Cancer-Treatment-Induced Bone Loss, Part 2

Laura Boehnke Michaud; Susan Goodin

Disclosures

Am J Health Syst Pharm. 2006;63(6):534-546. 

In This Article

Treatment of CTIBL

The goal of CTIBL management is to optimize bone mass, thus preventing osteoporosis.[4,10] For patients with existing bone loss, the goal of CTIBL management is to prevent further bone loss, fractures, subsequent clinical sequelae (e.g., pain), and decreased functional capabilities.[4,10] The treatment of CTIBL includes diet and lifestyle changes and pharmacologic therapy.

Diet and Lifestyle Changes

Patients at risk of or those who have CTIBL can make lifestyle changes that help to maintain or improve bone mass, including consuming sufficient calcium and vitamin D, exercising regularly, and modifying behaviors that increase the risk of bone loss. Clinical trials evaluating these interventions in patients with cancer have not yet been conducted; thus, the recommendation for these interventions is primarily based on clinical trials evaluating these interventions in others at risk of bone loss, such as postmenopausal women and elderly men.

Calcium and Vitamin D Intake. Because calcium deposition is an important step in bone formation, maintaining adequate serum calcium levels by optimizing calcium intake is important for patients with or at risk of bone loss.[10] Administration of vitamin D maximizes intestinal calcium absorption; therefore, daily supplementation of both calcium and vitamin D is recommended for all adult women and men with or at risk of osteoporosis.[10] Results of clinical trials evaluating calcium supplementation (750-1000 mg daily) in postmenopausal women and elderly men have consistently shown a moderate reduction in bone loss over two to four years.[124,125] Furthermore, the results of one study suggest that fractures may be prevented in postmenopausal women receiving calcium supplementation.[124] While the effect of vitamin D supplementation alone on fracture rate in elderly patients is unclear, combining calcium and vitamin D supplementation in men and women 65 years or older has been shown to be effective in preventing bone loss and fractures.[126,127,128] In one large, randomized, double-blind, placebo-controlled study, patients received 500 mg of calcium citrate and 700 IU of vitamin D or a placebo daily for three years.[128] Those who received calcium and vitamin D supplementation had significant increases in BMD of the femoral neck (0.5% versus -0.7%, p = 0.02) and spine (2.1% versus 1.2%, p = 0.04) compared with patients who received placebo. In addition, fewer patients who received calcium and vitamin D supplementation suffered a fracture during the study compared with the placebo group (5.9% and 12.9%, respectively) (p = 0.02).

Because calcium and vitamin D are beneficial in reducing bone loss in patients without cancer, these agents are essential components of CTIBL prevention and treatment but are not a substitute for pharmacologic therapy in cancer patients with CTIBL. The most effective daily dose of calcium and vitamin D in patients with or at risk of CTIBL is unknown. However, the recommended daily dose for other patients at risk of bone loss is likely to be effective in patients with CTIBL. The recommended daily calcium intake for adults at risk of bone loss is 1200-1500 mg.[10,105] A daily vitamin D intake of 400-600 IU is appropriate for most adults; however, patients at risk of vitamin D deficiency, such as elderly, chronically ill, housebound, or institutionalized patients, should receive at least 800 IU of vitamin D daily.[10,105]

Exercise. Regular physical activity is beneficial in reducing fractures in patients at risk of bone loss.[10] Results of a prospective cohort study of women 65 years or older showed that increasing levels of physical activity correlated with a reduced relative risk of hip fracture, with the most physically active women having a 42% lower risk of hip fracture than the least active women.[129]

