Introduction
Osteoporosis, a skeletal condition common in postmenopausal women and aging men, is characterized by low bone mass, destruction of bone microarchitecture, and increased bone turnover resulting in decreased bone strength and consequent susceptibility to fractures. 1 , 2 Osteoporotic fractures, such as fractures of the hip, vertebral body, and distal forearm, may lead to decreased quality of life (QOL), disability, and possibly death. In the last decade, bisphosphonates, compounds that inhibit osteoclastic bone resorption, have been the most significant contribution to the advancement in osteoporosis treatment; clinical trials have demonstrated a reduction in vertebral fractures of 40% to 50% and nonvertebral fractures (including hip fractures) of 20% to 40%. 1 , 3 Bisphosphonates approved by the United States Food and Drug Administration (FDA) for the prevention and/or treatment of osteoporosis include alendronate, alendronate plus vitamin D, ibandronate, risedronate, risedronate with calcium, and zoledronic acid. 4 – 10 Because their bioavailability is quite low, oral agents usually require daily or weekly administration (with the exception of ibandronate, which may be administered monthly) that can contribute to low patient compliance rates. 6 – 9 Intravenous (IV) bisphosphonates may be administered less frequently (eg, on a monthly, quarterly, or yearly basis). 6 , 10 – 12 In general, patient compliance rates with prescribed IV bisphosphonate regimens are higher than with oral bisphosphonates.
In addition to osteoporosis, bisphosphonates have been used to prevent and/or treat cancer-related bone complications. 3 , 13 Patients who develop bone metastases are at increased risk for developing skeletal-related events (SREs), such as intractable bone pain requiring opioid analgesics or palliative radiation therapy, pathologic fractures, spinal cord compression, a need for surgery, and hypercalcemia of malignancy (HCM). 14 SREs are a consequence of excessive bone metabolism, primarily bone resorption, which characterizes malignant bone lesions. 3 Local bone pain requiring radiation therapy and pathologic fractures are the most commonly reported SREs. 3
As a result of advancements in the primary treatment of several solid tumors and hematologic malignancies, patients are surviving longer, placing them at an increased risk for developing bone metastasis and SREs that may complicate their clinical course, adversely affect QOL, and increase medical costs. 14 – 16 Bone metastases are particularly prevalent in patients with advanced metastatic breast or prostate cancers, affecting approximately 70% of patients. 3 Although observed less frequently, bone metastases also occur in patients with lung, kidney, and thyroid tumors. 17 Nearly all patients with advanced multiple myeloma (MM) develop bone involvement during the course of their disease since this malignancy colonizes in the bone marrow. 14 , 18
Metastatic bone disease
Under normal circumstances, bone homeostasis is achieved through balanced resorption of old bone by osteoclasts and formation of new bone by osteoblasts. 19 Metastatic bone disease alters the normal bone remodeling process by causing osteolytic bone destruction and abnormal osteoblastic bone formation, often with one process more dominant than the other, resulting in an imbalance in normal bone homeostasis. 18 – 20 Although historically bone metastases from breast cancer or MM have been characterized as osteolytic lesions and prostate cancer bone metastases have been primarily osteoblastic in nature, recent evidence suggest that both bone processes are present in many patients. 18 , 20 Without bisphosphonate treatment, it is estimated that patients with bone metastases from advanced cancer will experience, on average, 2 to 4 SREs per year. 17 Thus, bone complications of cancer are a considerable clinical concern, and preventing or delaying the occurrence of such events is an important treatment objective. Although palliation has traditionally been the primary goal of therapy, the introduction of bisphosphonates has afforded oncologists with an effective therapeutic option for preventing and/or treating SREs associated with bone metastases.
