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Evaluation and management of aromatase inhibitor-induced bone loss

Last literature review version 17.3: September 2009  |  This topic last updated: September 23, 2009   (More)

INTRODUCTION — Aromatase inhibitors (AIs) are an important component of adjuvant endocrine therapy in postmenopausal women with estrogen receptor positive breast cancer. AIs inhibit the cytochrome P450 CYP-19 enzyme responsible for the peripheral conversion of androgens to estrogens [1,2]. Treatment with AIs, therefore, results in bone loss due to 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 therapy for postmenopausal women with early stage 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. 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 'Role of systemic hormones in osteoporosis'.)

AI-induced estrogen deficiency — Although the primary source of estrogen in premenopausal women is the ovaries, the primary source in postmenopausal women is the adrenal gland, where aromatase converts adrenal androgens to estrogens. Aromatase inhibitors prevent conversion of androgens to estrogens. In postmenopausal women, AIs cause relatively rapid decreases in circulating estrogen [4,5]. (See "Androgen production and therapy in women", section on 'Postmenopausal women'.)

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 [6,7]. Nonsteroidal inhibitors, like letrozole or anastrazole, 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 [4,8,9]. The half-life of these compounds varies from 27 hours for exemestane to 48 hours for letrozole and anastrazole [7,10,11].

In vivo animal studies suggest that exemestane may be more bone sparing than letrozole, owing to its androgenic structure [12,13]. However, there are no human trials showing a differential effect of the individual AIs on bone. The MA-27 trial is a comparative trial of exemestane versus anastrozole as adjuvant therapy in postmenopausal women. It includes end points such as bone mineral density (BMD) and fractures. The results are likely to provide more conclusive information about the skeletal effects of the steroidal versus nonsteroidal AIs.

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 and cause bone loss and increase the risk of fractures [14-20]. The more sudden and severe the estrogen deprivation occurs, the greater the magnitude of bone loss [15,16,21,22]. Bone loss is most rapid in premenopausal women receiving both ovarian suppression therapy (GnRH agonist) and an AI.

Bone mineral density — In several of the AI trials, BMD and bone turnover markers were evaluated in a subset of women. BMD of the LS and total hip (TH) were significantly reduced in postmenopausal women receiving AIs versus tamoxifen or placebo [13,21,23-25].

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 TH (6 and 7.2 percent, respectively) compared with those assigned to tamoxifen (increase of 2.8 and 0.74 percent, respectively) [21].
  • 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, subjects who switched to exemestane experienced a greater decline in BMD at the LS (2.7 percent) and TH (1.4 percent) after six months compared with those who remained on tamoxifen (no change at either site) [23]. Bone loss slowed in the remaining 18 months of the study, declining an additional 1.0 and 0.8 percent at the LS and TH, respectively, in subjects assigned to exemestane.

In premenopausal women, in whom the primary source of estrogen is the ovaries, AIs alone are not effective. However, in combination with the gonadotropin releasing hormone (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 [14]. Half of each group received zoledronic acid (ZA). Significant bone loss occurred in the subset of patients who did not receive ZA (17.3 and 11.6 percent reductions in patients receiving anastrozole/goserelin and tamoxifen/goserelin, respectively).

Biochemical markers of bone turnover — In several of the trials described above, markers of bone resorption (urine n-telopeptide and serum C-telopeptide [CTX]) and formation (serum bone specific alkaline phosphatase [BALP], N-terminal propeptide of type 1 procollagen [P1NP]) were significantly increased with AI treatment [23,24,26]. In contrast, bone turnover markers remained constant [23] or decreased [26] with tamoxifen therapy. (See "Bone physiology and biochemical markers of bone turnover" and "Use of biochemical markers of bone turnover in osteoporosis".)

In short-term trials (6 months) comparing the effects of exemestane (steroidal AI), anastrozole (nonsteroidal AI), and letrozole (nonsteroidal AI) on bone turnover markers (BTMs) in healthy postmenopausal women, all three AIs increased markers of bone resorption [27,28]. In one trial, there were small (BALP) to moderate (P1NP) increases in bone formation markers, without any differences between groups [28]. In another trial, the increase in P1NP was significantly greater in the exemestane group [27]. Whether this difference in P1NP has any clinical relevance is unclear. Comparative studies (nonsteroidal versus steroidal AIs) with skeletal endpoints are in progress.

