Bisphosphonates and Other Bone-Targeted Therapies



Bisphosphonates and Other Bone-Targeted Therapies


Philip J. Saylor

Matthew R. Smith



Bone metastases and treatment-induced osteoporosis are major causes of morbidity for many patients with cancers. Bone metastases can cause hypercalcemia, pain, fracture, and spinal cord compression. Changes in hormonal status induced by androgen or estrogen deprivation lead to osteoporosis and fractures. Most of these complications result from excessive osteoclast activation due to tumor infiltration of bone or cytokine release from tumor or from immune cells. Osteoclast-targeted therapy is a rational approach to prevention or management of these complications.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and were introduced for the promotion of bone mineralization in patients with osteoporosis or Paget’s disease. Because of the frequency of both disease-related and treatment-related bone complications in cancer, they have won an increasingly important role in the management of cancer patients. Bisphosphonates are the treatment of choice for hypercalcemia of malignancy. They decrease the risk of skeletal complications for patients with multiple myeloma and patients with bone metastases from breast cancer, prostate cancer, and other solid tumors. Bisphosphonates may also prevent the development of recurrent disease in women with high-risk primary breast cancer, and they are increasingly used for prevention of bone loss related to hormone deprivation therapy in cancer.

Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor-κ-B ligand (RANKL) and produces potent osteoclast inhibition. Landmark studies reported in 2009 showed that denosumab promotes bone mineralization and reduces fractures in postmenopausal women with osteoporosis1 and in high-risk men with prostate cancer.2 It also improves bone mineral density among women receiving aromatase inhibition for the treatment of breast cancer.3 Denosumab is also the subject of several ongoing clinical trials that examine its potential for other cancer-related applications.

This chapter considers the pharmacology and specific roles of bisphosphonates and other osteoclast-targeted therapies in management of bone disease in cancer patients.


The Biology of Bone Homeostasis

Bone mineralization is a complex process that centrally features calcium homeostasis. Bone density is the result of a balance between deposition by osteoblasts and resorption by osteoclasts. Calcium absorption, storage, and mobilization are under tight hormonal regulation in the intestine, bones, and kidneys. Calcium absorption from the intestinal tract is promoted by the active form of vitamin D (1,24-dihydroxycalciferol). Resorption in the kidneys is under the tight control of parathyroid hormone (PTH). These processes maintain serum calcium at physiological levels. The major reserve of calcium resides in bone, which contains 99% of bodily calcium. When overproduced, PTH enhances osteoclast activity, promotes bone turnover, and can produce hypercalcemia and osteopenia. Parathyroid hormone-related protein (PTHrP) can be secreted by epithelial cancers and can have a similar effect. Bone mineral density declines with age at least partially as a result of declining levels of estrogen and androgens. This physiological and gradual change contributes to progressively elevated fracture risk later in life. Several other clinical factors such as tobacco smoking,4 alcohol intake,5 chronic glucocorticoid use,6 and inflammation due to rheumatoid arthritis7 have also clearly been associated with bone fragility fractures independent of their effects on bone mineral density.

Bone health is the product of a perpetual process of skeletal remodeling. Bone formation by osteoblasts and bone resorption by osteoclasts are ongoing and balanced processes. Osteoclasts are bone-specific macrophages that differentiate from monocyte/macrophage progenitors. Bone resorption results from osteoclast binding to bone and secretion of lytic enzymes into a sealed and acidified resorption vacuole. Tartarate-resistant acid phosphatase and cathepsin are the two most active enzymes within the compartment.8

Though at least 24 additional genes and loci have been identified as involved in osteoclast regulation, the receptor activator of nuclear factor-κ-B (RANK) signaling pathway is a central regulator of osteoclast maturation and activity. RANKL has two receptors: RANK and osteoprotegerin. Osteoprotegerin is a decoy receptor for RANKL and competitively inhibits RANK activation. Activation of RANK by RANKL on the surface of osteoclast precursors leads to gene expression and cellular differentiation to mature multinucleated osteoclasts (Fig. 40-1). RANK activation on mature osteoclasts leads to survival and increased bone resorption.


Bisphosphonates


Mechanism of Action

Bisphosphonates inhibit osteoclast-mediated bone resorption by several mechanisms. Etidronate and clodronate are metabolized
to cytotoxic analogs of adenosine triphosphate. More potent nitrogen-containing bisphosphonates (risedronate, pamidronate, zoledronic acid) inhibit farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway, and decrease prenylation of essential GTP-binding proteins. Bisphosphonates also increase osteoblast secretion of two important cytokines: (a) an inhibitor of osteoclast recruitment and (b) transforming growth factor-β, a signal for osteoclast apoptosis.






