Bisphosphonates: Against Skeletal Lesions + Direct Anti-Tumor Action

Background:

Many cancers either metastasize to the skeleton or grow primarily within the bone marrow, where this growth frequently leads to hypercalcemia, severe bone pain, skeletal destruction, and pathologic fractures. Indeed, the skeleton is the most common site of metastatic disease, and some of the patients with advanced cancer may develop skeletal lesions (Ref.).

Bisphosphonates (BPs) are FDA aproved drugs that are potent inhibitors of osteoclast-mediated bone resorption. They are widely used in the management of osteoporosis and other diseases of high bone turnover. They are currently the most important and effective class of drugs for metabolic bone disorders such as osteoporosis, Paget’s disease, and osteogenesis imperfecta (Ref.). Due to their mode of action, Bisphosphonates (BPs) are effective inhibitors of tumor-induced bone resorption and as a result, private clinics in Germany treating cancer patients are administrating low dose Bisphosphonates to all patients at high risk of developing bone metastasis, (as Bisphosphonates have been also shown to reduce that risk) or those cancer patients at risk of bone loss due to hormonal treatments (such as breast and prostate cancer patients (Ref.)).

Therefore, at the tissue level, Bisphosphonates reduce bone turnover, increase bone mass and mineralization, measured clinically as a rise in bone mineral density, increase bone strength and reduce fracture risk. (Ref.) This leads to decrease in pain and prevents deterioration of quality of life in metastatic bone disease.

Bisphosphonates drugs Zoledronic acid and Pamidronic acid are the most potent and widely-used intravenous bisphosphonates today. Intravenous clodronate and etidronate are less potent, with less affinity to bone, requiring prolonged infusion time and thus becoming less popular. Zoledronic acid is the most potent: about 850 times more potent than pamidronate (Ref.).

Interestingly, in addition to skeletal benefits, clinical studies have shown that bisphosphonates can also directly suppress the proliferation of cancer cells, including prostate, breast, and colorectal cancers, as well as glioblastoma and multiple myeloma (MM) but other cancers too (Ref.) The mechanisms responsible for the observed anti-tumor effects of BPs are beginning to be elucidated and are discussed in the Mechanism section below.

Case Report in Humans:

Antitumoral effect of the bisphosphonate zoledronic acid against visceral metastases in an adrenocortical cancer patient http://annonc.oxfordjournals.org/content/20/10/1747.1.full#ref-3

• A 40-year-old man presented in July 2002 with a large nonsecreting tumor of the left adrenal gland with liver metastases. Left adrenalectomy confirmed the diagnosis of Weiss 6 ACC. Extended surgery removed all the macroscopic lesions. Four months later, the patient experienced rapidly progressive disease with liver and lung metastases; a hepatic radiofrequency ablation was carried out. Then, he experienced disease progression with painful s.c. metastases under o,p′-DDD despite a sufficient blood level (>10 μg/ml). The ACC also progressed within 2 months despite chemotherapy with oxaliplatin and gemcitabine. Chemotherapy was stopped. In March 2004, ZOL was initiated as a monthly 4 mg i.v. 30-min infusion for lung, peritoneal and liver progression. After five infusions, computed tomography (CT) scan showed a complete disappearance of lung metastases and necrosis of the liver metastases. In June 2005, a second hepatectomy was carried out and histological examination confirmed massive tumor necrosis with negative margins. The patient continued ZOL until April 2006 and had ultimately in March 2007 the resection of a residual small-bowel metastasis. In June 2009, 6 years after the diagnosis of liver metastases, and after a 3-year off-therapy follow-up, the patient is currently alive without evidence of metastasis on CT scan.

Antitumor effect of zoledronic acid in previously untreated patients with multiple myeloma. https://www.ncbi.nlm.nih.gov/pubmed/17848748

• Actuarial 5 yr OS was 80% in the zoledronic acid arm, and 46% in the control group (p < 0.01). Sketeletal events were more frequent in the control group when compared to zoledronic acid. Toxicity was mild. We confirm the efficacy of zoledronic acid to prevent skeletal events, but we felt that we can demonstrate that zoledronic acid has a clinical antitumor effect measured from a increase in complete response rate and EFS and OS that were better when compared with the control group. We began a controlled clinical trial with modern treatment (including transplant procedures) in combination with zoledronic acid to define the role of zoledonic acid in this setting of patients.

