The evolving role of bisphosphonates

The

Evolving

Role

Richard Bisphosphonates, bone

at

settings lytic

analogs sites

of

of rapid activity, effects.

bone,

osteoporosis

osteolysis

in

therapy

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cal background

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for

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need

testing

of new

Oncol

and

28:284-290.

or

for

and of

effective

adjuvant

more

therapy. the

new

potent Copyright

by preclini-

of bisphosphonates

of these

as well

pain,

prevention

use for

of

bone

provided

success

and

prevention

radiation

metastasis

impetus

malignancy,

be

including

have

The

strong

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Saunders

and bone

cancers.

provided

Semin

morbidity,

of

of

hypercalcemia delay

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clinical

research the

trials on

2001

by

Bisphosphonates are analogs of pyrophosphate. The carbon substitution for oxygen in the basic structure makes them resistant to endogenous hydrolysis. Fleisch et al first reported on the in vitro and in vivo effects of diphosphonates in 1968.14 A wide variety of bisphosphonates can be created by modifying the side chain (R) in relation to the central carbon of the bisphosphonate structure (Fig 1). The bisphosphonates have a strong affinity for calcium.

bone

Effects on Bone

development

bisphosphonates. 0

are providing a basis for beginthe metastatic process in bone. BACKGROUND

disease causes,

to

bisphosphonates ning to elucidate

osteo-

inhibition

shown

the

treatment

in primary disease

been

for

fractures, models

bisphosphonate

has

has

N. Hortobagyi

beneficial

of clinical

Bisphosphonate

skeletal

Animal

have

to

clinical

excessive Paget’s

malignancy-associated

cancer-related

In

to

include

a variety

disease. cancer

as adjunctive pathologic

shown

settings from

bone

and/or

been

and Gabriel

bind

remodeling.

turnover

have

These

malignant

pyrophosphate,

bone

bone they

clinical

of

active

L. Theriault

of Bisphosphonates

WB.

Company.

T

HERE HAVE BEEN numerous advances in cancer care that have had a substantial impact on outcomes for those with cancer. Studies of the neuropharmacology of chemotherapy-induced emesis have resulted in more effective antiemetics.iJ The use of colony stimulating factors such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoetin have resulted in more rapid hematologic recovery from cytotoxic therapies, and in some clinical settings permit more dose-intensive therapy.s-13 An expanding role for bisphosphonates in cancer care parallels these developments. Bisphosphonates have followed a path from treatment for malignancy-associated hypercalcemia to use as an adjunct to standard care in the adjuvant setting of breast cancer for the prevention or delay of osseous metastasis development. The study and use of

Bisphosphonates inhibit bone resorption in vitro and in vivo. In animal model systems the breakdown of cartilage and bone is inhibited by bisphosphonates. Bone destruction associated with exposure to retinoids, vitamin D, and parathyroid hormone can be inhibited.i5J6 The development of osteoporosis can be retarded, as can experimentally induced tumor-related hypercalcemia.17Js Mechanisms

of

Action

The final common pathway for bisphosphonate action appears to be inhibition of osteoclast function. A variety of specific mechanisms have been proposed, including anatomic alteration of osteoclast ruffled border, decrease in acid production, decrease in lyzosomal enzyme production, inhibition of osteoclast cell differentiation, and decrease in recruitment from the monocyte/macrophage cell line.19 A direct toxic effect, apoptosis, has also been suggested as a mechanism for the dramatic decrease in osteoclast numbers reported with bisphosphonate exposure.20 Pharrnacokinerics

From The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Gabriel N. Hortobagyi, MD, UT M.D. Anderson Cancer Center, 1515 Ho&& Blud, PO Box 424, Houston, TX 77030. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2803-0009$35.00/O doi:10.1053/sonc.2001.23494 284