FIGURE 40-1 Hormonal regulation of bone remodeling. This schematic depicts several factors involved in regulation of the balance between bone resorption and bone formation. Osteoblast precursors express RANKL. Osteoclast differentiation, activation, and survival are promoted by RANKL binding to RANK on the cell surface.

The growth of bone metastases involves reciprocal interactions between tumor cells and metabolically active bone.9 Development and progression of bone metastases proceed through several steps: tumor cell adhesion to bone, invasion, new blood vessel formation, and proliferation. Preclinical studies suggest that bisphosphonates inhibit each of these steps.10,11 The clinical relevance of the observed antitumor properties of bisphosphonates in preclinical models is not known.


Pharmacology

Bisphosphonates are synthetic analogs of pyrophosphate characterized by a phosphorus-carbon-phosphorus backbone that renders them resistant to hydrolysis (Fig. 40-2). The properties of bisphosphonates are determined by the R1 and R2 carbon side chains.12 Most bisphosphonates contain a hydroxyl group at the R1 position that confers high-affinity binding to calcium phosphate. The R2 side chain is the critical determinant of antiresorptive potency (Table 40-1). Bisphosphonates that contain a primary amino group (pamidronate and alendronate) are approximately 100 times more potent than first-generation bisphosphonates that do not contain an amino group (etidronate and clodronate). Bisphosphonates that contain a secondary or tertiary amino group (ibandronate, risedronate, and zoledronic acid) are even more potent bisphosphonates, with approximately 10,000-fold more activity than etidronate.


Pharmacokinetics

Bisphosphonates are poorly absorbed. Bioavailability is less than 1% after oral administration. Bisphosphonates bind calcium. Calciumcontaining foods, beverages, and medications may reduce oral drug absorption. For treatment of hypercalcemia of malignancy, or for prevention of bone resorption related to cancer treatment, intravenous preparations of bisphosphonates are preferred. Bisphosphonates are not metabolized. They are slowly eliminated by renal excretion. Though serum half-life is of the order of days (e.g., zoledronic acid half-life is 146 hours), effects on bone turnover markers can persist for months.

Bisphosphonates adsorb to calcium phosphate (hydroxyapatite) crystals in bone. Approximately one half of an intravenously
administered dose accumulates in the skeleton, preferentially binding to sites of active bone remodeling. Bisphosphonates become biologically inactive after they are incorporated into quiescent bone, and repetitive administration appears to be required to maintain inhibition of bone resorption.






FIGURE 40-2 General structure of bisphosphonates. The biological activity of bisphosphonates depends on the P-C-P group and structure of the R1 and R2 side chains.








TABLE 40.1 Preclinical potency of selected bisphosphonates



























Generic name

Trade name

Relative potency


Etidronate

Didronel

1


Clodronate

Ostac

10


Pamidronate

Aredia

100


Ibandronate

Bondronat

10,000


Zoledronic acid

Zometa

10,000


Etidronate (Didronel), pamidronate disodium (Aredia), and zoledronic acid (Zometa) are marketed for oncology in the United States. Guidelines for dosing are provided in Table 40-2. Clodronate (Ostac) and ibandronate (Bondronat) are marketed for oncology in other countries but are not available in the United States. Alendronate is a less potent bisphosphonate that is marketed for treatment of osteoporosis.


Toxicity

Bisphosphonates have been associated with short- and long-term toxicities. The most common side effects of intravenous bisphosphonates are asymptomatic hypocalcemia and a self-limited flu-like acute phase reaction. Rare but feared complications include nephrotoxicity and osteonecrosis of the jaw (ONJ).

Bisphosphonate-induced renal toxicity results from the R1 carbon side chain attached to the parent molecule. Because most bisphosphonates share the same R1 hydroxyl side chain, renal toxicity is a potential adverse effect of all bisphosphonates. Renal toxicity has been most closely associated with high total drug dose, short infusion time, and poor baseline renal function. To minimize nephrotoxicity, all doses of zoledronic acid should be infused over ≥15 minutes (≥2 hours for pamidronate) and dose is reduced in patients with stable baseline creatinine clearance less than 60 mL/min.13 Dosing should be held in patients with creatinine clearance less than 35 mL/min or actively declining kidney function.