Fracture — In several of the AI trials, fracture data were reported (table 1) [23,29-33]. The majority of the trials were not designed to explore fracture outcomes as primary events; therefore, fracture and other skeletal events were collected as adverse events as part of a long-term safety and tolerability assessment. With exception of the MA-17 trial, all adjuvant AI trials demonstrated a significant increase in the rate of overall fractures compared with tamoxifen.

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) [32]. 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 [34], it may have contributed to decreasing the fracture rates in the AI treatment arm. The IES and combined ABCSG8/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 anastrazole (11 versus 7.7 percent) throughout the five years of treatment [35]. However, beginning in the sixth year, the fracture rate decreased in the women previously assigned to anastrazole treatment such that in years 7 to 9, the fracture rates with both treatments were similar [31]. This suggests that AI-related fracture rates will decrease upon cessation of the drug.

EVALUATION

Assessment of fracture risk — Because AIs are associated with bone loss and fracture, women who will be initiating AIs require fracture risk assessment. Many studies have demonstrated that low BMD is associated with an increased risk of fracture. However, there are several clinical risk factors for fracture that are independent of BMD, such as advancing age, prior history of fragility fracture, chronic glucocorticoid use, low BMI, parental history of hip fracture, cigarette smoking, and excess alcohol. Thus, fracture risk assessment should include evaluation of the following:

  • Clinical risk factors for osteoporosis
  • Bone mineral density (BMD) measured by dual energy x-ray absorptiometry (DXA)

Osteoporosis risk factor assessment is reviewed in detail separately. (See "Osteoporotic fracture risk assessment", section on 'Dual-energy x-ray absorptiometry (DXA)', section on Skeletal site to measure, and section on Clinical risk factor assessment).

We typically perform a history and physical examination to elicit clinical risk factors for fracture and lifestyle factors which contribute to bone loss, including smoking, excessive alcohol, physical inactivity, and poor nutrition (table 2). We obtain a bone mineral density study (DXA LS and hip) in women who will be starting AIs.

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 [36-39].

  • The American Society of Clinical Oncology (ASCO) recommends BMD testing (DXA) for postmenopausal women taking AIs and for premenopausal women who develop treatment-related premature menopause following treatment (table 3) [40].
  • The Belgian Bone Club recommends measuring BMD (DXA) and assessing risk factors for fracture in all women starting AIs or medical castration therapy [41]

  • A consensus statement from a UK 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 BMD [42] (see 'Candidates for therapy' below)

A recent 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 [43]. 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 secondary cause of bone loss, other than cancer or cancer-related therapies [44]. 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 4).

Women with low bone mass (T-score 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
  • Complete blood count

Measuring urinary calcium excretion (24-hour collection) may identify women with idiopathic hypercalciuria. However, patients often find it inconvenient to collect a 24 hour urine specimen.

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 5). The evaluation of osteoporosis is reviewed in detail separately. (See "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 weight bearing exercise, reducing or stopping smoking, and taking calcium and vitamin D supplements [45-47]. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Nonpharmacologic therapy'.)

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. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Efficacy'.)

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 [36,40,48]. We suggest 1200 mg of elemental calcium (total diet plus supplement) and 800 international units of vitamin D daily.

In women with low vitamin D levels (25-hydroxyvitamin D level <20 ng/mL), 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 "Treatment of vitamin D deficient states", section on 'Vitamin D repletion' and "Bisphosphonates in the management of osteoporosis in postmenopausal women", section on 'Hypocalcemia'.)

Bisphosphonates — Bisphosphonates are specific inhibitors of osteoclast-mediated bone resorption [49]. They are considered first- line pharmacologic therapy for postmenopausal women with osteoporosis. (See "Overview of the management of osteoporosis in postmenopausal women".)

Efficacy — In several randomized trials, bisphosphonates prevented or reduced bone loss in women receiving AIs [50-55]. The two largest randomized trials were the Zometa-Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST) [50-52]. In both trials, zoledronic acid (4 mg every six months) was evaluated for prevention of AI-induced bone loss. Postmenopausal women with estrogen receptor-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) [50]. All patients received 500 mg of calcium and 400 to 800 international units of vitamin D.