Increases in BMD have also been observed with consistent exercise programs. Weight-bearing exercise, such as walking, weight training, or high-impact exercise, induces a 1-2% increase in BMD at some, but not all, skeletal sites.[130] Results of a recent randomized trial comparing the BMD of elderly patients who followed a six-month high- or low-intensity resistance exercise program with those who did not exercise demonstrated that a high-intensity resistance exercise program significantly increased femoral neck BMD by 1.96%.[131] Furthermore, bone formation markers increased significantly, suggesting that a long-term, high-intensity resistance program may further improve BMD. A routine exercise program also may provide other benefits, such as improved muscle strength, coordination, balance, and mobility, which may decrease the risk of fracture, and improves overall quality of life and reduces body fat and fatigue.[7,10] Based on the positive effects of exercise on osteoporosis-associated complications, a routine exercise program consisting of both weight-bearing and muscle-strengthening exercises for up to four sessions each week is also recommended to minimize or prevent CTIBL in cancer patients. However, the type of exercise program (e.g., weight machines versus resistance exercises, walking versus jogging) should be customized for each patient.[7,105]

Lifestyle Modification. Modification of lifestyle behaviors, such as smoking and excessive alcohol and caffeine consumption, that may increase the risk of bone loss and fractures is another important aspect of managing patients with or at risk of developing CTIBL.[5,7] Patients should be encouraged to stop smoking and to limit alcohol and caffeine consumption to two or fewer servings per day.[10] A metaanalysis showed that bone loss is greater in current smokers than in former smokers,[132] and a recent animal study found that smoking cessation reverses bone loss, suggesting that smoking cessation not only prevents further bone loss but can reverse existing bone loss.[133] Furthermore, patients should be educated about fall-prevention strategies, such as using nonskid rugs, having adequate lighting, and holding on to handrails when using stairs.[10]

Pharmacologic Therapy

Drugs that stimulate bone formation (i.e., anabolic agents) or inhibit bone resorption (i.e., antiresorptive agents) are used to prevent or treat bone loss in patients with and without cancer.[10] Anabolic agents increase osteoblast activity and life span, thereby increasing bone formation; antiresorptive agents inhibit bone resorption by decreasing osteoclastic function, slowing the bone remodeling process, and reducing the number and depth of resorption sites. Available anabolic agents include teriparatide, and available antiresorptive therapies include HRT, SERMs, calcitonin, and bisphosphonates.[10] None of these therapies have FDA-approved labeling for the prevention or treatment of CTIBL; however, they do have approved labeling for the prevention or treatment of osteoporosis in other high-risk populations (e.g., postmenopausal women, patients with glucocorticoid-induced osteoporosis), and many of these therapies have been evaluated in CTIBL patients ( Table 1 and Table 2 ).[1,15,44,54,55,65,67,73,74,92,123,134,135,136,137,138]

Teriparatide. Teriparatide is a recombinant human parathyroid hormone approved for the treatment of osteoporosis in postmenopausal women and elderly men at high risk of bone fractures.[139] This drug increases BMD and decreases the likelihood of both vertebral and non-vertebral fractures in patients with existing osteoporosis but is not recommended for the treatment or prevention of CTIBL.[5,105,139] Animal studies have shown that teriparatide caused an increased rate of osteosarcoma, depending on the dosage and duration of therapy.[139] Patients at risk of developing osteosarcoma include breast and prostate cancer patients because they have an increased risk of bone metastases, patients with skeletal malignancies, and patients who have received radiation therapy of bone. Patients with or at risk of developing hypercalcemia should not receive teriparatide because it may exacerbate the condition.[139] Teriparatide may be an option for cancer patients who cannot tolerate other CTIBL therapies and are not at risk of developing hypercalcemia or bone metastases (e.g., ovarian cancer).

HRT. HRT with estrogen or testosterone in patients with hypogonadism inhibits bone resorption.[10] Increases in BMD of 2-10% over one to three years have been reported with estrogen therapy alone or in combination with progesterone in postmenopausal women at risk of bone loss; fracture-risk reductions of 30-50% have also been reported.[10,130] Similarly, spinal BMD increases have been reported in men with hypogonadism receiving testosterone replacement therapy.[10]

Although HRT may be effective in treating bone loss in patients with CTIBL caused by hypogonadism, it is generally contraindicated in patients with breast or prostate cancer because estrogen and testosterone may stimulate estrogen receptor (ER)-positive breast cancer and prostate cancer cell growth, respectively, increasing the risk of recurrence or metastasis.[3,10] Estrogen replacement therapy may also increase the risk of developing a second primary breast cancer.[140] However, no direct evidence supporting this therory exists.

