental calcium (total diet plus supplement) and 800 international units of vitamin D daily for women receiving aromatase inhibitors (AIs). (See "Calcium and vitamin D supplementation in osteoporosis".)
In women with low vitamin D levels (25-hydroxyvitamin D [25(OH)D] level <20 ng/mL [<50 nmol/L]), vitamin D supplementation should be provided prior to therapy with bisphosphonates. Administration of bisphosphonates in the setting of vitamin D deficiency increases the risk of hypocalcemia. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement' and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Hypocalcemia'.)
Pharmacologic therapy
Patient selection — Data from some, but not all, clinical trials suggest that zoledronic acid (ZA) or oral bisphosphonate (when added to antiestrogen treatment or adjuvant chemotherapy) improves disease-free survival in the subset of women with low endogenous estrogen (ie, postmenopausal or premenopausal receiving gonadotropin-releasing hormone [GnRH] agonists). This subject is reviewed in detail elsewhere (see "Use of osteoclast inhibitors in early breast cancer", section on 'Adjuvant bone-modifying treatment for higher-risk breast cancers'). This topic deals with administration of pharmacologic therapy when no decision to administer for breast cancer effect has been made.
Women with the highest risk of fracture are the ones most likely to benefit from drug therapy; therefore, selection of women based upon fracture risk, as determined by a combination of bone mineral density (BMD) and clinical risk factors, is desirable. For the prevention of fracture in patients taking aromatase inhibitors (AIs), we suggest pharmacologic therapy in patients at high risk for fracture, including patients with:
●Osteoporosis (T-score ≤-2.5 or history of fragility fracture).
●T-scores between -1.0 and -2.5 who have risks for fracture other than AI therapy (table 2). In these women, the Fracture Risk Assessment Tool (FRAX) can be used to select candidates for osteoporosis treatment, although FRAX is not designed to estimate fracture risk in women with breast cancer, and it may underestimate fracture risk in women taking AIs. A 2017 consensus guideline (from seven international societies) recommends ticking the "rheumatoid arthritis" box in FRAX to allow for the fracture effect of starting AIs as it appears that the fracture risk in women taking AIs is equivalent to that seen in rheumatoid arthritis [47].
A reasonable cutpoint for therapeutic intervention that may be cost effective in some settings is a 10-year probability of hip fracture or combined major osteoporotic fracture of ≥3.0 or ≥20 percent, respectively. These are the same cutpoints used to identify women without a history of breast cancer for osteoporosis treatment. These cutpoints have not specifically been assessed in women taking AIs. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Patient selection'.)
The trials described below (see 'Bisphosphonates' below) evaluate two different approaches to osteoporosis prevention. In the Zometa-Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST) and denosumab trials, pharmacologic therapy was administered to all women in the immediate treatment arm, irrespective of the baseline T-score. The Study of Anastrozole with the Bisphosphonate Risedronate (SABRE) trial used risk stratification, and treatment was based upon a low T-score. In the five-year report from the Z-FAST trial, only 25 percent of women in the delayed treatment arm met criteria for receiving ZA [57], suggesting that treatment of all women regardless of BMD results is unnecessary. Choosing candidates for bisphosphonate therapy based upon a combination of BMD and clinical risk factors to quantify fracture probability is a more clinically relevant approach and represents a model for subsequent trials.
Choice of initial therapy — The pharmacologic agents available for the prevention of AI-induced bone loss in postmenopausal women are bisphosphonates and denosumab. We favor bisphosphonates over denosumab as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data. In addition, when denosumab is stopped there is an increased risk in multiple vertebral fractures (see "Denosumab for osteoporosis", section on 'Increased vertebral fractures'). This has also been observed in patients taking AIs [58-60], and it is common practice to consider following denosumab with bisphosphonate therapy [61]. There are no randomized trials comparing bisphosphonates with denosumab for the prevention of bone loss and fracture in women taking AIs.
There are few other treatment options for AI-induced bone loss. Raloxifene, a selective estrogen receptor modulator (SERM) like tamoxifen, should not be given to breast cancer patients. Although recombinant human parathyroid hormone (eg, teriparatide) is available for the treatment of postmenopausal osteoporosis, it is contraindicated in women with breast cancer and bone metastases or prior radiotherapy. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)
Bisphosphonates — We favor bisphosphonates over denosumab as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data.