Mechanism of action of bisphosphonates
Because of their ability to diminish bone resorption and subsequently normalize calcium levels, prevent development of new osteolytic lesions, and reduce the risk of fractures, bisphosphonates are the treatment of choice for skeletal complications of malignancy. 21 Bisphosphonates are pyrophosphate analogs that preferentially bind to bone at sites of active metabolism, are released from the bone matrix during bone resorption, and inhibit osteoclast activity and survival. 3 , 21 Variable side chains determine the potency and side effect profile of each agent. 21 These compounds can be grouped into two classes according to their chemical structure and molecular mechanism of action ( Figure 1 ). 22 The newer nitrogen (N)-containing, second- or third-generation compounds, including alendronate, ibandronate, pamidronate, risedronate, and zoledronic acid, inhibit the enzyme farnesyl diphosphate synthase in the cholesterol mevalonate pathway and thereby suppress osteoclast-mediated bone resorption, whereas the non – N-containing, first-generation bisphosphonates, such as clodronate, etidronate, and tiludronate, induce osteoclast apoptosis via metabolism into cytotoxic analogues of adenosine 5′-triphosphate. 21 , 23 , 24 The N-containing agents are more potent than the non – N-containing bisphosphonates, inhibiting bone resorption at micromolar concentrations. 3 Only IV zoledronic acid and IV pamidronate are approved by the FDA for cancer-related indications. 25 , 26 In Europe, oral clodronate, IV pamidronate, and oral and IV ibandronate have received regulatory approval for patients with bone metastases secondary to breast cancer. 3 , 27 Only zoledronic acid has received US and European approval for the treatment of bone metastases independent of the primary tumor type. 25 , 28
Evaluating efficacy of bisphosphonates
Developing composite end points of similar clinical significance may be appropriate when the clinical benefit of a drug is multifaceted as is the case with bisphosphonates. 29 Using a SRE as a quantifiable clinical end point was first applied to studies assessing pamidronate for prevention of SREs. This end point included one or more of the following: pathologic fracture, radiation therapy for local pain, surgery to stabilize near-fractures, or spinal cord compression. Subsequently, SREs were used as the primary end points for most of the trials assessing a bisphosphonate for this indication. However, the definition or names for SREs have differed slightly between studies (see Tables 1 – 4 ), sometimes being referred to as skeletal complications or bone events. 30 – 55 Furthermore, HCM has been excluded from the definition of a SRE in some trials because bisphosphonates have been shown to be effective for the treatment of HCM before studies investigating bisphosphonates as preventive therapy for SREs were developed. 31 , 56
Several clinical studies designed to evaluate bisphosphonates to prevent skeletal complications have demonstrated clinical benefit. This article reviews the results of clinical studies assessing bisphosphonates as prevention and/or treatment for cancer-related bone complications in a variety of tumor types.
Clinical studies
Breast cancer
Clinical trial results show that bisphosphonates reduce the occurrence of skeletal complications in patients with breast cancer and bone metastases ( Table 1 ). 30 – 42 Based on the results of two randomized, placebo-controlled clinical studies in patients with osteolytic bone metastases from breast cancer being treated with either chemotherapy or hormonal therapy, IV pamidronate was approved by the FDA for preventing SREs. 35 , 37 Pamidronate (90 mg administered IV over 2–4 hours q 3–4 weeks) significantly prolonged the time to the first SRE and reduced the overall incidence of SREs for up to 2 years (see Table 1 ). 35 – 38 In another placebo-controlled trial of breast cancer patients with at least one osteolytic lesion, zoledronic acid significantly lowered the risk of SREs by 39% (p = 0.027), reduced the proportion of patients experiencing a SRE at 1 year by 20% (29.8% vs 49.6%, p = 0.003), and significantly prolonged the time to first SRE excluding HCM (median not reached vs 364 days, p = 0.007). 33 Only one study has directly compared zoledronic acid with pamidronate (see Table 1 ). 30 , 31 This large, randomized phase 3 study was designed to demonstrate the equivalence of zoledronic acid and pamidronate in reducing the incidence of SREs in patients with breast cancer or MM. Among the breast carcinoma stratum, the overall incidence of SREs other than HCM was comparable between the two study groups. 31 The median time to first SRE was also similar; however, in patients receiving hormonal therapy for breast cancer, zoledronic acid 4 mg IV significantly delayed the time to first SRE (415 vs 370 days; p = 0.047). Oral and IV ibandronate have also been evaluated in breast cancer patients with metastatic bone disease; compared with placebo, both formulations of ibandronate (6 mg IV and 50 mg oral) have significantly reduced the proportion of patients with an on-study SRE and delayed the time to first SRE (see Table 1 ). 39 , 40 Oral clodronate also appears to reduce the rate and delay onset of SREs, and may reduce bone pain (see Table 1 ). 41 , 42 Neither of these drugs, however, has been directly compared with zoledronic acid or pamidronate in this setting.
IV bisphosphonates are recommended for the prevention of skeletal complications in breast cancer patients with bone metastases. Treatment guidelines from the American Society of Clinical Oncology (ASCO) recommend either IV pamidronate (90 mg) or IV zoledronic acid (4 mg) every 3 to 4 weeks for patients with radiographic evidence of bone destruction; the panel concluded that there is insufficient evidence to recommend one bisphosphonate over the other. 57 The National Comprehensive Cancer Network (NCCN) recommends either IV zoledronic acid or IV pamidronate for patients with bone metastases secondary to breast cancer as well. 58 However, the NCCN guidelines suggest that zoledronic acid may be superior to pamidronate therapy for treating osteolytic metastases from breast cancer. Neither clodronate nor ibandronate were recommended; clodronate is not commercially available in the US, and ibandronate does not have a cancer-related FDA indication. Moreover, the Cochrane Breast Cancer Review Group has reported the results of their meta-analysis of 21 randomized trials evaluating bisphosphonates; in 9 studies, bisphosphonates reduced the risk of skeletal complications by 17% compared with placebo or no bisphosphonate (relative risk [RR] 0.83; 95% confidence interval [CI], 0.78–0.89; p = 0.00001). 59 Like the ASCO panel, the authors concluded that zoledronic acid appears to have equivalent efficacy when compared with pamidronate.