Most case-control studies evaluating HRT in patients with a history of breast cancer suggest that HRT does not adversely affect recurrence or survival time.[140,141] However, the results of a recent randomized study show that HRT in breast cancer survivors increases the risk of recurrence.[142] Therefore, the routine use of HRT for breast cancer patients is not recommended.[3] However, HRT may be indicated for some breast cancer patients, such as those with uncontrollable menopausal symptoms (e.g., hot flashes, vaginal atrophy), as long as the possible risks and benefits have been thoroughly discussed with the patient.[141,143] Breast cancer survivors with ER-negative disease who are disease free for at least two years may be candidates for HRT, as long as the patient understands the risks and benefits that accompany this therapy.[144] For the prevention and treatment of CTIBL, bisphosphonates are generally considered more effective than HRT and would therefore be a more appropriate therapeutic option for most breast cancer survivors.

The use of testosterone replacement therapy is contraindicated in men with prostate cancer. However, because estrogen plays a fundamental role in bone metabolism of men, the use of estrogen replacement therapy in hypogonadal men with low levels of estrogen is rational. Results of a small, randomized, double-blind, placebo-controlled study evaluating the effects of estradiol 1 mg/day and placebo on bone metabolism in prostate cancer patients receiving Gn-RH agonist therapy suggest that estradiol may be useful in preventing or treating CTIBL.[145] In this study, bone resorption markers decreased significantly from baseline in patients receiving estradiol, whereas bone formation markers were unchanged, suggesting that estradiol inhibits bone resorption. Whether estradiol therapy in prostate cancer patients receiving Gn-RH agonist therapy also increases BMD is unknown.

HRT is also an effective therapy in patients with CTIBL caused by hypogonadism due to non-hormone-dependent tumors (e.g., NHL).[4] Prompt initiation of HRT after cancer-treatment-induced hypogonadism is necessary, however, to fully prevent bone loss. If bone loss has already occurred, HRT may prevent further bone loss caused by hypogonadism but will not reverse existing bone loss. These patients may therefore benefit from bisphosphonate therapy, which has been shown to reverse bone loss.[4]

SERMs. SERMs interact with estrogen receptors as an estrogen agonist or antagonist, depending on the tissue involved and the hormonal status of the patient.[54,146] In estrogen-deficient states, such as menopause, commonly used SERMs (tamoxifen and raloxifene) act as estrogen antagonists on breast tissue and estrogen agonists on bone.[146] Because of their antiresorptive properties, tamoxifen and raloxifene may be useful in preventing or treating CTIBL in some patients.

Tamoxifen. Tamoxifen is commonly administered to ER-positive breast cancer patients to treat metastatic disease or prevent recurrence.[3] Although tamoxifen increases bone loss in premenopausal women, results of studies evaluating bone loss in postmenopausal breast cancer patients receiving tamoxifen suggest that it may reduce bone loss, increasing BMD as much as 2.4% in one year.[48,50,51,52,55,56] Tamoxifen reduces bone loss by approximately 50% in breast cancer patients undergoing premature menopause as a result of adjuvant chemotherapy.[146] Nonetheless, tamoxifen is not a standalone CTIBL therapy.[5] Breast cancer patients receiving tamoxifen and who have a high risk of bone loss should be screened for osteoporosis and receive the appropriate therapy (Figure 2). Tamoxifen has not been evaluated for the treatment of CTIBL in patients with other types of cancer.

Figure 2.

American Society of Clinical Oncology's 2003 bone health guidelines for breast cancer patients. AIs = aromatase inhibitors, BMD = bone mineral density, DEXA = dual energy x-ray absorptiometry. Reprinted from reference 5, with permission from the American Society of Clinical Oncology.
aSequential use of raloxifene with tamoxifen and concurrent use of raloxifene with aromatase inhibitors is not recommended.