In several randomized trials, bisphosphonates prevented or reduced bone loss in women receiving AIs [62-69]. None of the trials were designed or powered to assess fractures as a primary outcome. Fracture data were collected as adverse events. In a meta-analysis of six trials evaluating bisphosphonates in women with breast cancer receiving AIs, bisphosphonates did not significantly decrease the number of fractures compared with placebo or no treatment (odds ratio [OR] 0.79, 95% CI 0.53-1.17) [70]. The wide confidence interval suggests that the estimate of the treatment effect is imprecise, likely due to the low number of fractures in both groups. These trials were not designed to study fracture reduction specifically in women at highest risk for fracture. In an observational study, women with early breast cancer taking aromatase inhibitors were found to have higher risk of fracture than those taking tamoxifen, but the concurrent use of oral bisphosphonates with aromatase inhibitors reduced the risk of fracture [71].
The two largest randomized trials were the Z-FAST and ZO-FAST [62-64]. In both trials, ZA (4 mg every six months) was evaluated for prevention of AI-induced bone loss. Postmenopausal women with estrogen receptor (ER)-positive, early-stage breast cancer who were receiving adjuvant letrozole were randomly assigned to immediate treatment with ZA for five years or to delayed administration (when spine or hip T-score decreased to <-2.0 or the occurrence of fracture) [62]. All patients received 500 mg of calcium and 400 to 800 international units of vitamin D.
Results are as follows:
●By month 12, only 8 to 10 percent of the subjects who did not receive ZA at the outset had a fall in T-score to <-2.0 and received ZA, and no subjects with normal BMD at baseline developed osteoporosis.
Lumbar spine (LS) and total hip (hip) BMD were better in the immediate treatment group. The differences between the immediate and delayed treatment groups in LS and hip BMD were 5.7 and 3.6 percent, respectively, in ZO-FAST and 4.4 and 3.3 percent, respectively, in Z-FAST [62,63].
There was no difference in the incidence of fractures (1 to 2 percent) between groups in either study. Fractures were recorded as adverse events.
●After 36 months of follow-up in the Z-FAST trial, between-group differences in LS and hip BMD were 6.7 and 5.2 percent, respectively [72]. At this time point, 15 percent of women in the delayed group required ZA for a T-score decrease to <-2.0. There was no difference in the incidence of fractures between the two groups (5.7 versus 6.3 percent).
After 36 months of follow-up in the ZO-FAST trial, between-group differences in LS and hip BMD were 9.3 and 5.4 percent, respectively [73]. At this time point, 21 percent of women in the delayed group required ZA for a T-score decrease to <-2.0. There was no difference in the incidence of fractures between the two groups (5 versus 6 percent).
●After 61 months of follow-up in the Z-FAST trial, between-group differences in LS and hip BMD were 8.9 and 6.7 percent, respectively [57]. Approximately 25 percent of women in the delayed group required ZA for a T-score decrease to <-2.0. There was no difference in the incidence of fractures (9.3 versus 11 percent).
The SABRE trial was designed to evaluate the effect of weekly oral risedronate on bone loss in postmenopausal women receiving anastrozole [65]. In the SABRE trial, postmenopausal women receiving anastrozole were stratified by their baseline T-scores into low risk (T-score ≥-1.0), moderate risk (T-score between -1.0 and -2.0), and high risk (T-score <-2.0). The women with moderate risk were randomized in a double-blind fashion to receive oral risedronate 35 mg/week or placebo, whereas women at low risk received anastrozole alone, and women at high risk received anastrozole and risedronate [65]. After 24 months, there was a significant difference in the change in LS and hip BMD from baseline in moderate-risk women, favoring risedronate (2.2 versus -1.8 percent and 1.8 versus -1.1 percent, respectively). LS and hip BMD increased significantly (2 to 3 percent) in women in the high-risk group, and LS decreased significantly (-2.1 percent) in the low-risk group.
Choice of bisphosphonate and dosing — Either oral or intravenous (IV) bisphosphonates are acceptable options, depending upon patient preference, availability of drugs, and potential cost issues. When using oral bisphosphonates as initial therapy, we prefer weekly risedronate or alendronate. When using IV bisphosphonates, we prefer ZA. Although 4 mg IV every six months was the dose used in most of the AI-induced bone loss trials [74], ZA (5 mg) once yearly is a reasonable dosing option and is the dose recommended for postmenopausal women with osteoporosis unrelated to breast cancer treatment. (See "Bisphosphonate therapy for the treatment of osteoporosis".)