TABLE 40.2 FDA-approved bisphosphonates for oncology



































Generic name

Trade name

Approved indication(s) in oncology


Etidronate

Didronel

Hypercalcemia of malignancy


Pamidronate

Aredia

Hypercalcemia of malignancy


Bone lesions from multiple myeloma


Bone metastases from breast cancer


Zoledronic acid

Zometa

Hypercalcemia of malignancy


Bone lesions from multiple myeloma


Bone metastases from any solid tumor







FIGURE 40-3 Bisphosphonate-associated osteonecrosis of the jaw (ONJ). ONJ is characterized by exposed necrotic maxillofacial bone as pictured here. In retrospective analyses, risk is associated with the use of zoledronic acid, dental extractions during bisphosphonate therapy, and long treatment duration.17 (From Kuehn BM. Long-term risks of bisphosphonates probed. JAMA 2009;301[7]:710-711. Ref [18].) (Please see Color Insert.)

Bisphosphonate-associated ONJ was described after the more potent bisphosphonates had become widely available14,15 and has become a feared complication of treatment. ONJ is characterized by exposed necrotic maxillofacial bone (Fig. 40-3). Incidence is not precisely known but appears to be higher with intravenous than with oral bisphosphonates.16,17 In retrospective analyses, the risk of ONJ is associated with the use of zoledronic acid, dental extractions during bisphosphonate therapy, and longer duration of treatment.17 Completed trials with intravenous bisphosphonates have not featured treatment durations beyond 24 months.

Oral administration of bisphosphonates may cause gastrointestinal toxicity and even erosive esophagitis.19 Though some have suggested the possibility of esophageal cancer associated with oral bisphosphonate therapy,20 currently available data do not support this association.21


Denosumab


Mechanism of Action

The RANK signaling pathway is important to osteoclast regulation as it is involved in multiple steps of the process of osteoclast maturation. RANKL binding to RANK on the surface of osteoclast precursors causes differentiation into mature multinucleated
osteoclasts. RANKL binding to mature osteoclasts promotes their activation and survival. As RANKL regulates osteoclast maturation and activation, RANKL inhibition is a rational strategy for the management of osteoclast-mediated disease. Denosumab, a fully human monoclonal antibody, binds to and inhibits RANKL with high affinity and specificity. The stimulatory actions of RANKL are naturally suppressed by the action of osteoprotegerin, a decoy receptor that acts as a sink for RANKL. Pharmacologic administration of denosumab acts similarly to deplete RANKL and inhibit bone resorption. Denosumab is in advanced stage of development for use in a number of clinical settings, several of which are relevant to oncology.


Pharmacology

Denosumab is administered as an intravenous or subcutaneous injection. When given subcutaneously, it is 60% to 80% bioavailable at typical doses. Serum levels are detectable within 1 hour. Peak concentration occurs 1 to 4 weeks after administration at typical doses. Denosumab suppresses markers of bone turnover (N-telopeptide) within hours of administration and can sustain this suppression for more than 6 months in some clinical settings. Clearance is slow (half-life in plasma is 33 to 46 days at highest doses) and nonlinear; serum exposure escalates out of proportion to dose increases. Pharmacokinetics is not substantially altered by serial dosing.

Denosumab suppresses bone turnover in patients with bone metastases, including in patients not adequately suppressed with high potency bisphosphonates. One study enrolled patients with bone metastases from various carcinomas or myeloma; bone resorption had been suboptimally suppressed by intravenous bisphosphonate therapy. Subjects were randomized to continued intravenous bisphosphonate or to denosumab (180 mg subcutaneous every 4 weeks). The bone resorption marker urinary N-telopeptide normalized more frequently in patients treated with denosumab (71% versus 29%; P < 0.001).22


Safety

Denosumab has been generally well tolerated in studies performed to date. Asymptomatic transient hypocalcemia has also been observed, generally within 2 weeks of administration. Other reported adverse events include arthralgia, upper respiratory infection, nasopharyngitis, headache, and back pain. One early meta-analysis of over 10,000 postmenopausal women treated with denosumab found an increase in the risk of serious infections.23 Nephrotoxicity has not been observed. Its potential to cause ONJ, a feared side effect of potent osteoclast inhibition with bisphosphonates, is not known.

Denosumab and zoledronic acid are compared in Table 40-3.


Hypercalcemia

Hypercalcemia of malignancy results primarily from increased release of calcium from bone. In the presence of bone metastases, calcium is released from the skeleton by local osteoclast-mediated bone destruction. In addition, hypercalcemia of malignancy may result from tumor secretion of PTHrP.24 PTHrP may be ectopically produced by ovarian cancer, lung cancers, pancreatic cancer, and others.

Several bisphosphonates have demonstrated efficacy for the management of hypercalcemia of malignancy.