Prostate cancer
Although prostate cancer is most commonly associated with osteoblastic lesions, increased osteoclastic activity also disrupts normal bone metabolism when prostate cancer invades the skeleton. 60 Thus, inhibition of bone resorption by bisphosphonates may be beneficial for osteoblastic metastases. Several bisphosphonates have been evaluated in patients with prostate cancer and metastatic bone disease, but only zoledronic acid has been shown to decrease SREs ( Table 2 ). 43 – 46 In a randomized study, patients with hormone-refractory prostate cancer (HRPC) were treated for up to 2 years with zoledronic acid or placebo; zoledronic acid significantly reduced the proportion of patients experiencing at least one SRE (38% vs 49%, 95% CI, −20.2% to −1.3%, p = 0.028) and prolonged the time to the first SRE (488 vs 321 days, p = 0.009) compared with placebo. 43 , 44 In this setting, pamidronate did not significantly reduce the SRE rate or reduce bone pain compared with placebo (see Table 2 ). 45 Compared with placebo, oral clodronate (2080 mg daily) improved bone progression-free survival (defined as the time from randomization to the development of symptomatic bone metastases or death from prostate cancer) and the overall survival time; however, differences in these end points were not statistically significant. 46 Bone progression-free survival is similar to SRE except that it includes only symptomatic events rather than also including asymptomatic events (eg, metastasis identified on bone scan, asymptomatic vertebral fractures). The Cochrane Prostatic Diseases and Urologic Cancers Group has corroborated these findings in its meta-analysis of 10 studies evaluating bisphosphonates in metastatic prostate cancer; compared with controls, bisphosphonates reduced the risk of skeletal events by 21% (odds ratio 0.79; 95% CI, 0.62–1.00; p = 0.05). 61 Currently, risedronate and zoledronic acid are also being evaluated in patients with bone metastases from androgen-sensitive prostate cancer. 62 , 63 According to consensus guidelines from the NCCN, bisphosphonate therapy should be considered for all patients with HRPC; however, the panel does not recommend a specific bisphosphonate. 60
Lung cancer and other solid tumors
Only zoledronic acid 4 mg has demonstrated significant long-term clinical benefits in patients with bone metastases from a broad range of solid tumors ( Table 3 ). 47 – 50 In a randomized, placebo-controlled, phase 3 study assessing patients with lung cancer or other solid tumors (excluding breast or prostate cancer), zoledronic acid 4 mg significantly reduced the proportion of patients developing at least one SRE, including HCM at 21 months (39% vs 48%, p = 0.039) and delayed the onset of skeletal complications (236 vs 155 d, p = 0.009). 47 , 48 Moreover, when HCM was included, zoledronic acid 4 mg reduced the risk of developing a SRE, including HCM, by 31% (hazard ratio, 0.693; p = 0.003) compared with placebo. 48 Non – small cell lung cancer, renal cell carcinoma, and small cell lung cancer were the most common diagnoses of enrolled patients. Oral clodronate (1600 mg/day for 1 year) was also evaluated in patients with bone metastases from solid tumors poorly responsive to chemotherapy; clodronate did not significantly reduce mean pain scores compared with placebo but significantly reduced use of analgesics (p = 0.042). 50 Ibandronate 6 mg IV, administered every 4 weeks for 9 months to patients with metastatic bone disease from colorectal cancer, significantly reduced the proportion of patients who experienced SREs (39% vs 78%, p = 0.019) and delayed time to the first SRE by at least 6 months (>279 vs 93 days, p = 0.009) compared with placebo. 49 Ibandronate has not been evaluated in other solid tumors. For bone metastases related to solid tumors other than breast or prostate cancer, zoledronic acid is the only bisphosphonate that has received worldwide regulatory approval. 25 Consensus guidelines for the use of bisphosphonates for patients with lung cancer or other solid tumors (except breast and prostate cancer) are not available. 64
Multiple myeloma
The long-term efficacy and safety of bisphosphonate therapy for prevention of SREs in patients with advanced MM and osteolytic lesions is well established ( Table 4 ). 30 , 31 , 51 – 55 In a randomized, placebo-controlled trial, pamidronate (90 mg IV administered over 4 hours q 4 weeks) significantly delayed the onset (p = 0.016) and reduced the incidence of skeletal complications (p = 0.016) for up to 21 months. 51 . 52 Consequently, a large, international, randomized, phase 3 trial was designed to demonstrate equivalence (defined as difference in SRE rate of less than 8%) between either 4 or 8 mg zoledronic acid and standard-dose pamidronate (90 mg). 