Bisphosphonates are poorly absorbed when administered orally (< 10% absorption) and increasing oral doses frequently results in gastrointestinal toxicity, primarily nausea and vomiting.ziJz The half-life of circulating bisphosphonates is short, less than 2 hours323 Bisphosphonates accumulate at sites of active bone remodeling and/or osteoclastic activity. They have a long resident time in Seminars

in Oncology,

Vol

28, No

3 (lune),

2001:

pp 284-290

THE

EVOLVING

ROLE

OF

285

BISPHOSPHONATES

A

B Bisphosphonate

Alendronate

R’ R”

0-h)~ OH

Clodronate

R i F? ”

Cl Cl

Etidronate

R ’ n ”

CH3 OH

Pamidronate

R ’ I? ”

OH

- NH2

R 0

R’

0

=

0

Risedronate

(CH2)2 - NH2

R’

CH2

OH Tiludronate

R’

943

lbandronate

R’

I (CH2)2

Fig I.

Bisphosphonate:

(A)

structure

and

bone, being released only with turnover at the site of prior incorporation in bone.24 The half-life in bone has been estimated at approximately 1 year. Clinical

R”

(B) analogs.

Uses

The most frequent clinical use of bisphosphonates is in radionuclide bone scanning to assess for metastasis from primary cancers. Increased osteoblastic activity associated with osteolysis at meta-

static sites allows active disease.

=

OH

for increased

BISPHOSPHONATES

uptake

AND

in areas of

CANCER

Malignancy-AssociatedHypercalcemia Cancer-related hypercalcemia was the first area in which bisphosphonates demonstrated clinical efficacy. Randomized controlled trials have shown

286

THERIAULT

that etidronate, clodronate, and pamidronate can restore normocalcemia in 40% to 100% of treated patients. A variety of schedules and doses have demonstrated efficacy. Clodronate and etidronate have been shown to have some benefit when administered orally; however, the gastrointestinal symptoms (nausea/vomiting) associated with hy percalcemia, poor oral absorption of bisphosphonates, and dose-related gastrointestinal toxicity of oral bisphosphonates make the intravenous route of administration preferable. The newer agents with greater antiosteoclast potency-pamidronate, alendronate, and ibandronate-have shown a dose-response effect. For example, Thiebaud et al demonstrated that a single intravenous dose of pamidronate was effective in achieving normocalcemia.zs This was confirmed in a study reported by Nussbaum et al in which 30-, 60-, and 90-mg doses of pamidronate were compared in a randomized fashion with increasing efficacy demonstrated with increasing dose.26 A variety of administration schedules has been tried for pamidronate. A 4-hour infusion has been shown to be as effective and safe as a 24-hour infusion.27 A single infusion appears to be as effective as multiple daily infusions, and in osteolytic metastases studies, a 2-hour infusion time has been used.28 A 2-hour infusion of alendronate is as effective for hypercalcemia as a 24-hour infusion,29 and a recent review by Body reported that zoledronate, an agent 100 to 800 times more potent than pamidronate, can be administered intravenously in as brief a time as 5 minutes.30 It was reported to be 90% to 100% effective for treating hypercalcemia in a phase 1 study. Commonly used doses and schedules of etidronate, clodronate, and pamidronate are shown in Table 1. As a practical matter, in the United

fable

I. ‘Doses

and

Schedule

for Commonly

Used

Etidronate Clodronate

5-7.5 mgkgld IV. 3-5 days 1,500 mg over 24 hours IV 300 mg IV daily, 2-3 days

Pamidronate

15-30 mg IV daily until normocalcemia 60-90 mg IV over 4 hours

Abbreviation:

IV, intravenous.

1

AND

HORTOBAGYI

States, pamidronate is most commonly used because of ease of administration, efficacy, and safety.