Treatment with intravenous pamidronate disodium (90 mg) achieves normocalcemia in more than 90% of patients with hypercalcemia of malignancy.25 Pamidronate achieves more complete and significantly longer lasting responses than clodronate (median duration of normocalcemia was 28 days after pamidronate therapy compared with 14 days after clodronate treatment).26 Ibandronate appeared to be comparable to pamidronate for hypercalcemia of malignancy in a 72patient randomized trial.27 The mean decreases in serum calcium were similar as were the rates of normocalcemia (and 77% with ibandronate versus 76% with pamidronate; P = 0.30).

Zoledronic acid is superior to pamidronate for hypercalcemia of malignancy. In a double-blind study, 287 patients with moderate to severe hypercalcemia of malignancy (corrected serum calcium 3.0 mmol) were randomly assigned to zoledronic acid (4 or 8 mg) or pamidronate (90 mg).28 Both doses of zoledronic acid were superior to pamidronate. The rate of normalization of serum calcium at day 10 was 87% for zoledronic acid versus 70% for pamidronate. The median duration of normocalcemia was greater than 30 days for zoledronic acid and 18 days for pamidronate.

Bisphosphonates should be administered to all patients with hypercalcemia of malignancy and a corrected serum calcium level greater than 3.0 mmol (12 mg/dL).29 Bisphosphonates should also be administered to symptomatic patients with more moderate hypercalcemia. Etidronate, pamidronate, and zoledronic acid are FDA-approved for this indication.


Osteoclast-Targeted Agents for Specific Cancers


Multiple Myeloma

Multiple myeloma is a malignancy characterized by osteolytic bone lesions and accumulation of mature plasma cells in the bone marrow. Interactions between myeloma cells and bone marrow stromal cells lead to local release of osteoclast activating factors and subsequent osteoclast-mediated resorption. The osteoclast activating factors include interleukin (IL)-6, tumor necrosis factor, parathyroid hormone-related peptide, hepatocyte growth factor, IL-1, IL-11, macrophage inflammatory protein-1, and others.

Eight large randomized trials of bisphosphonate administration for multiple myeloma have been reported (Table 40-4). As a result of these trials, pamidronate and zoledronic acid have become standard-of-care treatments for the reduction of skeletal events. These two bisphosphonates warrant specific discussion.


Intravenous Pamidronate

In a Myeloma Aredia Study Group trial, 392 patients with Durie-Salmon stage III multiple myeloma and at least one osteolytic lesion were treated with antimyeloma therapy and either placebo or pamidronate (90 mg intravenously every month for 9 months).35 The proportion of patients who had any skeletal events (pathologic fracture, irradiation of or surgery on bone, or spinal cord compression) was significantly lower in the pamidronate group than in the placebo group (24% versus 41%, P < 0.001). The patients who received pamidronate had significant decreases in bone pain and improved quality of life. Overall survival was similar for both groups. Among patients receiving second-line chemotherapy at study entry, median survival was significantly longer in the pamidronate-treated group than in the placebo-treated group (21 versus 14 months, P = 0.041). Further follow-up from this trial revealed that after 21 monthly cycles the subjects treated with pamidronate had experienced significantly fewer skeletal events (P = 0.015).38 The number of skeletal events per year was significantly lower with pamidronate treatment than with placebo (1.3 versus 2.2, P = 0.008).










TABLE 40.3 Key features of zoledronic acid and denosumab

Zoledronic acid

Denosumab


Classification

Bisphosphonate

Fully human monoclonal antibody


Mechanism of action

Zoledronic acid is rapidly incorporated into bone where it inhibits osteoclast activity and induces osteoclast apoptosis.

Monoclonal antibody binds avidly (Kd 3 × 10−12 M) and specifically to RANKL. Binding of RANKL inhibits osteoclast differentiation, activation, and survival.


Clinical pharmacology

Bioavailability: Rapidly partitions to bone after intravenous administration.

Bioavailability: In healthy subjects treated with of doses from 0.03 to 3 mg/kg subcutaneous (SC), bioavailability is 60%-80%.

Pharmacokinetic parameters: Onset of response and time to peak response dependent on the clinical setting. Concentration falls to <1% of Cmax 24 h postinfusion. Plasma area under the curve rises with renal impairment.

Pharmacokinetic parameters: Single subcutaneous or intravenous dose suppresses markers of bone turnover in a dose-dependent manner. Marker suppression can be observed within 12 h of administration. At doses of 1 and 3 mg/kg, duration of suppression is at least 6 mo in postmenopausal women and 3 mo in most subjects with multiple myeloma or breast cancer with bone metastases. Denosumab did not accumulate appreciably at any of the doses or dosing frequencies investigated for postmenopausal bone loss. Pharmacokinetics did not appear to be altered upon multiple dosing. When given 180 mg every 4 wk, denosumab was observed to have 2.5-fold accumulation by the third dose.