There are insufficient data to determine relative efficacy of the individual bisphosphonates. In the Z- and ZO-FAST trials, ZA (4 mg) was administered intravenously every six months for five years [62,63]. However, other bisphosphonates and other schedules may be equally effective. In small trials in postmenopausal women with breast cancer taking AIs, oral risedronate and ibandronate were effective in reducing bone loss [66,67]. In these trials, bisphosphonates were administered using the same dose and schedule as those used for postmenopausal osteoporosis (without breast cancer). In healthy postmenopausal women with osteoporosis, ZA (5 mg) administered intravenously once yearly has been shown to prevent fracture. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Choice of bisphosphonate'.)
Adverse effects of bisphosphonates — Prolonged therapy with bisphosphonates is generally well tolerated. However, patients should be periodically monitored for a number of complications, including transient flu-like symptoms, renal insufficiency, hypocalcemia, and osteonecrosis of the jaw (ONJ). (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Risks of bisphosphonate therapy in patients with osteoporosis".)
ONJ is a rare problem that is dependent upon the dose and duration of bisphosphonate treatment. It is most common in cancer patients with bone metastases who are treated with monthly doses of IV bisphosphonates for longer than two years. In patients with early-stage breast cancer, the incidence of IV ZA-related ONJ is approximately 0.25 percent [75].
In Z-FAST, women who were randomized to receive immediate ZA experienced more bone pain (11 to 12 percent versus 4 to 7 percent) and fevers (15 versus <1 percent), temporally associated with the ZA infusions, than women in the delayed ZA group. No moderate or severe renal dysfunction was observed. In the Z-FAST and ZO-FAST trials [62,63,72] and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial [17], there were no confirmed cases of ONJ in women receiving ZA every six months.
Bisphosphonate intolerance or contraindications — Denosumab is an alternative option for women who do not tolerate or are unresponsive to oral and IV bisphosphonates.
Denosumab — Denosumab is a humanized monoclonal antibody against receptor activator of nuclear factor kappa B ligand (RANKL) that reduces osteoclastogenesis. In addition to its potential use in women at high risk for fracture receiving AIs for breast cancer, it may be used in the treatment of postmenopausal osteoporosis, in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and for skeletal metastases in patients with solid tumors. (See "Denosumab for osteoporosis" and "Side effects of androgen deprivation therapy", section on 'Denosumab' and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Denosumab'.)
●Efficacy – For women taking AIs, denosumab has been shown to improve BMD and reduce the risk of clinical fractures compared with placebo. It has not been directly compared with bisphosphonates.
•In a two-year, randomized trial of denosumab (60 mg subcutaneously every six months) versus placebo in 250 postmenopausal, osteopenic (mean T-scores -0.88 to -1.33) women receiving adjuvant AI therapy, patients in the denosumab group had significant increases in LS, total hip, and femoral neck BMD compared with placebo (between-group differences of 7.6, 4.7, and 3.6 percent, respectively) [76]. There were no vertebral fractures, and nonvertebral fractures occurred in eight subjects in each group. The most common side effects included arthralgia, back pain, and fatigue.
•In the ABCSG-18 trial, 3420 women with nonmetastatic ER- or progesterone receptor (PR)-positive breast cancer receiving an adjuvant AI were randomly assigned to denosumab or placebo administered every six months [77,78]. Compared with placebo, denosumab:
-Delayed the time to first clinical fracture (hazard ratio [HR] 0.50, 95% CI 0.39-0.65). At 36 months, fracture had occurred in 5 and 10 percent of patients in the denosumab and placebo groups, respectively.
-Reduced the incidence of new vertebral fractures (3.2 versus 6 percent, HR 0.53, 95% CI 0.33-0.85).
-Increased BMD at the LS, total hip, and femoral neck (between-group differences of 10, 7.9, and 6.5 percent, respectively).
-Improved disease-free survival (based on non-histologically verified recurrences) after five years (89.2 versus 87.3 percent, HR 0.82, 95% CI 0.69-0.98) [79], although this finding is controversial as the histologically verified local and distant recurrences were the same in the denosumab and placebo groups, respectively.