Results, thus far, are as follows (table 6):

  • 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.
  • LS and TH BMD were better in the immediate treatment group. The differences between the immediate and delayed treatment groups in LS and TH BMD were 5.7 and 3.6 percent, respectively, in ZO-FAST and 4.4 and 3.3 percent, respectively, in Z-FAST [50,51].
  • There was no difference in the incidence of fractures (1.0 to 2.0 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 TH BMD were 6.7 and 5.2 percent, respectively [56]. 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).

The ongoing SABRE trial was designed to evaluate the effect of weekly oral risedronate on bone loss in postmenopausal women receiving anastrazole [53]. In the SABRE trial, postmenopausal women receiving anastrazole were stratified by their baseline T-scores into low risk (T-score of ≥-1.0), moderate-risk (T-score between -1.0 and -2.0) and high risk (T-score <-2). 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 anastrazole alone and at high-risk received anastrazole and risedronate [53]. Preliminary results show a small absolute difference in LS and TH BMD favoring risedronate (table 6).

Candidates for therapy — Data from ABCSG-12 suggest that ZA (added to anti-estrogen treatment with GnRH agonist goserelin and either tamoxifen or AI) improves disease-free survival. (See "Bisphosphonates in breast, prostate, and other solid tumors", section on 'Breast cancer outcomes'.) Results from several large trials in early stage breast cancer addressing the benefit of bisphosphonates (in addition to adjuvant chemotherapy, anti-estrogen therapy, or both) to reduce the risks of systemic recurrences are pending. These data should provide a definitive answer as to whether or not a bisphosphonate should be a standard component of adjuvant systemic therapy. This topic deals with administration of bisphosphonates when no decision to administer for breast cancer effect has been made.

The trials described above evaluate two different approaches to osteoporosis prevention. In the Z- and ZO-Fast trials, ZA was administered to all subjects in the immediate treatment arm, irrespective of the baseline T-score. The SABRE trial uses risk stratification, and treatment is based upon a low T-score. In the three-year report from the Z-FAST trial, only 15 percent of subjects in the delayed treatment arm met criteria for receiving ZA, 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.

For the prevention of fracture in patients taking AIs, we suggest bisphosphonates in patients at high risk for fracture, including patients with osteoporosis (T-score <-2.5 or history of fragility fracture) and patients with T-scores between -1.0 and -2.5 who have risks for fracture other than AI therapy (table 2). (See "Osteoporotic fracture risk assessment", section on 'Clinical risk factor assessment' and "Diagnosis and evaluation of osteoporosis in postmenopausal women", section on 'T-score'.)

Guidelines from societies and expert groups are as follows:

  • Current ASCO guidelines suggest pharmacologic therapy (bisphosphonates) in those with a BMD T-score ≤-2.5. In patients with BMD T-scores above -2.5, annual BMD testing is recommended with initiation of bisphosphonates when BMD T-score falls to <-2.5 [40]. The guidelines are currently being updated, and the recommendations for annual DXA scans and threshold for treatment based on T-scores may change.
  • The UK Expert Group recommends bisphosphonate therapy for elderly women (>75 years) who have one or more risk factors for osteoporotic fracture, regardless of BMD [42]. In addition, they recommend bisphosphonates for postmenopausal women <75 years of age with T-scores <-2.0 or if bone loss in women with pre-existing osteopenia (T-score between -1.0 and -2.0) occurs at a rate ≥ to 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 DXA after 24 months and initiation of bisphosphonates when the above criteria are met.

  • The Belgian Bone Club 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.

Choice of bisphosphonate and dosing — There are currently 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 [50,51]. 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 [54,55]. 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 "Bisphosphonates in the management of osteoporosis in postmenopausal women", section on 'Zoledronic acid'.)

Thus, until additional data are available, choice of bisphosphonate depends upon patient preferences and potential cost issues. We favor weekly oral risedronate or alendronate as initial therapy. However, ZA is an option if the patient does not tolerate an oral bisphosphonate. Although there are currently no published randomized trials using an annual dose of ZA (5 mg) for women on AIs, this is also a reasonable dosing option. (See "Bisphosphonates in the management of osteoporosis in postmenopausal women", section on 'Choice of bisphosphonate'.)