Raloxifene. Raloxifene, a second-generation SERM, is commonly used to prevent and treat osteoporosis in healthy postmenopausal women. Like tamoxifen, second-generation SERMs have estrogen agonist effects on both bone tissue and lipid metabolism and have estrogen antagonistic effects on breast tissue.[146] Unlike tamoxifen, raloxifene only minimally affects endometrial tissue.

As clinical trials evaluating raloxifene in breast cancer patients have not been conducted, the use of raloxifene to treat CTIBL is based on results from clinical trials evaluating raloxifene in postmenopausal women with osteoporosis.[147] The pivotal clinical trial in this population, the Multiple Outcomes of Raloxifene Evaluation trial, evaluated the BMD effects of raloxifene 60 or 120 mg administered daily for three years compared with placebo in 7705 postmenopausal women with osteoporosis and no history of breast cancer.[148] The study found that raloxifene 60 mg daily (the FDA-approved dosage for bone loss treatment) increased spine and femoral neck BMD by approximately 2% and 3%, respectively.[10,148] The study also showed a 30% decrease in new vertebral fracture risk with 60 mg of raloxifene.[148] Overall, raloxifene was well tolerated in this study; however, patients receiving raloxifene had an increased rate of thromboembolism (relative risk, 3.1; 95% CI, 1.5-6.2), a rate comparable to that found in studies evaluating estrogen therapy in postmenopausal women.[130,148]

Although it is likely that the results of clinical trials evaluating raloxifene in postmenopausal women with osteoporosis can be extrapolated to breast cancer patients with CTIBL, concern exists about the use of raloxifene in two groups of breast cancer patients: (1) those who have received five years of adjuvant tamoxifen therapy and (2) those receiving concurrent aromatase inhibitors. It has been hypothesized that the consecutive use of SERMs (e.g., tamoxifen for adjuvant chemotherapy followed by raloxifene for treatment of CTIBL) in breast cancer patients may result in an increased breast cancer recurrence rate and higher death rates.[5] This concern is based on the observation that 10 years of adjuvant tamoxifen therapy is associated with more recurrences and deaths than 5 years of tamoxifen therapy[5] and the results of animal studies showing that raloxifene may stimulate tamoxifen-dependent cells.[149] Similarly, the concurrent use of tamoxifen with anastrozole in the ATAC trial resulted in decreased efficacy when compared with anastrozole alone.[59] Because raloxifene is similar to tamoxifen, concurrent raloxifene therapy may decrease the efficacy of aromatase inhibitors.[5] Therefore, the use of raloxifene to treat CTIBL in breast cancer patients previously treated with tamoxifen or currently receiving aromatase inhibitors is not recommended.

Raloxifene has been shown to be effective in preventing CTIBL in prostate cancer patients receiving Gn-RH agonist therapy. Recently, an open-label, randomized study evaluating the effects of raloxifene in patients with nonmetastatic prostate cancer receiving Gn-RH agonist therapy was completed ( Table 2 ).[138] In that study, 48 prostate cancer patients receiving Gn-RH agonist therapy for at least 6 months received either raloxifene 60 mg daily or no raloxifene therapy for 12 months; all patients received calcium 500 mg and a daily multivitamin containing 400 IU of vitamin D. Forty-one patients completed the study. The authors reported that hip BMD increased significantly over 12 months in raloxifene-treated patients compared with men who did not receive raloxifene (1.1% versus -2.6%, respectively) (p <0.001). BMD in the lumbar spine also increased with raloxifene therapy, but the difference was not significant when compared with men who did not receive raloxifene (1% versus -1%) (p = 0.07). Fracture rate was not assessed. Only one patient had a thromboembolic event; no other serious adverse events were reported. The results of this study suggest that raloxifene is an effective CTIBL therapy for prostate cancer patients undergoing Gn-RH agonist therapy, but larger studies are warranted to determine the effect of raloxifene on fracture rate in this population.