Bone Metastasis Bone metastasis is a frequent complication of many cancers. Once developed, the integrity of the skeleton can be compromised because of uncoupling of the bone remodeling unit and excess osteolytic activity. Osteoclast activation may occur as a result of tumor-derived products such as parathyroid hormone-related peptide (PTHrP) and interleukin-6 or because of bonederived cytokines released as part of the osteolytic process.31-33 Osteolysis leads to the well-known clinical presentations of bone disease such as bone pain, fractures, and nerve root or spinal cord compression. These in turn result in impaired performance status and quality of life. Many studies have demonstrated a reduction in one or more skeletal-related morbid events when patients with bone metastasis have been treated with bisphosphonates. Clodronate and pamidronate have both been assessed by oral and intravenous administration in human solid tumor and hematologic malignancies (breast cancer and multiple myeloma) . Breast Cancer In a study of oral clodronate, Elomaa et al reported decreased fracture risk, decrease in bone pain, and decrease in hypercalcemia for 34 patients with osteolytic metastases from breast cancer.34 In a placebo-controlled trial, Paterson et al treated 173 patients with 1,600 mg/d of oral clodronate as adjunctive therapy for osteolytic metastasis from breast cancer. These patients were shown to have decreases in fracture risks, need for radiation therapy, bone pain and hypercalcemia.35 Although the study of Elomaa et al suggested a survival advantage for the clodronate-treated patients, the larger study of Paterson et al did not. The effects of pamidronate on skeletal-related events have been assessed in randomized studies with oral and intravenous administration. In a study of 131 patients, the 70 treated with oral pamidronate 300 mg/d had a 50% reduction in skeletal morbidity, including reductions in hypercalcemia, bone pain, pathologic fractures, and requirement for radiation to bone.49 A follow-up to

THE

EVOLVING

ROLE

OF BISPHOSPHONATES

the original report with long-term results showed a decrease in hypercalcemia (65%), bone pain (30%), and impending fractures (50%) for the pamidronate treated patients. No impact on sur’viva1 was seen. Intravenous pamidronate has been assessed in multiple studies, including large randomized placebo-controlled trials. These studies added pamidronate 45, 60, or 90 mg intravenously every 3 to 4 weeks to standard chemotherapy or hormonal therapy for breast cancer .36Conte et al reported an increase in time to progression in bone favoring the pamidronate-treated patients, as well as a significant reduction in bone pain. A delay in first skeletal event and a significant decrease in number of skeletal events was reported in a trial of 401 patients randomized to pamidronate or placebo in addition to standard systemic therapy for breast cancer bone metastases.37 Recently, short- and long-term results of two large, randomized, multicenter placebo-controlled trials of intravenous pamidronate in osteolytic metastatic breast cancer have been reported. In the first, Hortobagyi et al28 reported an increase in time to first skeletal event: 7 months versus 13.1 months, respectively, for placebo versus pamidronate treatment. In addition, there was a significant decrease in the proportion of patients having any skeletal complication (43% v 56% for pamidronate v placebo), as well as significantly less deterioration in bone pain scores and performance status. Patients were treated with chemotherapy and the first analysis was at 12 months. Reductions in nonvertebral pathologic fractures, radiation to bone, surgery on bone, and hypercalcemia were clinically and statistically significant. Long-term, 24-month analysis of this trial showed that the statistically significant reductions in any skeletal complication, proportion of patients with any pathologic fracture, need for radiation or surgery to bone, and hypercalcemia persisted. No substantial pamidronate-related long-term toxicities were noted. A study of similar design for patients with osteolytic metastasis from breast cancer who were treated with hormonal therapy has been reported by Theriault et al.38 The time to first skeletal event was significantly delayed for the pamidronatetreated groups (10.4 e, 6.9 months, P = .049). Significant reductions in any skeletal event, pathologic fracture, radiation to bone, and hyper-

287

calcemia were observed for the pamidronatetreated patients. In both of these trials, the benefit of pamidronate a.dministration persisted for the 2 years of study follow-up. A subset analysis of the hormone therapy trial showed a survival advantage for patients less than 50 years of age who had been treated with pamidronate (26 months for pamidronate v 18 for months placebo, P = .029). Multi@