Adverse effects — Prolonged therapy with bisphosphonates is generally well tolerated. However, patients should be periodically monitored for a number of complications, including renal insufficiency, hypocalcemia, and osteonecrosis of the jaw. (See "Risks of bisphosphonate therapy in patients with malignancy" and "Bisphosphonates in the management of osteoporosis in postmenopausal women", section on 'Adverse effects'.)

Osteonecrosis of the jaw is an emerging problem that seems dependent upon the dose and duration of bisphosphonate treatment. Osteonecrosis of the jaw is reviewed separately. (See "Risks of bisphosphonate therapy in patients with malignancy", section on 'Osteonecrosis of the jaw' and "Bisphosphonates in the management of osteoporosis in postmenopausal women", section on 'Osteonecrosis of the jaw'.)

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 percent 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 and ZO-FAST trials [50,51,56] and the Austrian Breast and Colorectal Cancer Study Group trial [14], there are currently no confirmed cases of jaw osteonecrosis in women receiving ZA every six months.

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 osteoporosis in postmenopausal women", section on 'Monitoring the response to therapy'.)

Our approach is to measure 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 in a treated patient should trigger additional evaluation for contributing factors, which 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.

Other treatment options — There are currently few other treatment options for AI-induced bone loss. Raloxifene, a selective estrogen receptor modulator like tamoxifen, should not be given to breast cancer patients. Although recombinant human parathyroid hormone (PTH) is available for the treatment of postmenopausal osteoporosis, it is generally not used in breast cancer patients with AI-induced bone loss. In animal studies, high doses of PTH caused osteogenic sarcoma. Because radiation is a risk factor for the development of osteogenic sarcoma, PTH is contraindicated in patients who have had radiation therapy, which may prohibit its use in many patients with breast cancer. (See "Parathyroid hormone therapy for osteoporosis".)

Denosumab — RANKL, a member of the tumor necrosis factor (TNF) superfamily of ligands and receptors, is essential for the function of bone-resorbing osteoclasts; RANKL accelerates osteoclastogenesis when it binds to its receptor, RANK, but is blocked by osteoprotegerin, which is produced by osteoblasts. Denosumab is an investigational humanized monoclonal antibody against RANKL that reduces osteoclastogenesis. It has been shown to improve bone mineral density in postmenopausal women. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Denosumab'.)

In a two-year randomized trial of denosumab (60 mg subcutaneously every six months) versus placebo in 250 postmenopausal osteopenic women receiving adjuvant AI therapy, subjects in the denosumab group had significant increases in lumbar spine, total hip, and femoral neck BMD compared with placebo (between group differences of 7.6, 4.7, and 3.6 percent, respectively) [57]. 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.

Denosumab is also under investigation for the treatment of bone loss associated with prostate cancer and for skeletal metastases. (See "Mechanisms of bone metastases", section on 'Osteoclasts'.)

SUMMARY AND RECOMMENDATIONS

Evaluation and management

  • In patients initiating AIs, we suggest DXA of the hip and lumbar spine. (See 'Evaluation' above.)

  • Patients initiating AIs should also be assessed for other clinical risk factors for osteoporosis. The most robust non-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 'Evaluation' above.)

Lifestyle

  • 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 weight bearing exercise, reducing or stopping smoking, 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,").

Pharmacologic — Not all women receiving AIs will require treatment with bisphosphonates. Risk stratification based upon baseline BMD T-scores and clinical risk factors can identify who is more or less likely to benefit from bisphosphonates.

  • For women initiating AIs who have a BMD T-score ≤-2.5, we recommend treatment with a bisphosphonate (Grade 1A). We also suggest bisphosphonate 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). (See 'Candidates for therapy' above.)

  • In patients who do not meet the above criteria, we typically measure BMD (DXA) every two years and prescribe bisphosphonates as indicated above.
  • The choice of bisphosphonate depends upon patient preference and cost. We favor weekly oral risedronate or alendronate as initial therapy. However, zoledronic acid is an option if the patient does not tolerate oral bisphosphonates. 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 bisphosphonate therapy. (See 'Monitoring response to therapy' above.)

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