●Dosing and adverse effects – The dose of denosumab is 60 mg administered as a subcutaneous injection (upper arm, thigh, or abdomen) once every six months. It is not renally excreted, and therefore, dose adjustments for chronic kidney disease are not necessary. (See "Denosumab for osteoporosis".)
When denosumab is stopped, there is an increased risk in multiple vertebral fractures, which has also been observed in patients taking AIs [58-60]. It is common practice to begin bisphosphonate treatment immediately after completion of denosumab treatment [61]. (See "Denosumab for osteoporosis", section on 'Increased vertebral fractures' and "Denosumab for osteoporosis", section on 'Sequential osteoporosis therapy'.)
Other serious adverse effects include hypocalcemia, ONJ, atypical femur fractures, and serious infections. Overall, the most common adverse effects (>5 percent and more common than placebo) were back, extremity, and musculoskeletal pain; hypercholesterolemia; and cystitis. (See "Denosumab for osteoporosis", section on 'Adverse effects'.)
Guidelines from expert groups — Guidelines from societies and expert groups regarding the management of women taking AIs are as follows:
●A United Kingdom Expert Group recommends bisphosphonate therapy for older women (>75 years) who have one or more risk factors for osteoporotic fracture, regardless of BMD [46]. In addition, they recommend bisphosphonates for postmenopausal women <75 years of age with T-scores <-2.0 or if bone loss in women with preexisting osteopenia (T-score between -1.0 and -2.0) occurs at a rate ≥4 percent per year.
Due to the rapid bone loss that occurs in premenopausal women receiving ovarian suppression with a GnRH agonist and AI, they recommend bisphosphonates for such women if the T-score is ≤-1.0.
In women who are not candidates for bisphosphonates initially, they recommend repeat dual-energy x-ray absorptiometry (DXA) after 24 months and initiation of bisphosphonates when the above criteria are met.
●The Belgian Bone Club (BBC) recommends bisphosphonates for patients with a T-score <-2.5 or history of fragility fracture. In addition, they recommend treatment for patients with T-scores between -1.0 and -2.5 in the presence of risk factors (other than AIs). In patients not prescribed bisphosphonates, regular measurement of BMD is necessary. Bisphosphonates should be initiated if significant bone loss occurs.
●Although FRAX may underestimate bone loss attributed to AIs or other cancer treatments, the National Comprehensive Cancer Network (NCCN) incorporates FRAX into its guidelines. NCCN recommends treatment when the FRAX 10-year fracture risk is >20 percent for major fracture or >3 percent for hip fracture, or when the T-score is <-2.0 (<-1.5 if there has been significant loss of BMD as a result of cancer therapy) [55]. Bisphosphonates and denosumab are the antiresorptive therapies for preserving bone health in women with breast cancer who are treated with AIs.
●Seven international societies recommend that bone-directed therapy should be given to all patients with a T-score <-2.0 or with a T-score of <-1.0 SD with one additional risk factor, or with ≥2 risk factors (without BMD) for the duration of AI treatment [47,48]. They conclude that denosumab has the strongest evidence (as it has been shown to reduce fractures) but that bisphosphonates have other benefits, such as a 28 percent reduction in bone metastases.
●ASCO recommends offering treatment with bisphosphonates or denosumab for prevention of fracture to women with T-scores ≤-2.5 at the lumbar spine, femoral neck, or total hip, or to women who are at increased risk of osteoporotic fracture based on clinical assessment or risk assessment tool [44]. BMD should be monitored every two years.
MONITORING
Monitoring response to therapy — Monitoring the response to therapy is important for identifying patients who are not responding. While there are a number of approaches to monitoring therapy, there is no consensus on the optimal approach. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Monitoring response to initial pharmacotherapy'.)
Our approach is to measure bone mineral density (BMD) two years after initiation of therapy and every two years or less frequently thereafter. BMD that is stable or improving is evidence for a treatment response. The finding of a clinically significant BMD decrease (for example, 4 percent loss at spine or total hip) in a treated patient should trigger additional evaluation for contributing factors that may include poor adherence to therapy, inadequate gastrointestinal absorption, inadequate intake of calcium and vitamin D, or the development of a disease or disorder with adverse skeletal effects. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'BMD decreased or fracture during therapy'.)