Calcitonin. Calcitonin inhibits bone resorption by decreasing osteoclast formation and activity.[150] Clinical trials evaluating the efficacy of calcitonin in the treatment of CTIBL have not been conducted; however, nasal calcitonin is an effective treatment of postmenopausal osteoporosis and therefore may be effective in treating CTIBL.[3,4] The results of the large, double-blind, randomized, placebo-controlled Prevent Recurrence of Osteoporotic Fractures study showed that calcitonin 200 IU administered intranasally daily effectively treated osteoporosis in postmenopausal women.[150] Results show spinal BMD increases of 1-1.5% from baseline during each of the five years of the study in patients receiving calcitonin; the BMD of patients receiving placebo did not substantially change (<0.5% increase from baseline). Furthermore, a 33% reduction in the relative risk of developing a new vertebral fracture was observed in patients receiving calcitonin 200 IU compared with the placebo group. Calcitonin is usually well tolerated, with the most common adverse effect being mild to moderate rhinitis.[105,146]

Bisphosphonates. Bisphosphonates, analogs of pyrophosphate, a naturally occurring inhibitor of bone resorption, reduce bone resorption by binding to bone surfaces and inhibiting enzymes and proteins essential to osteoclast functioning.[4,10] Bisphosphonates may also interfere with osteoclast activation, differentiation, and attachment to bone.[4] Bisphosphonates are the most effective antiresorptive agents available because they significantly increase BMD (1-12% after two to three years of therapy) and reduce fractures in noncancer patients with osteoporosis.[10,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165] Furthermore, these drugs are the most thoroughly evaluated drugs used to prevent or treat CTIBL. Oral bisphosphonates currently available in the United States and Canada include alendronate, etidronate, and risedronate; clodronate is available only in Canada, and ibandronate and tiludronate are available only in the United States.[166,167] I.V. bisphosphonates available in the United States and Canada include pamidronate and zoledronic acid; i.v. clodronate and etidronate are available only in Canada and the United States, respectively.[166] Ibandronate and tiludronate are the only bisphosphonates that have not been evaluated in patients with CTIBL.

Although the bisphosphonates are generally well tolerated, rare reports of oral avascular necrosis have been reported in patients (with or without cancer) receiving oral or i.v. bisphosphonates to treat osteoporosis and metastatic bone disease, respectively.[168,169,170] Whether bisphosphonates directly or indirectly cause avascular necrosis is unknown; studies are ongoing to determine the possible relationship between bisphosphonates and avascular necrosis to discover risk factors for this adverse event, and to develop preventive strategies.[168,169,171] Until more is known about this effect, FDA and the manufacturers of pamidronate and zoledronic acid recommend that cancer patients receiving either drug have a dental examination with preventive dentistry performed before initiation of therapy and avoid dental procedures during therapy.[172,173,174] Although a similar recommendation has not been made for cancer patients receiving oral bisphosphonates, avascular necrosis with oral bisphosphonates has been reported; therefore, similar precautions should be used in cancer patients receiving such agents.

Alendronate. Alendronate is a potent oral bisphosphonate that selectively inhibits bone resorption without impairing bone mineralization.[152,175] Although the efficacy of alendronate in preventing and treating osteoporosis in patients without cancer is well documented, the efficacy in the prevention and treatment of CTIBL is not well defined. Only one pilot study has evaluated the efficacy of alendronate in the prevention of CTIBL.[134] In that study, 21 postmenopausal breast cancer survivors who had completed therapy (except for tamoxifen) for stage I or II breast cancer received alendronate 5 or 10 mg daily, calcium 1500 mg daily, and vitamin D 400 IU daily and participated in a strength-training program during the study. Of the 21 patients, 14 had osteopenia and 3 had osteoporosis at baseline. After 12 months of therapy, significant increases in lumbar spine BMD from baseline of approximately 2.5% were observed ( Table 1 ); however, 62% of these patients were also receiving tamoxifen, which may have confounded the results. No adverse effects were reported. Although these results suggest that alendronate may be effective in preventing further bone loss in postmenopausal breast cancer patients, large, randomized studies are warranted to determine its effectiveness and safety in treating CTIBL.