Myeloma

Myeloma is a malignancy characterized by pure osteolysis of bone and multiple radiographically apparent lytic bone lesions. Pathologic fractures and hypercalcemia are frequent clinical occurrences. The efficacy of clodronate and pamidronate has been assessed for reducing skeletal morbidity in myeloma. Lahtinen et al reported on a randomized, controlled trial in which 350 patients with multiple myeloma receiving standard chemotherapy were given clodronate or placebo daily for up to 24 months.39 Clodronate significantly reduced osteolytic disease progression. Reductions in frequency of hypercalcemia and severity of bone pain also occurred for the clodronate-treated group. A recent report of oral clodronate use in multiple myeloma confirmed the clinical benefit in a large group of patients (536) randomized to receive 1,600 mg/d of clodronate or placebo.4O There was a reduction in vertebral and nonvertebral fractures, decrease in frequency of hypercalcemia, and improvement in pain and performance status, all of which were clinically and mathematically significant. Berenson et al reported on an intravenous pamidronate trial in 392 patients with myeloma.41 Among the 196 patients who received pamidronate, there was a significant reduction in any skeletal complication, as well as significant reductions in bone pain and maintenance of performance status. The long-term results of the Berenson study have recently been published.4* The skeletal benefits persisted throughout 21 months of observation. A decrease in skeletal events and the number of events per year was seen in the pamidronatetreated group. Patients who had received antimy eloma chemotherapy before beginning pamidronate were shown to have a survival advantage compared with placebo-treated patients (2 1 months for pamidronate v 14 months for placebo,

THERIAULT

P = .041) even though no differences in antimyeloma therapy were demonstrable. All of these trials have reported that long-term bisphosphonate administration is safe, well tolerated, and effective in reducing osteolytic activity in bone as manifest by decreases in urinary markers of osteolytic activity.38,43 Bone Metastatic

Prevention

Bisphosphonate treatment has resulted in decreased frequency or prevention of bone metastasis in animal models.44 One proposed mechanism for these observations is inhibition of adhesion of tumor cells to bone matrices.45 Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracullar matrices.45 Two recent clinical reports support the observations in animals suggesting that the development of bone metastasis can be delayed or prevented. In a randomized trial reported by Die1 et al, 302 patients with primary breast cancer, in whom bone marrow specimens had been shown to contain tumor cells, were randomly assigned to clodronate 1,600 mg/d orally or usual care.4(j All patients received appropriate adjuvant therapy for breast cancer. At 36 months median observation time, 42 patients in the usual care group had developed metastases, while only 21 patients in the clodronate group had done so. In addition to a reduction in the frequency of bone metastasis, those in the clodronate group who did develop bone disease had significantly fewer sites of bone involvement than the control group. The observation of a decrease in visceral sites of metastasis associated with clodronate use was provocative and warrants further observation and study. Preliminary results of a randomized, placebocontrolled trial of oral clodronate in primary breast cancer have been reported by Powles et al.47 In this study, more than 1,000 patients were treated with clodronate 1,600 mg/d or placebo for 2 years. Clodronate reduced the frequency of bone metastases development, with the most noted effect in postmenopausal women, in whom there was a 50% reduction in the percentage of women developing bone metastases. Additional studies of more potent bisphosphonates are planned.

AND

HORTOBAGYI

New Agents More potent bisphosphonates have been developed and are in clinical trials for patients in whom osteolysis is a part of the malignant process. Zoledronate has been shown in phase I trials to be effective in treating malignancy-associated hypercalcemia. It can be administered as a rapid intravenous infusion (over 5 to 30 minutes), and may prove more convenient and less expensive than other agents. Phase 1 and 2 trials in lytic bone disease are underway.30 In addition, YM175 has shown substantial potency in inhibiting osteoclast activity in an animal model and is expected to enter clinical trial.48 SUMMARY Bisphosphonates have changed the way bone disease is managed. They provide potent and effective therapy for hypercalcemia of malignancy, and reduce the morbidities of extant skeletal metastases, including bone pain, fractures, and the need for radiation therapy intervention. Most importantly, they have kindled interest in developing a research framework for examining the osteotropism of metastasis by emphasizing the relevance and importance of bone metastasis for morbidity and quality of life of the cancer patient. Finally, they may have opened a path to the understanding of methods to prevent skeletal disease of malignancy. REFERENCES 1. Andrew visceral cology,

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