Monitoring women who are not candidates for therapy — For women who are not candidates for therapy, BMD should be measured in one to two years and pharmacologic treatment initiated in women who develop indications for pharmacologic treatment (eg, BMD T-score ≤-2.5, fragility fracture, Fracture Risk Assessment tool [FRAX] 10-year probability of hip fracture or combined major osteoporotic fracture of ≥3.0 or ≥20 percent, respectively) or in whom BMD loss occurs at a rate approximately ≥4 percent per year.
SUMMARY AND RECOMMENDATIONS
●Evaluation
•Assessment of fracture risk – In patients initiating aromatase inhibitors (AIs), we suggest dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine (LS). Patients initiating AIs should also be assessed for other clinical risk factors for osteoporosis. The most robust non-bone mineral density (BMD) risk factors are age and prevalent fracture. Others are long-term glucocorticoid therapy, parental history of hip fracture, cigarette smoking, and excess alcohol intake (table 2). (See 'Assessment of fracture risk' above.)
•Laboratory evaluation – Women with low bone mass (T-score ≤-2.5) who are initiating or already taking AIs should have the following basic tests: biochemistry profile (especially calcium, phosphorous, albumin, total protein, creatinine, liver enzymes including alkaline phosphatase, electrolytes), 25-hydroxyvitamin D (25[OH]D), and complete blood count (CBC). Women who have abnormalities on the initial laboratory testing or who have suspicious findings on history and physical examination may also require additional laboratory tests (table 4). (See 'Laboratory evaluation' above.)
●Nonpharmacologic therapy – We encourage all women to adopt lifestyle changes that promote not only bone health, but overall health as well. These include increasing physical activity (including weightbearing exercise), reducing or stopping smoking, reducing alcohol intake, and taking calcium and vitamin D supplements (1200 mg of elemental calcium [total diet plus supplement] and 800 international units of vitamin D daily are suggested). (See 'Nonpharmacologic' above.)
●Patient selection for pharmacologic therapy – Not all women receiving AIs require treatment with pharmacologic therapy. Risk stratification based upon baseline BMD T-scores and clinical risk factors can identify who is more or less likely to benefit from therapy.
•For women initiating AIs who have a BMD T-score ≤-2.5 or history of a fragility fracture, we recommend pharmacologic treatment (Grade 1A).
•We also suggest treatment for women with a BMD T-score between -1.0 and -2.5 who have risks for fracture other than AI therapy (table 2) (Grade 2B). In such women, a reasonable cutpoint for therapeutic intervention that may be cost effective in some settings is a 10-year probability of hip fracture or combined major osteoporotic fracture of ≥3.0 or ≥20 percent, respectively. The 10-year probability of hip and major osteoporotic fracture can be calculated for individual patients using the Fracture Assessment Tool (FRAX), although FRAX may underestimate fracture risk in women with breast cancer who are taking AIs. Ticking the "rheumatoid arthritis" box in FRAX allows for the fracture effect of starting AIs as it appears that the fracture risk in women taking AIs is equivalent to that seen in rheumatoid arthritis. (See 'Patient selection' above.)
●Choice of pharmacologic therapy – For the prevention of bone loss and fracture, we suggest bisphosphonates as first-line therapy (Grade 2B). Denosumab is an alternative option for women who do not tolerate or are unresponsive to oral and intravenous (IV) bisphosphonates. (See 'Pharmacologic therapy' above and 'Choice of bisphosphonate and dosing' above and 'Denosumab' above.)
Either oral or IV bisphosphonates are acceptable options, depending upon patient preference, availability of drugs, and potential cost. When using oral bisphosphonates as initial therapy, we prefer weekly risedronate or alendronate. When using IV bisphosphonates, we prefer zoledronic acid (ZA). The optimal schedule and duration of ZA has not been defined for AI-induced bone loss. Four mg every six months or 5 mg annually are reasonable dosing options. (See 'Choice of bisphosphonate and dosing' above.)
●Monitoring
•There is no consensus on the optimal strategy for monitoring patients on therapy. However, we typically measure BMD every two years after initiation of pharmacologic therapy. (See 'Monitoring response to therapy' above.)
•In patients who do not meet the above criteria, we typically measure BMD (DXA) every one to two years and prescribe pharmacologic therapy as indicated above, or in whom BMD loss occurs at a rate approximately ≥4 percent per year. (See 'Monitoring women who are not candidates for therapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Shubham Pant, MD and Charles L Shapiro, MD, who contributed to earlier versions of this topic review.
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