Mechanism (in bones):

BPs preferentially bind to the surface of bone at sites of active remodeling and become internalized into osteoclasts through endocytosis (Ref.). Once they are inside osteoclast, they inhibit osteoclast activity (and thus bone loss) in two different way depending on if the BPs are non-nitrogen containing (non-N-BPs) or nitrogen-containing bisphosphonates (N-BPs):

• The non-nitrogen containing bisphosphonates (non-N-BPs) inhibit bone resorption by generating the cytotoxic analogs of ATP which interfere with mitochondrial function and induce apoptosis of osteoclasts (Ref.)
• The more potent nitrogen-containing bisphosphonates (N-BPs) bind to and inhibit key enzymes of the intracellular mevalonate pathway, preventing the prenylation and activation of small GTPases that are essential for the bone-resorbing activity and survival of osteoclasts (Ref.)

Note that Zoledronic acid (Zometa), Pamidronic acid (Aredia), Alendronate (Fosamax), Risedronate (Actonel), Ibandronate (Bonva) are N-BP, while Clodronate (Bonefos), Eridronate (Didronel) and Tiludronate (Skelid) are non-N-BP.

Source for the figure: Ref.

The anti-tumor effect of bisphosphonates regarding the inhibition of the bone metastases formation is achieved mainly through inhibition of osteoclast-mediated bone resorption (Ref.).

Mechanism (in tumors):

Here is a list of several anti cancer mechanisms that are connected with bisphosphonates:

• Inhibition of tumor cell proliferation and induction of apoptosis via production of cytotoxic ATP analogs (Ref.)
• Augmentation of inhibitory effect of cytotoxic agents (additive and synergistic effect)
• Inhibition of angiogenesis (Ref.)
• Decrease in tumour cell adhesion to bone (Ref.)
• Decrease in tumour cells invasion and migration and disorganization of cell cytoskeleton (Ref.)
• Inhibition of mevalonate pathway & activation of γδ T cells (Ref.)
• Effects on tumour macrophage infiltration. (Ref.)

Production of cytotoxic ATP analogs:

Nitrogen-containing bisphosphonates (N-BPs) induce formation of a novel ATP analog (ApppI) as a consequence of the inhibition of farnesyl diphosphate synthase in the mevalonate pathway. Similar to AppCp-type metabolites of non-N-BPs, ApppI is able to induce apoptosis.

The production of cytotoxic ATP analogs in tumor cells after BP treatment is likely to depend on the activity of enzymes, such as farnesyl diphosphate synthase or aminoacyl-tRNA synthetases, responsible for ATP analog formation. Additionally, the potency of clodronate to inhibit cancer cell growth corresponds to ATP analog formation. (Ref.)

Mevalonate pathway inhibition

For more than 100 years, it has been known that cholesterol may accumulate in cancerous tissues and plays a critical role in cancer progression, thus emphasizing the therapeutic potential of lowering cholesterol and downregulating the mevalonate pathway in cancer prevention and treatment. The mevalonate pathway converts acetyl-coenzyme A (acetyl-CoA) to isoprenoids, thus supplying key metabolites for cholesterol and steroid synthesis. It comprises a series of enzymatic reactions that occur in the endoplasmic reticulum. The rate-limiting step is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate. This conversion is inhibited by statins, while bisphosphonates target more downstream reactions in this pathway, such as farnesylation and geranylgeranylation (Ref.), inhibiting FDPS and to some extend FDFT1 enzymes.

Mevalonate pathway is an important metabolic pathway which coverts mevalonate into sterol isoprenoids, such ascholesterol, and nonsterol isoprenoids, including isoprenoidintermediates-farnesyl pyrophosphate (FPP) and geranylger-anyl pyrophosphate (GGPP). These nonsterol iso-prenoid intermediates are essential for the posttranslationalprenylation of a multitude of proteins involved in intracellular signaling (especially the small GTP-binding proteins) and are essential in cell growth/differentiation, gene expression,protein glycosylation, and cytoskeletal assembly (Ref.) Inhibition of the mevalonate pathway influences the stability of the plasma membrane.