Despite the lack of studies evaluating alendronate to prevent or treat CTIBL, some clinicians recommend alendronate therapy for CTIBL patients based on the results of studies evaluating alendronate in postmenopausal women, elderly men, and patients receiving long-term glucocorticoid therapy.[4,5,123] When administered to prevent osteoporosis in postmenopausal women, alendronate 5 mg daily or 35 mg weekly effectively increased BMD by 1-4%, depending on the skeletal site, after 1 to 3 years of therapy.[151,152,153] Alendronate 10 mg daily or 70 mg weekly has also been shown to effectively treat osteoporosis in postmenopausal women and men, producing BMD increases of 2-12% after 1 to 3 years of therapy; BMD increases of up to 14% have been observed after 10 years of therapy in postmenopausal women with osteoporosis.[151,152,153,156] Furthermore, alendronate decreased the rate of clinical fractures, including vertebral fractures, by approximately 40% in postmenopausal women with osteoporosis and reduced the frequency of vertebral fractures in men with osteoporosis by approximately 55%.[156,176,177] Similarly, patients without cancer with glucocorticoid-induced osteoporosis had 1-3% increases in BMD and a 40% reduction in the rate of vertebral fractures after 1 year of alendronate (5 or 10 mg daily) therapy.[178] Although alendronate was well tolerated in clinical trials, many patients seen in clinical practice experience gastrointestinal adverse effects, such as nausea, diarrhea, gastritis, esophagitis, and esophageal reflux.[10] The frequency of these effects can be reduced with proper administration, but alendronate should not be administered to patients with a history of upper-gastrointestinal-tract disorders.[10]

Clodronate. Clodronate is a weak bisphosphonate and is commercially available only in Canada in both oral and i.v. formulations.[8,167] Four clinical trials have evaluated oral clodronate for the treatment of CTIBL in breast cancer patients ( Table 1 ).[44,55,135,136] These studies found that clodronate effectively reduces bone loss associated with chemotherapy and prevents bone loss in breast cancer patients receiving SERMs or chemotherapy. The most common adverse effects reported were diarrhea, nausea, and vomiting.[44,135] The use of clodronate to treat CTIBL is limited because it is not available in the United States.

Etidronate. Etidronate is another weak bisphosphonate available in both oral and i.v. formulations.[8,166] One small, crossover, pilot study evaluated the effects of cyclic oral etidronate (400 mg daily for two weeks every three months) in patients with metastatic prostate cancer receiving CAB ( Table 2 ).[74] Cyclic etidronate therapy administered during the first six months of CAB produced significant increases in lumbar spine BMD (7.8%) compared with six months of CAB alone (-6.6%) (p = 0.01). Although no adverse effects were reported, etidronate can cause osteomalacia when given in high, continuous dosages.[4,74] Therefore, etidronate must be administered as cyclic therapy.[4] Etidronate is not recommended for use in CTIBL patients because more potent bisphosphonates are available, and randomized clinical trials confirming the effects of etidronate on CTIBL have not been conducted.[7]

Ibandronate. Ibandronate is the most potent oral bisphosphonate available.[8] No studies have evaluated ibandronate for the prevention or treatment of CTIBL; however, ibandronate is effective in the prevention and treatment of osteoporosis in postmenopausal women. Ibandronate 2.5 mg daily or 150 mg monthly produced lumbar spine BMD increases of approximately 6.5% after three years of treatment and 5% after one year of treatment, respectively; however, the primary endpoint of the study was the rate of new vertebral fractures.[179,180] Daily ibandronate reduced the risk of new vertebral fractures by 52%.[180] No increase in gastrointestinal adverse events was observed in patients receiving oral ibandronate compared with placebo, despite the study's inclusion of patients with a history of gastrointestinal disorders.[17] Ibandronate 2.5 mg daily is also effective in preventing bone loss in postmenopausal women, increasing BMD by approximately 2% over two years.[180]

Pamidronate. Pamidronate is a second-generation i.v. bisphosphonate.[65] Although it is not commonly used to treat osteoporosis in patients without cancer, the results of two small studies evaluating pamidronate alone or in combination with sodium fluoride for the treatment of postmenopausal osteoporosis suggest that pamidronate may be an effective therapy for bone loss.[157,158] These studies reported BMD increases of approximately 3-13%, depending on the skeletal site, after two to three years of therapy.

