Bones are a common site for cancer metastasis resulting in worsened morbidity and mortality for patients as well as a burden on the health care system. The axial and appendicular skeletons are affected with symptoms from bone metastases and are often the first indication of malignancy in patients.^1,2 Cancers arising in the breast, prostate, lung, kidney, and thyroid, and multiple myeloma show a particularly strong predilection for bone, inducing bone loss, and weakening the structure of bone. The effect on bone leads to negative events such as pathological fractures, spinal cord compression, pain, myelosuppression, and hypercalcemia.³

The theory of metastasis has evolved over the years; initial theories were the mechanistic theory and the seed and soil. The mechanistic theory involves the embolization to distal vasculature, with cancer cells traveling via lymphatics and blood vessels supported by Dr Rudolph Virchow and Dr James Ewing.⁴ The seed and soil theory by Dr Stephen Paget suggested that certain tumor cells were able to spread and survive in specific conducive environments.⁵ The combination of these theories led to the understanding of metastasis to include certain cells with a metastatic phenotype that escapes into the vasculature, travel to distant organs, and escape and create an environment that is conducive for their growth. This microenvironment or “niche” allows for continued immune evasion and tumor proliferation by manipulating various factors.

The metastatic cells are able to activate pathways and affect protein expression by imitating the already existent mechanisms of bone turnover, a term known as osteomimicry.

For example, invasive breast tumor tissue over expresses cadherin-11, a cell adhesion molecule normally found in the bone. This leads to an increased affinity for bone and increases the interactions of the metastatic cells with cells within bone.⁶ Many other factors typically found in bone can be found in cancers that metastasize to bone including osteopontin (OPN), bone sialoprotein (BSP), alkaline phosphatase (ALP), osteoprotegerin (OPG), runt-related transcription factor-2 (Runx2), and receptor activator of nuclear factor kappa-B ligand (RANKL).⁷ These osteomimetic mechanisms and mutations continue to be elucidated, but they play a role in affecting osteoblast and osteoclast interactions.

The osteoclast plays a central role in bone resorption; they are multinucleated cells formed from the fusion of multiple mononuclear myeloid precursors.⁸
Osteoclast precursors express RANK which is activated by the binding of the RANK ligand secreted by osteoblasts.

This activation leads to a resorption of bone beginning with the adherence of integrins with vitronectin and fibronectin leading to cytoskeletal rearrangement producing a sealing zone and creating a resorptive ruffled membrane.⁹ Along the ruffled membrane protons are pumped into the lacunae between the osteoclast and the bone, proteases are secreted which degrade the collagen of the bone matrix.⁹ Osteoclast regulation is accomplished through osteoblast secretion of osteoprotegerin (OPG). OPG binds to RANKL preventing the binding of RANKL to RANK and the subsequent development of osteoclasts.¹⁰ Parathyroid hormone (PTH) stimulates RANKL upregulation and downregulates OPG. Calcitonin is another downregulator of osteoclast activity; it is secreted by the thyroid and inhibits osteoclasts by a mechanism that disrupts the cytoskeleton of osteoclasts inducing loss of polarity.¹¹

Osteoblasts are the primary mediators of bone deposition and their differentiation is stimulated by Runx2. Runx2 is activated by bone morphogenic proteins (BMPs) and the transcription factor distal-less homeobox 5 (Dlx5).¹² Once activated, it upregulates osteocalcin (OCN), osteopontin (OPN), and bone sialoprotein (BSP).⁹ Runx2 is downregulated by calcitriol, the biologically active form of vitamin D.¹³ Osteoblasts are inhibited by sclerostin, a protein encoded by the SOST gene, secreted by osteocytes.¹⁴ A mutation in the SOST gene leads to dysplastic disease such as sclerosteosis.¹⁴

Cancer cells are able to hijack this mechanism to affect bone structure molecularly. For example, approximately 90% of breast cancer bone metastases secrete parathyroid hormone-related peptide (PTHrP), causing the upregulation of RANKL and downregulation of OPG stimulating bone remodeling which in turn releases tumor growth factor beta (TGF-β). TGF-β induces the secretion of more PTHrP, leading to a continuous cycle of dysfunction and resultant bone loss.¹⁵ Prostate cancer cells often lead to osteoblastic lesions; they frequently express both PTHrP and RANKL. Similar to osteolytic lesions, there is a cycle that involves osteoblast and osteoclasts.⁷ PTH prevents osteoblast apoptosis and increases their activity, resulting in an increased rate of bone remodeling, but can increase bone deposition depending on the balance between osteoblast and osteoclast activity. Lung, kidney, and thyroid cancers most frequently produce osteolytic lesions, whereas metastases from prostate cancers tend to produce osteoblastic lesions.¹⁶ This disjointed remodeling leads to a decrease in trabecular connectivity, bone volume, and alters bone architecture. These structural changes impact bone strength and integrity making bones affected by metastatic tumors at greater risk of fracture.

The management of skeletal metastases involves a multidisciplinary approach often combining various degrees of pharmacological interventions, radiation therapy, and surgery. The goals of these management options are to limit these effects and potentially prevent negative skeletal events.

Diphosphonates have long been the standard for treatment of bone loss. They function by inducing apoptosis or deactivating osteoclasts. Diphosphonates include non-nitrogen-containing agents such as clodronate which induce apoptosis by means of toxic metabolites and nitrogen-containing agents such as alendronate and risedronate which inhibit farnesyl pyrophosphate synthase in the osteoclast causing breakdown of its cytoskeleton.

Since their development, each generation of diphosphonates has increased in strength from the first-generation diphosphonates (ie, etidronate, tiludronate, and clodronate). They have been replaced by more potent drugs such as zoledronic acid.¹⁷ Zoledronic acid is one of the most widely prescribed medications in the United States; current recommendations involve administering 4 mg of zoledronic acid intravenously every 3 to 4 weeks for maintenance of bone health in those with bone metastasis.¹⁸ Diphosphonates have been associated with improved outcomes in patients with metastasis, decreasing their risk for skeletal-related events (SREs) such as fracture¹⁹ and increasing bone density.²⁰. Despite their potential benefit, diphosphonate administration has its drawbacks. They are renally excreted and should be limited in renally deficient patients;²¹ they can cause hypocalcemia and can lead to atypical fractures of the femur^22,23 and osteonecrosis of the jaw, and, when taken orally, have been associated with esophagitis.²⁴ The optimal dosing for diphosphonates such as zoledronic acid is uncertain, but a recent randomized controlled trial showed no difference in skeletally related events when zoledronic acid was dosed every 4 weeks (standard) compared with a 12-week interval.²⁵ There was a trend toward less adverse events with the administration of zoledronic acid such as osteonecrosis of the jaw and elevated creatinine levels when zoledronic acid was administered at 12 week intervals.²⁵

Denosumab is a monoclonal antibody against RANKL. It competitively binds with RANKL preventing the binding of RANK and therefore limiting
osteoclastogenesis. Denosumab plays a similar role to OPG in down regulating bone resorption and shifting the bone remodeling balance toward bone deposition. Denosumab is an effective alternative to diphosphonates. Denosumab has been shown to reduce the risk of SREs in patients with bone metastasis. For SRE prophylaxis, 120 mg denosumab provided subcutaneously administered every four weeks¹⁸ is recommended. Denosumab use, like diphosphonates, has been associated with hypocalcaemia and a similar rate of jaw osteonecrosis.²⁶ An advantage of denosumab is the fact it is not renally excreted and dosing does not need to be adjusted with worsening renal function in patients.