Source for the figure above: https://www.pharmgkb.org/pathway/PA154423660

In tumors, the inhibition of mevalonate pathway via the inhibition of farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates leads to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid 1-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI). (Ref.)

Cytotoxic gama-delta-T cells (Vγ9Vδ2 T cells) have been shown to recognize IPP/ApppI. As a result, since the administration of bisphosphonates leads to the accumulation of IPP/ApppI, this process make visible the cancer cells to the immune system. In tumors where the mevalonate pathway activity is low the bisphosphonates are not showing anti-cancer effects. However, it has been shown that in these tumors the depletion of cholesterol can lead to the up-regulation of  mevalonate pathway that in turn will lead to anti cancer effects of nitrogen-containing bisphosphonates even in this type of tumors (Ref.)

Based on this, I would conclude that regardless of the tumor type for the best outcome of the nitrogen-containing bisphosphonates theraphy the best is to have a low-cholesterol diet and avoid the use of statin drugs (I like statins due to their anti cancer effects but should not be combined with bisphosphonates). Maybe is even good to avoid drugs such as Metformin and Doxycicline which can reduce mitochondria activity and as a result possibly reduce the activity on the mevalonate pathway. The point is that for the best outcome of bisphosphonates therapy we need an upregulated mevalonate pathway (which is typical some cancers) in order to maximize production of IPP/ApppI and thus visibility of cancer cells towards gama-delta-T cells.

Gamma delta T lymphocytes contribute to immune defense against infection through the production of cytokines, chemokines, anti-bacterial compounds, and killing of infected cells. Indeed, it is known that pyrophosphates including isopentenyl pyrophosphate (IPP) generated in mammalian cells through the mevalonate pathway activate Vgamma9Vdelta2 T cells (Ref.) It was suggested that treatment with nitrogen-containing bisphosphonates induces Vγ9Vδ2 cells to mature toward an IFNγ-producing effector phenotype, which may induce more effective antitumor responses (Ref.).

Other mevalonate pathway inhibitors that work in synergy with bisphosphonate are discussed on this website here and here.

Administration and Dose:

Pamidronate : The current recommended dosage of pamidronate for hypercalcemia of malignancy is as a 60–90 mg infusion over 2–24 h; for osteolytic lesions in myeloma, 90 mg over 4 h; and in breast cancer, 90 mg over 2 h. (Ref.) The administration time mainly depends on the renal status and is clearly discussed in the drug’s prescribing information document (Ref.)

Zoledronic acid: is administered as a 4-mg infusion not less than 15 min for all patients with bone metastasis who have normal renal function. The maximal recommended dose for hypercalcemia is 4 mg. (Ref.)

Ibandronate: the usual administration is 6 mg infusion over 1 to 2 h. (Ref.)

The typical dosing interval is every 3 to 4 weeks, but a repeat dose can be given sooner to treat hypercalcemia. Although the optimal duration of bisphosphonate therapy has never been subjected to clinical trials, treatment for cancer with bone metastatsis and myeloma with osteolytic lesion is generally recommended until patients cannot tolerate treatment or experience a substantial functional decline (Ref.)

In the absence of hypercalcemia, to prevent or minimize the risk of calcium or vitamin D deficiency, patients should be given oral calcium and vitamin D supplementation (Ref.)

Due to reasons discussed in the Mechanism paragraph, for the best outcome of the nitrogen-containing bisphosphonates theraphy the best is to have a low-cholesterol diet and avoid the use of statin drugs. Maybe is even good to avoid drugs such as Metformin and Doxycicline which can reduce mitochondria activity and as a result possibly reduce the activity on the mevalonate pathway.

Four-weekly or 6-monthly administration of this agent can improve the prognosis of cancer patients, while a 1 mg weekly low-dose may have stronger anti-tumor effects. However, these hypotheses need to be evaluated by further clinical studies. (Ref.)