The efficacy of pamidronate in preventing and treating CTIBL in lymphoma and prostate cancer patients has been documented in several clinical trials.[1,65,73] Pamidronate has also been evaluated in thyroid cancer patients receiving suppressive doses of thyroxine therapy.[92]

Results of a small, open-label, randomized, placebo-controlled study show that pamidronate is effective in preventing bone loss and vertebral fractures in patients with lymphoma.[1] Pamidronate 30 mg i.v. was administered every 3 months for one year to patients with newly diagnosed stage III or IV NHL or Hodgkin's lymphoma. After 12 months of therapy, decreases in spinal BMD were significantly lower in patients receiving pamidronate versus placebo (-2.7% versus -11.2%, respectively) (p = 0.005). Furthermore, pamidronate-treated patients suffered significantly fewer vertebral fractures (4%) than patients in the placebo group (30%) (p = 0.01).

Two clinical trials found that pamidronate was effective in preventing bone loss in prostate cancer patients undergoing ADT.[65,73] An open-label, randomized study evaluated the effects of pamidronate (60 mg administered every 12 weeks) and placebo in prostate cancer patients receiving leuprolide.[65] Although no significant changes in BMD occurred at any skeletal site in patients treated with pamidronate, placebo-treated patients developed bone loss, suggesting that pamidronate effectively prevented bone loss in these patients. Pamidronate was generally well tolerated. However, transient fevers and arthralgias were reported in 3 men (14%). A small, randomized, double-blind, placebo-controlled, crossover study evaluating the effects of a single 90-mg dose of pamidronate in prostate cancer patients undergoing CAB found that pamidronate significantly increased spine and femoral neck BMD in patients receiving pamidronate compared with those receiving placebo (spine: 7.8% versus -5.7%, respectively, p < 0.0001; femoral neck: 2% versus -2.3%, respectively, p < 0.0007).[73]

Pamidronate has been evaluated in thyroid cancer patients receiving suppressive thyroxine doses, but its efficacy in preventing CTIBL in these patients has not been established. The results of a prospective, randomized, double-blind, placebo-controlled study evaluating 55 women (primarily premenopausal) and men with thyroid cancer receiving pamidronate 30 mg every three months for two years showed a significant increase in lumbar spine BMD compared with baseline (p < 0.01). Patients receiving placebo demonstrated no bone loss.[92] Acute-phase reactions (i.e., fever and myalgias) occurred in 12% of patients receiving pamidronate compared with 4% of the placebo group (p = 0.001), but these reactions diminished significantly with subsequent infusions and did not require the discontinuation of therapy. Although these results suggest that pamidronate effectively increases bone mass, whether bone-loss therapy is needed in men or premenopausal women with thyroid cancer receiving suppressive thyroxine therapy is unknown.[92] Pamidronate may be effective in postmenopausal women with thyroid cancer receiving suppressive thyroxine therapy because they often have higher bone turnover than men and premenopausal women; however, further clinical trials to determine the benefits of pamidronate in these patients are warranted.[92]

Risedronate. Risedronate is one of the most potent oral bisphosphonates commercially available.[8] Like alendronate, its efficacy in treating and preventing postmenopausal and glucocorticoid-induced osteoporosis is well documented. Oral risedronate 5 mg daily or 35 mg weekly increases BMD by 1-7% and 1-5% after one to three years in patients with postmenopausal and glucocorticoid-induced osteoporosis, respectively.[159,160,161,162,163,164] In addition, new vertebral and nonvertebral fracture risk is reduced by 40-60% in postmenopausal women and 70-80% in patients with glucocorticoid-induced osteoporosis receiving risedronate.[159,160,161,162,164] Mildly to moderately severe adverse gastrointestinal effects (e.g., dyspepsia, abdominal pain, diarrhea) have been reported with risedronate, but risedronate is not associated with an increased risk of esophagitis.[10,130] Nonetheless, most clinicians carefully consider the risks and benefits of an oral bisphosphonate in patients with a known upper-gastrointestinal-tract disorder.[10]