Distribution: Drug binds to bone. Serum protein binding is 28%-53% in vitro.

Distribution: After intravenous administration, denosumab has a volume of distribution that is similar to plasma volume. After subcutaneous administration, absorption appears to be rapid and prolonged, with detectable concentrations within 1 h after dose and peak concentrations typically observed between 1 and 4 wk.

t1/2 life: 146 h, triphasic

t1/2 life: 33-46 d at highest doses

Metabolism: Zoledronic acid is not metabolized.

Elimination: Renal elimination within 24 h, 39% ± 16% unchanged.


Relevant FDA indications

Bone metastases due to solid tumors
Hypercalcemia of malignancy
Multiple myeloma
Osteoporosis in men
Secondary prophylaxis of osteoporosis after low-trauma hip fracture

Denosumab is not FDA-approved. A Biologic License Application was submitted to the FDA in December 2008 for:
Treatment and prevention of postmenopausal osteoporosis
Bone loss in patients undergoing hormone therapy for the treatment of prostate or breast cancer

Osteoporosis due to corticosteroids

Paget’s disease

Postmenopausal osteoporosis

Prophylaxis of postmenopausal osteoporosis


Route of administration

Intravenous

Subcutaneous


Typical dosage

Bone metastases due to solid tumors: 4 mg IV every 3-4 wk
Hypercalcemia of malignancy: 4 mg IV given as a single dose; may repeat after ≥7 d if serum calcium does not return to normal or remain normal after initial treatment
Multiple myeloma: 4 mg IV every 3-4 wk
Osteoporosis: 5 mg IV every 12 mo
Osteopenia secondary to androgen-deprivation therapy in prostate cancer patients: 4 mg IV every 3-12 mo

Dosing in phase III trials:
60 mg subcutaneously once every 6 mo for reduction of fragility fracture risk
120 mg subcutaneously once every 4 wk for various applications in the setting of metastatic cancer (e.g., reduction of risk for skeletal-related events)


Dose adjustment for renal insufficiency

Always infuse over ≥15 min to avoid nephrotoxicity. If chronic and stable renal insufficiency, start as follows:
3.5 mg if baseline CrCl = 50-60 mL/min
3.3 mg if baseline CrCl = 40-49 mL/min
3.0 mg if baseline CrCl = 30-39 mL/min
Not recommended for CrCl < 5 mL/min

None required.


Drug interactions

Aminoglycosides: Hypocalcemic effects may be enhanced.
Nonsteroidal anti-inflammatories: Gastrointestinal toxicity and nephrotoxicity may be enhanced.
Phosphate supplements: Hypocalcemic effects of phosphate supplements may be enhanced.
Thalidomide: Toxic effects may be enhanced.

None described.


Common toxicities

Self-limited acute phase reaction, incidence reduced with acetaminophen.
Asymptomatic hypocalcemia is common.
Common toxicities include peripheral edema, gastrointestinal upset, arthralgia, asthenia, fatigue, headache, and others.
Additional potential serious adverse effects possible; please see text.

Generally well tolerated. Most commonly reported adverse events in trials to date have included headache, back pain, upper respiratory tract infection, arthralgia, and nasopharyngitis. Hypocalcemia observed after administration of denosumab has been transient, mild, and within the first 2 wk after administration.


Warnings and precautions

Administer with an oral calcium supplement of 500 mg and a multiple vitamin containing 400 International Units of vitamin D unless in the setting of hypercalcemia of malignancy.
Observe recommended guidelines for dental care.
Contraindicated in hypocalcemia or known hypersensitivity.
FDA pregnancy class D.

Denosumab has never been tested in combination with other osteoclast-targeted therapies. In a preliminary report involving women with breast cancer, rates of ONJ were similar with zoledronic acid and with denosumab. Dental precautions should be observed as with bisphosphonate treatment.










TABLE 40.4 Major randomized controlled trials of bisphosphonates for multiple myeloma




















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May 27, 2016 | Posted by in ONCOLOGY | Comments Off on Bisphosphonates and Other Bone-Targeted Therapies

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Study

N

Treatment

Result


Canadian30

166

Etidronate versus placebo

No difference in skeletal morbidity


Finnish31

336

Clodronate versus placebo

No difference in skeletal morbidity


German32

170