Side Effects:

Most common potential side effects:

Osteonecrosis of the Jaw (Ref.)

Acute Inflammatory Response: Flulike symptoms (low-grade fever, myalgias and arthralgias, or headache) is increased in patients receiving IV rather than oral bisphosphonate treatment (Ref.) Approximately 10% to 30% of patients receiving their first nitrogen-containing bisphosphonate infusion will experience an acute phase reaction, most commonly characterized by transient pyrexia with associated myalgias, arthralgias, headaches, and influenza-like symptoms. This rate declines by more than half with each subsequent infusion, such that a rate of 2.8% was found after the third infusion. The acute phase response is believed to be the result of proinflammatory cytokine production by peripheral blood γδ T cells. Pretreatment with histamine receptor antagonists or antipyretics can reduce the incidence and severity of symptoms among susceptible patients. Occasionally corticosteroids are of benefit. (Ref.)

Acute Kidney Injury (AKI): Our findings may be attributed to low adverse event reporting to the FDA by clinicians who believe that AKI occurs infrequently and ascribe AKI to underlying premorbid disease, therapy, or cancer progression, or deem renal dysfunction (AKI) to be a well-known adverse effect of BP therapy and thus not subject to reporting as an adverse event. In addition, the newer AKI criteria (RIFLE and Acute Dialysis Quality Initiative II) have not been well disseminated among oncologists or integrated into the cancer literature, and the monitoring of renal function continues to be primarily through use of serum creatinine, resulting in an underdiagnosis of AKI. Undoubtedly, BPs are highly effective supportive therapy within the oncology arena, but their potential to cause AKI remains a challenge, and practicing oncologists need to be highly vigilant in terms of appropriate and guideline-driven renal monitoring when using these agents. (Ref.)

Update 16-8-2019: It has been recently suggested that addition of Geranylgeraniol (also discussed here) could offer protection against side effects of Bisphosphonates (Ref.).

Source:

Any pharmacy.

References:

Primary prevention of glucocorticoid-induced osteoporosis with intermittent intravenous pamidronate: a randomized trial. https://www.ncbi.nlm.nih.gov/pubmed/9312195

The aim of this study was to assess whether early intermittent I.V. administration of disodium pamidronate can effectively achieve primary prevention of glucocorticoid-induced osteoporosis (GIOP). A total of 27 in- or outpatients who required first-time, long-term corticosteroid therapy at a daily dose of at least 10 mg prednisolone were studied. Patients were randomly selected to receive either pamidronate and calcium or calcium alone. Patients allocated to pamidronate treatment (pamidronate group) received a first intravenous infusion of 90 mg pamidronate simultaneously with the initiation of their steroid treatment. Subsequently, they received 30 mg pamidronate, intravenously, every 3 months, for as long as steroid therapy was continued. As with the control patients (calcium group), they were put on a daily 800-mg elemental calcium supplement given as calcium carbonate. Lumbar spine and hip (total and subregions) bone mineral densities (BMDs) were measured at the start and every 3-months by dual-energy X-ray absorptiometry (Hologic(R) QDR-2000). Over 1 year, the pamidronate group showed a significant BMD increase in the lumbar spine (3.6%), and at all sites of the hip (2.2% at the femoral neck). In the calcium group, a significant BMD reduction was registered at the lumbar spine (-5.3%) and at the femoral neck (-5.3%). Differences between the groups were significant at all sites measured. Intermittent intravenous pamidronate effectively achieves primary prevention of GIOP, as assessed by BMD measurements over 1 year.

Bisphosphonates: Mechanism of Action and Role in Clinical Practice https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/

Bisphosphonates are primary agents in the current pharmacological arsenal against osteoclast-mediated bone loss due to osteoporosis, Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy. In addition to currently approved uses, bisphosphonates are commonly prescribed for prevention and treatment of a variety of other skeletal conditions, such as low bone density and osteogenesis imperfecta. However, the recent recognition that bisphosphonate use is associated with pathologic conditions including osteonecrosis of the jaw has sharpened the level of scrutiny of the current widespread use of bisphosphonate therapy. Using the key words bisphosphonate and clinical practice in a PubMed literature search from January 1, 1998, to May 1, 2008, we review current understanding of the mechanisms by which bisphosphonates exert their effects on osteoclasts, discuss the role of bisphosphonates in clinical practice, and highlight some areas of concern associated with bisphosphonate use.

Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. https://www.ncbi.nlm.nih.gov/pubmed/24080598

Cancer risk reduction using pharmacological means is an attractive modern preventive approach that supplements the classical behavioural prevention recommendations. Medications that are commonly used by large populations to treat a variety of common, non-cancer-related, medical situations are an attractive candidate pool. This Review discusses three pharmacological agents with the most evidence for their potential as cancer chemopreventive agents: anti-hypercholesterolaemia medications (statins), an antidiabetic agent (metformin) and antiosteoporosis drugs (bisphosphonates). Data are accumulating to support a significant negative association of certain statins with cancer occurrence or survival in several major tumour sites (mostly gastrointestinal tumours and breast cancer), with an augmented combined effect with aspirin or other non-steroidal anti-inflammatory drugs. Metformin, but not other hypoglycaemic drugs, also seems to have some antitumour growth activity, but the amount of evidence in human studies, mainly in breast cancer, is still limited. Experimental and observational data have identified bisphosphonates as a pharmacological group that could have significant impact on incidence and mortality of more than one subsite of malignancy. At the current level of evidence these potential chemopreventive drugs should be considered in high-risk situations or using the personalized approach of maximizing individual benefits and minimizing the potential for adverse effects with the aid of pharmacogenetic indicators.

Bisphosphonates and Cancer-Induced Bone Disease: Beyond Their Antiresorptive Activity https://www.ncbi.nlm.nih.gov/pubmed/15958534

Bisphosphonates are primarily known for their ability to inhibit osteoclast-mediated bone resorption. They are an indispensable part of therapy for patients with cancers that cause osteolysis. However, there is now a growing body of evidence from preclinical research showing that bisphosphonates also exhibit antitumor activity, both in vitro and in vivo. They can affect molecular mechanisms of tumor cell adhesion, invasion, and proliferation; reinforce the effects of cytotoxic agents in a synergistic manner; and exhibit antiangiogenic and immunomodulatory effects. These preclinical findings reveal exciting ways of optimizing bisphosphonate therapy in oncology to fully exploit their antitumor potential.

The anti-tumour effects of zoledronic acid. https://www.ncbi.nlm.nih.gov/pubmed/26909294

Bone is the most common site for metastasis in patients with solid tumours. Bisphosphonates are an effective treatment for preventing skeletal related events and preserving quality of life in these patients. Zoledronic acid (ZA) is the most potent osteoclast inhibitor and is licensed for the treatment of bone metastases. Clodronate and pamidronate are also licensed for this indication. In addition, ZA has been demonstrated to exhibit antitumour effect. Direct and indirect mechanisms of anti-tumour effect have been postulated and at many times proven. Evidence exists that ZA antitumour effect is mediated through inhibition of tumour cells proliferation, induction of apoptosis, synergistic/additive to inhibitory effect of cytotoxic agents, inhibition of angiogenesis, decrease tumour cells adhesion to bone, decrease tumour cells invasion and migration, disorganization of cell cytoskeleton and activation of specific cellular antitumour immune response. There is also clinical evidence from clinical trials that ZA improved long term survival outcome in cancer patients with and without bone metastases. In this review we highlight the preclinical and clinical studies investigating the antitumour effect of bisphosphonates with particular reference to ZA.

An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol. https://www.ncbi.nlm.nih.gov/pubmed/27026891

We will conduct a possible combinatory study of intrapleural administration of zoledronic acid and systemic administration of the first-line agent to a chemotherapy-naïve patient based on the maximum tolerance dose of zoledronic acid determined by the present clinical trial. We propose that administration of bisphosphonates in a closed cavity is a treatment strategy for tumors developed in the cavity probably through the direct cytotoxic activity.

Bisphosphonates as potential adjuvants for patients with cancers of the digestive system. https://www.ncbi.nlm.nih.gov/pubmed/26811636

Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.

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