Risedronate has been evaluated in a small, double-blind, placebo-controlled, Phase II study in 53 breast cancer patients with chemotherapy-induced menopause ( Table 1 ).[137] In that study, patients were randomized to receive cyclic risedronate (30 mg daily) or placebo and were stratified based on previous tamoxifen use. Thirty-six patients (68%) were previously treated with tamoxifen. Treatment consisted of 2 weeks of risedronate or placebo, followed by 10 weeks without a drug; each 12-week cycle was repeated eight times over two years. After therapy ended, patients were followed for an additional year. The annual increase in spinal BMD was 0.3% in the risedronate group, and spinal BMD decreased by 1.4% each year in the placebo group. The previous use of tamoxifen did not prevent bone loss in the placebo group. Bone loss occurred in both treatment groups following treatment cessation but was more pronounced in patients receiving placebo. Adverse effects were similar in both treatment groups; risedronate was well tolerated. These studies showed that risedronate effectively prevents bone loss in breast cancer patients with premature chemotherapy-induced menopause.

Zoledronic Acid. Zoledronic acid is the most potent i.v. bisphosphonate available and produces BMD increases of 3-5% in postmenopausal women with osteopenia or osteoporosis, similar to the BMD increases seen with oral bisphosphonates to treat postmenopausal osteoporosis.[165] However, the BMD increases associated with zoledronic acid can be achieved when administered every 6 to 12 months rather than the daily or weekly administration that is required with oral bisphosphonates.

Preliminary results of the Austrian Breast and Colorectal Cancer Study Group Trial evaluating the skeletal effects of zoledronic acid in premenopausal breast cancer patients receiving adjuvant goserelin plus anastrozole or tamoxifen revealed that zoledronic acid may also be effective in preventing CTIBL in this population.[182] After six months of treatment, patients receiving zoledronic acid (4 mg i.v. every six months) maintained baseline lumbar spine BMD values, while patients receiving hormonal therapy alone suffered bone loss (p < 0.0001). As expected, bone loss was more profound in patients receiving anastrozole and goserelin than in patients receiving tamoxifen and goserelin (p = 0.0125).

Similarly, preliminary results of the Z-FAST demonstrated that zoledronic acid effectively inhibits bone loss in postmenopausal breast cancer patients receiving adjuvant letrozole.[57] In that trial, patients were randomized to receive zoledronic acid (4 mg i.v. every 6 months) at the time of letrozole initiation or delayed treatment with zoledronic acid, postponing therapy until a postbaseline t score became less than -2 or until any clinical fracture occurred. After 12 months of treatment, patients receiving zoledronic acid at the time of letrozole therapy had a 1.9% increase in lumbar spine BMD and a 1.3% increase in total hip BMD; patients in the delayed treatment group had a 2.4% and 2% decrease in lumbar spine and total hip BMD, respectively. Zoledronic acid was initiated in 8% of patients in the delayed treatment group after a mean of 8.8 months because of a decrease in BMD or fracture rate, suggesting that upfront zoledronic acid may be most beneficial for patients receiving letrozole. Final results are eagerly awaited to confirm the preliminary findings of both of these studies.

Intermittent zoledronic acid has been shown to prevent bone loss in prostate cancer patients undergoing ADT. The efficacy of zoledronic acid (4 mg i.v. every three months for one year) was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial ( Table 2 ).[66] Patients enrolled had a diagnosis of nonmetastatic prostate cancer and were initiating ADT. Significant increases in both spinal and femoral neck BMD were observed (5.6% versus -2.2%, p < 0.001; 1.2% versus -2.1%, p < 0.001, respectively). Although this study was not designed to evaluate the effect of zoledronic acid on fracture rate, no symptomatic fractures were diagnosed in either group during the study. Only five patients receiving zoledronic acid and three patients receiving placebo experienced new or worsening vertebral fractures (p = 0.29). Zoledronic acid was well tolerated, and no adverse renal effects were reported. The results of this study show that zoledronic acid halts the bone loss associated with ADT and increases BMD above baseline values, which may reduce the long-term risk of fracture.

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