30 , 31 Because of renal safety concerns, the protocol was amended to reduce zoledronic acid from 8 mg to 4 mg. 30 After 25 months of follow-up, the percentage of MM patients who developed a SRE excluding HCM (47%, 4 mg zoledronic acid vs 51%, pamidronate), the median time to first SRE including HCM (380 vs 286 days, p = 0.538), and the risk of developing a skeletal complication (RR, 0.932; p = 0.593) were similar between the treatment groups. 31 Most of these studies assessed zoledronic acid administered every 3 to 4 weeks; however, because of its long half-life and evidence supporting the use of longer dosing intervals for other indications, less frequent dosing (every 12 wk) is being evaluated. 65 Furthermore, oral clodronate (1600 mg daily) has established its ability to significantly reduce the incidence of nonvertebral and vertebral fractures compared with placebo in MM patients. 54 Long-term follow-up indicates that clodronate treatment may also prolong survival time in patients without overt vertebral fractures at diagnosis. 55 Ibandronate has not been shown to reduce skeletal complications in this patient population. 53
ASCO recently released an update to their clinical practice guidelines for the role of bisphosphonates in MM. 66 For MM patients who have radiographic evidence of osteolytic bone destruction or spinal compression, ASCO recommends treatment with either pamidronate 90 mg IV delivered over at least 2 hours or zoledronic acid 4 mg IV delivered over 15 minutes every 3 to 4 weeks for a period of 2 years. IV or oral clodronate is an alternative in other countries, but it is not commercially available in the United States.
Duration of therapy
A consensus has not been reached regarding the appropriate duration of bisphosphonate therapy. Most studies of bisphosphonates in cancer patients with bone metastases did not treat patients beyond 2 years. However, ASCO has tried to place some clarity on the issue in both their clinical practice guidelines for patients with breast cancer and MM. 57 , 66 In patients with breast cancer metastatic to bone, ASCO advises to continue bisphosphonates until evidence of a progressive decline in performance status develops, even in the presence of SREs. 57 No evidence addressing the consequences of discontinuing bisphosphonate therapy after developing a SRE in breast cancer patients exists. Among patients with osteolytic metastases secondary to MM, 2 years of bisphosphonate therapy is recommended. 66 After 2 years, treating physicians should consider treatment discontinuation if the MM is responding to therapy or is stable. Guidelines addressing duration of therapy in other solid tumors are not available.
Bone turnover markers
Investigators frequently assess markers of bone turnover as secondary end points in bisphosphonate studies. Biochemical markers of bone metabolism are indicative of either bone formation or bone resorption and may help identify patients likely to respond to and benefit from bisphosphonate therapy. 67 N-telopeptide of type I collagen (NTX) is of particular interest; patients with bone metastases and elevated NTX levels in urine have a significantly increased risk of SREs, disease progression, and death compared with patients with low NTX levels. 68 In addition, urinary NTX normalization with pamidronate treatment has been linked with delays in bone lesion progression and a trend toward fewer fractures. 69 Thus, NTX may be useful for monitoring therapeutic response to bisphosphonate therapy. However, because of the lack of sufficient, rigorous, prospective trials validating this approach, ASCO’s clinical practice guidelines recommend that the use of these markers be confined to research protocols; currently, they should not be used in routine clinical practice. 57 , 66
Conclusion
Skeletal complications are a major source of cancer-related morbidity. In patients with bone metastases, bisphosphonates have become the standard of care for preventing or delaying SREs. In patients with breast cancer or MM involving bone, zoledronic acid and pamidronate were comparable in their ability to decrease the incidence of SREs and delay the onset of skeletal events. In patients with solid tumors (except breast cancer) that metastasize to the bone, only zoledronic acid has been proven effective; ibandronate is effective in colorectal cancer. Despite their impressive efficacy in the prevention of skeletal complications associated with malignancy, several questions related to bisphosphonate use remain. Studies are ongoing to evaluate the appropriate duration of therapy, validate the usefulness of bone markers in predicting response to therapy, understand management of toxicities such as osteonecrosis of the jaw, and determine the most appropriate and cost-effective time to initiate bisphosphonate therapy. 70
Acknowledgments
The author thanks Kristin Hennenfent, PharmD, MBA, BCPS and Terri Davidson, PharmD, BCOP, who assisted with writing and editorial services, respectively, and Novartis Pharmaceuticals Corporation, who sponsored development of this article.
Disclosures
The author has no conflicts of interest to disclose.
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